Exviera - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Exviera 250 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 250 mg of dasabuvir (as sodium monohydrate).

Excipient with known effect

Each film-coated tablet contains 45 mg lactose (as monohydrate).

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet (tablet).

Beige, ovaloid, film-coated tablets with dimensions of 14.0 mm x 8.0 mm and debossed on one side with ‘AV2’.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

Exviera is indicated in combination with other medicinal products for the treatment of chronic hepatitis C (CHC) in adults (see sections 4.2, 4.4 and 5.1).

For hepatitis C virus (HCV) genotype specific activity, see sections 4.4 and 5.1.

4.2 Posology and method of administration

Treatment with dasabuvir should be initiated and monitored by a physician experienced in the management of chronic hepatitis C.

Posology

The recommended dose is 250 mg of dasabuvir (one tablet) twice daily (morning and evening).

Dasabuvir must not be administered as monotherapy. Dasabuvir should be used in combination with other medicinal products for the treatment of HCV (see section 5.1). Refer to the Summary of Product Characteristics of the medicinal products that are used in combination with dasabuvir.

The recommended co-administered medicinal product(s) and treatment duration for dasabuvir combination therapy are provided in Table 1.

Table 1. Recommended co-administered medicinal product(s) and treatment duration for dasabuvir by patient population

Patient population	Treatment*	Duration
Genotype 1b, without cirrhosis or with compensated cirrhosis	dasabuvir + ombitasvir/pa­ritaprevir/ri­tonavir	12 weeks 8 weeks may be considered in previously untreated genotype 1b-infected patients with minimal to moderate fibrosis** (see section 5.1, GARNET study)
Genotype 1a, without cirrhosis	dasabuvir + ombitasvir/pa­ritaprevir/ri­tonavir + ribavirin*	12 weeks
Genotype 1a, with compensated cirrhosis	dasabuvir + ombitasvir/pa­ritaprevir/ri­tonavir + ribavirin*	24 weeks (see section 5.1.)
*Note: Follow the genotype 1a dosing recommendations in patients with an unknown genotype 1 subtype or with mixed genotype 1 infection. ** When assessing severity of liver disease using non-invasive methods, a combination of blood biomarkers or the combination of liver stiffness measurement and a blood test improves accuracy and should be undertaken prior to 8 week treatment in all patients with moderate fibrosis.

Missed doses

In case a dose of dasabuvir is missed, the prescribed dose can be taken within 6 hours. If more than 6 hours have passed since dasabuvir is usually taken, the missed dose should NOT be taken and the patient should take the next dose per the usual dosing schedule. Patients should be instructed not to take a double dose.

Special populations

HIV-1 Co-infection

The dosing recommendations in Table 1 should be followed. For dosing recommendations with HIV antiviral medicinal products, refer to sections 4.4 and 4.5. See sections 4.8 and 5.1 for additional information.

Liver transplant recipients

Dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir in combination with ribavirin is recommended for 24 weeks in liver transplant recipients. Lower ribavirin dose at initiation may be appropriate. In the post-liver transplant study, ribavirin dosing was individualized and most subjects received 600 to 800 mg per day (see section 5.1). For dosing recommendations with calcineurin inhibitors refer to section 4.5.

Elderly

No dose adjustment of dasabuvir is warranted in elderly patients (see section 5.2).

Renal impairment

No dose adjustment of dasabuvir is required for patients with mild, moderate, or severe renal impairment or end-stage-renal disease on dialysis (see section 5.2). For patients that require ribavirin, refer to the ribavirin Summary of Product Characteristics for information regarding use in patients with renal impairment.

Hepatic impairment

No dose adjustment of dasabuvir is required in patients with mild hepatic impairment (Child-Pugh A). Dasabuvir should not be used in patients with moderate to severe hepatic impairment (Child-Pugh B or C) (see section 5.2).

Paediatric population

The safety and efficacy of dasabuvir in children less than 18 years of age have not been established. No data are available.

Method of administration

The film-coated tablets are for oral use. Patients should be instructed to swallow the tablets whole (i.e. patients should not chew, break or dissolve the tablet). To maximise absorption, dasabuvir tablets should be taken with food, without regard to fat and calorie content (see section 5.2).

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Patients with moderate to severe hepatic impairment (Child-Pugh B or C) (see section 5.2).

Use of ethinyloestradiol-containing medicinal products such as those contained in most combined oral contraceptives or contraceptive vaginal rings (see sections 4.4 and 4.5).

Co-administration of dasabuvir with medicinal products that are strong or moderate enzyme inducers is expected to decrease dasabuvir plasma concentrations and reduce its therapeutic effect (see section 4.5. Examples of contraindicated inducers are provided below.

Enzyme inducers:

• • carbamazepine, phenytoin, phenobarbital
• • efavirenz, nevirapine, etravirine
• • apalutamide, enzalutamide
• • mitotane
• • rifampicin
• • St. John’s Wort (Hypericum perforatum)

Medicinal products that are strong CYP2C8 inhibitors may increase dasabuvir plasma concentrations and must not be co-administered with dasabuvir (see section 4.5). Examples of contraindicated CYP2C8 inhibitors are provided below.

CYP2C8 inhibitor:

• • gemfibrozil

Dasabuvir is administered with ombitasvir/ paritaprevir /ritonavir. For contra-indications with ombitasvir/ paritaprevir /ritonavir refer to the Summary of Product Characteristics.

4.4 Special warnings and precautions for use

General

Dasabuvir is not recommended for administration as monotherapy and must be used in combination with other medicinal products for the treatment of hepatitis C infection (see section 4.2 and 5.1).

Risk of hepatic decompensation and hepatic failure in patients with cirrhosis

Hepatic decompensation and hepatic failure, including liver transplantation or fatal outcomes, have been reported post-marketing in patients treated with dasabuvir with ombitasvir/pa­ritaprevir/ri­tonavir with and without ribavirin. Most patients with these severe outcomes had evidence of advanced or decompensated cirrhosis prior to initiating therapy. Although causality is difficult to establish due to background advanced liver disease, a potential risk cannot be excluded.

Dasabuvir should not be used in patients with moderate to severe hepatic impairment (Child-Pugh B or C) (see sections 4.2, 4.3, 4.8 and 5.2).

For patients with cirrhosis:

• • Monitoring should be performed for clinical signs and symptoms of hepatic decompensation

(such as ascites, hepatic encephalopathy, variceal haemorrhage).

• • Hepatic laboratory testing including direct bilirubin levels should be performed at baseline, during the first 4 weeks of starting treatment and as clinically indicated thereafter.
• • Treatment should be discontinued in patients who develop evidence of hepatic

decompensation.

ALT elevations

During clinical trials with dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir with or without ribavirin, transient elevations of ALT to greater than 5 times the upper limit of normal occurred in approximately 1% of subjects (35 of 3,039). ALT elevations were asymptomatic and generally occurred during the first 4 weeks of treatment, without concomitant elevations of bilirubin, and declined within approximately two weeks of onset with continued dosing of dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir with or without ribavirin.

These ALT elevations were significantly more frequent in the subgroup of subjects who were using ethinyloestradiol -containing medicinal products such as combined oral contraceptives or contraceptive vaginal rings (6 of 25 subjects); (see section 4.3). In contrast, the rate of ALT elevations in subjects using other types of oestrogens as typically used in hormonal replacement therapy (i.e., oral and topical oestradiol and conjugated oestrogens) was similar to the rate observed in subjects who were not using oestrogen-containing products (approximately 1% in each group).

Patients who are taking ethinyloestradiol -containing medicinal products (i.e. most combined oral contraceptives or contraceptive vaginal rings) must switch to an alternative method of contraception (e.g., progestin only contraception or non-hormonal methods) prior to initiating dasabuvir with ombitasvir/pa­ritaprevir/ri­tonavir therapy (see sections 4.3 and 4.5).

Although ALT elevations associated with dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir have been asymptomatic, patients should be instructed to watch for early warning signs of liver inflammation, such as fatigue, weakness, lack of appetite, nausea and vomiting, as well as later signs such as jaundice and discoloured faeces, and to consult a doctor without delay if such symptoms occur. Routine monitoring of liver enzymes is not necessary in patients that do not have cirrhosis (for cirrhotics, see above). Early discontinuation may result in drug resistance, but implications for future therapy are not known.

Pregnancy and concomitant use with ribavirin

Also see section 4.6.

Extreme caution must be taken to avoid pregnancy in female patients and female partners of male patients when dasabuvir is taken in combination with ribavirin (see section 4.6 and refer to the Summary of Product Characteristics for ribavirin for additional information).

Use with tacrolimus, sirolimus and everolimus

Co-administration of dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir with systemic tacrolimus, sirolimus or everolimus increases the concentrations of the immunosuppressant due to CYP3A inhibition by ritonavir (see section 4.5). Serious and/or life threatening events have been observed with co-administration of dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir with systemic tacrolimus, and a similar risk can be expected with sirolimus and everolimus.

Avoid concomitant use of tacrolimus or sirolimus with dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir unless the benefits outweigh the risks. If tacrolimus or sirolimus are used together with dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir, caution is advised, and recommended doses and monitoring strategies can be found in section 4.5. Everolimus cannot be used due to lack of suitable dose strengths for dose adjustments.

Tacrolimus or sirolimus whole blood concentrations should be monitored upon initiation and throughout co-administration with dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir and the dose and/or dosing frequency should be adjusted as needed. Patients should be monitored frequently for any changes in renal function or tacrolimus or sirolimus associated adverse reactions. Refer to the tacrolimus or sirolimus Summary of Product Characteristics for additional dosing and monitoring instructions.

Depression or psychiatric illness

Cases of depression and more rarely of suicidal ideation and suicide attempt have been reported with dasabuvir with or without ombitasvir/pa­ritaprevir/ri­tonavir treatment in combination with ribavirin in the majority of the cases. Although some cases had previous history of depression, psychiatric illness and/or substance abuse, a causal relation with dasabuvir with or without ombitasvir/pa­ritaprevir/ri­tonavir treatment cannot be excluded. Caution should be used in patients with a pre-existing history of depression or psychiatric illness. Patients and caregivers should be instructed to notify the prescriber of any changes in behaviour or mood and of any suicidal ideation.

Genotype-specific activity

Concerning recommended regimens with different HCV genotypes, see section 4.2. Concerning genotype-specific virological and clinical activity, see section 5.1.

The efficacy of dasabuvir has not been established in patients with HCV genotypes other than genotype 1; dasabuvir should not be used for the treatment of patients infected with other genotypes than 1.

Co-administration with other direct-acting antivirals against HCV

Dasabuvir safety and efficacy have been established in combination with ombitasvir/ paritaprevir /ritonavir with or without ribavirin. Co-administration of dasabuvir with other antivirals has not been studied and, therefore, cannot be recommended.

Retreatment

The efficacy of dasabuvir in patients previously exposed to dasabuvir, or to medicinal products anticipated to be cross-resistant, has not been demonstrated.

Use with statins

Rosuvastatin

Dasabuvir with ombitasvir/pa­ritaprevir/ri­tonavir is expected to increase the exposure to rosuvastatin more than 3-fold. If rosuvastatin treatment is required during the treatment period, the maximum daily dose of rosuvastatin should be 5 mg (see section 4.5, Table 2).

Pitavastatin and fluvastatin

The interactions with pitavastatin and fluvastatin have not been investigated. Theoretically, dasabuvir with ombitasvir/pa­ritaprevir/ri­tonavir is expected to increase the exposure to pitavastatin and fluvastatin. A temporary suspension of pitavastatin/flu­vastatin is recommended for the duration of treatment with ombitasvir/pa­ritaprevir/ri­tonavir. If statin treatment is required during the treatment period, a switch to a reduced dose of pravastatin/ro­suvastatin is possible (see section 4.5, Table 2).

Treatment of patients with HIV co-infection

Dasabuvir is recommended in combination with paritaprevir/om­bitasvir/rito­navir, and ritonavir may select for PI resistance in HIV co-infected patients without ongoing antiretroviral therapy. HIV coinfected patients without suppressive antiretroviral therapy should not be treated with dasabuvir.

Drug interactions need to be carefully taken into account in the setting of HIV co-infection (for details see section 4.5, Table 2).

Atazanavir can be used in combination with dasabuvir with ombitasvir/pa­ritaprevir/ri­tonavir if administered at the same time. To be noted, atazanavir should be taken without ritonavir, since ritonavir 100 mg once daily is provided as part of the ombitasvir/pa­ritaprevir/ri­tonavir fixed dose combination. The combination carries an increased risk for hyperbilirubinemia (including ocular icterus), in particular when ribavirin is part of the hepatitis C regimen.

Darunavir, dosed 800 mg once daily, if administered at the same time as ombitasvir/pa­ritaprevir/ri­tonavir, can be used in the absence of extensive PI resistance (darunavir exposure lowered). To be noted, darunavir should be taken without ritonavir, since ritonavir 100 mg once daily is provided as part of the ombitasvir/pa­ritaprevir/ri­tonavir fixed dose combination.

For the use of HIV protease inhibitors other than atazanavir and darunavir refer to the Summary of Product Characteristics of ombitasvir/ paritaprevir /ritonavir.

Raltegravir exposure is substantially increased (2-fold). The combination was not linked to any particular safety issues in a limited set of patients treated for 12–24 weeks.

Rilpivirine exposure is substantially increased (3-fold) when rilpivirine is given in combination with dasabuvir with ombitasvir/pa­ritaprevir/ri­tonavir, with a consequent potential for QT-prolongation. If an HIV protease inhibitor is added (atazanavir, darunavir), rilpivirine exposure may increase even further and is, therefore, not recommended. Rilpivirine should be used cautiously, in the setting of repeated ECG monitoring.

NNRTIs other than rilpivirine (efavirenz, etravirine, and nevirapine) are contraindicated (see section 4.3).

Hepatitis B virus reactivation

Cases of hepatitis B virus (HBV) reactivation, some of them fatal, have been reported during or after treatment with direct-acting antiviral agents. HBV screening should be performed in all patients before initiation of treatment. HBV/HCV co-infected patients are at risk of HBV reactivation, and should, therefore, be monitored and managed according to current clinical guidelines.

Use in diabetic patients

Diabetics may experience improved glucose control, potentially resulting in symptomatic hypoglycaemia, after initiating HCV direct acting antiviral treatment. Glucose levels of diabetic patients initiating direct acting antiviral therapy should be closely monitored, particularly within the first 3 months, and their diabetic medicinal products modified when necessary. The physician in charge of the diabetic care of the patient should be informed when direct acting antiviral therapy is initiated.

Lactose

Exviera contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

4.5 Interaction with other medicinal products and other forms of interaction

Dasabuvir must always be administered together with ombitasvir/pa­ritaprevir/ri­tonavir. When coadministered they exert mutual effects on each other (see section 5.2). Therefore, the interaction profile of the compounds must be considered as a combination.

Pharmacodynamic interactions

Coadministration with enzyme inducers may lead to an increased risk of adverse reactions and ALT elevations (see Table 2).

Coadministration with ethinyloestradiol may lead to increased risk of ALT elevations (see sections 4.3 and 4.4). Contraindicated enzyme inducers are provided in section 4.3.

Pharmacokinetic interactions

Potential for dasabuvir to affect the pharmacokinetics of other medicinal products

In vivo drug interaction studies evaluated the net effect of the combination treatment, including ritonavir. The following section describes the specific transporters and metabolizing enzymes that are affected by dasabuvir when combined with ombitasvir/pa­ritaprevir/ri­tonavir. See Table 2 for guidance regarding potential drug interactions and dosing recommendations for dasabuvir administered with ombitasvir/pa­ritaprevir/ri­tonavir.

Medicinal products metabolised by CYP3A4

Refer to the ombitasvir/pa­ritaprevir/ri­tonavir Summary of Product Characteristics for details. (see also Table 2).

Medicinal products transported by the OATP family

Refer to the ombitasvir/pa­ritaprevir/ri­tonavir Summary of Product Characteristics for details on OATP1B1, OATP1B3 and OATP2B1 substrates (see also Table 2).

Medicinal products transported by BCRP

Dasabuvir is an inhibitor of BCRP in vivo. Co-administration of dasabuvir with ombitasvir/pa­ritaprevir/ri­tonavir together with medicinal products that are substrates of BCRP may increase plasma concentrations of these transporter substrates, potentially requiring dose adjustment/clinical monitoring. Such medicinal products include sulfasalazine, imatinib and some of the statins (see Table 2). See also Table 2 for specific advice on rosuvastatin which has been evaluated in a drug interaction study.

Medicinal products transported by Pgp in the intestine

While dasabuvir is an in vitro inhibitor of P-gp, no significant change was observed in the exposure of the P-gp substrate, digoxin, when administered with dasabuvir with ombitasvir/pa­ritaprevir/ri­tonavir. It may not be excluded that the systemic exposure of dabigatran etexilate is increased by dasabuvir due to inhibition of P-gp in the intestine.

Medicinal products metabolised by glucuronidation

Dasabuvir is an inhibitor of UGT1A1 in vivo. Co-administration of dasabuvir with medicinal products that are primarily metabolized by UGT1A1 result in increased plasma concentrations of such medicinal products; routine clinical monitoring is recommended for narrow therapeutic index medicinal products (i.e. levothyroxine). See also Table 2 for specific advice on raltegravir and buprenorphine which have been evaluated in drug interaction studies. Dasabuvir has also been found to inhibit UGT1A4, 1A6 and intestinal UGT2B7 in vitro at in vivo relevant concentrations.

Medicinal products metabolised by CYP2C19

Co-administration of dasabuvir with ombitasvir/pa­ritaprevir/ri­tonavir can decrease exposures of medicinal products that are metabolized by CYP2C19 (e.g. lansoprazole, esomeprazole, s- mephenytoin), which may require dose adjustment/clinical monitoring. CYP2C19 substrates evaluated in drug interaction studies include omeprazole and escitalopram (Table 2).

Medicinal products metabolised by CYP2C9

Dasabuvir administered with ombitasvir/pa­ritaprevir/ri­tonavir did not affect the exposures of the CYP2C9 substrate warfarin. Other CYP2C9 substrates (NSAIDs (e.g. ibuprofen), antidiabetics (e.g. glimepiride, glipizide) are not expected to require dose adjustments.

Medicinal products metabolised by CYP2D6 or CYP1A2

Dasabuvir administered with ombitasvir/pa­ritaprevir/ri­tonavir did not affect the exposures of the CYP2D6 /CYP1A2 substrate duloxetine. Exposures of cyclobenzaprine, a CYP1A2 substrate, were decreased. Clinical monitoring and dose adjustment may be needed for other CYP1A2 substrates (e.g. ciprofloxacin, cyclobenzaprine, theophylline and caffeine). CYP2D6 substrates (e.g. desipramine, metoprolol and dextromethorphan) are not expected to require dose adjustments.

Medicinal products renally excreted via transport proteins

Dasabuvir does not inhibit organic anion transporter (OAT1) in vivo as shown by the lack of interaction with tenofovir (OAT1 substrate). In vitro studies show that dasabuvir is not an inhibitor of organic cation transporters (OCT2), organic anion transporters (OAT3), or multidrug and toxin extrusion proteins (MATE1 and MATE2K) at clinically relevant concentrations.

Therefore, dasabuvir is not expected to affect medicinal products which are primarily excreted by the renal route via these transporters (see section 5.2).

Potential for other medicinal products to affect the pharmacokinetics of dasabuvir

Medicinal products that inhibit CYP2C8

Co-administration of dasabuvir with medicinal products that inhibit CYP2C8 (e.g. teriflunomide, deferasirox) may increase dasabuvir plasma concentrations. Strong CYP2C8 inhibitors are contraindicated with dasabuvir (see section 4.3 and Table 2).

Enzyme inducers

Co-administration of dasabuvir with medicinal products that are moderate or strong enzyme inducers is expected to decrease dasabuvir plasma concentrations and reduce its therapeutic effect.

Contraindicated enzyme inducers are provided in section 4.3 and Table 2.

Dasabuvir is a substrate of P-gp and BCRP and its major metabolite M1 is a substrate of OCT1 in vitro. Inhibition of P-gp and BCRP is not expected to show clinically relevant increases in exposures of dasabuvir (Table 2).

Dasabuvir M1 metabolite was quantified in all the drug interaction studies. Changes in exposures of the metabolite were generally consistent with that observed with dasabuvir except for studies with CYP2C8 inhibitor, gemfibrozil, where the metabolite exposures decreased by up to 95% and CYP3A inducer, carbamazepine, where the metabolite exposures decreased by only up to 39%.

Patients treated with vitamin K antagonists

As liver function may change during treatment with dasabuvir administered with ombitasvir/pa­ritaprevir/ri­tonavir, a close monitoring of International Normalised Ratio (INR) values is recommended.

Drug interaction studies

Recommendations for co-administration of dasabuvir with ombitasvir/pa­ritaprevir/ri­tonavir for a number of medicinal products are provided in Table 2.

If a patient is already taking medicinal product(s) or initiating a medicinal product while receiving dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir for which potential for drug interaction is expected, dose adjustment of the concomitant medicinal product(s) or appropriate clinical monitoring should be considered (Table 2).

If dose adjustments of concomitant medicinal products are made due to treatment with dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir, doses should be re-adjusted after administration of dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir is completed.

Table 2 provides the Least Squares Means Ratio (90% Confidence Interval) effect on concentration of dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir and concomitant medicinal products.

The direction of the arrow indicates the direction of the change in exposures (Cmax, and AUC) in the paritaprevir, ombitasvir, dasabuvir and the co-administered medicinal product ($ = increase more than 20%, ^ = decrease more than 20%, ^ = no change or change less than 20%).

This is not an exclusive list. Dasabuvir is administered with ombitasvir/pa­ritaprevir/ri­tonavir. For interactions with ombitasvir/ paritaprevir /ritonavir refer to the Summary of Product Characteristics.

Table 2. Interactions between dasabuvir with ombitasvir/pa­ritaprevir/ri­tonavir and other medicinal products

Medicinal Product/ Possible Mechanism of Interaction	GIVE N WITH	EFFECT	C max	AUC	C trough		Clinical Comments
AMINOSALICYLATE
Sulfasalazine Mechanism: BCRP inhibition by paritaprevir, ritonavir and dasabuvir.	dasabu vir + ombitas vir/parit aprevir/ ritonavi r	Not Studied. Expected: t sulfasalazine					Caution should be used when sulfasalazine is co-administered with dasabuvir + ombitasvir/pa­ritaprevir/ ritonavir.
ANTIARRYTHMICS
Digoxin 0.5 mg single dose Mechanism: P-gP inhibition by dasabuvir, paritaprevir, and ritonavir.	dasabu vir + ombitas vir/parit aprevir/ ritonavi r	^ digoxin	1.15 (1.04–1.27)	1.16 (1.09–1.23)	1.01 (0.97–1.05)		While no dose adjustment is necessary for digoxin, appropriate monitoring of serum digoxin levels is recommended.
		^ dasabuvir	0.99 (0.92–1.07)	0.97 (0.91–1.02)	0.99 (0.92–1.07)
		^ ombitasvir	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 (SYS']		IEMIC ADMINISTRATION)
	dasabu vir + ombitas vir/parit	Î Sulfamethoxazole,	1.21 (1.15–1.28)	1.17 (1.14–1.20)		1.15 (1.10–1.20)	No dose adjustment needed for dasabuvir +
		Î trimethopri m	1.17 (1.12–1.22)	1.22 (1.18–1.26)		1.25 (1.19–1.31)

Medicinal Product/ Possible Mechanism of Interaction	GIVE N WITH	EFFECT	C max	AUC	C trough		Clinical Comments
Sulfamethoxazole, trimethoprim 800/160 mg twice daily Mechanism: increase in dasabuvir possibly due to CYP2C8 inhibition by trimethoprim	aprevir/r itonavir	t dasabuvir	1.15 (1.02–1.31)	1.33 (1.23–1.44)		NA	ombitasvir/pa­ritaprevir/ ritonavir.
		^ ombitasvir	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 AGE]		NTS
Apalutamide Enzalutamid e Mitotane Mechanism: CYP3A4 induction by apalutamide, enzalutamide or mitotane.	dasabu vir + ombitas vir/parit aprevir/ ritonavi r	Not studied. Expected: ^ dasabuvir ¿ombitasvir ^ paritaprevir					Concomitant use is contraindicated (see section 4.3).
Imatinib Mechanism: BCRP inhibition by paritaprevir, ritonavir and dasabuvir.	dasabu vir + ombitas vir/parit aprevir/ ritonavi r	Not Studied. Expected: t imatinib					Clinical monitoring and lower doses of imatinib are recommended.
ANTICOAGULANTS
Warfarin 5 mg single dose and other vitamin K antagonists	dasabu vir + ombitas vir/parit aprevir/r itonavir	^ R-warfarin	1.05 (0.95–1.17)	0.88 (0.81–0.95)	0.94 (0.84–1.05)		While no change in the pharmacokinetics of warfarin is expected, close monitoring of INR is recommended with all vitamin K antagonists. This is due to liver function changes during treatment with dasabuvir + ombitasvir/pa­ritaprevir/ ritonavir
		^ S-warfarin	0.96 (0.85–1.08)	0.88 (0.81–0.96)	0.95 (0.88–1.02)
		^ dasabuvir	0.97 (0.89–1.06)	0.98 (0.91–1.06)	1.03 (0.94–1.13)
		^ ombitasvir	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)

Medicinal Product/ Possible Mechanism of Interaction	GIVE N WITH	EFFECT	C max	AUC	C trough	Clinical Comments
Dabigatran etexilate Mechanism: Intestinal Pgp inhibition by paritaprevir and ritonavir.	dasabu vir + ombitas vir/parit aprevir/r itonavir	Not Studied. Expected: t dabigatran etexilate				dasabuvir + ombitasvir/pa­ritaprevir/ ritonavir may increase the plasma concentrations of dabigatran etexilate. Use with caution.
ANTICONVULSANTS
carbamazepine 200 mg once daily followed by 200 mg twice daily Mechanism: CYP3A4 induction by carbamazepi ne.	dasabu vir + ombitas vir/parit aprevir/ ritonavi r	^ carbamazepine	1.10 (1.07–1.14)	1.17 (1.13–1.22)	1.35 (1.27–1.45)	Concomitant use is contraindicated (see section 4.3).
		! carbamaze pine 10, 11-epoxide	0.84 (0.82–0.87)	0.75 (0.73–0.77)	0.57 (0.54–0.61)
		! dasabuvir	0.45 (0.41–0.50)	0.30 (0.27 0.33)	NA
		! ombitasvir	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
Phenobarbita l Mechanism: CYP3A4 induction by phenobarbita l.	dasabu vir + ombitas vir/parit aprevir/ ritonavi r	Not studied. Expected: ^ dasabuvir ^ paritaprevir ^ ombitasvir				Concomitant use is contraindicated (see section 4.3).
Phenytoin Mechanism: CYP3A4 induction by phenytoin.	dasabu vir + ombitas vir/parit aprevir/r itonavir	Not studied. Expected: ^ dasabuvir ^ paritaprevir ^ ombitasvir				Concomitant use is contraindicated (see section 4.3).
S-mephenytoin Mechanism: CYP2C19 induction by ritonavir.	dasabu vir + ombitas vir/parit aprevir/r itonavir	Not studied. Expected: ^ S-mephenytoin				Clinical monitoring and dose adjustment maybe needed for s-mephenytoin.
ANTIDEPRESSANTS
Escitalopram 10 mg single dose	dasabu vir + ombitas vir/parit aprevir/r itonavir	^ escitalopram	1.00 (0.96–1.05)	0.87 (0.80–0.95)	NA	No dose adjustment is necessary for escitalopram.
		Î S-Desmethyl citalopram	1.15 (1.10–1.21)	1.36 (1.03–1.80)	NA
		^ dasabuvir	1.10 (0.95–1.27)	1.01 (0.93–1.10)	0.89 (0.79–1.00)
		^ ombitasvir	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	dasabu vir +	! duloxetine	0.79 (0.67–0.94)	0.75 (0.67–0.83)	NA

