EXVIERA 250mg film-coated tablets medication leaflet

Exviera 250 mg film-coated tablets

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

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

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

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

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

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

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

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 withother 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 dasabuvircombination therapy are provided in Table 1.

Medici al product no longer authorised

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

Patient population Treatment* Duration12 weeks8 weeks may be considered in

Genotype 1b, without cirrhosis or dasabuvir +previously untreated genotype 1b-with compensated cirrhosis ombitasvir/paritaprevir/ritonavirinfected patients with minimal tomoderate fibrosis** (see section 5.1,

GARNET study)dasabuvir +

Genotype 1a,ombitasvir/paritaprevir/ritonavir + 12 weekswithout cirrhosisribavirin*dasabuvir +

Genotype 1a,ombitasvir/paritaprevir/ritonavir + 24 weeks (see section 5.1.)with compensated cirrhosisribavirin*

*Note: Follow the genotype 1a dosing recommendations in patients with an unknown genotype 1 subtype orwith mixed genotype 1 infection.

** When assessing severity of liver disease using non-invasive methods, a combination of blood biomarkers orthe combination of liver stiffness measurement and a blood test improves accuracy and should be undertakenprior to 8 week treatment in all patients with moderate fibrosis.

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

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

Dasabuvir and ombitasvir/paritaprevir/ritonavir in combination with ribavirin is recommended for24 weeks in liver transplant recipients. Lower ribavirin dose at initiation may be appropriate. In thepost-liver transplant study, ribavirin dosing was individualized and most subjects received 600 to800 mg per day (see section 5.1). For dosing recommendations with calcineurin inhibitors refer tosection 4.5.

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

No dose adjustment of dasabuvir is required for patients with mild, moderate, or severe renalimpairment 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 patientswith renal impairment.

Medicinal roduct no longer authorised

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 Bor C) (see section 5.2).

The safety and efficacy of dasabuvir in children less than 18 years of age have not been established.

No data are available.

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 tabletsshould be taken with food, without regard to fat and calorie content (see section 5.2).

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 oralcontraceptives or contraceptive vaginal rings (see sections 4.4 and 4.5).

Co-administration of dasabuvir with medicinal products that are strong or moderate enzyme inducersis expected to decrease dasabuvir plasma concentrations and reduce its therapeutic effect (see section4.5. 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 concentrationsand 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 withombitasvir/ paritaprevir /ritonavir refer to the Summary of Product Characteristics.

Medicinal product no longer authorise

Dasabuvir is not recommended for administration as monotherapy and must be used in combinationwith 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, havebeen reported post-marketing in patients treated with dasabuvir with ombitasvir/paritaprevir/ritonavirwith and without ribavirin. Most patients with these severe outcomes had evidence of advanced ordecompensated cirrhosis prior to initiating therapy. Although causality is difficult to establish due tobackground advanced liver disease, a potential risk cannot be excluded.

Dasabuvir should not be used in patients with moderate to severe hepatic impairment (Child-Pugh Bor C) (see sections 4.2, pct. 4.3, pct. 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 hepaticdecompensation.

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 inapproximately 1% of subjects (35 of 3,039). ALT elevations were asymptomatic and generallyoccurred during the first 4 weeks of treatment, without concomitant elevations of bilirubin, anddeclined within approximately two weeks of onset with continued dosing of dasabuvir andombitasvir/paritaprevir/ritonavir with or without ribavirin.

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

Patients who are taking ethinyloestradiol -containing medicinal products (i.e. most combined oralcontraceptives 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 withombitasvir/paritaprevir/ritonavir therapy (see sections 4.3 and 4.5).

Although ALT elevations associated with dasabuvir and ombitasvir/paritaprevir/ritonavir have beenasymptomatic, 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 asjaundice 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 (forcirrhotics, see above). Early discontinuation may result in drug resistance, but implications for futuretherapy are not known.

Med cinal product no longer authorised

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 malepatients 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 CYP3Ainhibition by ritonavir (see section 4.5). Serious and/or life threatening events have been observed withco-administration of dasabuvir and ombitasvir/paritaprevir/ritonavir with systemic tacrolimus, and asimilar risk can be expected with sirolimus and everolimus.

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

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

Depression or psychiatric illness

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

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

The efficacy of dasabuvir has not been established in patients with HCV genotypes other thangenotype 1; dasabuvir should not be used for the treatment of patients infected with other genotypesthan 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 beenstudied and, therefore, cannot be recommended.

Medicinal product no longer authorised

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

Use with statins

Dasabuvir with ombitasvir/paritaprevir/ritonavir is expected to increase the exposure to rosuvastatinmore than 3-fold. If rosuvastatin treatment is required during the treatment period, the maximum dailydose 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, dasabuvirwith ombitasvir/paritaprevir/ritonavir is expected to increase the exposure to pitavastatin andfluvastatin. A temporary suspension of pitavastatin/fluvastatin is recommended for the duration oftreatment with ombitasvir/paritaprevir/ritonavir. If statin treatment is required during the treatmentperiod, 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 mayselect for PI resistance in HIV co-infected patients without ongoing antiretroviral therapy. HIV co-infected 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 detailssee section 4.5, Table 2).

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

Darunavir, dosed 800 mg once daily, if administered at the same time asombitasvir/paritaprevir/ritonavir, can be used in the absence of extensive PI resistance (darunavirexposure lowered). To be noted, darunavir should be taken without ritonavir, since ritonavir 100 mgonce 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 anyparticular 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 withdasabuvir with ombitasvir/paritaprevir/ritonavir, with a consequent potential for QT-prolongation. Ifan HIV protease inhibitor is added (atazanavir, darunavir), rilpivirine exposure may increase evenfurther and is, therefore, not recommended. Rilpivirine should be used cautiously, in the setting ofrepeated ECG monitoring.

NNRTIs other than rilpivirine (efavirenz, etravirine, and nevirapine) are contraindicated (see section4.3).

Mdicinal product no longer authorised

Cases of hepatitis B virus (HBV) reactivation, some of them fatal, have been reported during or aftertreatment with direct-acting antiviral agents. HBV screening should be performed in all patients beforeinitiation 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.

Diabetics may experience improved glucose control, potentially resulting in symptomatichypoglycaemia, after initiating HCV direct acting antiviral treatment. Glucose levels of diabeticpatients initiating direct acting antiviral therapy should be closely monitored, particularly within thefirst 3 months, and their diabetic medicinal products modified when necessary. The physician incharge of the diabetic care of the patient should be informed when direct acting antiviral therapy isinitiated.

.

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

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

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

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

Potential for dasabuvir to affect the pharmacokinetics of other medicinal products

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

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 withombitasvir/paritaprevir/ritonavir together with medicinal products that are substrates of BCRP mayincrease plasma concentrations of these transporter substrates, potentially requiring dose

Medicinal product no longer authorisedadjustment/clinical monitoring. Such medicinal products include sulfasalazine, imatinib and some ofthe statins (see Table 2). See also Table 2 for specific advice on rosuvastatin which has been evaluatedin 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 ofthe 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 dueto 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 productsthat are primarily metabolized by UGT1A1 result in increased plasma concentrations of suchmedicinal products; routine clinical monitoring is recommended for narrow therapeutic indexmedicinal products (i.e. levothyroxine). See also Table 2 for specific advice on raltegravir andbuprenorphine which have been evaluated in drug interaction studies. Dasabuvir has also been foundto 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 ofmedicinal products that are metabolized by CYP2C19 (e.g. lansoprazole, esomeprazole,s- mephenytoin), which may require dose adjustment/clinical monitoring. CYP2C19 substratesevaluated in drug interaction studies include omeprazole and escitalopram (Table 2).

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, weredecreased. 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 ofinteraction with tenofovir (OAT1 substrate). In vitro studies show that dasabuvir is not an inhibitor oforganic cation transporters (OCT2), organic anion transporters (OAT3), or multidrug and toxinextrusion proteins (MATE1 and MATE2K) at clinically relevant concentrations.

Therefore, dasabuvir is not expected to affect medicinal products which are primarily excreted by therenal 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 arecontraindicated with dasabuvir (see section 4.3 and Table 2).

Enzyme inducers

Medicinal produc nlonger authorised

Co-administration of dasabuvir with medicinal products that are moderate or strong enzyme inducersis 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 invitro. Inhibition of P-gp and BCRP is not expected to show clinically relevant increases in exposuresof dasabuvir (Table 2).

Dasabuvir M1 metabolite was quantified in all the drug interaction studies. Changes in exposures ofthe 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 CYP3Ainducer, carbamazepine, where the metabolite exposures decreased by only up to 39%.

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

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

If a patient is already taking medicinal product(s) or initiating a medicinal product while receivingdasabuvir 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 beconsidered (Table 2).

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

Table 2 provides the Least Squares Means Ratio (90% Confidence Interval) effect on concentration ofdasabuvir 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 theparitaprevir, ombitasvir, dasabuvir and the co-administered medicinal product (↑= increase more than20%, ↓ = decrease more than 20%, ↔ = no change or change less than 20%).

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

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

Medicinal GIVE EFFECT Cmax AUC Ctrough Clinical Comments

Product/ N

Possible WITH

Mechanismof

Interaction

AMINOSALICYLATE

Medicina product no longer authorised

Medicinal GIVE EFFECT Cmax AUC Ctrough Clinical Comments

Product/ N

Possible WITH

Mechanismof

Interaction

Sulfasalazine dasabu Not Studied. Expected: Caution should be usedvir + when sulfasalazine is

Mechanism: ombitas ↑ sulfasalazine co-administered with

BCRP vir/parit dasabuvir +inhibition by aprevir/ ombitasvir/paritaprevir/paritaprevir, ritonavi ritonavir.

ritonavir and rdasabuvir.

ANTIARRYTHMICS

Digoxin dasabu ↔ digoxin 1.15 1.16 1.01 While no dose0.5 mg single vir + (1.04-1.27) (1.09-1.23) (0.97-1.05) adjustment is necessarydose ombitas ↔ 0.99 0.97 0.99 for digoxin, appropriatedasabuvir (0.92-1.07) (0.91-1.02) (0.92-1.07)vir/parit monitoring of serum↔ 1.03 1.00 0.99

Mechanism: aprevir/ digoxin levels isombitasvir (0.97-1.10) (0.98-1.03) (0.96-1.02)

P-gp ritonavi ↔ 0.92 0.94 0.92 recommended.

inhibition by r paritaprevir (0.80-1.06) (0.81-1.08) (0.82-1.02)dasabuvir,paritaprevir,and ritonavir.

ANTIBIOTICS (SYSTEMIC ADMINISTRATION)

Sulfameth- dasabu ↑ Sulfameth- 1.21 1.17 1.15 No dose adjustmentoxazole, vir + oxazole, (1.15-1.28) (1.14-1.20) (1.10-1.20) needed for dasabuvir +trimethoprim ombitas ↑ ombitasvir/paritaprevir/vir/parit trimethopri 1.17 1.22 1.25aprevir/r ritonavir.

m (1.12-1.22) (1.18-1.26) (1.19-1.31)800/160 mg itonavir↑ dasabuvir 1.15 1.33 NAtwice daily (1.02-1.31) (1.23-1.44)↔ 0.88 0.85

Mechanism: ombitasvir (0.83-0.94) (0.80-0.90) NAincrease in ↓ 0.78 0.87 NAdasabuvir paritaprevir (0.61-1.01) (0.72-1.06)possibly dueto CYP2C8inhibition bytrimethoprim

ANTICANCER AGENTS

Apalutamide dasabu Not studied. Expected: Concomitant use isvir + contraindicated (see

Enzalutamid ombitas ↓ dasabuvir section 4.3).evir/parit ↓ombitasvir↓ paritaprevir

Mitotane aprevir/ritonavi

Mechanism: r

CYP3A4induction byapalutamide,enzalutamideor mitotane.

Medicinal product no longer autho ised

Medicinal GIVE EFFECT Cmax AUC Ctrough Clinical Comments

Product/ N

Possible WITH

Mechanismof

Interaction

Imatinib dasabu Not Studied. Expected: Clinical monitoring andvir + lower doses of imatinib

Mechanism: ombitas ↑ imatinib are recommended.

BCRPvir/paritinhibition byparitaprevir, aprevir/ritonavir and ritonavidasabuvir. r

ANTICOAGULANTS

Warfarin dasabu ↔ 1.05 0.88 0.94 While no change in the5 mg single vir + R-warfarin (0.95-1.17) (0.81-0.95) (0.84-1.05) pharmacokinetics ofdose and ombitas ↔ 0.96 0.88 0.95 warfarin is expected,other vitamin vir/parit S-warfarin (0.85-1.08) (0.81-0.96) (0.88-1.02) close monitoring of INR

K aprevir/r ↔ 0.97 0.98 1.03 is recommended withantagonists itonavir dasabuvir (0.89-1.06) (0.91-1.06) (0.94-1.13) all vitamin K↔ 0.94 0.96 0.98 antagonists. This is dueombitasvir (0.89-1.00) (0.93-1.00) (0.95-1.02)to liver function↔ 0.98 1.07 0.96 changes duringparitaprevir (0.82-1.18) (0.89-1.27) (0.85-1.09)treatment withdasabuvir +ombitasvir/paritaprevir/ritonavir

Dabigatran dasabu Not Studied. Expected: dasabuvir +etexilate vir + ombitasvir/paritaprevir/

Mechanism: ombitas ↑ dabigatran etexilate ritonavir may increase

Intestinal P- vir/parit the plasmagp inhibition aprevir/r concentrations ofby itonavir dabigatran etexilate.

paritaprevir Use with caution.

and ritonavir.

ANTICONVULSANTScarbamaze- dasabu ↔ carba- 1.10 1.17 1.35 Concomitant use ispine vir + mazepine (1.07-1.14) (1.13-1.22) (1.27-1.45) contraindicated (see200 mg once ombitas ↓ 0.84 0.75 0.57 section 4.3).

daily vir/parit carbamaze (0.82-0.87) (0.73-0.77) (0.54-0.61)pine 10, 11-followed by aprevir/epoxide200 mg twice ritonavi ↓ 0.45 0.30 NAdaily r dasabuvir (0.41-0.50) (0.27-0.33)

Mechanism: ↓ 0.69 0.69 NA

CYP3A4 ombitasvir (0.61-0.78) (0.64-0.74)induction by ↓ 0.34 0.30 NAcarbamazepi paritaprevir (0.25-0.48) (0.23-0.38)ne.

Medicinal product no longer aut orised

Medicinal GIVE EFFECT Cmax AUC Ctrough Clinical Comments

Product/ N

Possible WITH

Mechanismof

Interaction

Phenobarbita dasabu Not studied. Expected: Concomitant use isl vir + contraindicated (seeombitas ↓ dasabuvir section 4.3).

Mechanism: vir/parit ↓ paritaprevir

CYP3A4 aprevir/ ↓ ombitasvirinduction by ritonaviphenobarbita rl.

Phenytoin dasabu Not studied. Expected: Concomitant use isvir + contraindicated (see

Mechanism: ombitas ↓ dasabuvir section 4.3).

CYP3A4 vir/parit ↓ paritaprevirinduction by aprevir/r ↓ ombitasvirphenytoin. itonavir

S- dasabu Not studied. Expected: Clinical monitoring andmephenytoin vir + dose adjustment maybe

Mechanism: ombitas ↓ S-mephenytoin needed for s-

CYP2C19 vir/parit mephenytoin.

induction by aprevir/rritonavir. itonavir

ANTIDEPRESSANTS

Escitalopram dasabu ↔ es- 1.00 0.87 NA No dose adjustment is10 mg single vir + citalopram (0.96-1.05) (0.80-0.95) necessary fordose ombitas ↑ S- 1.15 1.36 NA escitalopram.

vir/parit Desmethyl (1.10-1.21) (1.03-1.80)aprevir/r citalopramitonavir↔ 1.10 1.01 0.89dasabuvir (0.95-1.27) (0.93-1.10) (0.79-1.00)↔ 1.09 1.02 0.97ombitasvir (1.01-1.18) (1.00-1.05) (0.92-1.02)↔ 1.12 0.98 0.71paritaprevir (0.88-1.43) (0.85-1.14) (0.56-0.89)

Duloxetine dasabu ↓ 0.79 0.75 NA No dose adjustment is60 mg single vir + duloxetine (0.67-0.94) (0.67-0.83) necessary fordose ombitas ↔ 0.94 0.92 0.88 duloxetine.

vir/parit dasabuvir (0.81-1.09) (0.81-1.04) (0.76-1.01)aprevir/ ↔ 0.98 1.00 1.01 No dose adjustmentritonavi ombitasvir (0.88-1.08) (0.95-1.06) (0.96-1.06) needed for dasabuvir +r ↓ 0.79 0.83 0.77 ombitasvir/paritaprevirparitaprevir (0.53-1.16) (0.62-1.10) (0.65-0.91) /ritonavir.

ANTIFUNGALS

Ketoconazol dasabu ↑ keto- 1.15 2.17 NA Concomitant use ise vir + conazole (1.09-1.21) (2.05-2.29) contraindicated (see the400 mg once ombitas ↑ dasabuvir 1.16 1.42 NA Summary of Productdaily vir/parit (1.03-1.32) (1.26-1.59) Characteristics foraprevir/ ↔ 0.98 1.17 NA ombitasvir/paritaprevir/ritonavi ombitasvir (0.90-1.06) (1.11-1.24) ritonavir).

Mechanism:r

CYP3A4/P- ↑ 1.37 1.98 NAgp inhibition paritaprevir (1.11-1.69) (1.63-2.42)byketoconazole

Medicinal product no longer authorised

Medicinal GIVE EFFECT Cmax AUC Ctrough Clinical Comments

Product/ N

Possible WITH

Mechanismof

Interactionandparitaprevir/ritonavir/ombitasvir

ANTIHYPERLIPIDAEMICS

Gemfibrozil dasabu ↑ dasabuvir 2.01 11.25 NA Concomitant use is600 mg twice vir + (1.71-2.38) (9.05- contraindicated (seedaily paritapr 13.99) section 4.3).evir/ ↑ 1.21 1.38 NA

Mechanism: ritonavi paritaprevir (0.94-1.57) (1.18-1.61)

Increase in rdasabuvirexposure isdue to

CYP2C8inhibitionand increaseinparitapreviris possiblydue to

OATP1B1inhibition bygemfibrozil.

ANTIMYCOBACTERIALS

Rifampicin dasabu Not Studied. Expected: Concomitant use isvir + contra-indicated (see

Mechanism: Ombita ↓ dasabuvir section 4.3).

CYP3A4/CY svir/par ↓ ombitasvir

P2C8 itaprevi ↓ paritaprevirinduction by rrifampicin. /ritonavir

BIGUANIDE ORAL ANTIHYPERGLYCEMICS

Metformin dasabu ↓ 0.77 0.90 NA No dose adjustmentvir + metformin (0.71-0.83) (0.84-0.97) needed for metformin500 mg ombitas ↔ 0.83 0.86 0.95 when co-administeredvir/paritsingle dose dasabuvir (0.74-0.93) (0.78-0.94) (0.84-1.07)aprevir/r with dasabuvir +↔ 0.92 1.01 1.01itonavir ombitasvir/paritaprevir/ombitasvir (0.87-0.98) (0.97-1.05) (0.98-1.04)↓ 0.63 0.80 1.22 ritonavir.

paritaprevir (0.44-0.91) (0.61-1.03) (1.13-1.31)

CALCIUM CHANNEL BLOCKERS

Amlodipine dasabu ↑ 1.26 2.57 NA Decrease in amlodipine5 mg single vir + amlodipine (1.11-1.44) (2.31-2.86) dose by 50% anddose ombitas ↔ 1.05 1.01 0.95 monitor patients forvir/parit dasabuvir (0.97-1.14) (0.96-1.06) (0.89-1.01) clinical effects.aprevir/ ↔ 1.00 1.00 1.00ombitasvir (0.95-1.06) (0.97-1.04) (0.97-1.04)

Medicinal produt no longer authorised

Medicinal GIVE EFFECT Cmax AUC Ctrough Clinical Comments

Product/ N

Possible WITH

Mechanismof

Interaction

Mechanism: ritonavi ↓ 0.77 0.78 0.88

CYP3A4 r paritaprevir (0.64-0.94) (0.68-0.88) (0.80-0.95)inhibition byritonavir.

CONTRACEPTIVESethinyloestra dasabu ↔ ethinyl 1.16 1.06 1.12 Ethinyloestradioldiol/ vir + oestradiol (0.90-1.50) (0.96-1.17) (0.94-1.33) containing oralnorgestimate ombitas Norgestimate metabolites: contraceptives are0.035/0.25 m vir/parit ↑ norgestrel 2.26 2.54 2.93 contraindicatedg once daily aprevir/ (1.91-2.67) (2.09-3.09) (2.39-3.57)ritonavi (see section 4.3).↑ nor- 2.01 2.60 3.11

Mechanism: r elgestromin (1.77-2.29) (2.30-2.95) (2.51-3.85)possibly due eto UGT ↓ dasabuvir 0.51 0.48 0.53inhibition by (0.22-1.18) (0.23-1.02) (0.30- 0.95)paritaprevir, ↔ 1.05 0.97 1.00ombitasvir ombitasvir (0.81-1.35) (0.81-1.15) (0.88- 1.12)and ↓ 0.70 0.66 0.87dasabuvir. paritaprevir (0.40-1.21) (0.42-1.04) (0.67-1.14)nor- dasabu ↔ nor- 0.83 0.91 0.85 No dose adjustment isethindrone vir + ethindrone (0.69-1.01) (0.76-1.09) (0.64-1.13) necessary for(progestin ombitas ↔ 1.01 0.96 0.95 norethindrone oronly pill) vir/parit dasabuvir (0.90-1.14) (0.85-1.09) (0.80-1.13) dasabuvir +0.35 mg once aprevir/ ↔ 1.00 0.99 0.97 ombitasvir/paritaprevir/daily ritonavi ombitasvir (0.93-1.08) (0.94-1.04) (0.90-1.03) ritonavir.

r ↑ 1.24 1.23 1.43paritaprevir (0.95-1.62) (0.96-1.57) (1.13-1.80)

DIURETICS

Furosemide dasabu ↑ 1.42 1.08 NA Monitor patients for20 mg single vir + furosemide (1.17-1.72) (1.00-1.17) clinical effects; adose ombitas ↔ 1.12 1.09 1.06 decrease in furosemidevir/parit dasabuvir (0.96-1.31) (0.96-1.23) (0.98-1.14) dose of up to 50% may↔ 1.14 1.07 1.12 be required.

Mechanism: aprevir/ombitasvir (1.03-1.26) (1.01-1.12) (1.08-1.16)possibly due ritonavi ↔ 0.93 0.92 1.26 No dose adjustmentto UGT1A1 r paritaprevir (0.63-1.36) (0.70-1.21) (1.16-1.38) needed for dasabuvir +inhibition by ombitasvir/paritaprevir/paritaprevir, ritonavir.

ombitasviranddasabuvir.

Medicinal product no longer authorised

Medicinal GIVE EFFECT Cmax AUC Ctrough Clinical Comments

Product/ N

Possible WITH

Mechanismof

Interaction

HCV ANTIVIRAL

Sofosbuvir dasabu ↑ sofosbuvir 1.61 2.12 NA No dose adjustmentvir + (1.38-1.88) (1.91-2.37) needed for sofosbuvir400 mg once ombitas ↑ GS- 1.02 1.27 NA when administered331007 (0.90-1.16) (1.14-1.42)daily vir/parit with dasabuvir +↔ dasabuvir 1.09 1.02 0.85aprevir/r ombitasvir/paritaprevir(0.98-1.22) (0.95-1.10) (0.76-0.95)

Mechanism: itonavir ↔ 0.93 0.93 0.92 /ritonavir.

BCRP and P- ombitasvir (0.84-1.03) (0.87-0.99) (0.88-0.96)gp inhibition ↔ 0.81 0.85 0.82by paritaprevir (0.65-1.01) (0.71-1.01) (0.67-1.01)paritaprevir,ritonavir anddasabuvir

HERBAL PRODUCTS

St. John's dasabu Not Studied. Expected: Concomitant use is

Wort vir + contraindicated (see(hypericum ombitas ↓ dasabuvir section 4.3).

perforatum) vir/parit ↓ ombitasvir

Mechanism: aprevir/ ↓ paritaprevir

CYP3A4 ritonaviinduction by r

St. John's

Wort.

HIV ANTIVIRALS: PROTEASE INHIBITORS

For a general comment on treatment of HIV co-infected patients, including a discussion on differentantiretroviral 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 dasabu ↔ 0.91 1.01 0.90 The recommended dosevir + atazanavir (0.84-0.99) (0.93-1.10) (0.81-1.01) of atazanavir is 300 mg,300 mg once ombitas ↔ 0.83 0.82 0.79 without ritonavir, indasabuvirdaily (given vir/parit (0.71-0.96) (0.71-0.94) (0.66-0.94) combination withat the same aprevir/ dasabuvir +↓ 0.77 0.83 0.89time) ritonavi ombitasvir ombitasvir/paritaprevir/(0.70-0.85) (0.74- (0.78-1.02)r 0.94) ritonavir. Atazanavir

Medicinal product no longer authorised

Medicinal GIVE EFFECT Cmax AUC Ctrough Clinical Comments

Product/ N

Possible WITH

Mechanismof

Interaction

Mechanism: ↑ 1.46 1.94 3.26 must be administered at

Increase in paritaprevir (1.06-1.99) (1.34-2.81) (2.06-5.16) the same time asparitaprevir dasabuvirexposures +ombitasvir/paritaprevimay be due r/ritonavir. Ritonavirto inhibition dose inof OATPs by ombitasvir/paritaprevir/atazanavir. ritonavir will provideatazanavirpharmacokineticenhancement.

No dose adjustmentneeded for dasabuvir +ombitasvir/paritaprevir/ritonavir.

The combination ofatazanavir andombitasvir/paritaprevir/ritonavir + dasabuvirincrease bilirubinlevels, in particularwhen ribavirin is partof the hepatitis Cregimen, see sections4.4 and 4.8.

Atazanavir/ dasabu ↔ 1.02 1.19 1.68ritonavir vir + atazanavir (0.92-1.13) (1.11-1.28) (1.44-1.95)300/100 mg ombitas ↔ 0.81 0.81 0.80dasabuvir (0.73-0.91) (0.71-0.92) (0.65-0.98)once daily vir/parit↔ 0.83 0.90 1.00ombitasvir (0.72-0.96) (0.78-1.02) (0.89-1.13)

Medicinal product no longer authorised

Medicinal GIVE EFFECT Cmax AUC Ctrough Clinical Comments

Product/ N

Possible WITH

Mechanismof

Interaction(administere aprevir/r ↑ 2.19 3.16 11.95d in the itonavir paritaprevir (1.61-2.98) (2.40-4.17) (8.94-15.98)evening)

Mechanism:

Increase inparitaprevirexposuresmay be dueto inhibitionof

OATP1B1/B3 and

CYP3A byatazanavirand CYP3Ainhibition bytheadditionaldose ofritonavir.

Darunavir dasabu ↓ darunavir 0.92 0.76 0.52 The recommended dosevir + (0.87-0.98) (0.71-0.82) (0.47-0.58) of darunavir is 800 mg800 mg once ombitas ↔ 1.10 0.94 0.90 once daily, withoutvir/parit dasabuvir (0.88-1.37 (0.78-1.14) (0.76-1.06)daily (given ritonavir, whenaprevir/ ↔ 0.86 0.86 0.87 administered at theombitasvir (0.77-0.95) (0.79-0.94) (0.82-0.92)

Medicinal product no longer authorised

Medicinal GIVE EFFECT Cmax AUC Ctrough Clinical Comments

Product/ N

Possible WITH

Mechanismof

Interactionat the same ritonavi ↑ 1.54 1.29 1.30 same time astime) r paritaprevir (1.14-2.09) (1.04-1.61) (1.09-1.54) ombitasvir/paritaprevir/ritonavir + dasabuvir

Mechanism: (ritonavir dose in

Unknown ombitasvir/paritaprevir/ritonavir will providedarunavirpharmacokineticenhancement). Thisregimen can be used inthe absence ofextensive PI resistance(i.e. lack of darunavirassociated RAMs), seealso section 4.4.

Darunavir combinedwithombitasvir/paritaprevir/ritonavir + dasabuvir isnot recommended inpatients with extensive

PI resistance.

No dose adjustmentneeded for dasabuvir +ombitasvir/paritaprevir/ritonavir.

Darunavir/ dasabu ↔ 0.87 0.80 0.57ritonavir vir + darunavir (0.79-0.96) (0.74-0.86) (0.48-0.67)600/100 mg ombitas ↓ dasabuvir 0.84 0.73 0.54(0.67-1.05) (0.62-0.86) (0.49-0.61)twice daily vir/parit↓aprevir/ 0.76 0.73 0.73ombitasvir (0.65-0.88) (0.66-0.80) (0.64-0.83)

Mechanism: ritonavi↓ 0.70 0.59 0.83

Unknown r paritaprevir (0.43-1.12) (0.44-0.79) (0.69-1.01)

Darunavir/ dasabu ↑ darunavir 0.79 1.34 0.54ritonavir vir + (0.70-0.90) (1.25-1.43) (0.48-0.62)800/100 mg ombitas ↓ dasabuvir 0.75 0.72 0.65once daily vir/parit (0.64-0.88) (0.64-0.82) (0.58-0.72)(administere aprevir/ ↔ 0.87 0.87 0.87ombitasvir (0.82-0.93) (0.81-0.93) (0.80-0.95)d in the ritonavi↓ 0.70 0.81 1.59evening) r paritaprevir (0.50-0.99) (0.60-1.09) (1.23-2.05)

Mechanism:

Unknownlopinavir/dasabu ↔ 0.87 0.94 1.15 Lopinavir/ritonavirritonavir vir + lopinavir (0.76-0.99) (0.81-1.10) (0.93-1.42) 400/100 mg twice daily

Mdicinal product no longer aut o ised

Medicinal GIVE EFFECT Cmax AUC Ctrough Clinical Comments

Product/ N

Possible WITH

Mechanismof

Interaction400/100 mg ombitas ↔ 0.99 0.93 0.68 or 800/200 mg oncetwice daily1 vir/parit dasabuvir (0.75-1.31) (0.75-1.15) (0.57-0.80) daily is contraindicatedaprevir/ ↔ 1.14 1.17 1.24 with dasabuvir and

Mechanism: ritonavi ombitasvir (1.01-1.28) (1.07-1.28) (1.14-1.34) ombitasvir/paritaprevir/r

Increase in r ↑ 2.04 2.17 2.36 itonavir due to increaseparitaprevir paritaprevir (1.30-3.20) (1.63-2.89) (1.00-5.55) in paritaprevir exposuresexposures (see Summary ofmay be due Product Characteristicsto inhibition ofof ombitasvir/paritaprevir/r

CYP3A/efflu itonavir).

xtransportersby lopinavirand higherdose ofritonavir.

HIV ANTIVIRALS: NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS

Rilpivirine2 dasabu ↑ rilpivirine 2.55 3.25 3.62 Co-administration of25 mg once vir + (2.08-3.12) (2.80-3.77) (3.12-4.21) dasabuvir anddaily ombitas ↔ 1.18 1.17 1.10 ombitasvir/paritaprevir/administered vir/parit dasabuvir (1.02-1.37) (0.99-1.38) (0.89-1.37) ritonavir with↔ 1.11 1.09 1.05in the aprevir/ rilpivirine once dailyombitasvir (1.02-1.20) (1.04-1.14) (1.01-1.08)morning, ritonavi ↑ 1.30 1.23 0.95 should only bewith food r paritaprevir (0.94-1.81) (0.93-1.64) (0.84-1.07) considered in patientswithout known QT-

Mechanism: prolongation, and

CYP3A without other QT-inhibition by prolongation co-ritonavir. administered medicinalproducts. If thecombination is used,repeated ECG-monitoring should bedone, see section 4.4.

No dose adjustmentneeded for dasabuvir +ombitasvir/paritaprevir/ritonavir.

Efavirenz/ dasabu Co-administration of efavirenz (enzyme inducer) based Concomitant use withemtricitabine vir + regimens with paritaprevir /ritonavir + dasabuvir resulted efavirenz containing/ tenofovir ombitas in ALT elevations and therefore, early discontinuation of regimens isthe study.

disoproxil vir/parit contraindicated (seefumarate aprevir/ section 4.3).

600/300/200 ritonavimg once rdaily

Medicinal product no longer autho ised

Medicinal GIVE EFFECT Cmax AUC Ctrough Clinical Comments

Product/ N

Possible WITH

Mechanismof

Interaction

Mechanism:

possibleenzymeinduction byefavirenz.

Nevirapine dasabu Not Studied. Expected: Concomitant use isetravirine vir + contraindicated (seeombitas ↓ dasabuvir section 4.3).

vir/parit ↓ ombitasviraprevir/ ↓ paritaprevirritonavir

HIV ANTIVIRALS: INTEGRASE STRAND TRANSFER INHIBITOR

Dolutegravir dasabuvi ↑ 1.22 1.38 1.36 No dose adjustmentr + dolutegravir (1.15-1.29) (1.30-1.47) (1.19-1.55) needed for dolutegravir50 mg once ombitas ↔ 1.01 0.98 0.92 when administereddaily vir/parit dasabuvir (0.92-1.11) (0.92-1.05) (0.85-0.99) with dasabuvir +aprevir/r ombitasvir/paritaprevir/

Mechanism: itonavir ↔ 0.96 0.95 0.92 ritonavir.

possibly due ombitasvir (0.89-1.03) (0.90-1.00) (0.87-0.98)to UGT1A1inhibition by ↔ 0.89 0.84 0.66paritaprevir, paritaprevir (0.69-1.14) (0.67-1.04) (0.59-0.75)dasabuvirandombitasvirand CYP3A4inhibition byritonavir

Raltegravir dasabu ↑ 2.33 2.34 2.00 No dose adjustment isvir + raltegravir (1.66-3.27) (1.70-3.24) (1.17-3.42) necessary for400 mg twice ombitas raltegravir or dasabuvirvir/parit No clinically relevant changes in dasabuvir, paritaprevir,daily +and ombitasvir exposures (based on comparison withaprevir/ historical data) were observed during the co- ombitasvir/paritaprevir/

Mechanism: ritonavi administration. ritonavir.

UGT1A1 rinhibition byparitaprevir,ombitasviranddasabuvir.

HIV ANTIVIRALS: NUCLEOSIDE INHIBITORS

Abacavir/ dasabu ↔ abacavir 0.87 0.94 NA No dose adjustmentlamivudine vir + (0.78-0.98) (0.90-0.99) needed for abacavir orombitas ↓ 0.78 0.88 1.29 lamivudine whenvir/parit lamivudine (0.72-0.84) (0.82-0.93) (1.05-1.58) administered withaprevir/r ↔ 0.94 0.91 0.95 dasabuvir +itonavir dasabuvir (0.86-1.03) (0.86-0.96) (0.88-1.02)

Medicinl product no longer authorised

Medicinal GIVE EFFECT Cmax AUC Ctrough Clinical Comments

Product/ N

Possible WITH

Mechanismof

Interaction600/300 mg ↔ 0.82 0.91 0.92 ombitasvir/paritaprevir/once daily ombitasvir (0.76-0.89) (0.87-0.95) (0.88-0.96) ritonavir.

↔ 0.84 0.82 0.73paritaprevir (0.69-1.02) (0.70-0.97) (0.63-0.85)

Em- dasabu ↔ em- 1.05 1.07 1.09 No dose adjustment istricitabine/ vir + tricitabine (1.00-1.12) (1.00-1.14) (1.01-1.17) necessary fortenofovir ombitas ↔ 1.07 1.13 1.24 emtricitabine/tenofovir200 mg once vir/parit tenofovir (0.93-1.24) (1.07-1.20) (1.13-1.36) and dasabuvir +↔ 0.85 0.85 0.85daily/300 mg aprevir/ ombitasvir/paritaprevir/dasabuvir (0.74-0.98) (0.75-0.96) (0.73-0.98)once daily ritonavi ↔ 0.89 0.99 0.97 ritonavir.

r ombitasvir (0.81-0.97) (0.93-1.05) (0.90-1.04)↓ 0.68 0.84 1.06paritaprevir (0.42-1.11) (0.59-1.17) (0.83-1.35)

HMG CoA REDUCTASE INHIBITOR

Rosuvastatin dasabu ↑ 7.13 2.59 0.59 The maximum daily5 mg once vir + rosuvastatin (5.11-9.96) (2.09-3.21) (0.51-0.69) dose of rosuvastatindaily ombitas ↔ 1.07 1.08 1.15 should be 5 mg (seedasabuvir (0.92-1.24) (0.92-1.26) (1.05-1.25)vir/parit section 4.4).

Mechanism: aprevir/r↔ 0.92 0.89 0.88

OATP1B itonavir ombitasvir (0.82-1.04) (0.83-0.95) (0.83-0.94) No dose adjustmentinhibition by ↑ 1.59 1.52 1.43 needed for dasabuvir +paritaprevir paritaprevir (1.13-2.23) (1.23-1.90) (1.22-1.68) ombitasvir/paritaprevir/and BCRP ritonavir.

inhibition bydasabuvirparitaprevir,and ritonavir.

Pravastatin dasabu ↑ 1.37 1.82 Reduce pravastatin10 mg once vir + pravastatin (1.11-1.69) (1.60-2.08) dose by 50%.

daily ombitas ↔ 1.00 0.96 1.03vir/parit dasabuvir (0.87-1.14) (0.85-1.09) (0.91-1.15) No dose adjustment

Mechanism: aprevir/r needed for dasabuvir +

OATP1B1 itonavir ↔ 0.95 0.94 0.94 ombitasvir/paritaprevirinhibition by ombitasvir (0.89-1.02) (0.89-0.99) (0.89-0.99) /ritonavir.

paritaprevir. ↔ 0.96 1.13 1.39paritaprevi (0.69-1.32) (0.92-1.38) (1.21-1.59)r

Fluvastatin dasabu Not studied. Expected: Concomitant use withvir + fluvastatin and

Mechanism: ombitas ↑ fluvastatin pitavastatin is not

OATP1B/BC vir/parit ↑ pitavastatin recommended (see

RP inhibition aprevir/r ↔ dasabuvir section 4.4).

by itonavir ↔ ombitasvir A temporaryparitaprevir. ↔ paritaprevir suspension offluvastatin and

Pitavastatin pitavastatin isrecommended for the

Mechanism: duration of treatment. Ifstatin treatment is

Medicinal product no longer autho ised

Medicinal GIVE EFFECT Cmax AUC Ctrough Clinical Comments

Product/ N

Possible WITH

Mechanismof

Interaction

OATP1B required during theinhibition by treatment period, aparitaprevir. switch to dose reducedpravastatin orrosuvastatin is possible.

No dose adjustmentneeded for dasabuvir +ombitasvir/paritaprevir/ritonavir.

IMMUNOSUPPRESSANTS

Ciclosporin dasabu ↑ 1.01 5.82 15.8 When starting co-30 mg once vir + ciclosporin (0.85-1.20) (4.73-7.14) (13.8-18.09) administration withdaily single ombitas ↓ dasabuvir 0.66 0.70 0.76 dasabuvir and3 (0.58-0.75) (0.65-0.76) (0.71-0.82) ombitasvir/paritaprevir/dose vir/parit↔ 0.99 1.08 1.15 ritonavir, give one fifthaprevir/ombitasvir (0.92-1.07) (1.05-1.11) (1.08-1.23) of the total daily dose

Mechanism: ritonavi ↑ 1.44 1.72 1.85 of ciclosporin once

Effect on r paritaprevir (1.16-1.78) (1.49-1.99) (1.58-2.18) daily with ombitasvir/ciclosporin is paritaprevir /ritonavir.

due to Monitor ciclosporin

CYP3A4 levels and adjust doseand/or dosinginhibition byfrequency as needed.

ritonavir andincrease in No dose adjustmentparitaprevir needed for dasabuvir +exposures ombitasvir/paritaprevir/may be due ritonavir.

to

OATP/BCRP/P-gpinhibition byciclosporin.

Everolimus dasabu ↑ 4.74 27.1 16.1 Co-administration ofvir + everolimus (4.29-5.25) (24.5-30.1) (14.5-17.9)4dasabuvir +0.75 mg ombitas ombitasvir/paritaprevir/↔ 1.03 1.08 1.14single dose vir/parit dasabuvir (0.90-1.18) (0.98-1.20) (1.05-1.23) ritonavir withaprevir/ ↔ 0.99 1.02 1.02 everolimus is not

Mechanism: ritonavi ombitasvir (0.95-1.03) (0.99-1.05) (0.99-1.06) recommended because

Effect on r ↔ 1.22 1.26 1.06 of a significant increaseeverolimus is paritaprevir (1.03-1.43) (1.07-1.49) (0.97-1.16) in everolimusdue to exposures which cannot

CYP3A4 be properly doseinhibition by adjusted with availableritonavir. dose strengths.

Sirolimus dasabu ↑ Sirolimus 6.40 38.0 19.6 Concomitant use ofvir + (5.34-7.68) (31.5-45.8) (16.7-22.9) sirolimus withombitas dasabuvir +

Medicinl product no longer authr sed

Medicinal GIVE EFFECT Cmax AUC Ctrough Clinical Comments

Product/ N

Possible WITH

Mechanismof

Interaction0.5 mg single vir/parit ↔ 1.04 1.07 1.13 ombitasvir/paritaprevir/dose5 aprevir/ dasabuvir (0.89-1.22) (0.95-1.22) (1.01-1.25) ritonavir is notritonavi ↔ 1.03 1.02 1.05 recommended unless

Mechanism: r ombitasvir (0.93-1.15) (0.96-1.09) (0.98-1.12) the benefits outweigh

Effect on the risks (see sectionsirolimus is ↔ 1.18 1.19 1.16 4.4). If sirolimus isdue to paritaprevir (0.91-1.54) (0.97-1.46) (1.00-1.34) used together with

CYP3A4 dasabuvir +inhibition by ombitasvir/paritaprevir/ritonavir. ritonavir, administersirolimus 0.2 mg twicea week (every 3 or 4days on the same twodays each week).

Sirolimus bloodconcentrations shouldbe monitored every 4 to7 days until 3consecutive troughlevels have shownstable concentrations ofsirolimus. Sirolimusdose and/or dosingfrequency should beadjusted as needed.

5 days after completionof dasabuvir +ombitasvir/paritaprevir/ritonavir treatment, thesirolimus dose anddosing frequency priorto receiving dasabuvir+ombitasvir/paritaprevir/ritonavir should beresumed, along withroutine monitoring ofsirolimus bloodconcentrations.

Tacrolimus dasabu ↑ 3.99 57.1 16.6 Concomitant use of2 mg single vir + tacrolimus (3.21-4.97) (45.5- (13.0-21.2) tacrolimus withdose7 ombitas 71.7) dasabuvir and↔ 0.85 0.90 1.01 ombitasvir/paritaprevir/vir/paritdasabuvir (0.73-0.98) (0.80-1.02) (0.91-1.11) ritonavir is not

Mechanism: aprevir/↔ 0.93 0.94 0.94 recommended unless

Effect on ombitasvir (0.88-0.99) (0.89-0.98) (0.91-0.96) the benefits outweigh

Medicinal product no longer authorised

Medicinal GIVE EFFECT Cmax AUC Ctrough Clinical Comments

Product/ N

Possible WITH

Mechanismof

Interactiontacrolimus is ritonavi ↓ 0.57 0.66 0.73 the risks (see sectiondue to r paritaprevir (0.42-0.78) (0.54-0.81) (0.66-0.80) 4.4).

CYP3A4 If tacrolimus withdasabuvir andinhibition byombitasvir/paritaprevir/ritonavir. ritonavir are usedconcomitantly,tacrolimus should notbe administered on theday dasabuvir andombitasvir/paritaprevir/ritonavir are initiated.

Beginning the day afterdasabuvir andombitasvir/paritaprevir/ritonavir are initiated;reinitiate tacrolimus ata reduced dose basedon tacrolimus bloodconcentrations. Therecommendedtacrolimus dosing is0.5 mg every 7 days.

Tacrolimus wholeblood concentrationsshould be monitoredupon initiation andthroughout co-administration withdasabuvir andombitasvir/paritaprevir/ritonavir and the doseand/or dosingfrequency should beadjusted asneeded. Uponcompletion ofdasabuvir andombitasvir/paritaprevir/ritonavir treatment, theappropriate dose anddosing frequency oftacrolimus should beguided by assessmentof tacrolimus bloodconcentrations.

IRON CHELATORS

Medicinal product no longer authrised

Medicinal GIVE EFFECT Cmax AUC Ctrough Clinical Comments

Product/ N

Possible WITH

Mechanismof

Interaction

Deferasirox dasabu Not studied. Expected: Deferasirox mayvir + increase dasabuvirombitas exposures and should bevir/parit ↑ dasabuvir used with caution.

aprevir/ritonavir

MEDICINAL PRODUCTS USED IN MULTIPLE SCLEROSIS

Teriflunomid dasabu Not studied. Expected: Teriflunomide maye vir + increase dasabuvirombitas ↑ dasabuvir exposures and should bevir/parit used with caution.

aprevir/ritonavir

OPIOIDS

Methadone dasabu ↔ R- 1.04 1.05 0.94 No dose adjustment isvir + Methadone (0.98-1.11) (0.98-1.11) (0.87-1.01) necessary for20-120 mg ombitas ↔ S- 0.99 0.99 0.86 methadone and8 Methadone (0.91-1.08) (0.89-1.09) (0.76-0.96)once daily vir/parit dasabuvir +↔ ombitasvir/paritaprevir and dasabuvir (based on theaprevir/r ombitasvir/paritaprevir/cross-study comparison)itonavir ritonavir.

buprenorphin dasabu ↑ bu- 2.18 2.07 3.12 No dose adjustment ise/ naloxone vir + prenorphine (1.78-2.68) (1.78-2.40) (2.29-4.27) necessary for4-24 mg/1- ombitas ↑ norbu- 2.07 1.84 2.10 buprenorphine/naloxon6 mg once prenorphine (1.42-3.01) (1.30-2.60) (1.49- 2.97)vir/parit e and dasabuvir +8 ↑ naloxone 1.18 1.28 NAdaily aprevir/r ombitasvir/paritaprevir/(0.81-1.73) (0.92-1.79)itonavir ↔ ombitasvir /paritaprevir and dasabuvir (based on the ritonavir.

Mechanism: cross-study comparison)

CYP3A4inhibition byritonavir and

UGTinhibition byparitaprevir,ombitasviranddasabuvir.

MUSCLE RELAXANTS

Carisoprodol dasabu ↓ 0.54 0.62 NA No dose adjustment250 mg vir + Carisoprodol (0.47-0.63) (0.55-0.70) required forsingle dose ombitas carisoprodol; increase↔ dasabuvir 0.96 1.02 1.00 dose if clinicallyvir/parit (0.91-1.01) (0.97-1.07) (0.92-1.10) indicated.

Mechanism: aprevir/r ↔ 0.98 0.95 0.96

CYP2C19 itonavir ombitasvir (0.92-1.04) (0.92-0.97) (0.92-0.99)induction by ↔ 0.88 0.96 1.14ritonavir paritaprevir (0.75-1.03) (0.85-1.08) (1.02-1.27)dicinal product no longer authorised

Medicinal GIVE EFFECT Cmax AUC Ctrough Clinical Comments

Product/ N

Possible WITH

Mechanismof

Interaction

Cyclobenzap dasabu ↓ 0.68 0.60 NA No dose adjustment forrine 5 mg vir + cyclobenzap (0.61-0.75) (0.53-0.68) cyclobenzaprinesingle dose ombitas rine required; increase dose↔ dasabuvir if clinically indicated.vir/parit 0.98 1.01 1.13

Mechanism: aprevir/r (0.90-1.07) (0.96-1.06) (1.07-1.18)decrease itonavir ↔ 0.98 1.00 1.01possibly due ombitasvir (0.92-1.04) (0.97-1.03) (0.98-1.04)to CYP1A2 ↔ 1.14 1.13 1.13induction by paritaprevir (0.99-1.32) (1.00-1.28) (1.01-1.25)ritonavir

NARCOTIC ANALGESICS

Paracetamol dasabu ↔ 1.02 1.17 NA No dose adjustment is(given as vir + Paracetamo (0.89-1.18) (1.09-1.26) necessary forfixed dose ombitas l paracetamol whenhydrocodone ↔vir/parit 1.13 1.12 1.16 administered withdasabuvir (1.01-1.26) (1.05- (1.08-1.25)/paracetamol aprevir/r dasabuvir +1.19)) itonavir ombitasvir/paritaprevir/↔ 1.01 0.97 0.93ombitasvir ritonavir.

(0.93-1.10) (0.93-1.02) (0.90-0.97)300 mg↔ 1.01 1.03 1.10single dose paritaprevir (0.80-1.27) (0.89-1.18) (0.97-1.26)

Hydrocodone dasabu ↑ hydrocod 1.27 1.90 NA A reduction of(as given in a vir + one (1.14- (1.72- hydrocodone dose byfixed-dose ombitas 1.40) 2.10) 50% and/or clinicalhydrocodone vir/parit monitoring should be/paracetamol aprevir/r considered when) itonavir Changes for dasabuvir and ombitasvir, paritaprevir administered withare the same as shown for paracetamol above dasabuvir +5 mg single ombitasvir/paritaprevirdose /ritonavir.

Mechanism:

CYP3A4inhibition byritonavir

PROTON PUMP INHIBITORS

Omeprazole dasabu ↓ 0.62 0.62 NA If clinically indicated,40 mg once vir + omeprazole (0.48-0.80) (0.51-0.75) higher doses ofdaily ombitas ↔ 1.13 1.08 1.05 omeprazole should bedasabuvir (1.03-1.25) (0.98-1.20) (0.93-1.19)vir/parit used.↔ 1.02 1.05 1.04

Mechanism: aprevir/r No dose adjustmentombitasvir (0.95-1.09) (0.98-1.12) (0.98-1.11)

CYP2C19 itonavir ↔ 1.19 1.18 0.92 needed for dasabuvir +induction by paritaprevir (1.04-1.36) (1.03-1.37) (0.76-1.12) ombitasvir/paritaprevir/ritonavir. ritonavir.

Medicinal product no longer authorised

Medicinal GIVE EFFECT Cmax AUC Ctrough Clinical Comments

Product/ N

Possible WITH

Mechanismof

Interaction

Esomeprazol Not studied. Expected: If clinically indicated,e dasabu ↓ esomeprazole, lansoprazole higher doses of

Lansoprazole vir + esomeprazole/lansopraz

Mechanism: ombitas ole may be needed.

CYP2C19 vir/paritinduction by aprevir/rritonavir. itonavir

SEDATIVES/HYPNOTICS

Zolpidem dasabu ↔ 0.94 0.95 NA No dose adjustment is5 mg single vir + zolpidem (0.76-1.16) (0.74-1.23) necessary for zolpidem.

dose ombitas↔ 0.93 0.95 0.92vir/parit No dose adjustmentdasabuvir (0.84-1.03) (0.84-1.08) (0.83-1.01)aprevir/r↔ 1.07 1.03 1.04 needed for dasabuvir +itonavir ombitasvir (1.00-1.15) (1.00-1.07) (1.00-1.08) ombitasvir/paritaprevir/↓ 0.63 0.68 1.23 ritonavir.

paritaprevir (0.46-0.86) (0.55-0.85) (1.10-1.38)

Diazepam dasabu ↓diazepam 1.18 0.78 No dose adjustment

NAvir + (1.07-1.30) (0.73-0.82) required for diazepam;2 mg single ombitas ↓ 1.10 0.56 NA increase dose ifdose vir/parit nordiazepam (1.03-1.19) (0.45-0.70) clinically indicated.

aprevir/r ↔ 1.05 1.01 1.05

Mechanism: itonavir dasabuvir (0.98-1.13) (0.94-1.08) (0.98-1.12)

CYP2C19 ↔ 1.00 0.98 0.93induction by ombitasvir (0.93-1.08) (0.93-1.03) (0.88-0.98)ritonavir ↔ 0.95 0.91 0.92paritaprevir (0.77-1.18) (0.78-1.07) (0.82-1.03)

Alprazolam dasabu ↑ 1.09 1.34 NA Clinical monitoring of0.5 mg single vir + alprazolam (1.03-1.15) (1.15-1.55) patients isdose ombitas ↔ 0.93 0.98 1.00 recommended. Adasabuvir (0.83-1.04) (0.87-1.11) (0.87-1.15)vir/parit decrease in alprazolam↔ 0.98 1.00 0.98

Mechanism: aprevir/r dose can be consideredombitasvir (0.93-1.04) (0.96-1.04) (0.93-1.04)

CYP3A4 itonavir ↔ 0.91 0.96 1.12 based on clinicalinhibition by paritaprevir (0.64-1.31) (0.73-1.27) (1.02-1.23) response.

ritonavir.

No dose adjustmentneeded for dasabuvir +ombitasvir/paritaprevir/ritonavir.

THYROID HORMONES

Medicinal product no longer authorised

Medicinal GIVE EFFECT Cmax AUC Ctrough Clinical Comments

Product/ N

Possible WITH

Mechanismof

Interaction

Levothyroxin dasabu Not studied. Expected: Clinical monitoring ande vir + dose adjustment may beombitas ↑ levothyroxine required for

Mechanism: vir/parit levothyroxine.

UGT1A1 aprevir/rinhibition by itonavirparitaprevir,ombitasviranddasabuvir.1. Lopinavir/ritonavir 800/200 mg once daily (administered in the evening) was also administered withdasabuvir with ombitasvir/paritaprevir/ritonavir. The effect on Cmax and AUC of DAAs and lopinavirwas similar to that observed when lopinavir/ritonavir 400/100 mg twice daily was administered withdasabuvir 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 thatobserved 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 withdasabuvir + 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 withombitasvir/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 withdasabuvir + 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 exposuresobtained 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 exceptthe drug interaction studies with carbamazepine, gemfibrozil, ketoconazole, andsulfamethoxazole/trimethoprim.

Drug interaction studies have only been performed in adults.

Women of childbearing potential /contraception in males and females

Medicil product no longer authorised

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

Female patients: Women of childbearing potential should not receive ribavirin unless they are usingan 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 childbearingpotential must use a form of effective contraception during treatment with ribavirin and for 7 monthsafter treatment.

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

There are very limited data from the use of dasabuvir in pregnant women. Animal studies do notindicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As aprecautionary measure, it is preferable to avoid the use of dasabuvir during pregnancy.

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

Characteristics of ribavirin).

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

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

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

In subjects receiving dasabuvir and ombitasvir/paritaprevir/ritonavir with ribavirin, the mostcommonly reported adverse reactions (greater than 20% of subjects) were fatigue and nausea. The

Medicinal product no longer authorisedproportion 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.

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

The adverse reactions are listed below by system organ class and frequency. Frequencies are definedas 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 withombitasvir/paritaprevir/ritonavir or ombitasvir/paritaprevir/ritonavir and ribavirindasabuvir and dasabuvir andombitasvir/paritaprevir/ritonavir ombitasvir/paritaprevir/ritonavir

Frequency+ ribavirin*

N = 2,044 N = 588

Common Anaemia

Frequency

Anaphylactic reactions Anaphylactic reactionsunknown

Uncommon Dehydration

Very common Insomnia

Very common Nausea, Diarrhoea

Common Vomiting

Frequency Hepatic decompensation and Hepatic decompensation andunknown hepatic failure hepatic failure

Very common Pruritus

Common Pruritus

Rare Angioedema Angioedema

General disorders and administration and administration site conditions

Asthenia

Very common

*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.

Medicinal product no longer authorised

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

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

Table 4. Selected treatment emergent laboratory abnormalities

SAPPHIRE I and II PEARL II, III, and IV TURQUOISE II(subjects with cirrhosis)dasabuvir and dasabuvir and dasabuvir andombitasvir/paritaprevir ombitasvir/paritaprevir ombitasvir/paritaprevir

Laboratory parameters /ritonavir + ribavirin /ritonavir /ritonavir + ribavirin12 weeks 12 weeks 12 or 24 weeks

N = 770 N = 509 N = 380n (%) n (%) n (%)

ALT>5-20 × ULN* (Grade 3) 6/765 (0.8%) 1/509 (0.2%) 4/380 (1.1%)>20 × 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 × ULN (grade 3) 19/765 (2.5%) 2/509 (0.4%) 37/380 (9.7%)>10 × ULN (grade 4) 1/765 (0.1%) 0 0

*ULN: Upper Limit of Normal

Serum ALT elevations

In a pooled analysis of clinical trials with dasabuvir and ombitasvir/paritaprevir/ritonavir with andwithout ribavirin, 1% of subjects experienced serum ALT levels greater than 5 times the upper limit ofnormal (ULN) after starting treatment. As the incidence of such elevations was 26% among womentaking a concomitant ethinyloestradiol-containing medicine, such medicinal products arecontraindicated with dasabuvir and ombitasvir/paritaprevir/ritonavir. No increase in incidence of ALTelevations was observed with other types of systemic oestrogens commonly used for hormonereplacement therapy (e.g., oestradiol and conjugated oestrogens). ALT elevations were typicallyasymptomatic, generally occurred during the first 4 weeks of treatment (mean time 20 days, range 8-57 days) and most resolved with ongoing therapy. Two patients discontinued dasabuvir andombitasvir/paritaprevir/ritonavir due to elevated ALT, including one on ethinyloestradiol. Threeinterrupted dasabuvir and ombitasvir/paritaprevir/ritonavir for one to seven days, including one onethinyloestradiol. The majority of these ALT elevations were transient and assessed as related todasabuvir and ombitasvir/paritaprevir/ritonavir. Elevations in ALT were generally not associated withbilirubin elevations. Cirrhosis was not a risk factor for elevated ALT (see section 4.4).

Med cinal product no longer authorised

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

The overall safety profile in HCV-infected transplant recipients who were administered dasabuvir andombitasvir/paritaprevir/ritonavir and ribavirin (in addition to their immunosuppressant medicinalproducts) was similar to subjects treated with dasabuvir and ombitasvir/paritaprevir/ritonavir andribavirin in phase 3 clinical trials, although some adverse reactions were increased in frequency. 10subjects (29.4%) had at least one post baseline haemoglobin value of less than 10 g/dL. 10 of 34subjects (29.4%) dose modified ribavirin due to decrease in haemoglobin and 2.9% (1/34) had aninterruption of ribavirin. Ribavirin dose modification did not impact SVR rates. 5 subjects requirederythropoietin, all of whom initiated ribavirin at the starting dose of 1000 to 1200 mg daily. No subjectreceived 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 HCVmono-infected subjects. Transient elevations in total bilirubin >3 x ULN (mostly indirect) occurred in17 (27.0%) subjects; 15 of these subjects were receiving atazanavir. None of the subjects withhyperbilirubinemia had concomitant elevations of aminotransferases.

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

Dasabuvir and ombitasvir/paritaprevir/ritonavir with or without ribavirin were assessed in 68 subjectswith 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 thatseen in prior Phase 3 studies in subjects without severe renal impairment, except that a greaterproportion of subjects required intervention due to ribavirin-associated decreases in serumhaemoglobin. The mean baseline haemoglobin level was 12.1 g/dL and the mean decline inhaemoglobin at the end of treatment for subjects taking RBV was 1.2 g/dL. Thirty-nine of the 50subjects who received ribavirin required interruption of ribavirin, and 11 of these subjects were alsotreated with erythropoietin. Four subjects experienced a haemoglobin level < 8 g/dL. Two subjectsreceived a blood transfusion. Adverse events of anaemia were not seen in the 18 GT1b-infectedsubjects who did not receive ribavirin. Ombitasvir/paritaprevir/ritonavir with or without dasabuvir wasalso evaluated without ribavirin in 18 GT1a- and GT4-infected patients; no adverse events of anaemiawere seen in these subjects.

The safety of dasabuvir in children and adolescents aged < 18 years has not yet been established. Nodata are available.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Medicinal product no longer authorised

The highest documented single dose of dasabuvir administered to healthy volunteers was 2 g. Nostudy 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 ofadverse reactions or effects and appropriate symptomatic treatment instituted immediately.

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

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-actingantiviral medicinal products with distinct mechanisms of action and non-overlapping resistanceprofiles 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 cultureassays was 7.7 and 1.8 nM, respectively. The replicon activity of dasabuvir was attenuated 12- to 13-fold in the presence of 40% human plasma. The mean EC50 of dasabuvir against replicons containing

NS5B from a panel of treatment-naïve genotype 1a and 1b isolates in the HCV replicon cell cultureassay 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 metabolitewas attenuated 3- to 4-fold in the presence of 40% human plasma. Dasabuvir had reduced activity inbiochemical assays against NS5B polymerases from HCV genotypes 2a, 2b, 3a and 4a (IC50 valuesranging from 900 nM to >20 μM).

Resistance to dasabuvir conferred by variants in NS5B selected in cell culture or identified in Phase 2band 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 wasreduced 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 activityof dasabuvir against these variants could not be evaluated due to poor replication capacity. In genotype1b, substitutions C316N, C316Y, M414T, Y448H, and S556G in HCV NS5B reduced susceptibility todasabuvir. 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

Medicinal prouct nlonger authorised1b replicon. