Dasebuvir Sodium Tablets Instructions

Date of approval.
Date of revision.
 Dasebuvir Sodium Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
For drugs used in combination with this product, please refer to the relevant drug instructions
WARNING: Risk of Hepatitis B Virus Reactivation in HCV Coinfected HBV Infected Individuals
Clear evidence of current or prior hepatitis B virus (HBV) infection by testing in all patients before starting treatment with this product + obiparib. HBV reactivation has been reported in patients with HCV/HBV co-infection who received or had completed direct antiviral therapy for HCV and who were not receiving antiviral therapy for HBV. Fulminant hepatitis, liver failure, and death have occurred in some cases. HCV treatment and post-treatment follow-up should be monitored for hepatitis episodes and HBV reactivation in HCV/HBV co-infected patients. Initiate appropriate management of HBV-infected patients according to clinical indications (see [Precautions]). Drug Name]
Generic name: Dasebuvir sodium tablets
Trade Name: Exviera® Exviera®
English Name: Dasabuvir Sodium Tablets
Hanyu Pinyin: Dasaibuweina Pian
Ingredients
The main ingredient of this product is: Dasabuvir Sodium
Chemical Name: Sodium N-{6-[3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl]naphthalen-2-yl}methanesulfonamide monohydrate
Chemical structure formula.
 
 
 
 
 
 
 
Molecular formula: C26H26N3O5S-Na-H2O (salt, hydrate).
C26H27N3O5S (free acid, anhydrous)
Molecular weight: 533.57 (salt, hydrate)
493.57（free acid, anhydrous substance)
【Properties】.
This product is an oval beige film-coated tablet with “AV2” engraved on one side, and appears off-white after removing the film coating.
Indications
This product is suitable for the treatment of chronic hepatitis C (CHC) in adults in combination with other drugs (see [dosage], [precautions], [pharmacology and toxicology] and [clinical trials]).
For hepatitis C virus (HCV) genotype-specific activity, see [Precautions], [Pharmacology and Toxicology], and [Clinical Trials].
Specification
250mg
Dosage]
This product should be used under the supervision of a clinician experienced in the treatment of chronic hepatitis C.
Dosage
The recommended dose of this product is 250mg twice daily (one dose in the morning and one in the evening).
This product should not be used alone for the treatment of HCV, but in combination with other drugs used for the treatment of HCV. (See [Clinical Trials]). See the instructions for other drugs used in combination with this product.
Table 1 gives the recommended combination of drugs and the treatment period for the combination regimen of this product.
Table 1: Recommended combination drugs and treatment cycles for each patient population
Patient Population Treatment Drug* Treatment Cycle Genotype 1b.
No cirrhosis or compensated cirrhosis Benadryl + Obiparib 12-week genotype 1a.
cirrhosis-free Benadryl + Obiparib + Ribavirin* 12-week genotype 1a.
compensated cirrhosis Benadryl + Obiparib + Ribavirin* for 24 weeks (see [Clinical Trials]) *Note: Patients with genotype 1 subtype unknown or genotype 1 mixed subtype infection should follow the genotype 1a dosing regimen. Missed Doses
If a dose of this product is missed, the prescribed dose may be taken within 6 hours of the scheduled time of the missed dose. If more than 6 hours have elapsed since the regular dosing time for this product, the missed dose should not be replaced and the patient should take the next dose at the scheduled dosing time. Patients should be informed that double doses should not be taken.
Special Populations
HIV-1 co-infection
Follow the dosing recommendations in Table 1. For HIV antiviral dosing recommendations, see [Precautions] and [Drug Interactions] and for additional information see [Adverse Reactions] and [Clinical Trials].
Liver Transplant Recipients
This product + obiparib + ribavirin is recommended for the treatment of liver transplant recipients for a 24-week course. A lower starting dose of ribavirin is recommended. In post-liver transplantation studies, ribavirin was administered on an individualized regimen, with most subjects being administered at a dose of 600 to 800 mg daily (see [Clinical Trials]). For dosing recommendations for calcium-regulated phosphatase inhibitors, see [Drug Interactions].
Geriatric patients
No dose adjustment is required for administration in elderly patients (see [Pharmacokinetics]).
Renal Impairment
No dose adjustment is required in patients with mild, moderate, or severe renal impairment or in patients with end-stage renal disease on dialysis (see [Pharmacokinetics]). Patients requiring ribavirin should refer to the ribavirin instruction sheet for information on use in patients with renal impairment.
Hepatic Impairment
Mild hepatic impairment (Child-Pugh Class A)
Patients do not need to adjust the dose of this product to be administered. The combination regimen of Ribavirin + Obiparib is contraindicated in patients with moderate hepatic impairment (Child-Pugh B) or severe hepatic impairment (Child-Pugh C), or in patients with a past history of such impairment (see [Contraindications], [Precautions] and [Pharmacokinetics]).
Pediatric Use
No data are available on the efficacy and safety of this product in minors under 18 years of age.
Method of administration
Take tablets by mouth. Patients should be instructed to swallow the entire tablet (i.e., patients should not chew, break, or dissolve the tablet). To maximize drug absorption without regard to fat and calorie content, this product should be taken with food. (See [Pharmacokinetics]).
[Adverse Reactions].
Safety Summary of Global Studies
In the Global Study, the safety summary is based on pooled data from Phase 2 and Phase 3 clinical trials completed in more than 2,600 subjects treated with this product + obiparib +/- ribavirin.
The most frequently reported adverse reactions in subjects treated with this product + obiparib + ribavirin (more than 20% of subjects) were malaise and nausea. 0.2% (5/2,044) of subjects permanently discontinued treatment due to adverse reactions. 4.8% (99/2,044) of subjects had their ribavirin dose reduced due to adverse reactions.
The incidence of typical ribavirin-related adverse events (e.g., nausea, insomnia, anemia) was low in subjects treated with this product + olbiparib (without ribavirin), and no patient (0/588) permanently discontinued treatment due to an adverse reaction.
The safety profile of the combination of this product + obiparib in subjects with compensated cirrhosis was similar to that of subjects without cirrhosis (except for the increased incidence of transient hyperbilirubinemia when combined with ribavirin).
List of Adverse Reactions
The adverse reactions listed in Table 2 are those adverse events that are causally related to the combination of this product + obiparib +/- ribavirin and for which there is at least a reasonable probability of a causal relationship with the study drug. The majority of adverse reactions occurring during treatment with the combination regimen of Benadryl+Obiparib given in Table 2 were Grade 1 in severity.
The following table lists adverse reactions by system organ classification and frequency of occurrence. Frequencies are defined as indicated below: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 ~ <1/1,000), or extremely rare (<1/10,000).
Table 2. Adverse drug reactions occurring with the combination of Benadryl + Obiparib +/- ribavirin
Frequency Benadryl +Obiparib
+ ribavirin*
N = 2,044 Benadryl + olbiparib
N = 588 Anemia common in blood and lymphocyte disorders Insomnia very common in psychiatric disorders Nausea very common in gastrointestinal disorders
 Skin and subcutaneous tissue disorders very common Pruritus common Pruritus rare Angioedema Angioedema systemic disorders and various reactions at the site of administration very common Lethargy, fatigue *Data set includes all subjects infected with genotype 1 in Phase 2 and Phase 3 trials, including subjects with cirrhosis.
Note: See Table 3 for laboratory abnormal values.
Selected Adverse Reaction Descriptions
Laboratory Abnormal Values
Changes in selected laboratory parameters are shown in Table 3. for brevity, they are presented in side-by-side tables; however, direct comparisons between trials with different designs should not be made.
Table 3. selected laboratory abnormal values present at the time of treatment
Laboratory Parameters SAPPHIRE I and IIPEARL II, III and IVTURQUOISE II
(Subjects with cirrhosis) Benadryl + Obiparib + Ribavirin
12 weeks
N = 770
n (%) Benadryl + Obiparib
12 weeks
N = 509
n (%) Benadryl + Obiparib + Ribavirin
12 weeks or 24 weeks
N = 380
n (%) ALT >5-20 x ULN*
(Grade 3) 6/765 (0.8%) 1/509 (0.2%) 4/380 (1.1%) >20 x ULN
(Grade 4) 3/765 (0.4%) 0 2/380 (0.5%) Hemoglobin <100-80 g/L (Grade 2) 41/765 (5.4%) 0 30/380 (7.9%) <80-65 g/L (Grade 3) 1/765 (0.1%) 0 3/380 (0.8%) <65 g/L (Grade 4) 0 0 1/ 380 (0.3%) Total bilirubin >3-10 × ULN (grade 3) 19/765 (2.5%) 2/509 (0.4%) 37/380 (9.7%) >10 × ULN (grade 4) 1/765 (0.1%) 0 0 *ULN: Upper limit of normal value for each laboratory test Elevated serum ALT
In a pooled analysis of clinical trials receiving this product + obiparib +/- ribavirin, 1% of subjects had serum ALT levels more than 5 times higher than the upper limit of normal (ULN) after initiation of dosing. Because of the 26% incidence of ALT elevation in female patients taking concomitant ethinyl estradiol-containing drugs, the combination of these drugs with this product + obiparib is prohibited. An increased incidence of ALT elevation was not observed when treated with other estrogen types commonly used in hormone replacement therapy (e.g., estradiol and conjugated estrogens.) ALT elevations were usually asymptomatic and usually occurred within the first 4 weeks of treatment (mean time 20 days, range: 8-57 days), with most events resolving with continued treatment. Two patients discontinued this product + obiparib because of an increase in ALT, including one patient receiving ethinyl estradiol. Three patients discontinued treatment with this product + albiparib for 1 to 7 days, including one patient treated with ethinyl estradiol. The vast majority of ALT elevations were transient and judged to be drug-related. elevations in ALT are usually not associated with elevations in bilirubin. Liver cirrhosis is not a risk factor for ALT elevation (see [Caution]).
Elevated serum bilirubin
A transient increase in serum bilirubin (primarily indirect bilirubin) was observed in subjects treated with this product + obiparib + ribavirin, which was associated with inhibition of the bilirubin transport protein OATP1B1/1B3 by paritaprevir and ribavirin-induced hemolysis. The bilirubin elevation occurred after initiation of treatment, peaked at study week 1, and usually recovered with continued treatment. Bilirubin elevations were not associated with elevated transaminases. Subjects not receiving ribavirin combination therapy had a lower incidence of indirect bilirubin elevations.
Liver Transplant Recipients
The overall safety profile of HCV-infected liver transplant recipients (other than those receiving immunosuppressive therapy) treated with this product + obiparib + ribavirin was similar to that of subjects treated with this product + obiparib + ribavirin in the phase 3 trial, although the incidence of some adverse events was increased. 10 subjects (29.4%) had at least one post-baseline hemoglobin below 10 g/dL.10 /34 subjects (29.4%) had their ribavirin dose adjusted because of a decrease in hemoglobin, and 2.9% (1/34) subjects had their ribavirin dose suspended. Five subjects required erythropoietin administration, and these patients received a starting dose of ribavirin of 1000-1200 mg daily. no subjects received blood transfusions.
Patients with HIV/HCV co-infection
The overall safety profile of HCV/HIV-1 co-infected subjects was similar to that of HCV-only subjects. 17 (27.0%) subjects had a transient increase in total bilirubin to >3×ULN (mainly indirect bilirubin); 15 of these subjects received atazanavir. Of the subjects who developed hyperbilirubinemia, no patients had concomitant transaminase elevations.
Skin reactions
In PEARL-II, PEARL-III and PEARL-IV, rash-related events were reported in subjects treated with this product + obiparib (7%) and this product + obiparib in combination with ribavirin (10%). In SAPPHIRE-I and SAPPHIRE-II, 16% of subjects treated with this product + obiparib combined with ribavirin and 9% of subjects in the placebo treatment group reported skin reactions. In TURQUOISE-II, skin reactions were reported in 18% and 24% of subjects treated with 12 or 24 weeks of this product + obiparib combined with ribavirin, respectively. The majority of events were mild in severity. No serious events or severe skin reactions such as Stevens Johnson syndrome (SJS), toxic necrolytic epidermolysis bullosa (TEN), erythema multiforme (EM), or drug rash with eosinophilia and systemic symptoms (DRESS) were reported.
Post-marketing adverse reactions reported
Hepatobiliary systemic disease: Hepatic dysfunction and liver failure have been reported in patients treated with this product + obiparib +/- ribavirin (see [Precautions]). The frequency of these events is unknown.
Safety Summary of Phase 3 Clinical Trials in Asia
Safety results from the Phase 3 clinical trial in Asia were similar to those from the global study.
Pediatric Use
No safety data are available for use in minors under 18 years of age.
Contraindications
Contraindicated in patients with hypersensitivity to the raw material or excipients (see [Ingredients] Raw and Excipient Information).
The combination regimen of this product + obiparib is contraindicated in patients with combined moderate hepatic impairment (Child-Pugh B) and severe hepatic impairment (Child-Pugh C), or in patients with a past history of such impairment (see [Pharmacokinetics]).
Drugs containing ethinyl estradiol, such as most combination oral contraceptives or vaginal contraceptive rings, are contraindicated (see [Precautions] and [Drug Interactions]).
When this product is used in combination with a moderately or strongly potent enzyme inducer, the plasma concentration of dasebuvir may be reduced, thereby reducing efficacy (see [Drug Interactions]). Examples of prohibited inducers are as follows.
Enzyme inducers.
Carbamazepine, phenytoin, phenobarbital
Efavirenz, nevirapine, etravirine
Enzalutamide
Mitotane
Rifampin
St. John’s wort (Kanye)
CYP2C8 potent inhibitor drugs may increase plasma concentrations of dasebuvir, and these drugs should not be used in combination with this product (see [Drug Interactions]). Examples of prohibited CYP2C8 inhibitors are as follows.
CYP2C8 inhibitors.
Gemfibezil
This product should be used in combination with obiparib. See its product insert for contraindications for use in combination with olbiparib.
If this product + obiparib is used in combination with ribavirin, the contraindications to ribavirin also apply to this combination regimen. For the contraindications of ribavirin, please refer to its product insert.
[Precautions].
General Precautions
This product is not recommended for use alone and must be used in combination with other drugs used to treat hepatitis C virus infection (see [Dosage] and [Clinical Trials]).
Risk of hepatic decompensation and liver failure in patients with cirrhosis
There have been post-marketing reports of hepatic failure and liver failure, including the need for liver transplantation or fatal outcomes, in patients treated with this product + obiparib +/- ribavirin. Of the patients who developed these serious outcomes, most had been diagnosed with advanced or decompensated cirrhosis prior to initiation of therapy. Although it is difficult to determine a causal relationship between the occurrence of this event and the fact that the patient is in an advanced stage of liver disease, the potential risk cannot be ruled out.
The combination regimen of this product + obiparib is contraindicated in patients with combined moderate hepatic impairment (Child-Pugh B) and severe hepatic impairment (Child-Pugh C), or a prior history related to the above (see [Dosage], [Adverse Reactions] and [Pharmacokinetics]).
For patients with cirrhosis.
Monitor for clinical signs and symptoms of hepatic decompensation (e.g., ascites, hepatic encephalopathy, variceal bleeding).
Liver function laboratory tests should be performed at baseline, during the first 4 weeks of treatment, and later when clinically indicated, including
including direct bilirubin.
Discontinue therapy immediately in patients who show evidence of hepatic decompensation.
ALT elevation
In clinical trials of this product + obiparib +/- ribavirin, approximately 1% of subjects (35/3039) experienced a transient increase in ALT above 5 times the upper limit of normal.ALT elevations are usually asymptomatic, occur within the first 4 weeks of treatment, are not associated with bilirubin elevations, and decrease in ALT within approximately 2 weeks of continued treatment with this product + obiparib +/- ribavirin.
ALT elevations were significantly more common (6/25 subjects) in the subgroup of subjects receiving ethinyl estradiol-containing (e.g., combination oral contraceptive pills or vaginal contraceptive rings) medications (see [Contraindications]). In contrast, the incidence of ALT elevation in subjects receiving other types of estrogens (typically used in hormone replacement therapy, i.e., oral and topical estrogens versus combined estrogens) was similar to that observed in subjects not using estrogen medications (incidence of ALT elevation was approximately 1% in each group).
Patients receiving ethinyl estradiol-containing medications (i.e., mostly combination oral contraceptives or vaginal contraceptive rings) must be switched to an alternative method of contraception (e.g., progestin-only or non-hormonal contraceptive methods) prior to initiation of this product+Obiparib combination (see [Contraindications] and [Drug Interactions]).
Although ALT elevation due to the combination of this product + obiparib is generally asymptomatic, patients should be instructed to watch for early signs of liver inflammation (e.g., malaise, weakness, loss of appetite, nausea, and vomiting) and for later signs (e.g., jaundice and fecal discoloration) and to consult a physician immediately if such signs occur. Patients without cirrhosis do not need to follow the regular monitoring of liver enzymes for patients with cirrhosis (see above). Early discontinuation may lead to drug resistance, but the impact on subsequent therapy is not known.
Pregnancy and Combination with Ribavirin
See [Use in Pregnant and Lactating Women].
When this product is used in combination with ribavirin, women of childbearing potential or the female partner of a male patient must use effective contraception. For more information, see [For Pregnant and Lactating Women] and Ribavirin Drug Guide.
Combination with Tacrolimus, Sirolimus and Everolimus
Due to the inhibitory effect of ritonavir on CYP3A, the combination of this product and obiparib with systemically administered tacrolimus, sirolimus, or everolimus increases the blood levels of immunosuppressive drugs (see [Drug Interactions]). Serious and/or life-threatening events have been observed with the combination of this product and obiparib with systemically administered tacrolimus, and similar risks are expected with sirolimus and everolimus.
Combination of tacrolimus or sirolimus with this product + obiparib should be avoided unless the therapeutic benefit outweighs the potential risk. Caution should be exercised if tacrolimus or sirolimus is combined with this product and obiparib; see [Drug Interactions] for recommended dosing and monitoring. Combination with everolimus is not recommended because of the lack of appropriate specifications for dose adjustment.
Tacrolimus or sirolimus concentrations in whole blood should be monitored after and throughout the combined dosing period with this product + albiparib, and the dose and/or frequency of administration should be adjusted as needed. Patients should be monitored frequently for any changes in renal function or adverse events associated with tacrolimus or sirolimus. For additional dosing and monitoring instructions, please refer to the product insert for tacrolimus or sirolimus.
Genotype-Specific Activity
See [Dosage] for dosing regimens for different HCV genotypes and [Pharmacology and Toxicology] for virologic and clinical activity of different genotypes.
No information is available on the effectiveness of this product except for the treatment of patients infected with genotype 1. Therefore, it should not be used to treat patients infected with non-genotypes.
Combination with other HCV direct antiviral drugs
The safety and efficacy of this product + obiparib +/- ribavirin have been demonstrated. However, the combination of this product with other direct antiviral drugs is not available and is not recommended.
Retreatment
The effectiveness of this product has not been demonstrated in patients previously treated with this product or in patients who are expected to develop cross-resistance to this product.
Combination with statins
Rosuvastatin
Combination with this product + obiparib is expected to result in a more than 3-fold increase in exposure to resulvastatin. If the combination of Rosuvastatin is required during treatment, the maximum dose of Rosuvastatin should be adjusted to 5 mg/day (see [Drug Interactions], Table 4).
Pitavastatin and fluvastatin
The interaction of this product with pitavastatin and fluvastatin is not known. Theoretically, the combination with this product + olbiparib would be expected to result in increased exposure to pitavastatin and fluvastatin. Suspension of pitavastatin/fluvastatin is recommended during treatment with this product + olbiparib. If a statin is necessary to be given during treatment, switch to a lower dose of pravastatin/resvastatin (see [Drug Interactions], Table 4).
Treatment of HIV co-infected patients
For PI-resistant HIV co-infected patients not receiving antiretroviral therapy, a combination of this product + obiparib is recommended. Patients receiving antiretroviral therapy who have not achieved virologic suppression should not receive this product. Drug interactions need to be carefully considered in the HIV co-infected population. (See [Drug Interactions], Table 4 for details).
Atazanavir may be administered concurrently with this product + obiparib in combination. It is important to note that atazanavir is applied without the additional addition of ritonavir, as 100 mg of ritonavir is contained in the once-daily dose of ombiparib. This combination regimen carries an increased risk of hyperbilirubinemia (including scleral yellowing), especially when ribavirin is used as part of the hepatitis C regimen.
Darunavir (at a dose of 800 mg/day), indicated for patients without PI pan-resistance (whose exposure dose is lower), can be administered concurrently with this product in combination with obiparib. It is important to note that additional ritonavir is prohibited in the application of darunavir, as 100 mg of ritonavir is included in the once-daily administration of ombiparib.
Coadministration of HIV protease inhibitors other than atazanavir and darunavir is prohibited, see the product insert for Oripiparib.
Raltegravir exposure is substantially increased (2-fold). No specific safety concerns have been identified with this combination regimen in the limited number of patients receiving 12 to 24 weeks of therapy.
When rilpivirine is combined with this product + obiparib, there is a substantial increase (3-fold) in rilpivirine exposure, possibly secondary to a prolonged QT interval. If HIV protease inhibitors (atazanavir, darunavir) are added, the exposure to rilpivirine may even increase further, so the combination is not recommended. Rilpivirine should be used with caution and repeated ECG monitoring should be performed.
Co-administration of NNRTIs other than rilpivirine (efavirenz, etravirine, and nevirapine) is contraindicated (see [Contraindications]).
Hepatitis B virus reactivation
Cases of hepatitis B virus (HBV) reactivation, some fatal, have been reported during or after treatment with direct antivirals. All patients should be screened for HBV prior to initiating therapy. HBV/HCV co-infected individuals are at risk for HBV reactivation and should therefore be monitored and managed according to current clinical guidelines.
Pediatric Dosing
No data are available on the safety and efficacy of this product in the treatment of minors under 18 years of age.
Lactose
This product contains lactose. It should not be used in patients with rare genetic disorders such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.
Effects on the ability to drive and operate instruments
Patients should be informed that weakness has been reported during the combination of this product, obiparib and ribavirin (see [Adverse Reactions]).
Pregnant and lactating women]
Contraception for women of childbearing age/men and women
When this product is used in combination with ribavirin, female patients and female partners of male patients must take active measures to avoid conception. Ribavirin causes significant teratogenic and/or embryotoxic effects in all animal species. Therefore, ribavirin is contraindicated in pregnant women and in male patients whose sexual partners are pregnant. For more information, please refer to the product insert for ribavirin.
Female patients: Women of childbearing potential should not be treated with ribavirin unless they have been using effective contraception during and for 4 months after completion of ribavirin treatment.
Male patients and their female partners: Male patients or their female partners of childbearing potential must use effective contraception during ribavirin treatment and for up to 7 months after the end of treatment.
Combining ethinyl estradiol with this product is prohibited (see [Contraindications]). See [Contraindications] and [Precautions] for more information on specific hormonal contraceptives.
Pregnancy
Data on the use of this product in women during pregnancy are extremely limited. Animal studies have not shown direct or indirect reproductive toxicity (see [Pharmacologic Toxicology]). As a precautionary measure, it is best to avoid the use of this product during pregnancy.
Ribavirin should be contraindicated during pregnancy if ribavirin is used in combination with this product + obiparib (see product insert for ribavirin).
Lactation
It is not known whether dasebuvir and its metabolites are secreted via human milk. Available animal pharmacokinetic data indicate that dasebuvir and its metabolites can be detected in breast milk (see [Pharmacology and Toxicology]). This product may cause adverse reactions in breastfed infants and the decision to discontinue breastfeeding or discontinue treatment is based on the importance of treatment to the mother. Patients receiving ribavirin combination therapy should also refer to the product insert for ribavirin.
Fertility
There are no data on the effect of this product on fertility in humans. No adverse effects on fertility have been observed in animal studies. (See [Pharmacology and Toxicology]).
Pediatric use]
No data are available on the safety and efficacy of this product for use in minors under 18 years of age.
Geriatric Use
No dose adjustment is required for geriatric patients.
Drug Interactions
This product must be used in combination with Obiparib. When the two drugs are used in combination, an interaction can occur. (See [Pharmacokinetics]). Therefore, compound interactions must be considered when drugs are used in combination.
Pharmacodynamic interactions
Combination with enzyme inducers may increase the risk of adverse reactions and ALT elevation (see Table 4).
Combination with ethinyl estradiol may increase the risk of ALT elevation (see [Contraindications] and [Precautions]). See [Contraindications] for prohibited enzyme inducers.
Pharmacokinetic interactions
Potential effects of this product on the pharmacokinetics of other drugs
In vivo drug interaction studies have evaluated the net effect of combination (including ritonavir) therapy. Subsequent sections describe the specific transporter proteins and metabolic enzymes affected by the combination of this product with obiparib. Potential interactions with other drugs and dosing recommendations are shown in Table 4.
Drugs metabolized by CYP3A4
See the Obiparib product insert for details (see Table 4).
Drugs transported via the OATP family
OATP1B1, OATP1B3 and OATP2B1 substrates are described in detail in the product insert for Obiparib (see Table 4).
Drugs transported via BCRP
In vivo, dasebuvir is an inhibitor of BCRP. The combination of this product + obiparib with drugs that are BCRP substrates may increase plasma concentrations of these transporter protein substrates and may require dose adjustment/clinical monitoring. Such drugs include salazosulfapyridine, imatinib, and certain statins (see Table 4). Recommendations related to the BCRP substrate risuvastatin that have been evaluated in drug interaction studies are shown in Table 4.
Drugs that transport P-gp via the intestinal tract
Although dasebuvir is an in vitro inhibitor of P-gp, no significant changes in P-gp substrate (digoxin) exposure were observed with the combination of this product + obiparib. It is not possible to exclude that this product increases the systemic exposure of dabigatranate due to the inhibition of P-gp in the intestine.
Drugs metabolized via glucuronidation
Dasebuvir is an in vivo inhibitor of UGT1A1. The combination of dasebuvir with drugs metabolized primarily by UGT1A1 results in increased plasma concentrations of such drugs; routine clinical monitoring is recommended for drugs with narrow therapeutic indices (ie: levothyroxine). Special recommendations for raltegravir and buprenorphine that have been evaluated in drug interaction studies are shown in Table 4. dasebuvir, which reaches relevant concentrations in vivo, was also found to inhibit UGT1A4, UGT1A6, and intestinal UGT2B7 in vitro.
Drugs metabolized by CYP2C19
Combination with this product + obiparib may reduce exposure to drugs metabolized by CYP2C19 (e.g., lansoprazole, esomeprazole, S- mephentermine) and may require dose adjustment/clinical monitoring for administration. CYP2C19 substrates evaluated in drug interaction studies include omeprazole and citalopram (see Table 4).
Drugs metabolized by CYP2C9
The combination of this product + obiparib does not affect the exposure of CYP2C9 substrates (warfarin). No dose adjustment of other CYP2C9 substrates (NSAIDs, e.g., ibuprofen; hypoglycemic agents, e.g., glimepiride, glipizide) administration is anticipated.
Drugs metabolized by CYP2D6 or CYP1A2
The combination of this product + obiparib does not affect the exposure of CYP2D6 /CYP1A2 substrate (duloxetine). Exposure to cyclobenzaprine (a CYP1A2 substrate) is reduced when combined with this product. For other CYP1A2 substrates (e.g., ciprofloxacin, ciprofloxacin, theophylline, and caffeine), clinical monitoring and dose adjustment for administration may be required. No dose adjustment of CYP2D6 substrates (e.g., desipramine, metoprolol, and dextromethorphan) administration is anticipated.
Drugs that are excreted via the kidney via transporter proteins
The absence of interaction with tenofovir (OAT1 substrate) may indicate that dasebuvir is unlikely to inhibit the organic anion transporter protein (OAT1) in vivo. In vitro studies have shown that dasebuvir is not an inhibitor of organic cation transporter protein (OCT2), organic anion transporter protein (OAT3), or multidrug and toxin efflux proteins (MATE1 and MATE2K) at clinically relevant concentrations.
Therefore, it is not expected to affect drugs that are excreted primarily via these transporter proteins in the kidney (see [Pharmacokinetics]).
Potential Effects of Other Drugs on Dasebuvir Pharmacokinetics
Drugs that inhibit CYP2C8
The combination of dasebuvir with drugs that inhibit CYP2C8 (e.g., teriflunomide, deferasirox) may increase the plasma concentration of dasebuvir. combination of potent inhibitors of CYP2C8 with dasebuvir sodium is contraindicated (see [Contraindications] and Table 4).
Enzyme Inducers
It is expected that the combination of dasebuvir and a mid-acting enzyme-inducing agent drug will decrease the plasma concentration of dasebuvir and thus reduce the efficacy of dasebuvir. Contraindicated enzyme-inducing agents are listed in [Contraindications] and Table 4.
Dasebuvir is a substrate for P-gp and BCRP, and in vitro, the major metabolite of dasebuvir, M1, is a substrate for OCT1. Inhibition of P-gp and BCRP is not expected to result in a clinically relevant increase in dasebuvir exposure (Table 4).
All drug interaction studies quantified M1, the major metabolite of dasebuvir. Changes in metabolite exposure were generally consistent with those observed for dasebuvir, except for studies with CYP2C8 inhibitors (gemfibezil; which had up to 95% reduction in metabolite exposure) and CYP3A inducers (carbamazepine, which had up to 39% reduction in metabolite exposure).
Patients treated with vitamin K antagonists
Because alterations in hepatic function may occur during treatment with this product + obiparib, close monitoring of the prothrombin time (INR) in patients is recommended.
Drug Interaction Studies
Recommendations for the combination of Benadryl+Obiparib with multiple drugs are shown in Table 4.
While a patient is being treated with Benadryl+Obiparib, consideration should be given to adjusting the dose of concomitant drug administration or giving appropriate clinical monitoring if the patient is receiving or starting to receive other drugs with which drug interactions may occur (Table 4).
If concomitant drug dose adjustment is required because of the combination with Benadryl+Obiparib, the concomitant drug dose should be readjusted when the administration of Benadryl+Obiparib is complete.
The least squares mean ratios (90% confidence intervals) for the effects on the concentrations of Benadryl+Obiparib and concomitant drugs are shown in Table 4.
The direction of change in exposure (Cmax and AUC) for paritaprevir, ombitasvir, dasebuvir, and concomitant drugs is indicated by arrows (↑ = increase of more than 20%, ↓ = decrease of more than 20%, ↔ = no change or change of less than 20%).
This table is not a complete list. This product is used in combination with Obiparib. Interactions with ombitasvir/paritaprevir/ritonavir can be found in the product insert for ombiparib.
Table 4: Interactions between this product + Obiparib and other drugs
Drug/Possible Mechanism of Interaction Combined Dosing Effect CmaxAUC Cmin Clinical Review Aminosalicylic acid salazosulfapyridine
Mechanism: inhibition of BCRP by paritaprevir, ritonavir and dasabuvir This product + ombiparib was not studied and is expected to.
↑ salazosulfapyridine
 Caution should be used when combining salazosulfapyridine with this product + obiparib. Anti-arrhythmic drug digoxin
0.5 mg single dose
Mechanism: Dasebuvir, paritaprevir and ritonavir inhibit P-gp This product + Obiparib ↔ Digoxin 1.15
(1.04-1.27) 1.16 (1.09-1.23) 1.01
(0.97-1.05) Although no digoxin dose adjustment is necessary, appropriate monitoring of digoxin serum concentrations is recommended. ↔ Dasebuvir 0.99
(0.92-1.07) 0.97
(0.91-1.02) 0.99
(0.92-1.07)↔ Obetasvir
1.03
(0.97-1.10)1.00
(0.98-1.03) 0.99
(0.96-1.02) ↔ Paritaprevir 0.92
(0.80-1.06) 0.94
(0.81-1.08) 0.92
(0.82-1.02) Antibiotics (systemic) Sulfamethoxazole, methotrexate
800/160 mg
Twice daily
Mechanism: Methotrexate inhibition of CYP2C8 may lead to increased exposure to dasebuvir Benadryl + Obiparib ↑ Sulfamethoxazole 1.21 (1.15-1.28) 1.17 (1.14-1.20) 1.15 (1.10-1.20) No dose adjustment required for Benadryl + Obiparib treatment. ↑ Methotrexate 1.17(1.12-1.22) 1.22(1.18-1.26) 1.25(1.19-1.31) ↑ Dasabuvir 1.15(1.02-1.31) 1.33(1.23-1.44) NA ↔ Obetasvir 0.88(0.83-0.94) 0.85(0.80-0.90) NA ↓ Paritaprevir 0.78(0.61-1.01)0.87(0.72-1.06)NA anticancer drug enzalutamide
Mitotane
Mechanism: enzalutamide or mitotane induces CYP3A4 This product + obiparib was not studied and is expected to.
 ↓ dasebuvir
↓ ombitasvir
↓ Paritaprevir prohibited in combination (see [contraindication]) Imatinib
Mechanism: inhibition of BCRP by paritaprevir, ritonavir and dasebuvir This product + ombiparib Not studied, expected to.
↑ Imatinib recommended for clinical monitoring, Imatinib administered at a lower dose of anticoagulant drug warfarin
5 mg single dose + other vitamin K antagonist Benadryl + Obiparib
↔ R-warfarin 1.05
(0.95-1.17) 0.88
(0.81-0.95) 0.94
(0.84-1.05) Although the pharmacokinetics of warfarin are not expected to change, monitoring of the INR is recommended in combination with all vitamin K antagonists, as altered hepatic function occurs with this product + obiparib treatment. ↔ S-warfarin 0.96
(0.85-1.08) 0.88
(0.81-0.96) 0.95
(0.88-1.02) ↔ Dasebuvir 0.97
(0.89-1.06) 0.98
(0.91-1.06)1.03
(0.94-1.13) ↔ Obetasvir 0.94
(0.89-1.00)0.96
(0.93-1.00)0.98
(0.95-1.02) ↔ Paritaprevir 0.98
(0.82-1.18)1.07
(0.89-1.27) 0.96
(0.85-1.09) Dabigatranate
Mechanism: inhibition of intestinal P-gp by paritaprevir and ritonavir This product + obiparib was not studied and is expected to.
 ↑ dabigatranate This product + obiparib may increase plasma concentrations of dabigatranate. Needs to be used with caution. Anticonvulsants Carbamazepine
200 mg once daily, followed by 200 mg twice daily
Mechanism: Carbamazepine induces CYP3A4 Benadryl + Obipiparib ↔ Carbamazepine 1.10
(1.07-1.14)1.17
(1.13-1.22)1.35
(1.27-1.45) Combination prohibited
(See [Contraindications]) ↓ Carbamazepine 10, 11-epoxides 0.84
(0.82-0.87) 0.75
(0.73-0.77)0.57
(0.54-0.61) ↓ Dasebuvir 0.45
(0.41-0.50) 0.30
(0.27-0.33) NA ↓ Obetasvir 0.69
(0.61-0.78) 0.69
(0.64-0.74) NA ↓ Paritaprevir 0.34
(0.25-0.48) 0.30
(0.23-0.38) NA phenobarbital
Mechanism: phenobarbital induces CYP3A4 This product + obiparib was not studied and is expected to.
 ↓ dasebuvir
↓ paritaprevir
↓ Obetavir prohibited in combination (see [contraindications])
phenytoin
Mechanism: phenytoin induces CYP3A4 this product + obiparib not studied, expected to
 ↓ dasabuvir
↓ paritaprevir
↓ Obetavir prohibited in combination
(see [contraindications])
S-mephentermine
Mechanism: ritonavir induces CYP2C19 This product + ombiparib was not studied and is expected to.
 ↓ S-mephentermine may require clinical monitoring and adjustment of the dose of s-mephentermine administered. Antidepressant escitalopram
10 mg, single dose administration of this product + ombiparib ↔ escitalopram 1.00
(0.96-1.05) 0.87
(0.80-0.95) NA No need to adjust escitalopram dose. ↑ S-desmethylcitalopram 1.15
(1.10-1.21) 1.36
(1.03-1.80) NA ↔ Dasebuvir 1.10
(0.95-1.27)1.01
(0.93-1.10)0.89
(0.79-1.00) ↔ Obetasvir 1.09
(1.01-1.18)1.02
(1.00-1.05)0.97
(0.92-1.02) ↔ Paritaprevir 1.12
(0.88-1.43) 0.98
(0.85-1.14)0.71
(0.56-0.89) Duloxetine
60 mg, single dose of this product + obiparib
↓ Duloxetine 0.79
(0.67-0.94) 0.75
(0.67-0.83) NA No dose adjustment of duloxetine is required.
No dose adjustment is required for this product + obiparib administration. ↔ Dasebuvir 0.94
(0.81-1.09) 0.92
(0.81-1.04) 0.88
(0.76-1.01) ↔ Obetasvir 0.98
(0.88-1.08)1.00
(0.95-1.06)1.01
(0.96-1.06) ↓ Paritaprevir 0.79
(0.53-1.16) 0.83
(0.62-1.10) 0.77
(0.65-0.91) Antifungal ketoconazole, 400 mg once daily
Mechanism: Inhibition of CYP3A4/P-gp by ketoconazole and obiparib Benadryl + obiparib
↑ Ketoconazole 1.15
(1.09-1.21) 2.17
(2.05-2.29) NA prohibited in combination (see product insert for obiparib)
↑ Dasebuvir 1.16
(1.03-1.32) 1.42
(1.26-1.59) NA ↔ Obetasvir 0.98
(0.90-1.06)1.17
(1.11-1.24) NA ↑ Paritaprevir 1.37
(1.11-1.69)1.98
(1.63-2.42) NA Lipid-lowering drug gemfibezil
600 mg twice daily
Mechanism: increase in dasebuvir exposure due to CYP2C8 inhibition; increase in paritaprevir exposure may be due to gefiberzil inhibition of OATP1B1 this product + obiparib ↑ dasebuvir 2.01
(1.71-2.38) 11.25
(9.05-13.99) NA Combination prohibited (see [Contraindications])
 ↑ Paritaprevir 1.21 (0.94-1.57) 1.38
(1.18-1.61) NA Anti-branched bacillus drug rifampicin
Mechanism: Rifampicin induces CYP3A4/CYP2C8 This product + Obiparib was not studied and is expected to.
 ↓ dasebuvir
↓ ombitasvir
↓ Paritaprevir prohibited in combination (see [Contraindications]) Metformin oral hypoglycemic drug Metformin
 500 mg, single dose of this product + obiparib
↓ Metformin 0.77 (0.71-0.83) 0.90 (0.84-0.97) NA No dose adjustment of metformin administration is required when combined with this product + obiparib. ↔ Dasebuvir 0.83 (0.74-0.93) 0.86 (0.78-0.94) 0.95 (0.84-1.07) ↔ Obetasvir 0.92 (0.87-0.98) 1.01 (0.97-1.05) 1.01 (0.98-1.04) ↓ Paritaprevir 0.63 (0.44-0.91) 0.80 (0.61- 1.03)1.22(1.13-1.31)Calcium channel blocker amlodipine
5 mg, single dose
Mechanism: ritonavir inhibits CYP3A4 This product + obiparib ↑ amlodipine 1.26
(1.11-1.44) 2.57
(2.31-2.86) NA Amlodipine dose needs to be reduced by 50% and patients monitored for clinical efficacy. ↔ Dasebuvir 1.05
(0.97-1.14) 1.01
(0.96-1.06) 0.95 (0.89-1.01) ↔ Obetasvir 1.00
(0.95-1.06)1.00
(0.97-1.04) 1.00 (0.97-1.04) ↓ Paritaprevir 0.77
(0.64-0.94) 0.78
(0.68-0.88) 0.88 (0.80-0.95) Contraceptives ethinyl estradiol/norgestrel
0.035/0.25 mg once daily
Mechanism: probably because paritaprevir, ombitasvir
and dasabuvir inhibit UGT this product + obiparib ↔ ethinyl estradiol 1.16
(0.90-1.50) 1.06
(0.96-1.17)1.12
(0.94-1.33) Oral contraceptives containing ethinylestradiol are contraindicated (see [Contraindications]) Norethindrone metabolite ↑ norethindrone 2.26
(1.91-2.67) 2.54
(2.09-3.09) 2.93
(2.39-3.57) ↑ Norethindrone 2.01
(1.77-2.29) 2.60
(2.30-2.95) 3.11
(2.51-3.85) ↓ Dasebuvir 0.51
(0.22-1.18) 0.48
(0.23-1.02) 0.53 (0.30- 0.95) ↔ Obetasvir 1.05
(0.81-1.35) 0.97
(0.81-1.15) 1.00 (0.88- 1.12) ↓ Paritaprevir 0.70
(0.40-1.21) 0.66
(0.42-1.04) 0.87 (0.67-1.14) Norethindrone (progestogen-only drug)
0.35 mg once daily This product + Obiparib ↔ Norethindrone 0.83
(0.69-1.01) 0.91
(0.76-1.09) 0.85
(0.64-1.13) No adjustment of the administered dose of norethindrone or this product + obiparib is required. ↔ Dasebuvir 1.01
(0.90-1.14) 0.96
(0.85-1.09) 0.95
(0.80-1.13)↔ Obetasvir 1.00
(0.93-1.08) 0.99
(0.94-1.04) 0.97
(0.90-1.03) ↑ Paritaprevir 1.24
(0.95-1.62) 1.23
(0.96-1.57) 1.43 (1.13-1.80) Diuretic furosemide
20 mg, single dose
Mechanism: probably because paritaprevir, ombitasvir
and dasabuvir inhibit UGT1A1 this product + obiparib ↑ furosemide 1.42
(1.17-1.72) 1.08
(1.00-1.17) NA Monitor patients for clinical efficacy; may require up to 50% reduction in furosemide dose
No adjustment of the dose administered for this product + obiparib is required. ↔ Dasebuvir 1.12
(0.96-1.31) 1.09
(0.96-1.23) 1.06 (0.98-1.14) ↔ Obetasvir 1.14
(1.03-1.26)1.07
(1.01-1.12) 1.12 (1.08-1.16) ↔ Paritaprevir 0.93
(0.63-1.36) 0.92
(0.70-1.21) 1.26 (1.16-1.38) HCV antiviral drug sofosbuvir
400 mg once daily
 Mechanism: inhibition of BCRP and P-gp by paritaprevir, ritonavir, and dasabuvir This product + ombiparib ↑ sofosbuvir 1.61
(1.38-1.88)2.12
(1.91-2.37)NA No dose adjustment of sofosbuvir administration is required when used in combination with this product + obiparib ↑ GS-3310071.02
(0.90-1.16)1.27
(1.14-1.42)NA↔ Dasebuvir1.09
(0.98-1.22)1.02
(0.95-1.10)0.85
(0.76-0.95)↔ Obetasvir 0.93
(0.84-1.03)0.93
(0.87-0.99)0.92
(0.88-0.96)↔ Paritaprevir 0.81
(0.65-1.01) 0.85
(0.71-1.01) 0.82
(0.67-1.01) Chinese herb St. John’s wort
(Onychomycetes)
Mechanism: Guan Ye Lian Qiao induces CYP3A4 This product + Obiparib was not studied and is expected to.
 ↓ Dasebuvir
↓ ombitasvir
↓ Paritaprevir is prohibited in combination
(see [Contraindications]) HIV antivirals: protease inhibitors
For a summary aimed at treating HIV co-infected patients (including a discussion of the different antiretroviral regimens that may be used), see [Precautions] (Treatment of HIV co-infected patients) and the product insert for Obiparib. Atazanavir
300 mg once daily (concurrent dosing)
Mechanism: The increase in paritaprevir exposure may be due to atazanavir inhibition of OATPs This product + Obiparib ↔ Atazanavir 0.91
(0.84-0.99)1.01
(0.93-1.10)0.90
(0.81-1.01) The recommended dose of atazanavir is 300 mg, when used in combination with this product + obiparib (not in combination with ritonavir). Atazanavir must be administered concurrently with this product + obiparib. The ritonavir dose in obiparib may enhance the pharmacokinetics of atazanavir.
No dose adjustment is necessary for the administration of this product + omaparib.
The combination of atazanavir with this product + obiparib has raised bilirubin levels, particularly when ribavirin is used as part of a hepatitis C regimen, see [Precautions] and [Adverse Reactions]. ↔ Dasebuvir 0.83
(0.71-0.96) 0.82
(0.71-0.94) 0.79
(0.66-0.94) ↓ Obetavir 0.77
(0.70-0.85) 0.83
(0.74-0.94) 0.89
(0.78-1.02) ↑ Paritaprevir 1.46
(1.06-1.99) 1.94
(1.34-2.81) 3.26
(2.06-5.16) Atazanavir/ritonavir
300/100 mg once daily
(evening dose)
Mechanism: The increase in paritaprevir exposure may be due to inhibition of OATP1B1/B3 and CYP3A by atazanavir and inhibition of CYP3A by additional doses of ritonavir Benadryl + Obiparib ↔ Atazanavir 1.02
(0.92-1.13)1.19
(1.11-1.28)1.68
(1.44-1.95) ↔ Dasabuvir 0.81
(0.73-0.91)0.81
(0.71-0.92)0.80
(0.65-0.98) ↔ Obetasvir 0.83
(0.72-0.96)0.90
(0.78-1.02)1.00
(0.89-1.13) ↑ Paritaprevir 2.19
(1.61-2.98) 3.16
(2.40-4.17) 11.95
(8.94-15.98) Darunavir
800 mg once daily (concurrent dosing)
Mechanism: unknown This product + Obiparib ↓ Darunavir 0.92
(0.87-0.98) 0.76
(0.71-0.82) 0.52
(0.47-0.58) Because the ritonavir-containing dose of this product enhances the pharmacokinetics of darunavir, the recommended dose of darunavir is 800 mg once daily (without additional ritonavir co-administration) when darunavir is administered concomitantly with this product + ombiparib.
This regimen may be used when no widespread PI resistance exists (i.e., lack of RAMs associated with darunavir), see [Precautions].
Dalunavir in combination with this product + obiparib is not recommended to be given to extensively PI-resistant patients.
No adjustment of the dose administered with this product + obiparib is required. ↔ Daselbovir 1.10
(0.88-1.370.94
(0.78-1.14) 0.90
(0.76-1.06) ↔ Obetasvir 0.86
(0.77-0.95)0.86
(0.79-0.94) 0.87
(0.82-0.92) ↑ Paritaprevir 1.54
(1.14-2.09) 1.29
(1.04-1.61) 1.30
(1.09-1.54) Darunavir/ritonavir
600/100 mg twice daily
Mechanism: unknown this product + Obiparib ↔ Darunavir 0.87
(0.79-0.96) 0.80
(0.74-0.86) 0.57
(0.48-0.67) ↓ Dasabuvir 0.84
(0.67-1.05) 0.73
(0.62-0.86) 0.54
(0.49-0.61) ↓ Obetavir 0.76
(0.65-0.88) 0.73
(0.66-0.80) 0.73
(0.64-0.83) ↓ Paritaprevir 0.70
(0.43-1.12) 0.59
(0.44-0.79) 0.83
(0.69-1.01) Darunavir/ritonavir
800/100 mg once daily
(evening dosing)
Mechanism: unknown
This product + Obiparib ↑ Darunavir 0.79
(0.70-0.90) 1.34
(1.25-1.43) 0.54
(0.48-0.62) ↓ Dasabuvir 0.75
(0.64-0.88) 0.72
(0.64-0.82) 0.65
(0.58-0.72) ↔ Obetasvir 0.87
(0.82-0.93) 0.87
(0.81-0.93)0.87
(0.80-0.95) ↓ Paritaprevir 0.70
(0.50-0.99) 0.81
(0.60-1.09) 1.59
(1.23-2.05) Lopinavir / ritonavir
400/100 mg twice daily1
Mechanism: Increased exposure to paritaprevir may be due to inhibition of CYP3A/exocytosis transporter protein by lopinavir and the effect of high doses of ritonavir Benadryl + ombiparib ↔ lopinavir 0.87
(0.76-0.99) 0.94
(0.81-1.10)1.15
(0.93-1.42) The combination of lopinavir/ritonavir at 400 mg/100 mg twice daily or 800 mg/200 mg once daily with this product + ombiparib is prohibited because of increased exposure to paritaprevir (see product insert for ombiparib). ↔ Dasebuvir 0.99
(0.75-1.31) 0.93
(0.75-1.15) 0.68
(0.57-0.80) ↔ Obetasvir 1.14
(1.01-1.28)1.17
(1.07-1.28)1.24
(1.14-1.34) ↑ Paritaprevir 2.04
(1.30-3.20) 2.17
(1.63-2.89) 2.36
(1.00-5.55) HIV antivirals: non-nucleoside reverse transcriptase inhibitor rilpivirine2
25 mg once daily with food in the morning.
Mechanism: Ritonavir inhibits CYP3A
This product + Obiparib ↑ Rilpivirine2.55
(2.08-3.12) 3.25
(2.80-3.77) 3.62
(3.12-4.21) The combination of Benadryl + Obiparib and rilpivirine (once daily) should only be used in patients with known absence of QT interval prolongation and should not be used in combination with other drugs that can cause QT interval prolongation. If co-administered, repeated ECG monitoring is required, see [Precautions].
No adjustment of the dose administered with this product + obiparib is required. ↔ Dasebuvir 1.18
(1.02-1.37) 1.17
(0.99-1.38)1.10
(0.89-1.37) ↔ Obetavir 1.11
(1.02-1.20)1.09
(1.04-1.14)1.05
(1.01-1.08) ↑ Paritaprevir
1.30
(0.94-1.81) 1.23
(0.93-1.64) 0.95
(0.84-1.07) Efavirenz/emtricitabine/ tenofovir disoproxil
600/300/200 mg once daily
Mechanism: Possible induction of liver enzymes by efavirenz This product + obiparib An efavirenz (enzyme inducer)-based regimen in combination with paritaprevir/ritonavir + this product resulted in elevated ALT and therefore led to early termination of the study. Combination with efavirenz-containing regimens is prohibited (see [Contraindications]) Nevirapine
Etravirine
This product + obiparib was not studied and is expected to.
↓ Dasebuvir
↓ ombitasvir
↓ Paritaprevir prohibited in combination (see [Contraindications]) HIV antivirals: integrase strand transfer inhibitor dolutegravir
50 mg once daily
 Mechanism: probably due to inhibition of UGT1A1 by paritaprevir, dasabuvir, and ombitasvir and inhibition of CYP3A4 by ritonavir This product + ombiparib ↑ dortelavir 1.22
(1.15-1.29) 1.38 (1.30-1.47) 1.36 (1.19-1.55) No dose adjustment of dotilaprevir administration is required when used in combination with this product + ombiparib. ↔ Dasabuvir 1.01 (0.92-1.11) 0.98 (0.92-1.05) 0.92 (0.85-0.99) ↔ Obetasvir 0.96 (0.89-1.03) 0.95 (0.90-1.00) 0.92 (0.87-0.98) ↔ Paritaprevir 0.89 (0.69-1.14) 0.84 (0.67- 1.04) 0.66 (0.59-0.75) raltegravir
400 mg twice daily
Mechanism: inhibition of UGT1A1 by paritaprevir, ombitasvir, and dasabuvir This product + ombiparib ↑ raltegravir
2.33
(1.66-3.27) 2.34
(1.70-3.24) 2.00
(1.17-3.42) No adjustment needed for raltegravir
(1.17-3.42) No adjustment of the dose of raltegravir or this product + obiparib is required.
No clinically relevant changes in exposure to dasabuvir, paritaprevir, or ombitasvir were observed during the drug combination (based on results compared with historical data). HIV antivirals: nucleoside inhibitors abacavir/lamivudine
 600/300 mg once daily Benadryl + Obiparib ↔ Abacavir 0.87 (0.78-0.98) 0.94 (0.90-0.99) NA In combination with Benadryl + Obiparib, no dose adjustment of abacavir/lamivudine administration is required. ↓ Lamivudine 0.78 (0.72-0.84) 0.88 (0.82-0.93) 1.29 (1.05-1.58) ↔ Dasebuvir 0.94 (0.86-1.03) 0.91 (0.86-0.96) 0.95 (0.88-1.02) ↔ Obetavir 0.82 (0.76-0.89) 0.91 (0.87- 0.95) 0.92 (0.88-0.96) ↔ Paritaprevir 0.84 (0.69-1.02) 0.82 (0.70-0.97) 0.73 (0.63-0.85) Emtricitabine/tenofovir
200mg/300mg of this product once daily + Obiparib ↔ Emtricitabine 1.05
(1.00-1.12)1.07
(1.00-1.14)1.09
(1.01-1.17) No adjustment needed for emtricitabine/tenofovir
and the dose administered for this product + obiparib. ↔ Tenofovir 1.07
(0.93-1.24)1.13
(1.07-1.20)1.24
(1.13-1.36) ↔ Dasebuvir
0.85
(0.74-0.98) 0.85
(0.75-0.96)0.85
(0.73-0.98) ↔ Obetasvir 0.89
(0.81-0.97)0.99
(0.93-1.05)0.97
(0.90-1.04)↓ Paritaprevir
0.68
(0.42-1.11) 0.84
(0.59-1.17)1.06
(0.83-1.35) HMG CoA reductase inhibitor resulvastatin, 5 mg once daily
Mechanism: Paritaprevir inhibits OATP1B; dasabuvir, paritaprevir, and ritonavir inhibit BCRP this product + obiparib ↑ Rosuvastatin 7.13
(5.11-9.96) 2.59
(2.09-3.21) 0.59
(0.51-0.69) The maximum daily dose of Rosuvastatin should be 5 mg (see [Precautions]).
No adjustment of the dose administered for this product + obiparib is necessary. ↔ Dasebuvir
1.07
(0.92-1.24)1.08
(0.92-1.26)1.15
(1.05-1.25)↔ Obetasvir 0.92
(0.82-1.04)0.89
(0.83-0.95) 0.88
(0.83-0.94) ↑ Paritaprevir
1.59
(1.13-2.23) 1.52
(1.23-1.90) 1.43
(1.22-1.68) Pravastatin
10 mg once daily
Mechanism: Paritaprevir inhibits OATP1B1 this product + Obiparib ↑ Pravastatin 1.37
(1.11-1.69) 1.82
(1.60-2.08) NA Pravastatin dose reduction by 50%.
No adjustment of the dose administered for this product + obiparib is required. ↔ Dasebuvir
1.00
(0.87-1.14) 0.96
(0.85-1.09)1.03
(0.91-1.15)↔ Obetasvir 0.95
(0.89-1.02) 0.94
(0.89-0.99)0.94
(0.89-0.99) ↔ Paritaprevir 0.96
(0.69-1.32)1.13
(0.92-1.38)1.39
(1.21-1.59) Fluvastatin
Mechanism: Inhibition of OATP1B/BCRP by paritaprevir
 Pitavastatin
Mechanism.
Paritaprevir inhibits OATP1B. this product + obiparib not studied, expected to.
 ↑ Fluvastatin
↑ Pitavastatin
↔ Dasebuvir
↔ Obetasvir
↔ Paritaprevir
Combination with fluvastatin and pitavastatin is not recommended (see [Precautions]).
During the treatment period, temporary discontinuation of fluvastatin and pitavastatin is recommended. If statin therapy is required during the treatment period, it may be necessary to switch to a lower dose of pravastatin or resulvastatin.
No adjustment of the dose administered with this product + obiparib is necessary. Immunosuppressant cyclosporine
30 mg once daily3
Mechanism: Effect on cyclosporine may be due to ritonavir inhibition of CYP3A4. increased paritaprevir exposure may be due to cyclosporine inhibition of OATP/BCRP/P-gp Benadryl + Obiparib ↑ Cyclosporine1.01
(0.85-1.20) 5.82
(4.73-7.14) 15.8
(13.8-18.09) When cyclosporine is initiated in combination with this product + obiparib, one-fifth of the total cyclosporine dose is given once daily and one dose of obiparib is given while cyclosporine concentrations are monitored and the dose and/or dosing frequency is adjusted if needed.
No adjustment of the administered dose of this product + obiparib is required. ↓ Dasebuvir
0.66
(0.58-0.75) 0.70
(0.65-0.76) 0.76
(0.71-0.82) ↔ Obetasvir
0.99
(0.92-1.07)1.08
(1.05-1.11)1.15
(1.08-1.23) ↑ Paritaprevir
1.44
(1.16-1.78) 1.72
(1.49-1.99) 1.85
(1.58-2.18) Everolimus
0.75 mg single dose
 Mechanism: effect on everolimus because ritonavir inhibits CYP3A4 This product + obiparib ↑ everolimus 4.74
(4.29-5.25) 27.12
(24.5-30.1) 16.1
(14.5-17.9) 44 It is not recommended that this product + obiparib be used in combination with everolimus because the combination leads to a significant increase in exposure to everolimus and there are no suitable specifications to adjust the dose (see [Precautions]. ↔ Dasebuvir 1.03
(0.90-1.18)1.08
(0.98-1.20)1.14
(1.05-1.23) ↔ Obetasvir 0.99
(0.95-1.03)1.02
(0.99-1.05)1.02
(0.99-1.06) ↔ Paritaprevir 1.22
(1.03-1.43)1.26
(1.07-1.49)1.06
(0.97-1.16) Sirolimus
0.5 mg single dose 5
 Mechanism: effect on sirolimus because ritonavir inhibits CYP3A4 This product + obiparib ↑ sirolimus 6.40
(5.34-7.68) 38.0
(31.5-45.8) 19.6
(16.7-22.9)6 The combination of sirolimus with this product + obiparib is not recommended unless the therapeutic benefit outweighs the risk (see [Precautions]). If sirolimus is used in combination with this product + obiparib, sirolimus is given 0.2 mg twice weekly (every 3 or 4 days, administered on the same two days of the week). Patients’ sirolimus blood levels should be monitored every 4-7 days until 3 consecutive trough concentrations show steady-state sirolimus concentrations. Adjust the dose and/or dosing frequency of sirolimus administration as needed.
The sirolimus dose and dosing frequency prior to receiving treatment with obiparib should be readministered 5 days after the end of treatment with this product + obiparib, and sirolimus blood concentrations should be routinely monitored. ↔ Dasebuvir 1.04
(0.89-1.22)1.07
(0.95-1.22) 1.13
(1.01-1.25) ↔ Obetasvir 1.03
(0.93-1.15)1.02
(0.96-1.09)1.05
(0.98-1.12) ↔ Paritaprevir 1.18
(0.91-1.54)1.19
(0.97-1.46)1.16
(1.00-1.34) Tacrolimus
2 mg in a single dose7
Mechanism: effect on tacrolimus because ritonavir inhibits CYP3A4 This product + obiparib ↑ tacrolimus 3.99
(3.21-4.97) 57.1
(45.5-71.7) 16.6
(13.0-21.2) The combination of tacrolimus with this product + obiparib is not recommended unless the benefit of treatment outweighs the risk (see [Precautions]).
If tacrolimus is used in combination with this product + obiparib, tacrolimus should not be given on the same day that this product + obiparib is started. Starting on the day following the start of treatment with this product + albiparib, a reduced dose of tacrolimus should be reintroduced based on the tacrolimus blood level. The recommended dose of tacrolimus is 0.5 mg every 7 days.
Tacrolimus blood levels should be monitored after initiation of the combination with this product + albiparib and throughout the combined dosing period, and the dose and/or frequency of administration should be adjusted as needed. After the end of treatment with Benadryl + Obiparib, the appropriate dose and dosing frequency should be given based on the tacrolimus blood level. ↔ Dasebuvir
0.85
(0.73-0.98) 0.90
(0.80-1.02)1.01
(0.91-1.11)↔ Obetasvir 0.93
(0.88-0.99)0.94
(0.89-0.98)0.94
(0.91-0.96) ↓ Paritaprevir
0.57
(0.42-0.78) 0.66
(0.54-0.81) 0.73
(0.66-0.80) Iron ion chelator dilalocet this product + obiparib not studied, expected to.
 ↑ Dasebuvir Delarox may increase exposure to dasebuvir and should be used with caution. Drugs used to treat multiple sclerosis Teriflunomide this product + Obiparib not studied, expected to.
 ↑ Dasebuvir Teriflunomide may increase exposure to dasebuvir and should be used with caution. Opioid methadone
20-120 mg once daily 8 Benadryl + Obiparib ↔ R-methadone 1.04
(0.98-1.11) 1.05
(0.98-1.11) 0.94
(0.87-1.01) No adjustment of the administered dose of methadone and Benadryl + Obiparib is required. ↔ S-methadone 0.99
(0.91-1.08) 0.99
(0.89-1.09) 0.86
(0.76-0.96) ↔ Obetavir/paritaprevir and dasebuvir
(based on crossover study comparisons) Buprenorphine/naloxone
4-24 mg/1-6 mg once daily8
Mechanism: ritonavir inhibits CYP3A4, paritaprevir, ombitasvir, and dasebuvir inhibit UGT This product + ombiparib ↑ buprenorphine2.18
(1.78-2.68) 2.07
(1.78-2.40) 3.12
(2.29-4.27) No dose adjustment required for buprenorphine/naloxone and this product + obiparib administration ↑Norbuprenorphine 2.07
(1.42-3.01) 1.84
(1.30-2.60) 2.10
(1.49- 2.97) ↑ Naloxone 1.18
(0.81-1.73) 1.28
(0.92-1.79) NA ↔ Obetavir/paritaprevir and dasebuvir
(based on cross-sectional study comparison results) Myorelaxant carisoprodol
250 mg
Single dose
Mechanism: ritonavir induces CYP2A19 Benadryl + ombiparib ↓ caripridol 0.54
(0.47-0.63) 0.62 (0.55-0.70) NA No adjustment of the administered dose of calipridol is required; if clinically indicated, the administered dose may be increased. ↔ Dasabuvir 0.96 (0.91-1.01) 1.02 (0.97-1.07) 1.00 (0.92-1.10) ↔ Obetavir 0.98 (0.92-1.04) 0.95 (0.92-0.97) 0.96 (0.92-0.99) ↔ Paritaprevir 0.88 (0.75-1.03) 0.96 (0.85- 1.08)1.14(1.02-1.27)Cyclobenzaprine
5 mg
Single dose
Mechanism: reduction may be due to ritonavir induction of CYP1A2 This product + obiparib ↓ cyclobenzaprine 0.68
(0.61-0.75) 0.60 (0.53-0.68) NA No adjustment of the dose of cyclobenzaprine administered is required; if clinically indicated, the dose administered may be increased. ↔ Dasabuvir 0.98 (0.90-1.07) 1.01 (0.96-1.06) 1.13 (1.07-1.18) ↔ Obetasvir 0.98 (0.92-1.04) 1.00 (0.97-1.03) 1.01 (0.98-1.04) ↔ Paritaprevir 1.14 (0.99-1.32) 1.13 (1.00- 1.28)1.13(1.01-1.25)Narcotic analgesic acetaminophen (give a fixed dose of hydrocodone/acetaminophen)
300 mg, single administration of this product + Obiparib ↔ Acetaminophen
Acetaminophen 1.02
(0.89-1.18) 1.17
(1.09-1.26) NA No dose adjustment of acetaminophen administration is required when used in combination with this product and olpiparib. ↔ Dasabuvir 1.13 (1.01-1.26) 1.12 (1.05-1.19) 1.16 (1.08-1.25) ↔ Obetasvir 1.01 (0.93-1.10) 0.97 (0.93-1.02) 0.93 (0.90-0.97) ↔ Paritaprevir 1.01 (0.80-1.27) 1.03 (0.89- 1.18)1.10 (0.97-1.26)Hydrocodone (give a fixed dose of hydrocodone/acetaminophen)
5 mg, single dose administration
Mechanism: ritonavir inhibits CYP3A4 This product + obiparib ↑ hydrocodone 1.27
(1.14-1.40)1.90
(1.72-2.10)NA In combination with Benadryl + Obiparib, the dose of hydrocodone administered should be reduced by 50% and monitored clinically. Changes for ombitasvir, paritaprevir, and dasebuvir are the same as for acetaminophen as described above. Proton pump inhibitor omeprazole
40 mg once daily
Mechanism: Ritonavir induces CYP2C19. this product + obiparib ↓ omeprazole 0.62
(0.48-0.80) 0.62
(0.51-0.75) NA Higher doses of omeprazole may be given if clinically indicated.
No adjustment of the administered dose of this product + Obiparib is required. ↔ Dasebuvir 1.13
(1.03-1.25) 1.08
(0.98-1.20)1.05
(0.93-1.19) ↔ Obetavir 1.02
(0.95-1.09)1.05
(0.98-1.12)1.04
(0.98-1.11) ↔ Paritaprevir 1.19
(1.04-1.36)1.18
(1.03-1.37) 0.92
(0.76-1.12) Esomeprazole
Lansoprazole
Mechanism: Ritonavir induces CYP2C19.
This product + obiparib was not studied and is expected to.
↓ Esomeprazole, lansoprazole Higher doses of esomeprazole/lansoprazole may be given if clinically indicated. Sedative/hypnotic zolpidem
5 mg, single dose of this product + obiparib ↔ zolpidem
0.94
(0.76-1.16) 0.95
(0.74-1.23) NA No need to adjust zolpidem dosing.
No adjustment of the administered dose of this product + obiparib is required. ↔ Dasebuvir
0.93
(0.84-1.03) 0.95
(0.84-1.08) 0.92
(0.83-1.01) ↔ Obetasvir 1.07
(1.00-1.15)1.03
(1.00-1.07)1.04
(1.00-1.08) ↓ Paritaprevir
0.63
(0.46-0.86) 0.68
(0.55-0.85) 1.23
(1.10-1.38) Diazepam
2 mg
Single dose
Mechanism: ritonavir inhibits CYP2C19 this product + obiparib
↓ diazepam 1.18
(1.07-1.30) 0.78
(0.73-0.82) NA No adjustment of diazepam dosing is required; dosing may be increased if clinically indicated ↓ Desmethyl diazepam 1.10
(1.03-1.19) 0.56
(0.45-0.70) NA ↔ Dasabuvir 1.05 (0.98-1.13) 1.01 (0.94-1.08) 1.05 (0.98-1.12) ↔ Obetasvir 1.00 (0.93-1.08) 0.98 (0.93-1.03) 0.93 (0.88-0.98) ↔ Paritaprevir 0.95 (0.77- 1.18)0.91 (0.78-1.07)0.92 (0.82-1.03)Alprazolam
0.5 mg, single dose
Mechanism: ritonavir inhibits CYP3A4 This product + obiparib ↑ alprazolam 1.09
(1.03-1.15) 1.34
(1.15-1.55) NA Clinical monitoring of patients is recommended. Depending on clinical response, alprazolam dose reduction may be considered.
No adjustment of the dose administered for this product + obiparib is required. ↔ Dasebuvir
0.93
(0.83-1.04) 0.98
(0.87-1.11)1.00
(0.87-1.15)↔ Obetasvir 0.98
(0.93-1.04)1.00
(0.96-1.04) 0.98
(0.93-1.04) ↔ Paritaprevir
0.91
(0.64-1.31) 0.96
(0.73-1.27)1.12
(1.02-1.23) Thyroid hormone levothyroxine
Mechanism: inhibition of UGT1A1 by paritaprevir, ombitasvir and dasebuvir This product + ombiparib was not studied and is expected to.
 ↑ Clinical monitoring and dose adjustment is required when levothyroxine is used in combination with levothyroxine. Lopinavir/ritonavir (evening dosing) once daily at 800/200 mg may be used in combination with this product + ombiparib. The effects on DAAs and lopinavir Cmax and AUC were similar to those observed with lopinavir/ritonavir at 400/100 mg twice daily and the combination of this product + obiparib.
In the study, rilpivirine was administered in the evening and with food, and this product + obiparib was administered 4 hours after dinner. The effect on rilpivirine exposure was similar to that observed with rilpivirine administered with food in the morning and concomitantly with this product + obiparib.
100 mg cyclosporine alone, or 30 mg cyclosporine and this product + obiparib in combination. There was a drug interaction between cyclosporine and this product + albiparib at standardized doses.
C12: Blood levels 12 hours after single administration of everolimus.
2 mg sirolimus alone or 0.5 mg sirolimus in combination with this product + obiparib. Drug interactions exist between sirolimus and this product + obiparib at standardized doses.
C24: Blood levels 24 hours after a single administration of cyclosporine, tacrolimus, or sirolimus.
2 mg tacrolimus alone or 2 mg tacrolimus in combination with this product + obiparib. Drug interactions exist between tacrolimus and this product + obiparib at standardized doses.
Dose calibration parameters have been reported for methadone, buprenorphine, and naloxone.
Note: The doses of each drug in the combination regimen of this product + ombiparib are shown below: ombitasvir 25 mg, paritaprevir 150 mg, ritonavir 100 mg (once daily), and dasebuvir (400 mg twice daily or 250 mg twice daily). Exposures were similar for dasebuvir 400 mg tablets and 250 mg tablets. This product + ombiparib was given multiple times in drug interaction studies except for those with carbamazepine, gemfibezil, ketoconazole and and sulfamethoxazole/methoprene. Pediatric Dosing
Drug interaction studies were conducted in adults only.
Drug overdose]
The highest single dose administered in healthy subjects was 2 g. No adverse reactions or clinically significant abnormalities in laboratory tests associated with the study drug were observed. In the event of an overdose, it is recommended that patients be monitored for signs or symptoms of adverse reactions and given immediate symptomatic treatment.
Clinical Trials]
Clinical efficacy and safety
The following clinical trials have been conducted overseas
Seven phase 3 clinical trials (including two in patients with compensated cirrhosis [Child-Pugh class A] only) evaluated the efficacy and safety of this product + obiparib +/- ribavirin combination in more than 2360 patients with genotype 1 chronic hepatitis C, as shown in Table 5.
Table 5. Phase 3, global multicenter trials completed with this product + olbiparib +/- ribavirin (RBV)
Number of patients treated in the trial HCV genotype
(GT) Study Design Summary Primary, cirrhosis-free SAPPHIRE I 631 GT1 Group A: Benadryl + Obiparib + Ribavirin
Group B: Placebo PEARL III 419 GT1b Group A: Benadryl + Obiparib + Ribavirin
Group B: Benadryl + Obiparib
PEARL IV 305 GT1a Group A: this product + obiparib + ribavirin
Group B: this product + obiparib
PEGylated interferon + ribavirin treated, without cirrhosis SAPPHIRE II 394 GT1 Group A: this product + obiparib + ribavirin
Group B: Placebo PEARL II
(Open) 179 GT1b Group A: this product + obiparib + ribavirin
Group B: This product + obiparib primary and pegylated interferon + ribavirin treated, with compensated cirrhosis TURQUOISE II (open) 380 GT1 Group A: This product + obiparib + ribavirin (12 weeks)
Group B: Benadryl + Obiparib + Ribavirin (24 weeks) TURQUOISE III (open) 60 GT1b Benadryl + Obiparib (12 weeks) In all 7 clinical trials, Benadryl was administered at a dose of 250 mg twice daily and Obiparib was administered at a dose of 25 mg/150 mg/100 mg once daily. for patients receiving Ribavirin For patients treated with ribavirin, the dose of ribavirin is 1000 mg daily for patients weighing less than 75 kg and 1200 mg daily for patients weighing equal to or greater than 75 kg.
Sustained virologic response (SVR) is the primary endpoint for evaluating HCV cure rates in Phase 3 studies and is defined as undetectable or non-quantifiable HCV RNA 12 weeks after the end of treatment (SVR12). The treatment period for each trial was fixed and independent of the patient’s HCV RNA level (no treatment guidance based on response was required). During the clinical trials, HCV RNA is detected using the COBAS TaqMan HCV assay (version 2.0), which is based on the High Pure system. the lower limit of quantification (LLOQ) of the High Pure system is 25 IU/mL.
Clinical trials in primary care adult patients
SAPPHIRE-I – gene type 1, primary treatment
The SAPPHIRE-I trial was a randomized, global, multicenter, double-blind, placebo-controlled trial completed in 631 adult patients with primary treatment of genotype 1 chronic hepatitis C virus infection (without cirrhosis). This product + obiparib was treated for 12 weeks in combination with ribavirin. Patients assigned in the placebo control group received 12 weeks of placebo treatment, followed by 12 weeks of open treatment with Benadryl + Obiparib + Ribavirin.
The median age of treated patients (N=631) was 52 years (range: 18-70 years); 54.5% of patients were male; 5.4% were black; 16.2% had a body mass index of at least 30 kg/m2; 15.2% had a history of depression or bipolar disorder; 69.3% were IL28B non-CC genotype; 79.1% had a baseline HCV RNA level of at least 800,000 IU/mL; 15.4% patients had confluent zone fibrosis (F2) and 8.7% patients had bridge-like fibrosis (F3); 67.7% patients were infected with HCV genotype 1a; 32.3% patients were infected with HCV genotype 1b.
The SVR12 response rates of genotype 1 infected primary patients in the SAPPHIRE-I study who received this product + obiparib + ribavirin for 12 weeks are shown in Table 6.
Table 6. SVR12 in genotype 1 primed patients in the SAPPHIRE-I study
Treatment outcome Benadryl + Obiparib + Ribavirin for 12 weeks n/N % 95% CI Total SVR12 rate 456/473 96.4 94.7, 98.1 HCV genotype 1a 308/322 95.7 93.4, 97.9 HCV genotype 1b 148/151 98.0 95.8, 100.0 Patients who did not obtain SVR12   VFa1/473 during treatment 0.2 Recurrence7/463 1.5 Otherb9/473 1.9 Confirmation is required that the patient reappeared with HCV RNA ≥ 25 IU/mL after achieving HCV RNA < 25 IU/mL during treatment, confirmation that HCV RNA levels increased by 1 log10 IU/mL from the nadir, or that HCV RNA remained after at least 6 weeks of treatment ≥ 25 IU/mL after at least 6 weeks of treatment
Other outcomes include early discontinuation not due to virologic failure (missing HCV RNA test values within the SVR12 time window)
No patients with HCV genotype 1b infection experienced virologic failure on treatment and 1 patient with HCV genotype 1b infection experienced a relapse.
PEARL-III – genotype 1b, primary treatment
The PEARL-III trial was a randomized, global, multicenter, double-blind, controlled trial completed in 419 adult patients with primary treatment of genotype 1b chronic hepatitis C virus infection (without cirrhosis). Patients were randomized in a 1:1 ratio to receive treatment with this product + obiparib +/- ribavirin for 12 weeks.
The median age of treated patients (N=419) was 50 years (range: 19-70 years); 45.8% of patients were male; 4.8% were black; 16.5% had a body mass index of at least 30 kg/m2; 9.3% had a history of depression or bipolar disorder; 79.0% had IL28B non-CC genotype; 73.3% had baseline HCV RNA levels of at least 800,000 IU/mL; 20.3% of patients had confluent zone fibrosis (F2) and 10.0% had bridge-like fibrosis (F3).
The SVR12 response rates in patients with primary treatment of genotype 1b infection who received this product + obiparib +/- ribavirin for 12 weeks in the PEARL III study are shown in Table 7. In this study, the SVR12 response rate for treatment with this product + obiparib (not in combination with ribavirin) (100%) was similar to that for treatment with this product + obiparib + ribavirin (99.5%).
Table 7. SVR12 in genotype 1b first-treatment patients in the PEARL III study
Treatment outcome Benadryl + Obiparib for 12 weeks + Ribavirin- Ribavirin n/N % 95% CI n/N % 95% CI SVR12 rate 209/210 99.5 98.6, 100.0 209/209 100 98.2, 100.0 Outcome in patients without SVR12 VF1/210 on treatment 0.5 0/209 0 Relapse 0/ 210 0 0/209 0 Other 0/210 0 0/209 0  
 Genotype 1a, primary treatment
PEARL-IV is a randomized, global, multicenter, double-blind, controlled clinical trial completed in 305 adult patients with primary treatment genotype 1a chronic hepatitis C virus infection (without cirrhosis). Patients were randomized in a 1:2 ratio to receive this product + obiparib +/- ribavirin for 12 weeks.
The median age of treated patients (N=305) was 54 years (range: 19-70 years); 65.2% of patients were male; 11.8% were black; 19.7% had a body mass index of at least 30 kg/m2; 20.7% had a history of depression or bipolar disorder; 69.2% were IL28B non-CC genotype; 86.6% had a baseline HCV RNA levels were at least 800,000 IU/mL; 18.4% of patients had confluent zone fibrosis (F2) and 17.7% had bridge-like fibrosis (F3).
The SVR12 response rates in patients with primary genotype 1a infection treated with this product + obiparib +/- ribavirin for 12 weeks in the PEARL IV study are shown in Table 8. The SVR12 response rate in patients treated with this product + obiparib was not inferior to that in patients treated with this product + obiparib + ribavirin.
Table 8. SVR12 in genotype 1a first-treatment patients in the PEARL IV study
Treatment outcome Benadryl+Obiparib treatment for 12 weeks + Ribavirin-Ribavirin n/N % 95% CI n/N % 95% CI SVR12 rate 97/100 97.0 93.7, 100.0 185/205 90.2 86.2, 94.3 Outcome in patients without SVR12 VF1/100 on treatment 1.0 6/205 2.9 Relapse 1/ 98 1.0 10/194 5.2 Other 1/100 1.0 4/205 2.0 Clinical trial of pegylated interferon + ribavirin in treated adults
SAPPHIRE-II – genotype 1 pegylated interferon + ribavirin-treated patients
SAPPHIRE-II is a randomized, global, multicenter, double-blind, placebo-controlled trial completed in 394 patients with genotype 1 chronic hepatitis C virus infection (without cirrhosis) who were previously treated with pegIFN/RBV and did not achieve SVR. this product + obiparib + ribavirin combination was administered for 12 weeks. Patients randomly assigned in the placebo control group received placebo first for 12 weeks followed by 12 weeks of the combination of this product + obiparib + ribavirin.
Patients treated (N=394) had a median age of 54 years (range: 19-71 years); 49.0% were non-responders to prior pegIFN/RBV therapy; 21.8% were partial responders to prior pegIFN/RBV therapy; 29.2% were relapsed patients to prior pegIFN/RBV therapy; and 57.6% were male. 8.1% of patients were black; 19.8% had a body mass index of at least 30 kg/m2; 20.6% had a history of depression or bipolar disorder; 89.6% had IL28B non-CC genotype; 87.1% had a baseline HCV RNA level of at least 800,000 IU/mL; 17.8% had fibrosis of the confluent area (F2), and 14.5% of patients developed bridge-like fibrosis (F3); 58.4% of patients were infected with HCV genotype 1a; 41.4% of patients were infected with HCV genotype 1b staining.
The SVR12 response rates in treated patients with genotype 1 infection treated with this product + obiparib + ribavirin for 12 weeks in the SAPPHIRE-II study are shown in Table 9.
Table 9. SVR12 in genotype 1, pegylated interferon + ribavirin-treated patients in the SAPPHIRE-II study
Treatment outcome Benadryl + Obiparib + Ribavirin
12 weeks of treatment n/N % 95% CI total SVR12 rate 286/297 96.3 94.1, 98.4 HCV genotype 1a 166/173 96.0 93.0, 98.9 Previous pegIFN/RBV treatment non-responders 83/87 95.4 91.0, 99.8 Previous pegIFN/RBV treatment partial responders 36/36 100 100.0, 100.0 Patients with relapse on previous pegIFN/RBV treatment 47/50 94.0 87.4, 100.0 HCV genotype 1b 119/123 96.7 93.6, 99.9 Patients with no response on previous pegIFN/RBV treatment 56/59 94.9 89.3, 100.0 Patients with relapse on previous pegIFN/RBV treatment 28/28 100.0 Partial responders 28/28 100 100.0, 100.0 Patients with relapse on prior pegIFN/RBV treatment 35/36 97.2 91.9, 100.0 Outcomes not obtained for patients with SVR12 VF during treatment 0/297 0 Relapse 7/293 2.4 Other 4/297 1.3 No HCV genotype 1b patients with virologic failure on treatment , 2 patients with HCV genotype 1b infection developed relapse.
PEARL-II – genotype 1b, pegylated interferon combined with ribavirin via treatment
PEARL-II was a randomized, global, multicenter, open trial completed in 179 adult patients with chronic genotype 1b hepatitis C virus infection (without cirrhosis) who were previously treated with pegIFN/RBV. Patients were randomized in a 1:1 ratio to receive this product + obiparib +/- ribavirin for 12 weeks.
The median age of treated patients (N=179) was 57 years (range: 26-70 years); 35.2% patients were prior pegIFN/RBV non-responders; 28.5% patients were prior pegIFN/RBV treatment partial responders; 36.3% patients were prior pegIFN/RBV treatment relapsed patients; 54.2% patients were male; 3.9% patients were black; 21.8% had a body mass index of at least 30 kg/m2; 12.8% had a history of depression or bipolar disorder; 90.5% had IL28B non-CC genotype; 87.7% had a baseline HCV RNA level of at least 800,000 IU/mL; 17.9% had confluent zone fibrosis (F2) and 14.0% had bridge-like fibrosis (F3).
The SVR12 response rates in treated patients with genotype 1b infection treated with this product + obiparib +/- ribavirin for 12 weeks in the PEARL II study are shown in Table 10. This study showed that the response rate for the combination of this product + obiparib (without ribavirin) (100%) was similar to that of the combination of this product + obiparib + ribavirin (97.7%).
Table 10. SVR in genotype 1b pegylated interferon + ribavirin-treated patients in the PEARL II study12
Treatment outcome Benadryl + Obiparib for 12 weeks + Ribavirin-ribavirin n/N % 95% CIn/N % 95% CI Total SVR12 rate 86/88 97.794.6, 100.091/9110095.9, 100.0 Previous pegIFN/RBV treatment non-responders 30/31 96.890.6, 100.032/ 3210089.3, 100.0 previous pegIFN/RBV treatment partial responders24/25 96.088.3, 100.026/2610087.1, 100.0 previous pegIFN/RBV treatment relapsed patients32/32 10089.3, 100.033/3310089.6, 100.0 not obtained Outcomes in SVR12 patients VF during treatment 0/88 0 0/910 Relapses 0/88 0 0/910 Other 2/88 2.3 0/910 Clinical trials in patients with compensated cirrhosis
TURQUOISE-II-genotype 1 primary or pegylated interferon + ribavirin-treated patients with compensated cirrhosis
The TURQUOISE-II trial is a randomized, global, multicenter, open trial including only 380 patients with compensated cirrhosis (Child-Pugh Class A) with genotype 1 infection who are either primary or treated with pegIFN/RBV and have not achieved SVR. This product + obiparib + ribavirin treatment for 12 or 24 weeks.
Median age of treated patients (N=380) was 58 years (range: 21-71 years); 42.1% patients were primary patients; 36.1% patients were prior pegIFN/RBV non-responders; 8.2% patients were prior pegIFN/RBV treatment partial responders; 13.7% patients were prior pegIFN/RBV treatment relapsed patients. 70.3% patients were male; 3.2% patients were black; 28.4% patients had a body mass index of at least 30 kg/m2; 14.7% patients had a platelet count less than 90 x 109/L; 49.7% patients had an albumin level less than 40 g/L; 86.1% patients had a baseline HCV RNA level of at least 800,000 IU/mL; 81.8% patients were IL28B non-CC genotype; 24.7% had a history of depression or bipolar disorder; 68.7% were infected with HCV genotype 1a; and 31.3% were infected with genotype 1b.
The SVR12 response rates in primary or pegIFN/RBV treated patients with genotype 1 infection combined with compensated cirrhosis are shown in Table 11.
Table 11. SVR12 in primary or pegIFN/RBV-treated patients with genotype 1 with compensated cirrhosis
Treatment outcome Benadryl + Obiparib + Ribavirin 12 weeks 24 weeks n/N % CIan/N % CIa Total SVR12 rate 191/208 91.8 87.6, 96.1 166/172 96.5 93.4, 99.6 HCV genotype 1a 124/140 88.6 83.3, 93.8 115/121 95.0 91.2, 98.9 Primary patients 59/64 92.2 53/56 94.6 Previous pegIFN/RBV treatment non-responders 40/50 80.0 39/42 92.9 Previous pegIFN/RBV treatment partial responders 11/11 100 10/10 100 Previous pegIFN/RBV treatment relapsed patients 14/15 93.3 13/13 100 HCV genotype 1b 67/68 98.5 95.7, 100 51/51 100 93.0, 100 Primary patients 22/22 100 18/18 100 Previous pegIFN/RBV treatment non-responders 25/25 100 20/20 100 Previous pegIFN/RBV treatment partial responders 6/7 85.7 3/3100  Patients with relapse on prior pegIFN/RBV treatment 14/14 100 10/10 100 Patients without SVR12 outcome on treatment VF1/208 0.5 3/172 1.7 Relapse 12/203 5.9 1/164 0.6 Other 4/208 1.9 2/172 1.21 97.5% Confidence intervals are used to describe the primary effectiveness endpoint (total SVR12 rate); 95% confidence intervals were used to describe other effectiveness endpoints (SVR12 rate in patients with HCV genotype 1a and 1b).
Relapse rates for patients with GT1a cirrhosis with different baseline laboratory test values are shown in Table 12.
Table 12. TURQUOISE-II study: relapse rates at 12 and 24 weeks after drug discontinuation in patients with genotype 1a with compensated cirrhosis according to different baseline laboratory test values
 Benadryl+Obiparib+Ribavirin
12-week treatment group Benadryl+Obiparib+Ribavirin
Number of patients with a response at the end of treatment in the 24-week treatment group135 113 Before treatment, AFP* < 20 ng/mL, platelets ≥ 90 x 109/L albumin ≥ 35 g/L
Yes (all three parameters above) 1/87 (1%) 0/68 (0%)
No
(any of the above parameters) 10/48 (21%) 1/45 (2%) *AFP= Patients who met three baseline laboratory indices for serum alpha fetoprotein (AFP< 20 ng/mL, platelets ≥ 90 x 109/L, albumin ≥ 35 g/L) had similar recurrence rates for patients treated for 12 or 24 weeks.
TURQUOISE-III: Clinical Trial in Patients with Genotype 1b with Cirrhosis Treated with this Product without Combination Ribavirin
TURQUOISE-III is a phase IIIb, open, single-arm, multicenter study to evaluate the efficacy and safety of 12 weeks of treatment with this product + obiparib (not in combination with ribavirin) in adult HCV GT1b-infected patients with primary and pegIFN/RBV-treated concomitant compensated cirrhosis.
Sixty patients were randomized and treated with the drug, and 60/60 (100%) patients achieved SVR.12 Key patient characteristics are shown below.
Table 13 Key demographic data from the TURQUOISE-III study
Characteristics N = 60 Age, median (range) Age 60.5 (26 ~ 78) Male, n (%) 37 (61) IL28B non-CC genotype, n (%) 50 (83) Prior HCV treatment history: primary treatment 27 (45) Peg-IFN + RBV treatment, n (%) 33 (55) Baseline albumin, median (g/L) 40.0< 35, n (%) 10 (17) ≥ 35, n (%) 50 (83) Baseline platelet count, median value (×109/L) 132.0< 90, n (%) 13 (22) ≥ 90, n (%) 47 (78) Pooled analysis of clinical trials
Persistence of response
Overall, 660 patients in phase 2 and 3 clinical trials were tested for HCV RNA for the assessment of SVR12 and SVR24. In these patients, the positive predictive rate of SVR12 for SVR24 was 99.8%.
Pooled analysis of validity
In the phase 3 clinical trial, 1075 patients with HCV genotype 1 (including 181 patients with compensated cirrhosis) were treated with the recommended regimen (see [Dosage]). The SVR rates for these patients are shown in Table 15.
Of the patients treated with the recommended regimen, 97% of them achieved SVR (97% of 181 patients with compensated cirrhosis), only 0.5% experienced virologic breakthrough, and 1.2% experienced relapse after discontinuation of the regimen.
Table 14. SVR12 rates in different patient populations receiving recommended regimens
 HCV gene type 1b
Benadryl+Obiparib HCV genotype 1a
Benadryl + Obiparib + Ribavirin No cirrhosis compensated cirrhosis No cirrhosis compensated cirrhosis treatment cycle 12 weeks 12 weeks 12 weeks 24 weeks primary 100% (210/210) 100% (27/27) 96% (403/420) 95% (53/56) pegIFN + RBV treated 100% (91/91) 100% (33/33) 96% (166/173) 95% (62/65) relapsed patients 100% (33/33) 100% (3/3) 94% (47/50) 100% (13/13) partial responders 100% (26/26) 100% (5/5) 100% (36/36) 100% (10/10) non-responders 100% (32/32) 100% (7/7) 95% (83/87) 93% (39/42) pegIFN/RBV treatment failure in other cases 0100% (18/18) + 00 total 100% (301/301) 100% (60/60) 96% (569/593) 95% (115/121) + pegIFN/RBV treatment failure in Other conditions include unconfirmed non-response, relapse/virologic breakthrough or other conditions of pegIFN treatment failure.
Impact of Ribavirin Dose Adjustment on SVR
During treatment in the phase 3 clinical trial, 91.5% of patients did not require ribavirin dose adjustment. 8.5% of patients required ribavirin dose adjustment during treatment, and their SVR rate (98.5%) was comparable to the SVR rate in patients who maintained the starting ribavirin dose throughout the treatment period.
Clinical trials in patients with HCV genotype 1/HIV-1 co-infection
The efficacy and safety of the combination of this product + obiparib + ribavirin was evaluated in 63 patients with genotype 1 chronic hepatitis C co-infection with HIV-1 in an open clinical trial (TURQUOISE-I) for 12 or 24 weeks of treatment. See [DOSAGE] for dosing recommendations for HCV/HIV-1 co-infection. Patients receiving HIV-1 antiretroviral stabilization therapy (ART) regimens (including ritonavir in combination with atazanavir or raltegravir, tenofovir + emtricitabine or lamivudine regimens).
The recommended dose for HCV/HIV-1 co-infection is described in [Dosage]. Patients receiving HIV-1 antiretroviral stabilization therapy (ART) regimens, including basal regimens of atazanavir or raltegravir potentiated by ritonavir in combination with tenofovir + emtricitabine or lamivudine.
The median age of treated patients (N=63) was 51 years (range: 31-69 years); 24% were black; 81% were IL28B non-CC genotype; 19% had combined compensated cirrhosis; 67% were primed for HCV; 33% were prior pegIFN/RBV treatment failures; and 89% were infected with HCV genotype 1a.
The SVR12 response rates in patients with HCV genotype 1 infection and HIV-1 co-infection in the TURQUOISE-I study are shown in Table 15.
Table 15. SVR12 in HIV-1 co-infected patients in the TURQUOISE-I study
Treatment outcome Group A
12 weeks N = 31 Group B
24 weeks N = 32SVR12, n/N (%) [95% CI]
29/31 (93.5) [79.3, 98.2] 29/32 (90.6) [75.8, 96.8] Patient outcomes without SVR12 Virologic failure during treatment 0 1 Relapse after discontinuation 1 2a Other 1 0 Based on the results of blood tests at baseline and when virologic failure occurred, virologic failure was considered likely to be attributable to reinfection
SVR12 response rates in HCV/HIV-1 co-infected patients in the TURQUOISE-I study were consistent with SVR12 rates in HCV-only patients in the phase 3 trial. 7/7 genotype 1b patients and 51/56 genotype 1a patients achieved SVR12. 5/6 patients with compensated cirrhosis in each group achieved SVR12.
Clinical Trials in Liver Transplant Recipients
In the CORAL-1 study, the efficacy and safety of the combination of this product + obiparib + ribavirin for 24 weeks was studied in 34 HCV genotype 1-infected liver transplant recipients who were at least 12 months post-transplant at study entry. The dose of ribavirin was determined by the investigator, with most patients receiving a starting dose of 600 to 800 mg/day and an end-of-treatment dose of 600 to 800 mg/day.
Thirty-four patients (29 HCV genotype 1a and 5 HCV genotype 1b) who did not receive anti-HCV therapy after transplantation with METAVIR fibrosis stage F2 or less were included. 33/34 patients (97.1%) achieved SVR12 (96.6% response rate in genotype 1a patients and 100% response rate in genotype 1b patients). 1 HCV genotype 1a patient presented with relapse after drug discontinuation.
Clinical trial in patients receiving long-term opioid replacement therapy
A phase 2, multicenter, open, single treatment group study included 38 primary or pegIFN/RBV treated patients without cirrhosis genotype 1 who received stable doses of methadone (N=19) or buprenorphine (+/- naloxone) (N=19) with concomitant treatment with this product + ombiparib + ribavirin for 12 weeks. Median age of treated patients was 51 years (range: 26-64 years); 65.8% of patients were male and 5.3% were black; most patients (86.8%) had baseline HCV RNA levels of at least 800,000 IU/mL and the vast majority (84.2%) were genotype 1a; 68.4% were IL28B non-CC genotype. 15.8% of patients had confluent zone fibrosis (F2) and 5.3% had bridge-like fibrosis (F3); 94.7% of patients had never received anti-HCV therapy.
Overall, 37/38 patients (97.4%) received SVR.12 No patients experienced virologic failure or relapse during treatment.
The following clinical trials were conducted in China, Korea and Taiwan
Clinical trials in patients without cirrhosis
ONYX I study – genotype 1b, primary or interferon combined with ribavirin in patients treated without cirrhosis
Trial design: randomized, Asian regional, multicenter, double-blind, placebo-controlled
Treatment regimen: 12 weeks of treatment with this product + obiparib
Of the 650 patients enrolled, 410 (63.1%), 120 (18.5%) and 120 (18.5%) were from China, Korea and Taiwan, respectively. Of the patients who received antiviral therapy in the double-blind phase, 184 were primary patients and 141 were treated patients. The median age of primary patients was 50 years (range: 18-71 years) and 45.1% were male; the majority of patients (79.9%) had baseline HCV RNA ≥ 800,000 IU/mL and 3.8% had baseline fibrosis stage ≥ F3.
The median age of treated patients was 51 years (range: 21-68 years) and the proportion of men was 47.5%; 55.3% of patients were non-responders to prior IFN/RBV therapy and 44.7% were relapsed; 82.3% had baseline HCV RNA ≥ 800,000 IU/mL and 5.0% had baseline fibrosis stage ≥ F3.
≥ Patient SVR results are shown in Table 16 (for total number of patients in China and total number of all patients).
Table 16: ONYX-I Study
SVR12 and SVR24 in patients with genotype 1b cirrhosis-free
SVR12 and SVR24* This product + obiparib treated for 12 weeks Primary patients Treated patients n/N % 95% CI n/N % 95% CI China
Patients* 103/104 99.0 94.8, 99.8 101/101 100 96.3, 100.0 All patients* 183/184 99.5 97.0, 99.9 141/141 100 97.4, 100.0 No SVR12 and SVR24 patient outcomes present during treatment VF1/184 0.5 0/141 0 * SVR12 and SVR24 results were the same.
Note: HCV RNA assays in clinical trials were performed using the COBAS® AmpliPrep/COBAS® TaqMan® HCV Test v. 2.0 method. The lower limit of quantification (LLOQ) is 15 IU/ mL.
Clinical trials in patients with compensated cirrhosis
ONYX II-genotype 1b, primary or interferon combined with ribavirin, in patients with compensated cirrhosis
Trial design: Asian regional, multicenter, open-label
Treatment regimen: this product + obiparib + ribavirin (based on body weight) for 12 weeks
Of the 104 patients included, 63 (60.6%), 21 (20.2%) and 20 (19.2%) were from China, Korea and Taiwan, respectively. The median age of the patients was 56 years (range: 24-69 years) and the proportion of males was 38.5%. 42.3% of the patients were primary patients, and the proportions of patients with no response to prior IFN/RBV therapy, relapsed after therapy, and intolerant to prior IFN/RBV therapy were 24.0%, 27.9%, and 5.8%, respectively. 72.1% of the patients had baseline HCV RNA ≥ The SVR results for patients are shown in Table 17 (for total number of patients in China and total number of patients).
Table 17: ONYX-II study
SVR12 and SVR24 in patients with genotype 1b with compensated cirrhosis
SVR12 and SVR24* Benadryl + Obiparib + Ribavirin
Treatment 12 weeks n/N % 95% CI China
Patients 63/63 10094.3, 100.0 All patients 104/104 100 96.4, 100.0 No results obtained for SVR12 and SVR24 patients   
VF0/104 0 * SVR12 and SVR24 results were the same during treatment.
Note: HCV RNA assays in clinical trials were performed using the COBAS® AmpliPrep/COBAS® TaqMan® HCV Test v. 2.0 method. The lower limit of quantification (LLOQ) is 15 IU/ mL.
Pharmacology and Toxicology
Pharmacological effects
Dasebuvir is a non-nucleotide inhibitor of the RNA-dependent RNA polymerase encoded by the HCV NS5B gene, which is required for viral genome replication.
Dasebuvir, in combination with ombitasvir, paritaprevir, and ritonavir, contains three direct antiviral components with well-defined mechanisms of action and non-overlapping resistance that act in multiple parts of the HCV life cycle. For the pharmacological profile of Obiparib, please refer to the [Pharmacological Toxicology] of its product insert.
Antiviral activity
In HCV replicon cell culture assays, the EC50 of dasebuvir against genotype 1a-H77 and 1b-Con1 strains was 7.7 nM and 1.8 nM, respectively; the activity of dasebuvir was reduced 12-13-fold in the presence of 40% human plasma. In biochemical assays, dasebuvir inhibited genotype 1a and 1b polymerases with a mean IC50 of 4.2 nM (range: 2.2 to 10.7 nM; n=7).
In HCV replicon cell culture assays, the metabolite of dasebuvir, M1, acted on viral strains such as genotype 1a-H77 and genotype 1b-Con1 with EC50s of 39 nM and 8 nM, respectively; the activity of M1 was attenuated 3- to 4-fold when 40% human plasma was present. Biochemical assays showed that dasebuvir attenuated the activity of HS5B polymerase against HCV genotypes 2a, 2b, 3a and 4a (IC50 range: 900 nM~>20 μM)
Toxicological studies
Genotoxicity.
Dasebuvir Ames test, human peripheral blood lymphocyte chromosome aberration test, and mouse micronucleus test results were all negative.
Reproductive toxicity.
Dasebuvir at doses up to 800 mg/kg/day had no effect on the viability or fertility of rat embryos-fetuses, and the exposure in rats was approximately 16 times the human clinical dose. No teratogenic or fetal toxicity was observed in pregnant rats and rabbits at doses up to 800 mg/k/day and 400 mg/kg/day, respectively, and the exposure in pregnant rats and rabbits was approximately 24 and 6 times the human clinical dose, respectively.
In a perinatal toxicity test in rats, no drug-related effects on offspring behavior, reproduction or development were observed at doses of up to 800 mg/kg/day of dasebuvir, and maternal exposure was approximately 44 times the human clinical dose.
In the milk of lactating rats, dasebuvir was the major component detected, and no effects were seen in nursing pups. The elimination half-life in rat milk was slightly shorter than the half-life in plasma, and the exposure in milk was approximately twice as high as the exposure in plasma. Because dasebuvir is a substrate of BCRP, its distribution in milk may be altered if this transporter protein is inhibited or induced by other co-administered drugs. Dasebuvir derivatives barely pass through the placenta of pregnant rats.
Carcinogenicity.
No carcinogenicity was observed in transgenic mice at 6 months and rats at 2 years in carcinogenicity tests, where doses up to 2000 mg/kg/day and 800 mg/kg/day were administered to mice and rats, respectively. The exposure in mice and rats was 19 times the human clinical dose of 500mg.
[Pharmacokinetics].
The pharmacokinetics of this product + obiparib have been evaluated in healthy adult subjects and in subjects with chronic hepatitis C. Table 19 shows the mean values of Cmax and AUC for multiple doses of this drug given twice daily at 250 mg in combination with 25 mg/150 mg/100 mg once daily with food in healthy volunteers.
Table 19. Geometric mean values of Cmax and AUC after multiple doses of 250 mg twice daily in combination with 25 mg/150 mg/100 mg once daily with food in healthy volunteers
 Cmax (ng/ml) (CV%) AUC (ng*hr/ml) (CV%) Dasebuvir 1030 (31) 6840 (32) Absorption
Dasebuvir sodium is absorbed after oral administration with a mean Tmax of 4 to 5 hours. The exposure of this product increases proportionally with increasing dose and little accumulation is seen. The pharmacokinetics of this product reached steady state after 12 days of multiple administration with ombiparib (ombitasvir/paritaprevir/ritonavir).
Food Effects
This product should be taken with food. In all clinical trials, this product was administered with food.
Food increased the exposure (AUC) of this product by up to 30% relative to the fasted state. The incremental increase in exposure was similar regardless of food type (e.g., high fat vs. medium fat) or calorie content (600 kcal vs. 1000 kcal). To maximize drug absorption, this product should be taken with food without regard to fat and calorie content.
Distribution
Dasebuvir is highly bound to plasma proteins. There is no significant change in plasma protein binding in patients with impaired renal or hepatic function. The ratio of whole blood to plasma concentrations in humans is 0.5 to 0.7, which indicates that dasebuvir is preferentially distributed in the plasma of whole blood. The concentration range was 0.05 to 5 μg/mL, and the binding of dasebuvir to human plasma proteins was 99.5%, and the binding of M1, the major metabolite of dasebuvir, to human plasma proteins was 94.5%. the ratio of steady-state exposure of M1 to dasebuvir was approximately 0.6. considering the protein binding rate and the in vitro activity of M1 against HCV genotype 1, the contribution of M1 to efficacy is expected to be similar to that of dasebuvir. In addition, M1 is a substrate for the hepatic uptake of the OATP family of transporter proteins and OCT1; therefore, M1 hepatocyte concentrations and its contribution to efficacy may be greater than that of dasebuvir.
Biotransformation
Dasebuvir is primarily metabolized by CYP2C8, with a small portion metabolized by CYP3A. When 14C-dasebuvir was given to humans at a dose of 400 mg, the prototype dasebuvir drug was the major component of drug-related radioactivity in human plasma (approximately 60%). A total of seven metabolites were identified in human plasma. The most abundant metabolite in plasma was M1, which accounted for 21% of the drug-associated radioactivity in the circulation after a single dose; M1 was formed mainly by oxidative metabolism by CYP2C8.
Clearance
When dasebuvir sodium was administered in combination with ombiparib (ombitasvir/paritaprevir /ritonavir), the mean plasma half-life of the product was approximately 6 h. The radioactivity detected in feces and urine after 400 mg 14C-dasebuvir administration was 94% and 2%, respectively. The prodrug accounted for 26.2% of the total radioactivity in feces and 31.5% for M1. M1 was cleared primarily by direct biliary excretion, with a portion cleared by UGT-mediated glucuronidation and oxidative metabolism.
At clinically relevant concentrations, it does not inhibit organic anion transporter protein (OAT1) in vivo and is not expected to inhibit organic cation transporter protein (OCT2), organic anion transporter protein (OAT3), multidrug and toxic compound efflux transporter proteins (MATE1 and MATE2K); therefore, it does not affect these protein-transporting drugs.
Special Populations
Elderly
Based on data from a population pharmacokinetic analysis in a Phase 3 clinical trial, each 10-year increase or decrease in age from 54 years (median age in the Phase 3 study) resulted in a change in dasebuvir exposure of <10%. Pharmacokinetic information is not yet available for patients over 75 years of age.
Gender or weight
Based on data from a population pharmacokinetic analysis in a phase 3 clinical trial, dasebuvir exposure was 14-30% higher in female subjects than in male subjects, respectively. Each 10-kg change in body weight from 76 kg (mean body weight in the Phase 3 study) resulted in a change in dasebuvir exposure of <10%.
Ethnicity or race
Based on population pharmacokinetic analysis from the Phase 3 clinical study, exposure to this product was 29% to 39% higher in Asian subjects than in non-Asian subjects.
Exposure to paritaprevir, ombitasvir, dasabuvir and ritonavir in combination with or without ribavirin was tested in 388 Asian subjects (with or without cirrhosis) with HCV GT1, including China, in the phase 3 clinical trial. After multiple doses of ombitasvir, paritaprevir, and ritonavir combined with dasabuvir, exposure to each component in Chinese subjects was comparable to that in Western subjects.
Renal impairment
The pharmacokinetics of ombitasvir 25 mg, paritaprevir 150 mg, and ritonavir 100 mg administered in combination with or without dasabuvir 400 mg were evaluated in subjects with mild (CrCl: 60 to 89 ml/min), moderate (CrCl: 30 to 59 ml/min), and severe (CrCl: 15 to 29 ml/min) renal impairment.
The AUC of dasebuvir was increased by 21%, 37% and 50% in patients with mild, moderate and severe renal impairment, respectively. Dasebuvir M1 AUC values were reduced by 6%, 10%, and 13%, respectively.
Changes in dasebuvir exposure in patients with mild, moderate, and severe renal impairment were not clinically significant. Clinical data in patients with end-stage renal disease on dialysis are limited, but the change in exposure in this patient population was also not clinically significant. No dose adjustment is required for use in patients with mild, moderate, or severe renal impairment and end-stage renal dialysis (see [DOSAGE AND ADMINISTRATION]).
Hepatic impairment
The pharmacokinetics of dasebuvir 400 mg in combination with ombiparib (ombitasvir 25 mg/paritaprevir 200 mg/ritonavir 100 mg) were evaluated in subjects with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment and compared to subjects with normal liver function .
The AUC of dasebuvir increased by 17%, decreased by 16%, and increased by 325% in subjects with mild, moderate, and severe hepatic impairment, respectively. The AUC of dasebuvir M1 metabolite was unchanged, decreased by 57%, and increased by 77% in subjects with mild, moderate, and severe hepatic impairment, respectively. There was no significant difference in the plasma protein binding of dasebuvir and its M1 metabolite in subjects with normal liver function compared to subjects with normal liver function. (See [Dosage], [Precautions] and [Adverse Reactions]).
Pediatric Use
The pharmacokinetics of this product in combination with obiparib in pediatric patients has not been performed (see [Dosage]).
Storage
Seal and store at not more than 30°C.
Packaging
Packed in PVC/PE/PCTFE aluminum foil blister.
14 tablets/box
Expiration date
36 months
【Execution standard    
Imported drug registration standard: JX20160175
【Approval number】    
Imported drug registration certificate no.
【Manufacturing Company
Company name: AbbVie AG.
Address: Neuhofstrasse 23,CH-6341 Baar, Switzerland.
Production plant: AbbVie Ireland NL B.V.
Manorhamilton Road, Sligo, Ireland.
Packaging plant: Abbvie Deutschland GmbH Co. KG.
Knollstrasse, 67061, Ludwigshafen, Germany.
 Domestic contact company: Abbvie Pharmaceutical Trading (Shanghai) Co.
Address: 17/F, Chongxing Financial Center, 288 Nanjing West Road, Shanghai
Postal Code: 200003
Telephone number: 021-62631300
Fax number: 021-53079101