Medicinal Product/ Possible Mechanism of Interaction	GIVE N WITH	EFFECT	C max	AUC	C trough	Clinical Comments
60 mg single dose	ombitas vir/parit aprevir/ ritonavi r	^ dasabuvir	0.94 (0.81–1.09)	0.92 (0.81–1.04)	0.88 (0.76–1.01)	No dose adjustment is necessary for
		^ ombitasvir	0.98 (0.88–1.08)	1.00 (0.95–1.06)	1.01 (0.96–1.06)	duloxetine. No dose adjustment needed for dasabuvir + ombitasvir/pa­ritaprevir /ritonavir.
		! paritaprevir	0.79 (0.53–1.16)	0.83 (0.62–1.10)	0.77 (0.65–0.91)
ANTIFUNGALS
Ketoconazol e 400 mg once daily Mechanism: CYP3A4/P-gp inhibition by ketoconazole and paritaprevir/ ritonavir/ ombitasvir	dasabu vir + ombitas vir/parit aprevir/ ritonavi r	t ketoconazole	1.15 (1.09–1.21)	2.17 (2.05–2.29)	NA	Concomitant use is contraindicated (see the Summary of Product Characteristics for ombitasvir/pa­ritaprevir/ ritonavir).
		t dasabuvir	1.16 (1.03–1.32)	1.42 (1.26–1.59)	NA
		^ ombitasvir	0.98 (0.90–1.06)	1.17 (1.11–1.24)	NA
		t paritaprevir	1.37 (1.11–1.69)	1.98 (1.63–2.42)	NA
ANTIHYPERLIPI­DAEMICS
Gemfibrozil 600 mg twice daily Mechanism: Increase in dasabuvir exposure is due to CYP2C8 inhibition and increase in paritaprevir is possibly due to OATP1B1 inhibition by gemfibrozil.	dasabu vir + paritapr evir/ ritonavi r	t dasabuvir	2.01 (1.71–2.38)	11.25 (9.0513.99)	NA	Concomitant use is contraindicated (see section 4.3).
		t paritaprevir	1.21 (0.94–1.57)	1.38 (1.18–1.61)	NA
ANTIMYCOBACTE­RIALS
Rifampicin Mechanism: CYP3A4/CY P2C8 induction by rifampicin.	dasabu vir + Ombita svir/par itaprevi r /ritonav ir	Not Studied. Expected: ! dasabuvir ! ombitasvir ! paritaprevir				Concomitant use is contra-indicated (see section 4.3).
BIGUANIDE ORAL ANTIHYPERGLYCEMICS

Medicinal Product/ Possible Mechanism of Interaction	GIVE N WITH	EFFECT	C max	AUC	C trough	Clinical Comments
Metformin 500 mg single dose	dasabu vir + ombitas vir/parit aprevir/r itonavir	! metformin	0.77 (0.71–0.83)	0.90 (0.84–0.97)	NA	No dose adjustment needed for metformin when co-administered with dasabuvir + ombitasvir/pa­ritaprevir/ ritonavir.
		^ dasabuvir	0.83 (0.74–0.93)	0.86 (0.78–0.94)	0.95 (0.84–1.07)
		^ ombitasvir	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 BLOCKERS
Amlodipine 5 mg single dose Mechanism: CYP3A4 inhibition by ritonavir.	dasabu vir + ombitas vir/parit aprevir/ ritonavi r	Î amlodipine	1.26 (1.11–1.44)	2.57 (2.31–2.86)	NA	Decrease in amlodipine dose by 50% and monitor patients for clinical effects.
		^ dasabuvir	1.05 (0.97–1.14)	1.01 (0.96–1.06)	0.95 (0.89–1.01)
		^ ombitasvir	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
ethinyloestra diol/ norgestimate 0.035/0.25 m g once daily Mechanism: possibly due to UGT inhibition by paritaprevir, ombitasvir and dasabuvir.	dasabu vir + ombitas vir/parit aprevir/ ritonavi r	^ ethinyl oestradiol	1.16 (0.90–1.50)	1.06 (0.96–1.17)	1.12 (0.94–1.33)	Ethinyloestradiol containing oral contraceptives are contraindicated (see section 4.3).
		Norgestimate metabolites:
		Î norgestrel	2.26 (1.91–2.67)	2.54 (2.09–3.09)	2.93 (2.39–3.57)
		Î nor-elgestromin e	2.01 (1.77–2.29)	2.60 (2.30–2.95)	3.11 (2.51–3.85)
		! dasabuvir	0.51 (0.22–1.18)	0.48 (0.23–1.02)	0.53 (0.30–0.95)
		^ ombitasvir	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)
nor-ethindrone (progestin only pill) 0.35 mg once daily	dasabu vir + ombitas vir/parit aprevir/ ritonavi r	^ nor-ethindrone	0.83 (0.69–1.01)	0.91 (0.76–1.09)	0.85 (0.64–1.13)	No dose adjustment is necessary for norethindrone or dasabuvir + ombitasvir/pa­ritaprevir/ ritonavir.
		^ dasabuvir	1.01 (0.90–1.14)	0.96 (0.85–1.09)	0.95 (0.80–1.13)
		^ ombitasvir	1.00 (0.93–1.08)	0.99 (0.94–1.04)	0.97 (0.90–1.03)
		Î paritaprevir	1.24 (0.95–1.62)	1.23 (0.96–1.57)	1.43 (1.13–1.80)
DIURETICS
Furosemide 20 mg single dose Mechanism: possibly due to UGT1A1 inhibition by paritaprevir, ombitasvir and dasabuvir.	dasabu vir + ombitas vir/parit aprevir/ ritonavi r	Î furosemide	1.42 (1.17–1.72)	1.08 (1.00–1.17)	NA	Monitor patients for clinical effects; a decrease in furosemide dose of up to 50% may be required. No dose adjustment needed for dasabuvir + ombitasvir/pa­ritaprevir/ ritonavir.
		^ dasabuvir	1.12 (0.96–1.31)	1.09 (0.96–1.23)	1.06 (0.98–1.14)
		^ ombitasvir	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)

Medicinal Product/ Possible Mechanism of Interaction	GIVE N WITH	EFFECT	C max	AUC		C trough		Clinical Comments
HCV ANTIVIRAL
Sofosbuvir 400 mg once daily Mechanism: BCRP and Pgp inhibition by paritaprevir, ritonavir and dasabuvir	dasabu vir + ombitas vir/parit aprevir/r itonavir	î sofosbuvir	1.61 (1.38–1.88)		2.12 (1.91–2.37)		NA	No dose adjustment needed for sofosbuvir when administered with dasabuvir + ombitasvir/pa­ritaprevir /ritonavir.
		î GS-331007	1.02 (0.90–1.16)		1.27 (1.14–1.42)		NA
		^ dasabuvir	1.09 (0.98–1.22)		1.02 (0.95–1.10)		0.85 (0.76–0.95)
		^ ombitasvir	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)
HERBAL PRODUCTS
St. John's Wort (hypericum perforatum ) Mechanism: CYP3A4 induction by St. John's Wort.	dasabu vir + ombitas vir/parit aprevir/ ritonavi r	Not Studied. Expected: ! dasabuvir ! ombitasvir ! paritaprevir						Concomitant use is contraindicated (see section 4.3).
HIV ANTIVIRALS: PROTEASE INHIBITORS For a general comment on treatment of HIV co-infected patients, including a discussion on different antiretroviral regimens that may be used, please see section 4.4 (Treatment of HIV co-infected patients) and the Summary of Product Characteristics of ombitasvir/ paritaprevir /ritonavir.
Atazanavir 300 mg once daily (given at the same time)	dasabu vir + ombitas vir/parit aprevir/ ritonavi r	^ 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, without ritonavir, in combination with dasabuvir + ombitasvir/pa­ritaprevir/ ritonavir. Atazanavir must be administered at
		^ dasabuvir	0.83 (0.71–0.96)	0.82 (0.71–0.94)		0.79 (0.66–0.94)
		! ombitasvir	0.77 (0.70–0.85)	0.83 (0.74 0.94)		0.89 (0.78–1.02)

Medicinal Product/ Possible Mechanism of Interaction	GIVE N WITH	EFFECT	C max	AUC	C trough	Clinical Comments
Mechanism: Increase in paritaprevir exposures may be due to inhibition of OATPs by atazanavir.		T paritaprevir	1.46 (1.06–1.99)	1.94 (1.34–2.81)	3.26 (2.06–5.16)	the same time as dasabuvir +ombitasvir/pa­ritaprevi r/ritonavir. Ritonavir dose in ombitasvir/pa­ritaprevir/ ritonavir will provide atazanavir pharmacokinetic enhancement. No dose adjustment needed for dasabuvir + ombitasvir/pa­ritaprevir/ ritonavir. The combination of atazanavir and ombitasvir/pa­ritaprevir/ ritonavir + dasabuvir increase bilirubin levels, in particular when ribavirin is part of the hepatitis C regimen, see sections 4.4 and 4.8.
Atazanavir/ ritonavir 300/100 mg once daily (administere d in the evening) Mechanism: Increase in paritaprevir exposures may be due to inhibition of OATP1B1/B 3 and CYP3A by atazanavir and CYP3A inhibition by the additional dose of ritonavir.	dasabu vir + ombitas vir/parit aprevir/r itonavir	^ 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)
		^ ombitasvir	0.83 (0.72–0.96)	0.90 (0.78–1.02)	1.00 (0.89–1.13)
		T paritaprevir	2.19 (1.61–2.98)	3.16 (2.40–4.17)	11.95 (8.94–15.98)

Medicinal Product/ Possible Mechanism of Interaction	GIVE N WITH	EFFECT	C max	AUC	C trough	Clinical Comments
Darunavir 800 mg once daily (given at the same time) Mechanism: Unknown	dasabu vir + ombitas vir/parit aprevir/ ritonavi r	^ darunavir	0.92 (0.87–0.98)	0.76 (0.71–0.82)	0.52 (0.47–0.58)	The recommended dose of darunavir is 800 mg once daily, without ritonavir, when administered at the same time as ombitasvir/pa­ritaprevir/ ritonavir + dasabuvir (ritonavir dose in ombitasvir/pa­ritaprevir/ ritonavir will provide darunavir pharmacokinetic enhancement). This regimen can be used in the absence of extensive PI resistance (i.e. lack of darunavir associated RAMs), see also section 4.4. Darunavir combined with ombitasvir/pa­ritaprevir/ ritonavir + dasabuvir is not recommended in patients with extensive PI resistance. No dose adjustment needed for dasabuvir + ombitasvir/pa­ritaprevir/ ritonavir.
		^ dasabuvir	1.10 (0.88–1.37	0.94 (0.78–1.14)	0.90 (0.76–1.06)
		^ ombitasvir	0.86 (0.77–0.95)	0.86 (0.79–0.94)	0.87 (0.82–0.92)
		T 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	dasabu vir + ombitas vir/parit aprevir/ ritonavi r	^ 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)
		! ombitasvir	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 (administere d in the evening) Mechanism: Unknown	dasabu vir + ombitas vir/parit aprevir/ ritonavi r	T 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)
		^ ombitasvir	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	dasabu vir + ombitas vir/parit	^ lopinavir	0.87 (0.76–0.99)	0.94 (0.81–1.10)	1.15 (0.93–1.42)	Lopinavir/ritonavir 400/100 mg twice daily or 800/200 mg once daily is contraindicated
		^ dasabuvir	0.99 (0.75–1.31)	0.93 (0.75–1.15)	0.68 (0.57–0.80)

Medicinal Product/ Possible Mechanism of Interaction	GIVE N WITH	EFFECT	C max	AUC	C trough	Clinical Comments
400/100 mg twice daily1 Mechanism: Increase in paritaprevir exposures may be due to inhibition of CYP3A/efflu x transporters by lopinavir and higher dose of ritonavir.	aprevir/ ritonavi r	^ ombitasvir	1.14 (1.01–1.28)	1.17 (1.07–1.28)	1.24 (1.14–1.34)	with dasabuvir and ombitasvir/pa­ritaprevir/r itonavir due to increase in paritaprevir exposures (see Summary of Product Characteristics of ombitasvir/pa­ritaprevir/r itonavir).
		T 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 INHIBITORS
Rilpivirine2 25 mg once daily administered in the morning, with food Mechanism: CYP3A inhibition by ritonavir.	dasabu vir + ombitas vir/parit aprevir/ ritonavi r	T rilpivirine	2.55 (2.08–3.12)	3.25 (2.80–3.77)	3.62 (3.12–4.21)	Co-administration of dasabuvir and ombitasvir/pa­ritaprevir/ ritonavir with rilpivirine once daily should only be considered in patients without known QT-prolongation, and without other QT-prolongation coadministered medicinal products. If the combination is used, repeated ECG-monitoring should be done, see section 4.4. No dose adjustment needed for dasabuvir + ombitasvir/pa­ritaprevir/ ritonavir.
		^ dasabuvir	1.18 (1.02–1.37)	1.17 (0.99–1.38)	1.10 (0.89–1.37)
		^ ombitasvir	1.11 (1.02–1.20)	1.09 (1.04–1.14)	1.05 (1.01–1.08)
		T paritaprevir	1.30 (0.94–1.81)	1.23 (0.93–1.64)	0.95 (0.84–1.07)
Efavirenz/ emtricitabine / tenofovir disoproxil fumarate 600/300/200 mg once daily Mechanism: possible enzyme induction by efavirenz.	dasabu vir + ombitas vir/parit aprevir/ ritonavi r	Co-administration of efavirenz (enzyme inducer) based regimens with paritaprevir /ritonavir + dasabuvir resulted in ALT elevations and therefore, early discontinuation of the study.				Concomitant use with efavirenz containing regimens is contraindicated (see section 4.3).

Medicinal Product/ Possible Mechanism of Interaction	GIVE N WITH	EFFECT	C max	AUC	C trough	Clinical Comments
Nevirapine etravirine	dasabu vir + ombitas vir/parit aprevir/ ritonavi r	Not Studied. Expected: ! dasabuvir ! ombitasvir ! paritaprevir				Concomitant use is contraindicated (see section 4.3).
HIV ANTIVIRALS: INTEGRASE STRAND TRANSFER INHIBITOR
Dolutegravir 50 mg once daily Mechanism: possibly due to UGT1A1 inhibition by paritaprevir, dasabuvir and ombitasvir and CYP3A4 inhibition by ritonavir	dasabuvi r + ombitas vir/parit aprevir/r itonavir	Î dolutegravir	1.22 (1.15–1.29)	1.38 (1.30–1.47)	1.36 (1.19–1.55)	No dose adjustment needed for dolutegravir when administered with dasabuvir + ombitasvir/pa­ritaprevir/ ritonavir.
		^ dasabuvir	1.01 (0.92–1.11)	0.98 (0.92–1.05)	0.92 (0.85–0.99)
		^ ombitasvir	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: UGT1A1 inhibition by paritaprevir, ombitasvir and dasabuvir.	dasabu vir + ombitas vir/parit aprevir/ ritonavi r	Î raltegravir	2.33 (1.66–3.27)	2.34 (1.70–3.24)	2.00 (1.17–3.42)	No dose adjustment is necessary for raltegravir or dasabuvir + ombitasvir/pa­ritaprevir/ ritonavir.
		No clinically relevant changes in dasabuvir, paritaprevir, and ombitasvir exposures (based on comparison with historical data) were observed during the coadministration.
HIV ANTIVIRALS: NUCLEOSIDE INHIBITORS
Abacavir/ lamivudine 600/300 mg once daily	dasabu vir + ombitas vir/parit aprevir/r itonavir	^ abacavir	0.87 (0.78–0.98)	0.94 (0.90–0.99)	NA	No dose adjustment needed for abacavir or lamivudine when administered with dasabuvir + ombitasvir/pa­ritaprevir/ ritonavir.
		! lamivudine	0.78 (0.72–0.84)	0.88 (0.82–0.93)	1.29 (1.05–1.58)
		^ dasabuvir	0.94 (0.86–1.03)	0.91 (0.86–0.96)	0.95 (0.88–1.02)
		^ ombitasvir	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)

Medicinal Product/ Possible Mechanism of Interaction	GIVE N WITH	EFFECT	C max	AUC	C trough	Clinical Comments
Em-tricitabine/ tenofovir 200 mg once daily/300 mg once daily	dasabu vir + ombitas vir/parit aprevir/ ritonavi r	^ em-tricitabine	1.05 (1.00–1.12)	1.07 (1.00–1.14)	1.09 (1.01–1.17)	No dose adjustment is necessary for emtricitabine/te­nofovir and dasabuvir + ombitasvir/pa­ritaprevir/ ritonavir.
		^ tenofovir	1.07 (0.93–1.24)	1.13 (1.07–1.20)	1.24 (1.13–1.36)
		^ dasabuvir	0.85 (0.74–0.98)	0.85 (0.75–0.96)	0.85 (0.73–0.98)
		^ ombitasvir	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
Rosuvastatin 5 mg once daily Mechanism: OATP1B inhibition by paritaprevir and BCRP inhibition by dasabuvir paritaprevir, and ritonavir.	dasabu vir + ombitas vir/parit aprevir/r itonavir	T 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 section 4.4). No dose adjustment needed for dasabuvir + ombitasvir/pa­ritaprevir/ ritonavir.
		^ dasabuvir	1.07 (0.92–1.24)	1.08 (0.92–1.26)	1.15 (1.05–1.25)
		^ ombitasvir	0.92 (0.82–1.04)	0.89 (0.83–0.95)	0.88 (0.83–0.94)
		T 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: OATP1B1 inhibition by paritaprevir.	dasabu vir + ombitas vir/parit aprevir/r itonavir	T pravastatin	1.37 (1.11–1.69)	1.82 (1.60–2.08)		Reduce pravastatin dose by 50%. No dose adjustment needed for dasabuvir + ombitasvir/pa­ritaprevir /ritonavir.
		^ dasabuvir	1.00 (0.87–1.14)	0.96 (0.85–1.09)	1.03 (0.91–1.15)
		^ ombitasvir	0.95 (0.89–1.02)	0.94 (0.89–0.99)	0.94 (0.89–0.99)
		^ paritaprevi r	0.96 (0.69–1.32)	1.13 (0.92–1.38)	1.39 (1.21–1.59)
Fluvastatin Mechanism: OATP1B/BC RP inhibition by paritaprevir. Pitavastatin Mechanism: OATP1B inhibition by paritaprevir.	dasabu vir + ombitas vir/parit aprevir/r itonavir	Not studied. Expected: T fluvastatin T pitavastatin ^ dasabuvir ^ ombitasvir ^ paritaprevir				Concomitant use with fluvastatin and pitavastatin is not recommended (see section 4.4). A temporary suspension of fluvastatin and pitavastatin is recommended for the duration of treatment. If statin treatment is required during the treatment period, a switch to dose reduced pravastatin or rosuvastatin is possible. No dose adjustment needed for dasabuvir + ombitasvir/pa­ritaprevir/ ritonavir.

Medicinal Product/ Possible Mechanism of Interaction	GIVE N WITH	EFFECT	C max	AUC	C trough	Clinical Comments
IMMUNOSUPPRES­SANTS
Ciclosporin 30 mg once daily single dose3 Mechanism: Effect on ciclosporin is due to CYP3A4 inhibition by ritonavir and increase in paritaprevir exposures may be due to OATP/BCRP /P-gp inhibition by ciclosporin.	dasabu vir + ombitas vir/parit aprevir/ ritonavi r	Î ciclosporin	1.01 (0.85–1.20)	5.82 (4.73–7.14)	15.8 (13.8–18.09)	When starting coadministration with dasabuvir and ombitasvir/pa­ritaprevir/ ritonavir, give one fifth of the total daily dose of ciclosporin once daily with ombitasvir/ paritaprevir /ritonavir. Monitor ciclosporin levels and adjust dose and/or dosing frequency as needed. No dose adjustment needed for dasabuvir + ombitasvir/pa­ritaprevir/ ritonavir.
		¿ dasabuvir	0.66 (0.58–0.75)	0.70 (0.65–0.76)	0.76 (0.71–0.82)
		^ ombitasvir	0.99 (0.92–1.07)	1.08 (1.05–1.11)	1.15 (1.08–1.23)
		Î 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 is due to CYP3A4 inhibition by ritonavir.	dasabu vir + ombitas vir/parit aprevir/ ritonavi r	Î. everolimus	4.74 (4.29–5.25)	27.1 (24.5–30.1)	16.1 (14.5–17.9)4	Co-administration of dasabuvir + ombitasvir/pa­ritaprevir/ ritonavir with everolimus is not recommended because of a significant increase in everolimus exposures which cannot be properly dose adjusted with available dose strengths.
		^ dasabuvir	1.03 (0.90–1.18)	1.08 (0.98–1.20)	1.14 (1.05–1.23)
		^ ombitasvir	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 dose5 Mechanism: Effect on sirolimus is	dasabu vir + ombitas vir/parit aprevir/ ritonavi r	Î Sirolimus	6.40 (5.34–7.68)	38.0 (31.5–45.8)	19.6 (16.7–22.9)6	Concomitant use of sirolimus with dasabuvir + ombitasvir/pa­ritaprevir/ ritonavir is not recommended unless the benefits outweigh the risks (see section 4.4). If sirolimus is
		^ dasabuvir	1.04 (0.89–1.22)	1.07 (0.95–1.22)	1.13 (1.01–1.25)
		^ ombitasvir	1.03 (0.93–1.15)	1.02 (0.96–1.09)	1.05 (0.98–1.12)

Medicinal Product/ Possible Mechanism of Interaction	GIVE N WITH	EFFECT	C max	AUC	C trough	Clinical Comments
due to CYP3A4 inhibition by ritonavir.		^ paritaprevir	1.18 (0.91–1.54)	1.19 (0.97–1.46)	1.16 (1.00–1.34)	used together with dasabuvir + ombitasvir/pa­ritaprevir/ ritonavir, administer sirolimus 0.2 mg twice a week (every 3 or 4 days on the same two days each week). Sirolimus blood concentrations should be monitored every 4 to 7 days until 3 consecutive trough levels have shown stable concentrations of sirolimus. Sirolimus dose and/or dosing frequency should be adjusted as needed. 5 days after completion of dasabuvir + ombitasvir/pa­ritaprevir/ ritonavir treatment, the sirolimus dose and dosing frequency prior to receiving dasabuvir + ombitasvir/pa­ritaprevir/ ritonavir should be resumed, along with routine monitoring of sirolimus blood concentrations.
Tacrolimus 2 mg single dose7 Mechanism: Effect on	dasabu vir + ombitas vir/parit aprevir/ ritonavi r	T tacrolimus	3.99 (3.21–4.97)	57.1 (45.5 71.7)	16.6 (13.0–21.2)	Concomitant use of tacrolimus with dasabuvir and ombitasvir/pa­ritaprevir/ ritonavir is not recommended unless the benefits outweigh
		^ dasabuvir	0.85 (0.73–0.98)	0.90 (0.80–1.02)	1.01 (0.91–1.11)
		^ ombitasvir	0.93 (0.88–0.99)	0.94 (0.89–0.98)	0.94 (0.91–0.96)

Medicinal Product/ Possible Mechanism of Interaction	GIVE N WITH	EFFECT	C max	AUC	C trough	Clinical Comments
tacrolimus is due to CYP3A4 inhibition by ritonavir.		! paritaprevir	0.57 (0.42–0.78)	0.66 (0.54–0.81)	0.73 (0.66–0.80)	the risks (see section 4.4). If tacrolimus with dasabuvir and ombitasvir/pa­ritaprevir/ ritonavir are used concomitantly, tacrolimus should not be administered on the day dasabuvir and ombitasvir/pa­ritaprevir/ ritonavir are initiated. Beginning the day after dasabuvir and ombitasvir/pa­ritaprevir/ ritonavir are initiated; reinitiate tacrolimus at a reduced dose based on tacrolimus blood concentrations. The recommended tacrolimus dosing is 0.5 mg every 7 days. Tacrolimus whole blood concentrations should be monitored upon initiation and throughout coadministration with dasabuvir and ombitasvir/pa­ritaprevir/ ritonavir and the dose and/or dosing frequency should be adjusted as needed. Upon completion of dasabuvir and ombitasvir/pa­ritaprevir/ ritonavir treatment, the appropriate dose and dosing frequency of tacrolimus should be guided by assessment of tacrolimus blood concentrations.
IRON CHELATORS
Deferasirox	dasabu vir + ombitas vir/parit aprevir/ ritonavi r	Not studied. Expected: t dasabuvir				Deferasirox may increase dasabuvir exposures and should be used with caution.

Medicinal Product/ Possible Mechanism of Interaction	GIVE N WITH	EFFECT	C max	AUC	C trough		Clinical Comments
MEDICINAL PRODUCTS USED IN MULTIPLE SCLEROSIS
Teriflunomid e	dasabu vir + ombitas vir/parit aprevir/r itonavir	Not studied. Expected: t dasabuvir					Teriflunomide may increase dasabuvir exposures and should be used with caution.
OPIOIDS
Methadone 20–120 mg once daily8	dasabu vir + ombitas vir/parit aprevir/r itonavir	~ R-Methadone	1.04 (0.98–1.11)	1.05 (0.98–1.11)	0.94 (0.87–1.01)		No dose adjustment is necessary for methadone and dasabuvir + ombitasvir/pa­ritaprevir/ ritonavir.
		^ S- Methadone	0.99 (0.91–1.08)	0.99 (0.89–1.09)	0.86 (0.76–0.96)
		^ ombitasvir/pa­ritaprevir and dasabuvir (based on the cross-study comparison)
buprenorphin e/ naloxone 4–24 mg/1–6 mg once daily8 Mechanism: CYP3A4 inhibition by ritonavir and UGT inhibition by paritaprevir, ombitasvir and dasabuvir.	dasabu vir + ombitas vir/parit aprevir/r itonavir	t buprenorphine	2.18 (1.78–2.68)	2.07 (1.78–2.40)	3.12 (2.29–4.27)		No dose adjustment is necessary for buprenorphine/na­loxon e and dasabuvir + ombitasvir/pa­ritaprevir/ ritonavir.
		t norbuprenorphine	2.07 (1.42–3.01)	1.84 (1.30–2.60)	2.10 (1.49–2.97)
		t naloxone	1.18 (0.81–1.73)	1.28 (0.92–1.79)	NA
		^ ombitasvir /paritaprevir and dasabuvir (based on the cross-study comparison)
MUSCLE RELAXANTS
Carisoprodol 250 mg single dose Mechanism: CYP2C19 induction by ritonavir	dasabu vir + ombitas vir/parit aprevir/r itonavir	! Carisoprodol	0.54 (0.47–0.63)	0.62 (0.55–0.70)		NA	No dose adjustment required for carisoprodol; increase dose if clinically indicated.
		^ dasabuvir	0.96 (0.91–1.01)	1.02 (0.97–1.07)		1.00 (0.92–1.10)
		^ ombitasvir	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)
Cyclobenzap rine 5 mg single dose Mechanism: decrease possibly due to CYP1A2 induction by ritonavir	dasabu vir + ombitas vir/parit aprevir/r itonavir	! cyclobenzap rine	0.68 (0.61–0.75)	0.60 (0.53–0.68)		NA	No dose adjustment for cyclobenzaprine required; increase dose if clinically indicated.
		^ dasabuvir	0.98 (0.90–1.07)	1.01 (0.96–1.06)		1.13 (1.07–1.18)
		^ ombitasvir	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 ANALGESICS
Paracetamol (given as fixed dose	dasabu vir + ombitas	^ Paracetamo l	1.02 (0.89–1.18)	1.17 (1.09–1.26)	NA		No dose adjustment is necessary for paracetamol when

Medicinal Product/ Possible Mechanism of Interaction	GIVE N WITH	EFFECT	C max	AUC	C trough	Clinical Comments
hydrocodone /paracetamol ) 300 mg single dose	vir/parit aprevir/r itonavir	^ dasabuvir	1.13 (1.01–1.26)	1.12 (1.051.19)	1.16 (1.08–1.25)	administered with dasabuvir + ombitasvir/pa­ritaprevir/ ritonavir.
		^ ombitasvir	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 (as given in a fixed-dose hydrocodone /paracetamol ) 5 mg single dose Mechanism: CYP3A4 inhibition by ritonavir	dasabu vir + ombitas vir/parit aprevir/r itonavir	t hydrocod one	1.27 (1.14 1.40)	1.90 (1.722.10)	NA	A reduction of hydrocodone dose by 50% and/or clinical monitoring should be considered when administered with dasabuvir + ombitasvir/pa­ritaprevir /ritonavir.
		Changes for dasabuvir and ombitasvir, paritaprevir are the same as shown for paracetamol above
PROTON PUMP INHIBITORS
Omeprazole 40 mg once daily Mechanism: CYP2C19 induction by ritonavir.	dasabu vir + ombitas vir/parit aprevir/r itonavir	i omeprazole	0.62 (0.48–0.80)	0.62 (0.51–0.75)	NA	If clinically indicated, higher doses of omeprazole should be used. No dose adjustment needed for dasabuvir + ombitasvir/pa­ritaprevir/ ritonavir.
		^ dasabuvir	1.13 (1.03–1.25)	1.08 (0.98–1.20)	1.05 (0.93–1.19)
		^ ombitasvir	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)
Esomeprazol e Lansoprazole Mechanism: CYP2C19 induction by ritonavir.	dasabu vir + ombitas vir/parit aprevir/r itonavir	Not studied. Expected: ^ esomeprazole, lansoprazole				If clinically indicated, higher doses of esomeprazole/lan­sopraz ole may be needed.
SEDATIVES / HYPNOTICS
Zolpidem 5 mg single dose	dasabu vir + ombitas vir/parit aprevir/r itonavir	^ zolpidem	0.94 (0.76–1.16)	0.95 (0.74–1.23)	NA	No dose adjustment is necessary for zolpidem. No dose adjustment needed for dasabuvir + ombitasvir/pa­ritaprevir/ ritonavir.
		^ dasabuvir	0.93 (0.84–1.03)	0.95 (0.84–1.08)	0.92 (0.83–1.01)
		^ ombitasvir	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: CYP2C19	dasabu vir + ombitas vir/parit aprevir/r itonavir	¿diazepam	1.18 (1.07–1.30)	0.78 (0.73–0.82)	NA	No dose adjustment required for diazepam; increase dose if clinically indicated.
		! nordiazepam	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)
		^ ombitasvir	1.00 (0.93–1.08)	0.98 (0.93–1.03)	0.93 (0.88–0.98)

Medicinal Product/ Possible Mechanism of Interaction	GIVE N WITH	EFFECT	C max	AUC	C trough	Clinical Comments
induction by ritonavir		^ 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: CYP3A4 inhibition by ritonavir.	dasabu vir + ombitas vir/parit aprevir/r itonavir	T alprazolam	1.09 (1.03–1.15)	1.34 (1.15–1.55)	NA	Clinical monitoring of patients is recommended. A decrease in alprazolam dose can be considered based on clinical response. No dose adjustment needed for dasabuvir + ombitasvir/pa­ritaprevir/ ritonavir.
		^ dasabuvir	0.93 (0.83–1.04)	0.98 (0.87–1.11)	1.00 (0.87–1.15)
		^ ombitasvir	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 HORMONES
Levothyroxin e Mechanism: UGT1A1 inhibition by paritaprevir, ombitasvir and dasabuvir.	dasabu vir + ombitas vir/parit aprevir/r itonavir	Not studied. Expected: t levothyroxine				Clinical monitoring and dose adjustment may be required for levothyroxine.

Medicinal Product/ Possible Mechanism of Interaction	GIVE N WITH	EFFECT	C max	AUC	C trough	Clinical Comments
1. Lopinavir/ri­tonavir 800/200 mg once daily (administered in the evening) was also administered with dasabuvir with ombitasvir/pa­ritaprevir/ri­tonavir. The effect on Cmax and AUC of DAAs and lopinavir was similar to that observed when lopinavir/ritonavir 400/100 mg twice daily was administered with dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir. 2. Rilpivirine was also administered with food in the evening and 4 hours after dinner with dasabuvir + ombitasvir/pa­ritaprevir/ri­tonavir in the study. The effect on rilpivirine exposures was similar to that observed when rilpivirine was administered in the morning with food with dasabuvir + ombitasvir/pa­ritaprevir/ri­tonavir.
3. Ciclosporin 100 mg dosed alone and 30 mg administered with dasabuvir + ombitasvir/pa­ritaprevir/ri­tonavir. Dose normalized cyclosporine ratios are shown for interaction with dasabuvir + ombitasvir/pa­ritaprevir/ri­tonavir.
4. C12:= concentration at 12 hours following single dose of everolimus.
5. Sirolimus 2 mg was dosed alone, 0.5 mg administered with dasabuvir + ombitasvir/pa­ritaprevir/ri­tonavir. Dose normalized sirolimus ratios are shown for interaction with ombitasvir/pa­ritaprevir/ri­tonavir + dasabuvir.
6. C24:= concentration at 24 hours following single dose of cyclosporine, tacrolimus or sirolimus.
7. Tacrolimus 2 mg was dosed alone and 2 mg was administered with dasabuvir + ombitasvir/pa­ritaprevir/ri­tonavir. Dose normalized tacrolimus ratios are shown for interaction with dasabuvir + ombitasvir/pa­ritaprevir/ri­tonavir.
8. Dose normalised parameters reported for methadone, buprenorphine and naloxone.
Note: Doses used for dasabuvir + ombitasvir/pa­ritaprevir/ri­tonavir were: ombitasvir 25 mg paritaprevir 150 mg, ritonavir 100 mg, once daily and dasabuvir 400 mg twice daily or 250 mg twice daily. The dasabuvir exposures obtained with the 400 mg formulation and the 250 mg tablet are similar. dasabuvir + ombitasvir/pa­ritaprevir/ri­tonavir was administered as multiple doses in all the drug interaction studies except the drug interaction studies with carbamazepine, gemfibrozil, ketoconazole, and sulfamethoxazo­le/trimethoprim.

Paediatric population

Drug interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential /contraception in males and females

Extreme caution must be taken to avoid pregnancy in female patients and female partners of male patients when dasabuvir is used with ribavirin. Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin; therefore, ribavirin is contraindicated in women who are pregnant and in the male partners of women who are pregnant. Refer to the Summary of Product Characteristics for ribavirin for additional information.

Female patients: Women of childbearing potential should not receive ribavirin unless they are using an effective form of contraception during treatment with ribavirin and for 4 months after treatment.

Male patients and their female partners: Either male patients or their female partners of childbearing potential must use a form of effective contraception during treatment with ribavirin and for 7 months after treatment.

Ethinyloestradiol is contraindicated in combination with dasabuvir (see section 4.3). See additional information on specific hormonal contraceptives in sections 4.3 and 4.4.

Pregnancy

There are very limited data from the use of dasabuvir in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of dasabuvir during pregnancy.

If ribavirin is co-administered with dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir, the contraindications regarding use of ribavirin during pregnancy apply (see also the Summary of Product Characteristics of ribavirin).

Breast-feeding

It is not known whether dasabuvir and metabolites are excreted in human breast milk. Available pharmacokinetic data in animals have shown excretion of dasabuvir and metabolites in milk (see section 5.3). Because of the potential for adverse reactions from the medicinal product in breastfed infants, a decision must be made whether to discontinue breastfeeding or discontinue treatment with dasabuvir, taking into account the importance of the therapy to the mother. Patients receiving ribavirin should also refer to the Summary of Product Characteristics of ribavirin.

Fertility

No human data on the effect of dasabuvir on fertility are available. Animal studies do not indicate harmful effects on fertility (see section 5.3).

4.7 Effects on ability to drive and use machines

Dasabuvir has no or negligible influence on the ability to drive and use machines. Patients should be informed that fatigue has been reported during treatment with dasabuvir in combination with ombitasvir/pa­ritaprevir/ri­tonavir and ribavirin (see section 4.8).

4.8 Undesirable effects

Summary of the safety profile

In subjects receiving dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir with ribavirin, the most commonly reported adverse reactions (greater than 20% of subjects) were fatigue and nausea. The proportion of subjects who permanently discontinued treatment due to adverse reactions was 0.2% (5/2,044) and 4.8% (99/2,044) of subjects had ribavirin dose reductions due to adverse reactions.

Tabulated list of adverse reactions

The safety summary is based on pooled data from phase 2 and 3 clinical trials in subjects who received dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir with or without ribavirin. The majority of adverse reactions presented in Table 3 were of grade 1 severity in dasabuvir- and ombitasvir/pa­ritaprevir/ri­tonavir-containing regimens.

The adverse reactions are listed below by system organ class and frequency. Frequencies are defined as follows: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1,000 to <1/100), rare (>1/10,000 to <1/1,000) or very rare (<1/10,000).

Table 3. Adverse reactions identified with dasabuvir in combination with ombitasvir/pa­ritaprevir/ri­tonavir or ombitasvir/pa­ritaprevir/ri­tonavir and ribavirin

Frequency	dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir + ribavirin* N = 2,044	dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir N = 588
Blood and lymphatic system disorders
Common	Anaemia
Immune system disorders
Frequency unknown	Anaphylactic reactions	Anaphylactic reactions
Metabolism and nutrition disorders
Uncommon	Dehydration
Psychiatric disorders
Very common	Insomnia
Gastrointestinal disorders
Very common	Nausea, Diarrhoea
Common	Vomiting
Hepatobiliary disorders
Frequency unknown	Hepatic decompensation and hepatic failure	Hepatic decompensation and hepatic failure
Skin and subcutaneous tissue disorders
Very common	Pruritus
Common		Pruritus
Rare	Angioedema	Angioedema
General disorders and administration and administration site conditions
Very common	Asthenia Fatigue

Data set includes all genotype 1-infected subjects in Phase 2 and 3 trials including subjects with cirrhosis. Note: For laboratory abnormalities refer to Table 4.

Description of selected adverse reactions

Compared to subjects without cirrhosis, in subjects with compensated cirrhosis there was an increased rate of indirect hyperbilirubinemia when ribavirin was part of the regimen.

Laboratory abnormalities

Changes in selected laboratory parameters are described in Table 4. A side-by-side tabulation is provided to simplify presentation; direct comparisons should not be made across trials that differ in trial designs.

Table 4. Selected treatment emergent laboratory abnormalities

Laboratory parameters	SAPPHIRE I and II	PEARL II, III, and IV	TURQUOISE II (subjects with cirrhosis)
	dasabuvir and ombitasvir/pa­ritaprevir /ritonavir + ribavirin 12 weeks N = 770 n (%)	dasabuvir and ombitasvir/pa­ritaprevir /ritonavir 12 weeks N = 509 n (%)	dasabuvir and ombitasvir/pa­ritaprevir /ritonavir + ribavirin 12 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%)
Haemoglobin
<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 x ULN (grade 3)	19/765 (2.5%)	2/509 (0.4%)	37/380 (9.7%)
>10 x ULN (grade 4)	1/765 (0.1%)	0	0
*ULN: Upper Limit of Normal

Serum ALT elevations

In a pooled analysis of clinical trials with dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir with and without ribavirin, 1% of subjects experienced serum ALT levels greater than 5 times the upper limit of normal (ULN) after starting treatment. As the incidence of such elevations was 26% among women taking a concomitant ethinyloestradiol-containing medicine, such medicinal products are contraindicated with dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir. No increase in incidence of ALT elevations was observed with other types of systemic oestrogens commonly used for hormone replacement therapy (e.g., oestradiol and conjugated oestrogens). ALT elevations were typically asymptomatic, generally occurred during the first 4 weeks of treatment (mean time 20 days, range 857 days) and most resolved with ongoing therapy. Two patients discontinued dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir due to elevated ALT, including one on ethinyloestradiol. Three interrupted dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir for one to seven days, including one on ethinyloestradiol. The majority of these ALT elevations were transient and assessed as related to dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir. Elevations in ALT were generally not associated with bilirubin elevations. Cirrhosis was not a risk factor for elevated ALT (see section 4.4).

Serum bilirubin elevations

Transient elevations in serum bilirubin (predominantly indirect) were observed in subjects receiving dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir with ribavirin, related to the inhibition of the bilirubin transporters OATP1B1/1B3 by paritaprevir and ribavirin-induced haemolysis. Bilirubin elevations occurred after initiation of treatment, peaked by study Week 1, and generally resolved with ongoing therapy. Bilirubin elevations were not associated with aminotransferase elevations. The frequency of indirect bilirubin elevations was lower among subjects who did not receive ribavirin.

Liver transplant recipients

The overall safety profile in HCV-infected transplant recipients who were administered dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir and ribavirin (in addition to their immunosuppressant medicinal products) was similar to subjects treated with dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir and ribavirin in phase 3 clinical trials, although some adverse reactions were increased in frequency. 10 subjects (29.4%) had at least one post baseline haemoglobin value of less than 10 g/dL. 10 of 34 subjects (29.4%) dose modified ribavirin due to decrease in haemoglobin and 2.9% (1/34) had an interruption of ribavirin. Ribavirin dose modification did not impact SVR rates. 5 subjects required erythropoietin, all of whom initiated ribavirin at the starting dose of 1000 to 1200 mg daily. No subject received a blood transfusion.

HIV/HCV co-infected patients

The overall safety profile in HCV/HIV-1 co-infected subjects was similar to that observed in HCV mono-infected subjects. Transient elevations in total bilirubin >3 x ULN (mostly indirect) occurred in 17 (27.0%) subjects; 15 of these subjects were receiving atazanavir. None of the subjects with hyperbilirubinemia had concomitant elevations of aminotransferases.

GT1-infected subjects with or without cirrhosis with severe renal impairment or end-stage renal disease (ESRD)

Dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir with or without ribavirin were assessed in 68 subjects with genotype 1 infection with or without cirrhosis who have severe renal impairment or ESRD (see Section 5.1). The overall safety profile in subjects with severe renal impairment was similar to that seen in prior Phase 3 studies in subjects without severe renal impairment, except that a greater proportion of subjects required intervention due to ribavirin-associated decreases in serum haemoglobin. The mean baseline haemoglobin level was 12.1 g/dL and the mean decline in haemoglobin at the end of treatment for subjects taking RBV was 1.2 g/dL. Thirty-nine of the 50 subjects who received ribavirin required interruption of ribavirin, and 11 of these subjects were also treated with erythropoietin. Four subjects experienced a haemoglobin level < 8 g/dL. Two subjects received a blood transfusion. Adverse events of anaemia were not seen in the 18 GT1b-infected subjects who did not receive ribavirin. Ombitasvir/pa­ritaprevir/ri­tonavir with or without dasabuvir was also evaluated without ribavirin in 18 GT1a- and GT4-infected patients; no adverse events of anaemia were seen in these subjects.

Paediatric population

The safety of dasabuvir in children and adolescents aged < 18 years has not yet been established. No data are available.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in

4.9 Overdose

The highest documented single dose of dasabuvir administered to healthy volunteers was 2 g. No study drug-related adverse reactions or clinically significant laboratory abnormalities were observed. In case of overdose, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antivirals for systemic use; direct-acting antivirals, ATC code: J05AP09

Mechanism of action

Dasabuvir is a non-nucleoside inhibitor of the HCV RNA-dependent RNA polymerase encoded by the NS5B gene, which is essential for replication of the viral genome.

Co-administration of dasabuvir with ombitasvir/pa­ritaprevir/ri­tonavir combines three direct-acting antiviral medicinal products with distinct mechanisms of action and non-overlapping resistance profiles to target HCV at multiple steps in the viral lifecycle. Refer to the Summary of Product Characteristics of ombitasvir/pa­ritaprevir/ri­tonavir for its pharmacological properties.

Activity in cell culture and biochemical studies

The EC50 of dasabuvir against genotype 1a-H77 and 1b-Con1 strains in HCV replicon cell culture assays was 7.7 and 1.8 nM, respectively. The replicon activity of dasabuvir was attenuated 12– to 13fold in the presence of 40% human plasma. The mean EC50 of dasabuvir against replicons containing NS5B from a panel of treatment-naive genotype 1a and 1b isolates in the HCV replicon cell culture assay was 0.77 nM (range 0.4 to 2.1 nM; n=11) and 0.46 nM (range 0.2 to 2 nM; n=10), respectively. In biochemical assays, dasabuvir inhibited a panel of genotype 1a and 1b polymerases with a mean IC50 value of 4.2 nM (range 2.2 to 10.7 nM; n=7).

The M1 metabolite of dasabuvir had EC50 values of 39 and 8 nM against genotype 1a-H77 and 1b-Con1 strains in HCV replicon cell culture assays, respectively, and the activity of the M1 metabolite was attenuated 3-to 4-fold in the presence of 40% human plasma. Dasabuvir had reduced activity in biochemical assays against NS5B polymerases from HCV genotypes 2a, 2b, 3a and 4a (IC50 values ranging from 900 nM to >20 p.M).

Resistance

In cell culture

Resistance to dasabuvir conferred by variants in NS5B selected in cell culture or identified in Phase 2b and 3 clinical trials were phenotypically characterised in the appropriate genotype 1a or 1b replicons.

In genotype 1a, substitutions C316Y, M414T, Y448H, A553T, G554S, S556G/R, and Y561H in HCV NS5B reduced susceptibility to dasabuvir. In the genotype 1a replicon, the activity of dasabuvir was reduced 21– to 32-fold by the M414T, S556G or Y561H substitutions; 152– to 261-fold by the A553T, G554S or S556R substitutions; and 1472– and 975-fold by the C316Y and Y448H substitutions, respectively. G558R and D559G/N were observed as treatment-emergent substitutions but the activity of dasabuvir against these variants could not be evaluated due to poor replication capacity. In genotype 1b, substitutions C316N, C316Y, M414T, Y448H, and S556G in HCV NS5B reduced susceptibility to dasabuvir. The activity of dasabuvir was reduced by 5– and 11-fold by C316N and S556G, respectively; 46-fold by M414T or Y448H; and 1569-fold by the C316Y substitutions in the genotype 1b replicon. Dasabuvir retained full activity against replicons containing substitutions S282T in the nucleoside binding site, M423T in the lower thumb site, and P495A/S, P496S or V499A in the upper thumb site.

Effect of baseline HCV substitutions/po­lymorphisms on treatment response

A pooled analysis of subjects with genotype 1 HCV infection, who were treated with dasabuvir, ombitasvir and paritaprevir with or without ribavirin in Phase 2b and 3 clinical trials, was conducted to explore the association between baseline NS3/4A, NS5A or NS5B substitutions/po­lymorphisms and treatment outcome in these recommended regimens.

In the greater than 500 genotype 1a baseline samples in this analysis, the most frequently observed resistance-associated variants were M28V (7.4%) in NS5A and S556G (2.9%) in NS5B. Q80K, although a highly prevalent polymorphism in NS3 (41.2% of samples), confers minimal resistance to paritaprevir. Resistance-associated variants at amino acid positions R155 and D168 in NS3 were rarely observed (less than 1%) at baseline. In the greater than 200 genotype 1b baseline samples in this analysis, the most frequently observed resistance-associated variants observed were Y93H (7.5%) in NS5A, and C316N (17.0%) and S556G (15%) in NS5B. Given the low virologic failure rates observed

with recommended treatment regimens for HCV genotype 1a- and 1b-infected subjects, the presence of baseline variants appears to have little impact on the likelihood of achieving SVR.

In clinical studies

Of the 2,510 HCV genotype 1 infected subjects who were treated with regimens containing dasabuvir, ombitasvir and paritaprevir with or without ribavirin (for 8, 12 or 24 weeks) in Phase 2b and 3 clinical trials, a total of 74 subjects (3%) experienced virologic failure (primarily post-treatment relapse). Treatment-emergent variants and their prevalence in these virologic failure populations are shown in Table 5. In the 67 genotype 1a infected subjects, NS3 variants were observed in 50 subjects, NS5A variants were observed in 46 subjects, NS5B variants were observed in 37 subjects, and treatment-emergent variants were seen in all 3 drug targets in 30 subjects. In the 7 genotype 1b infected subjects, treatment-emergent variants were observed in NS3 in 4 subjects, in NS5A in 2 subjects, and in both NS3 and NS5A in 1 subject. No genotype 1b infected subjects had treatment-emergent variants in all 3 drug targets.

Table 5. Treatment-emergent amino acid substitutions in the pooled analysis of dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir, with and without RBV regimens in Phase 2b and Phase 3 clinical trials (N=2510)

Target	Emergent amino acid substitutions3	Genotype 1a N=67b % (n)	Genotype 1b N=7 % (n)
NS3	V55Ic	6 (4)	--
	Y56Hc I132Vc R155K D168A D168V D168Y	9 (6) 6 (4) 13.4 (9) 6 (4) 50.7 (34) 7.5 (5)	42.9 (3)d
			--
			--
			--
			42.9 (3)d
			--
	V36Ac, V36Mc, F43Lc, D168H, E357Kc	<5%	--
NS5A	M28T	20.9 (14)	--
	M28Ve Q30Re Y93H	9 (6) .....40.3 (27).........­.............­.............	-- – 28.6 (2)
	H58D, H58P, Y93N	<5%	--
NS5B	A553T	6.1 (4)	--
	S556G	33.3 (22)	--
	C316Y, M414T, G554S, S556R, G558R, D559G, D559N, Y561H	<5%	--

a. Observed in at least 2 subjects of the same subtype.

b. N=66 for the NS5B target.

c. Substitutions were observed in combination with other emergent substitutions at NS3 position R155 or D168.

d. Observed in combination in genotype 1b-infected subjects.

e. Observed in combination in 6% (4/67) of the subjects.

Note: The following variants were selected in cell culture but were not treatment-emergent: NS3 variants A156T in genotype 1a, and R155Q and D168H in genotype 1b; NS5A variants Y93C/H in genotype 1a, and L31F/V or Y93H in combination with L28M, L31F/V or P58S in genotype 1b; and NS5B variants Y448H in genotype 1a, and M414T and Y448H in genotype 1b.

Persistence of resistance-associated substitutions

The persistence of dasabuvir, ombitasvir and paritaprevir resistance-associated amino acid substitutions in NS5B, NS5A and NS3, respectively, was assessed in genotype 1a-infected subjects in Phase 2b trials. Dasabuvir treatment-emergent variants M414T, G554S, S556G, G558R or D559G/N in NS5B were observed in 34 subjects. Ombitasvir treatment-emergent variants M28T, M28V or Q30R in NS5A were observed in 32 subjects. Paritaprevir treatment-emergent variants V36A/M, R155K or D168V were observed in NS3 in 47 subjects.

NS3 variants V36A/M and R155K and NS5B variants M414T and S556G remained detectable at posttreatment Week 48, whereas NS3 variant D168V and all other NS5B variants were not observed at post-treatment Week 48. All treatment-emergent variants in NS5A remained detectable at posttreatment Week 48. Due to high SVR rates in genotype 1b, trends in persistence of treatment-emergent variants in this genotype could not be established.

The lack of detection of virus containing a resistance-associated substitution does not indicate that the resistant virus is no longer present at clinically significant levels. The long-term clinical impact of the emergence or persistence of virus containing dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir -resistance-associated substitutions on future treatment is unknown.

Cross-resistance

Cross-resistance is expected among NS5A inhibitors, NS3/4A protease inhibitors, and non-nucleoside NS5B inhibitors by class. The impact of prior dasabuvir, ombitasvir, or paritaprevir treatment experience on the efficacy of other NS5A inhibitors, NS3/4A protease inhibitors, or NS5B inhibitors has not been studied.

Clinical efficacy and safety

The efficacy and safety of dasabuvir in combination with ombitasvir/pa­ritaprevir/ri­tonavir with and without ribavirin was evaluated in eight Phase 3 clinical trials, including two trials exclusively in subjects with compensated cirrhosis (Child-Pugh A), in over 2,360 subjects with genotype 1 chronic hepatitis C infection as summarised in Table 6.

Table 6. Phase 3 global multicentre trials conducted with dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir with or without ribavirin (RBV).

Trial	Number of subjects treated	HCV genotype (GT)	Summary of study design
Treatment-naive, without cirrhosis
SAPPHIRE I	631	GT1	Arm A: dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir + RBV Arm B: Placebo
PEARL III	419	GT1b	Arm A: dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir + RBV Arm B: dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir
PEARL IV	305	GT1a	Arm A: dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir + RBV Arm B: dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir
GARNET (open-label)	166	GT1b	dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir (8 weeks)
Peginteferon+ri­bavirin-experienced, without cirrhosis
SAPPHIRE II	394	GT1	Arm A: dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir + RBV Arm B: Placebo
PEARL II (open-label)	179	GT1b	Arm A: dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir + RBV Arm B: dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir
Treatment-naive and peginterferon+ri­bavirin-experienced, with compensated cirrhosis
TURQUOISE II (open-label)	380	GT1	Arm A: dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir + RBV (12 weeks) Arm B: dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir + RBV (24 weeks)

dasabuvir and

GT1b        ombitas­vir/paritapre­vir/ritonavir (12

weeks)

In all eight trials, the dasabuvir dose was 250 mg twice daily and the ombitasvir/pa­ritaprevir/ri­tonavir dose was 25 mg/150 mg/100 mg once daily. For subjects who received ribavirin, the ribavirin dose was 1000 mg per day for subjects weighing less than 75 kg or 1200 mg per day for subjects weighing greater than or equal to 75 kg.

Sustained virologic response (SVR) was the primary endpoint to determine the HCV cure rate in the Phase 3 studies and was defined as unquantifiable or undetectable HCV RNA 12 weeks after the end of treatment (SVR12). Treatment duration was fixed in each trial and was not guided by subjects’ HCV RNA levels (no response guided algorithm). Plasma HCV RNA values were measured during the clinical trials using the COBAS TaqMan HCV test (version 2.0), for use with the High Pure System (except GARNET which used COBAS AmpliPrep/COBAS TaqMan HCV Test v2.0). The High Pure system assay had a lower limit of quantification (LLOQ) of 25 IU per mL and the AmpliPrep assay had a LLOQ of 15 IU per mL.

Clinical trials in treatment-naive adults

SAPPHIRE-I -genotype 1, treatment-naïve, without cirrhosis

Design:        randomised, global multicentre, double-blind, placebo-controlled

Treatment:     dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir with weight-based ribavirin for 12

weeks

Treated subjects (N=631) had a median age of 52 years (range: 18 to 70); 54.5% were male; 5.4% were Black; 15.2% had a history of depression or bipolar disorder; 79.1% had baseline HCV RNA levels of at least 800,000 IU/mL; 15.4% had portal fibrosis (F2) and 8.7% had bridging fibrosis (F3); 67.7% had HCV genotype 1a infection; 32.3% had HCV genotype 1b infection.

Table 7. SVR12 for genotype 1-infected treatment-naïve subjects in SAPPHIRE-I

dasabuvir and

Treatment outcome

ombitasvir/pa­ritaprevir/ri­tonavir with RBV for 12 weeks

	n/N	%	95% CI
Overall SVR12	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
Outcome for subjects without SVR12
On-treatment VFa	1/473	0.2
Relapse	7/463	1.5
Otherb	9/473	1.9

a. Confirmed HCV > 25 lU/mL after HCV RNA < 25 lU/mL during treatment, confirmed 1 logio lU/mL increase in HCV RNA from nadir, or HCV RNA persistently > 25 lU/mL with at least 6 weeks of treatment.

b. Other includes early drug discontinuation not due to virologic failure and missing HCV RNA values in the SVR12 window.

No subjects with HCV genotype 1b infection experienced on-treatment virologic failure and one subject with HCV genotype 1b infection experienced relapse.

PEARL-III -genotype 1b, treatment-naive, without cirrhosis

Design:        randomised, global multicentre, double-blind, regimen-controlled

Treatment:     dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir without ribavirin or with weight-based

ribavirin for 12 weeks

Treated subjects (N=419) had a median age of 50 years (range: 19 to 70); 45.8% were male; 4.8% were Black; 9.3% had a history of depression or bipolar disorder; 73.3% had baseline HCV RNA of at least 800,000 IU/mL; 20.3% had portal fibrosis (F2) and 10.0% had bridging fibrosis (F3).

Table 8. SVR12 for genotype Ib-infected treatment-naive subjects in PEARL III

dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir for 12 weeks

Treatment outcome	With RBV			Without RBV
	n/N	%	95% CI	n/N	%	95% CI
Overall SVR12	209/210	99.5	98.6, 100.0	209/209	100	98.2, 100.0
Outcome for subjects without SVR12
On-treatment VF	1/210	0.5		0/209	0
Relapse	0/210	0		0/209	0
Other	0/210	0		0/209	0

PEARL-IV - genotype 1a, treatment-naïve, without cirrhosis

Design:        randomised, global multicentre, double-blind, regimen-controlled

Treatment:     dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir without ribavirin or with weight-based

ribavirin for 12 weeks

Treated subjects (N=305) had a median age of 54 years (range: 19 to 70); 65.2% were male; 11.8% were Black; 20.7% had a history of depression or bipolar disorder; 86.6% had baseline HCV RNA levels of at least 800,000 IU/mL; 18.4% had portal fibrosis (F2) and 17.7% had bridging fibrosis (F3).

Table 9. SVR12 for genotype 1a-infected treatment-naive subjects in PEARL IV

Treatment outcome	dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir for 12 weeks With RBV                W­ithout RBV n/N    %    95% CI     n/N     %    95% CI
Overall SVR12	97/100    97.0   93.7, 100.0    185/205     90.2   86.2, 94.3

Outcome for subjects without SVR12

On-treatment VF Relapse Other

1/100     1.0                    6­/205        2.9 1/98      1.0                    1­0/194      5.2 1/100     1.0                    4­/205        2.0

GARNET – Genotype 1b, Treatment-Naive without cirrhosis.

Design:        open-label, single-arm, global multicentre

Treatment:     dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir for 8 weeks

Treated subjects (N=166) had a median age of 53 years (range: 22 to 82); 56.6% were female; 3.0% were Asian; 0.6% were Black; 7.2% had baseline HCV RNA levels of at least 6,000,000 IU per mL;

9% had advanced fibrosis (F3) and 98.2% had HCV genotype 1b infection (one subject each had genotype 1a, 1d, and 6 infection).

Table 10. SVR12 for Genotype 1b-infected treatment-naive subjects without cirrhosis

	dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir for 8 weeks n/N (%)
SVR12	160/163 (98.2)
95% CIa	96.1, 100.0
F0-F1	138/139 (99.3)b
F2	9/9 (100)
F3	13/15 (86.7)c

a. Calculated using the normal approximation to the binomial distribution

b. 1 patient discontinued due to non-compliance

c. Relapse in 2/15 patients (confirmed HCV RNA > 15 lU/mL post-treatment before or during SVR12 window among subjects with HCV RNA < 15 IU/mL at last observation with at least 51 days of treatment).

Clinical trials in peginterferon+ri­bavirin-experienced adults

SAPPHIRE-II- genotype 1, peglFN+RBV-experienced, without cirrhosis

Design:        randomised, global multicentre, double-blind, placebo-controlled

Treatment:     dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir with weight-based ribavirin for 12

weeks

Treated subjects (N=394) had a median age of 54 years (range: 19 to 71); 49.0% were prior pegIFN/RBV null responders; 21.8/% were prior pegIFN/RBV partial responders; and 29.2% were prior pegIFN/RBV relapsers; 57.6% were male; 8.1% were Black; 20.6% had a history of depression or bipolar disorder; 87.1% had baseline HCV RNA levels of at least 800,000 IU per mL; 17.8% had portal fibrosis (F2) and 14.5% had bridging fibrosis (F3); 58.4% had HCV genotype 1a infection; 41.4% had HCV genotype 1b infection.

Table 11. SVR12 for genotype 1-infected peginterferon+ri­bavirin-experienced subjects in SAPPHIRE-II

Treatment outcome	dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir with RBV for 12 weeks
	n/N	%	95% CI
Overall SVR12	286/297	96.3	94.1, 98.4
HCV genotype 1a	166/173	96.0	93.0, 98.9
Prior pegIFN/RBV null responder	83/87	95.4	91.0, 99.8
Prior pegIFN/RBV partial responder	36/36	100	100.0, 100.0
Prior peglFN/RBV relapser	47/50	94.0	87.4, 100.0
HCV genotype 1b	119/123	96.7	93.6, 99.9
Prior pegIFN/RBV null responder	56/59	94.9	89.3, 100.0
Prior pegIFN/RBV partial responder	28/28	100	100.0, 100.0
Prior pegIFN/RBV relapser	35/36	97.2	91.9, 100.0
Outcome for subjects without SVR12
On-treatment VF	0/297	0
Relapse	7/293	2.4
Other	4/297	1.3

No subjects with HCV genotype 1b infection experienced on-treatment virologic failure and 2 subjects with HCV genotype 1b infection experienced relapse.

PEARL-II- genotype 1b, pegIFN+RBV-experienced, without cirrhosis

Design:        randomised, global multicentre, open-label, regimen-controlled

Treatment:     dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir without ribavirin or with weight-based

ribavirin for 12 weeks

Treated subjects (N=179) had a median age of 57 years (range: 26 to 70); 35.2% were prior pegIFN/RBV null responders; 28.5% were prior pegIFN/RBV partial responders; and 36.3% were prior pegIFN/RBV relapsers; 54.2% were male; 3.9% were Black; ; 12.8% had a history of depression or bipolar disorder; 87.7% had baseline HCV RNA levels of at least 800,000 IU/mL; 17.9% had portal fibrosis (F2) and 14.0% had bridging fibrosis (F3).

Table 12. SVR12 for genotype 1b-infected peginterferon+ri­bavirin-experienced subjects in PEARL II

Treatment outcome	dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir for 12 weeks
	With RBV				Without RBV
	n/N	%	95% CI	n/N	%	95% CI
Overall SVR12	86/88	97.7	94.6, 100.0	91/91	100	95.9, 100.0
Prior pegIFN/RBV null responder	30/31	96.8	90.6, 100.0	32/32	100	89.3, 100.0
Prior pegIFN/RBV partial	24/25	96.0	88.3, 100.0	26/26	100	87.1, 100.0
responder
Prior pegIFN/RBV relapser	32/32	100	89.3, 100.0	33/33	100	89.6, 100.0
Outcome for subjects without SVR12
On-treatment VF	0/88	0		0/91	0
Relapse	0/88	0		0/91	0
Other	2/88	2.3		0/91	0

Clinical trial in subjects with compensated cirrhosis

TURQUOISE-II – treatment-naïve orpegIFN + RBV-experienced with compensated cirrhosis

Design:        randomised, global multicentre, open-label

Treatment:     dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir with weight-based ribavirin for 12 or

24 weeks

Treated subjects (N=380) had a median age of 58 years (range: 21 to 71); 42.1% were treatment-naive, 36.1% were prior pegIFN/RBV null responders; 8.2% were prior pegIFN/RBV partial responders, 13.7% were prior pegIFN/RBV relapsers; 70.3% were male; 3.2% were Black; 14.7% had platelet counts of less than 90 × 109/L; 49.7% had albumin less than 40 g/L; 86.1% had baseline HCV RNA levels of at least 800,000 IU/mL; 24.7% had a history of depression or bipolar disorder; 68.7% had HCV genotype 1a infection, 31.3% had HCV genotype 1b infection.

Table 13. SVR12 for genotype 1-infected subjects with compensated cirrhosis who were treatment-naive or previously treated with peglFN/RBV

Treatment outcome	dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir with RBV
	12 weeks			24 weeks
	n/N	%	CIa	n/N	%	CI a
Overall SVR12	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
Treatment naïve	59/64	92.2		53/56	94.6
Prior pegIFN/RBV null responders	40/50	80.0		39/42	92.9
Prior pegIFN/RBV partial responders	11/11	100		10/10	100
Prior pegIFN/RBV Prior relapsers	14/15	93.3		13/13	100
HCV genotype 1b	67/68	98.5	95.7, 100	51/51	100	93.0, 100
Treatment naïve	22/22	100		18/18	100
Prior pegIFN/RBV null responders	25/25	100		20/20	100
Prior pegIFN/RBV partial responders	6/7	85.7		3/3	100
Prior pegIFN/RBV Prior relapsers	14/14	100		10/10	100
Outcome for subjects without SVR12
On-treatment VF	1/208	0.5		3/172	1.7
Relapse	12/203	5.9		1/164	0.6
Other	4/208	1.9		2/172	1.21
a.  97.5% confidence intervals are used for the primary efficacy endpoints (overall SVR12 rate); 95%
confidence intervals are used for additional efficacy endpoints (SVR12 rates in HCV genotype 1a and
1b-infected subjects).

Relapse rates in GT1a cirrhotic subjects by baseline laboratory values are presented in Table 14.

Table 14. TURQUOISE-II: relapse rates by baseline laboratory values after 12 and 24 weeks of treatment in subjects with genotype 1a infection and compensated cirrhosis

	dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir with RBV 12-week arm	dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir with RBV 24-week arm
Number of Responders at the End of Treatment	135	113
AFP* < 20 ng/mL, platelets > 90 × 109/L, AND albumin > 35 g/L prior to treatment
Yes (for all three parameters listed above)	1/87 (1%)	0/68 (0%)
No (for any parameter listed above)	10/48 (21%)	1/45 (2%)
*AFP= serum alpha fetoprotein

In subjects with all three favourable baseline laboratory values (AFP < 20 ng/mL, platelets > 90 × 109/L, and albumin > 35 g/L), relapse rates were similar in subjects treated for 12 or 24 weeks.

TURQUOISE-III: treatment-naïve orpegIFN + RBV-experienced with compensated cirrhosis

Design:        global multicentre, open-label

Treatment:     dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir without ribavirin for 12 weeks

60 patients were randomized and treated, and 60/60 (100%) achieved SVR12. Main characteristics are shown below.

Table 15. Main demographics in TURQUOISE-III

Characteristics	N = 60
Age, median (range) years	60.5 (26–78)
Male gender, n (%)	37 (61)
Prior HCV Treatment:
naive, n (%)	27 (45)
Peg-IFN + RBV, n (%)	33 (55)
Baseline albumin, median g/L	40.0
< 35, n (%)	10 (17)
> 35, n (%)	50 (83)
Baseline platelet count, median (x 109/L)	132.0
< 90, n (%)	13 (22)
> 90, n (%)	47 (78)

Pooled analyses of clinical trials

Durability of response

Overall, 660 subjects in Phase 2 and 3 clinical trials had HCV RNA results for both the SVR12 and SVR24 time points. Among these subjects, the positive predictive value of SVR12 on SVR24 was 99.8%.

Pooled efficacy analysis

In Phase 3 clinical trials, 1075 subjects (including 181 with compensated cirrhosis) received the recommended regimen (see section 4.2). Table 16 shows SVR rates for these subjects.

In subjects who received the recommended regimen, 97% achieved SVR overall (among which 181 subjects with compensated cirrhosis achieved 97% SVR), while 0.5% experienced virologic breakthrough and 1.2% experienced post-treatment relapse.

Table 16. SVR12 rates for recommended treatment regimens by patient population

Treatment duration	HCV Genotype 1b dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir		HCV Genotype 1a dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir with RBV
	Without cirrhosis	With compensated cirrhosis	Without cirrhosis	With compensated cirrhosis
	12 weeks	12 weeks	12 weeks	24 weeks
Treatment-naive	100% (210/210)	100% (27/27)	96% (403/420)	95% (53/56)
peglFN + RBV-experienced	100% (91/91)	100% (33/33)	96% (166/173)	95% (62/65)
Prior relapse	100% (33/33)	100% (3/3)	94% (47/50)	100% (13/13)
Prior partial response	100% (26/26)	100% (5/5)	100% (36/36)	100% (10/10)
Prior null response	100% (32/32)	100% (7/7)	95% (83/87)	93% (39/42)
Other peglFN/RBV failures	0	100% (18/18)+	0	0
TOTAL	100% (301/301)	100% (60/60)	96% (569/593)	95% (115/121)

+Other types of pegIFN/RBV failure include less well documented non-response, relapse/break­through or other pegIFN failure.

Impact of ribavirin dose adjustment on probability of SVR

In Phase 3 clinical trials, 91.5% of subjects did not require ribavirin dose adjustments during therapy.

In the 8.5% of subjects who had ribavirin dose adjustments during therapy, the SVR rate (98.5%) was comparable to subjects who maintained their starting ribavirin dose throughout treatment.

TURQUOISE-I: treatment-naive orpegIFN + RBV-experienced with HCVGT1 or GT4/HIV-1 coinfection, without cirrhosis or with compensated cirrhosis

Design:        randomised, global multicentre, open-label

Treatment:     ombitasvir/pa­ritaprevir/ri­tonavir with or without dasabuvir coadminstered with or

without weight-based ribavirin for 12 or 24 weeks

See section 4.2 for dosing recommendations in HCV/HIV-1 co-infected patients. Subjects were on a stable HIV-1 antiretroviral therapy (ART) regimen that included ritonavir-boosted atazanavir or raltegravir, dolutegravir (Part 2 only), or darunavir (Part 1b and Part 2 GT4 only)-, co-administered with a backbone of tenofovir plus emtricitabine or lamivudine. Part 1 of the study was a Phase 2 pilot cohort consisting of 2 parts, Part 1a (63 subjects) and Part 1b (22 subjects). Part 2 was a Phase 3 cohort consisting of 233 subjects.

In Part 1a, all subjects received dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir with ribavirin for 12 or 24 weeks. Treated subjects (N = 63) had a median age of 51 years (range: 31 to 69); 24% were Black; 19% had compensated cirrhosis; 67% were treatment-naive; 33% had failed prior treatment with pegIFN/RBV; 89% had HCV genotype 1a infection.

In Part 1b, all subjects received dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir with ribavirin for 12 weeks. Treated subjects (N = 22) had a median age of 54 years (range: 34 to 68); 41% were Black; 14% had compensated cirrhosis; 86% were HCV treatment-naive; 14% had failed prior treatment with pegIFN/RBV; 68% had HCV genotype 1a infection.

In Part 2, subjects with HCV GT1 received dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir with or without ribavirin for 12 or 24 weeks. Subjects with HCV GT4 received ombitasvir/pa­ritaprevir/ri­tonavir with ribavirin for 12 or 24 Weeks. Treated subjects (N = 233) had a median age of 49 years (range: 26 to 69); 10% were Black; 12% had compensated cirrhosis; 66% were

treatment-naïve; 32% had failed prior treatment with pegIFN/RBV; 2% had failed prior treatment with sofosbuvir.

Table 17 shows the primary efficacy analysis of SVR12 performed on subjects with HCV GT1/HIV-1 co-infection that received recommended regimen in Part 2 of the TURQUOISE-I study.

Table 17. Primary SVR12 Assessment for Part 2, Subjects with HCV GT1/HIV-1 co-infection in TURQUOISE-I

Endpoint	dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir with or without ribavirin for 12 or 24 Weeks N = 200a
SVR12, n/N (%) [95% CI]	194/200 (97.0) [93.6, 98.6]
Outcome for subjects not achieving SVR12
On-treatment virologic failure	1
Post-treatment relapse	1
Other3	4

a. Includes all HCV GT1 subjects in Part 2 excluding Arm G subjects that did not receive recommended regimen.

b. Includes subjects who discontinued due to adverse event, lost to follow-up or subject withdrawal, and subjects with reinfection

Efficacy analyses performed on other parts of the study demonstrated similarly high SVR12 rates. In Part 1a, SVR12 was achieved by 29/31 (93.5%) subjects on the 12-week arm (95% CI: 79.3% –98.2%) and by 29/32 (90.6%) subjects on the 24-week arm (95% CI: 75.8% – 96.8%). There was 1 relapse in the 12-week arm and 1 on-treatment virologic failure in the 24-week arm. In Part 1b, SVR12 was achieved by 22/22 (100%) subjects (95% CI: 85.1%, 100%). In Part 2, SVR12 was achieved by 27/28 (96.4%) subjects with HCV GT4/HIV-1 coinfection (95% CI: 82.3%, 99.4%) with no virologic failures.

The SVR12 rates in HCV/HIV-1 co-infected subjects were thus consistent with SVR12 rates in the phase 3 trials of HCV mono-infected subjects.

CORAL-I: treatment-naïve or pegIFN + RBV-experienced, GT 1 or GT4 infected, at least 3 months post liver transplant or 12 months post renal transplant

Design:        randomised, global multicentre, open-label

Treatment:     dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir for 12 or 24 weeks with or without

ribavirin (investigator chosen dose) for GT1 and GT4 infection

In subjects with liver transplant, no cirrhosis and GT1 infection, patients were dosed with dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir for 12–24 weeks, with and without RBV. Liver transplant subjects with cirrhosis were dosed with dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir with RBV (GT1a for 24 weeks [n=4], GT1b for 12 weeks [n=2]). Subjects with renal transplant and no cirrhosis were dosed for 12 weeks (with RBV for GT1a [n=9], without RBV for GT1b [n=3]). Subjects with liver transplant and GT4 infection were dosed with ombitasvir/pa­ritaprevir/ri­tonavir with RBV (noncirrhotic for 12 weeks [n=2] and cirrhotic for 24 weeks [n=1]. The dose of ribavirin was individualized at the discretion of the investigator, with most subjects receiving 600 to 800 mg as a starting dose, and most subjects also receiving 600 to 800 mg per day at the end of treatment.

A total of 129 subjects were treated, 84 with GT1a, 41 with GT1b, 1 with GT1 other, 3 with GT4 infection. Overall, 61% had fibrosis stage F0-F1, 26% F2, 9% F3, and 4% F4. 61% had prior HCV treatment experience before transplant. For immunosuppressive medication, most subjects were taking tacrolimus (81%), with the remainder taking cyclosporine.

Among all GT1 subjects who were post liver transplant, 111/114 (97.4%) achieved SVR12; with 2 relapsing post treatment and 1 breakthrough on treatment. Among the GT1 subjects who were post renal transplant, 9/12 (75%) achieved SVR12; however, there were no virologic failures. All 3 (100%) subjects with GT 4 infection who were post liver transplant achieved SVR12

Clinical Trial in patients receiving chronic opioid substitution therapy

In a phase 2, multicentre, open-label, single arm study, 38 treatment-naïve or pegIFN/RBV treatment experienced, non-cirrhotic subjects with genotype 1 infection who were on stable doses of methadone (N=19) or buprenorphine with or without naloxone (N=19) received 12 weeks of dasabuvir in combination with ombitasvir/pa­ritaprevir/ri­tonavir and ribavirin. Treated subjects had a median age of 51 years (range: 26 to 64); 65.8% were male and 5.3% were Black. A majority (86.8%) had baseline HCV RNA levels of at least 800,000 IU/mL and a majority (84.2%) had genotype 1a infection; 15.8% had portal fibrosis (F2) and 5.3% had bridging fibrosis (F3); and 94.7% were naïve to prior HCV treatment.

Overall, 37 (97.4%) of 38 subjects achieved SVR12. No subjects experienced on-treatment virologic failure or relapse.

RUBY-I; treatment-naïve or pegIFN + RBVexperienced with or without cirrhosis who have severe renal impairment or end stage renal disease (ESRD)

Design:        multicentre, open-label

Treatment:     dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir with or without RBV for 12 or 24

weeks

Severe renal impairment or ESRD includes CKD Stage 4 defined as eGFR <30–15 mL/min/1.73 m2 or CKD Stage 5 defined as <15 mL/min/1.73 m2 or requiring haemodialysis. Treated subjects (N=68) had a median age of 58 years (range: 32–77 years); 83.8% were male; 58.8% were Black; 73.5% of subjects were infected with HCV GT1a; 75.0%% had Stage 5 CKD and 69.1% were on haemodialysis.

Sixty four of 68 (94.1%) subjects achieved SVR12. One subject experienced relapse at Post-Treatment Week 4, 2 subjects prematurely discontinued study drug and 1 subject had missing SVR12 data.

See also Section 4.8 for discussion of safety information for RUBY-I.

In another open-label phase 3b study evaluating 12 weeks of ombitasvir/pa­ritaprevir/ri­tonavir with or without dasabuvir and without RBV in non-cirrhotic, treatment-naive GT1a and GT4 patients with CKD stage 4 or 5 (Ruby II), the SVR12 rate was 94.4% (17/18), with no subjects experiencing on-treatment virologic failure or relapse.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with dasabuvir and ombitasvir/pa­ritaprevir/ri­tonavir in one or more subsets of the paediatric populations in the treatment of chronic hepatitis C (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

The pharmacokinetic properties of the combination of dasabuvir with ombitasvir/pa­ritaprevir/ri­tonavir have been evaluated in healthy adult subjects and in subjects with chronic hepatitis C. Table 18 shows mean Cmax and AUC of dasabuvir 250 mg twice daily with ombitasvir/pa­ritaprevir/ri­tonavir 25 mg/150 mg/100 mg once daily following multiple doses with food in healthy volunteers.

Table 18. Geometric mean C max , AUC of multiple doses of dasabuvir 250 mg twice daily and ombitasvir/pa­ritaprevir/ri­tonavir 25 mg/150 mg/100 mg once daily with food in healthy volunteers

	C max (ng/ml) (CV%)	AUC (ng*hr/ml) (CV%)
Dasabuvir	1030 (31)	6840 (32)

Absorption

Dasabuvir was absorbed after oral administration with mean Tmax of approximately 4 to 5 hours. Dasabuvir exposures increased in a dose proportional manner and accumulation is minimal. Pharmacokinetic steady state for dasabuvir when coadministered with ombitasvir/pa­ritaprevir/ri­tonavir is achieved after approximately 12 days of dosing.

Effects of food

Dasabuvir should be administered with food. All clinical trials with dasabuvir have been conducted following administration with food.

Food increased the exposure (AUC) of dasabuvir by up to 30% relative to the fasting state. The increase in exposure was similar regardless of meal type (e.g., high-fat versus moderate-fat) or calorie content (approximately 600 kcal versus approximately 1000 kcal). To maximise absorption, dasabuvir should be taken with food without regard to fat or calorie content.

Distribution

Dasabuvir is highly bound to plasma proteins. Plasma protein binding is not meaningfully altered in patients with renal or hepatic impairment. The blood to plasma concentration ratios in human ranged from 0.5 to 0.7 indicating that dasabuvir was preferentially distributed in the plasma compartment of whole blood. Dasabuvir was greater than 99.5%, and M1 major metabolite of dasabuvir was 94.5% bound to human plasma proteins over a concentration range of 0.05 to 5 p.g/mL. At steady-state the exposures ratio of M1 to dasabuvir is approximately 0.6. Taking into account the protein binding and in vitro activity of M1 against HCV genotype 1, its contribution to efficacy is expected to be similar to that of dasabuvir. In addition, M1 is a substrate of the hepatic uptake transporters OATP family and OCT1 and thus, the hepatocyte concentration and thereby contribution to efficacy, may be larger than dasabuvir.

Biotransformation

Dasabuvir is predominantly metabolised by CYP2C8 and to a lesser extent by CYP3A. Following a 400 mg 14C-dasabuvir dose in humans, unchanged dasabuvir was the major component (approximately 60%) of drug related radioactivity in plasma. Seven metabolites were identified in plasma. The most abundant plasma metabolite was M1, which represented 21% of drug-related radioactivity (AUC) in circulation following single dose; it’s formed via oxidative metabolism predominantly by CYP2C8.

Elimination

Following dosing of dasabuvir with ombitasvir/ paritaprevir /ritonavir, mean plasma half-life of dasabuvir was approximately 6 hours. Following a 400 mg 14C-dasabuvir dose, approximately 94% of the radioactivity was recovered in faeces with limited radioactivity (approximately 2%) in urine. Unchanged dasabuvir accounted for 26.2% and M1 for 31.5% of the total dose in faeces. M1 is mainly cleared through direct biliary excretion with the contribution of UGT-mediated glucuronidation and, to a small extent, oxidative metabolism.

Dasabuvir does not inhibit organic anion transporter (OAT1) in vivo and is not expected to inhibit organic cation transporters (OCT2), organic anion transporters (OAT3), or multidrug and toxin extrusion proteins (MATE1 and MATE2K) at clinically relevant concentrations; therefore, dasabuvir does not affect medicinal product transport by these proteins.

Special populations

Elderly

Based on population pharmacokinetic analysis of data from Phase 3 clinical studies, a 10 year increase or decrease in age from 54 years (median age in the Phase 3 studies) would results in <10% change in dasabuvir exposures. There is no pharmacokinetic information in patients >75 years.

Sex or body weight

Based on population pharmacokinetic analysis of data from Phase 3 clinical studies, female subjects would have approximately 14 to 30% higher dasabuvir exposures than male subjects. A 10 kg change in body weight from 76 kg (median weight in the Phase 3 studies) would result in <10% change in dasabuvir exposures.

Race or ethnicity

Based on population pharmacokinetic analysis of data from Phase 3 clinical studies, Asian subjects had 29% to 39% higher dasabuvir exposures than non-Asian subjects.

Renal impairment

Pharmacokinetics of the combination of ombitasvir 25 mg, paritaprevir 150 mg, and ritonavir 100 mg, with dasabuvir 400 mg were evaluated in subjects with mild (CrCl: 60to 89 ml/min), moderate (CrCl: 30 to 59 ml/min) and severe (CrCl: 15 to 29 ml/min) renal impairment, relative to subjects with normal renal function.

In subjects with mild, moderate and severe renal impairment, dasabuvir mean AUC values were 21% higher, 37% higher and 50% higher, respectively. Dasabuvir M1 AUC values were 6% lower, 10% lower, and 13% lower, respectively.

The changes in dasabuvir exposures in subjects with mild, moderate and severe renal impairment are not considered to be clinically significant. Limited data in patients with end-stage renal disease indicate no clinically significant changes in exposure also in this patient group. No dose adjustment of dasabuvir is required for patients with mild, moderate, or severe renal impairment, or end-stage-renal disease on dialysis (see section 4.2).

Hepatic impairment

Pharmacokinetics of the combination of dasabuvir 400 mg, with ombitasvir 25 mg, paritaprevir

200 mg, and ritonavir 100 mg were evaluated in subjects with mild (Child-Pugh A), moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment, relative to subjects with normal hepatic function.

In subjects with mild, moderate and severe hepatic impairment, dasabuvir AUC values were 17% higher, 16% lower and 325% higher, respectively. The AUC values of dasabuvir M1 metabolite were unchanged, 57% lower, and 77% higher, respectively. Plasma protein binding of dasabuvir and its M1 metabolite were not meaningfully different in subjects with hepatic impairment compared to normal control subjects (see sections 4.2, 4.4 and 4.8).

Paediatric population

The pharmacokinetics of dasabuvir with ombitasvir/pa­ritaprevir/ri­tonavir in paediatric patients has not been investigated (see section 4.2).

5.3 Preclinical safety data

Dasabuvir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo rat micronucleus assays.

Dasabuvir was not carcinogenic in a 6-month transgenic mouse study up to the highest dosage tested (2 g/kg/day), resulting in dasabuvir AUC exposures approximately 19-fold higher than those in humans at the recommended dose of 500 mg (250 mg twice daily).

Similarly, dasabuvir was not carcinogenic in a 2-year rat study up to the highest dose tested (800 mg/kg/day), resulting in dasabuvir exposures approximately 19-fold higher than those in humans at 500 mg.

Dasabuvir had no effects on embryo-foetal viability or on fertility in rodents and were not teratogenic in two species. No adverse effects on behaviour, reproduction or development of offspring were reported. The highest dasabuvir dose tested produced exposures equal to 16 to 24-fold (rat) or 6-fold (rabbit) the exposures in humans at the maximum recommended clinical dose.

Dasabuvir was the predominant component observed in the milk of lactating rats, without effect on nursing pups. Elimination half-life in rat milk was slightly shorter than in plasma, AUC was about 2 fold of that in plasma. Since dasabuvir is a BCRP substrate, distribution to the milk may change if this transporter is inhibited or induced by co-administration of other medicinal products. Dasabuvir-derived material was minimally transferred through the placenta in pregnant rats.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Tablet core

Microcrystalline cellulose (E 460(i))

Lactose monohydrate

Copovidone

Croscarmellose sodium

Colloidal anhydrous silica (E 551)

Magnesium stearate (E 470b)

Film-coating

Poly(vinyl alcohol) (E 1203)

Titanium dioxide (E 171)

Macrogol (3350)

Talc (E 553b)

Iron oxide yellow (E 172)

Iron oxide red (E 172)

Iron oxide black (E 172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

PVC/PE/PCTFE aluminium foil blister packs.

Pack-size of 56 tablets (multipack carton containing 4 inner cartons of 14 tablets each).

6.6 Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

AbbVie Deutschland GmbH & Co. KG

Knollstrasse

67061 Ludwigshafen

Germany

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/14/983/001

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 15 January 2015

Date of latest renewal: 26 September 2019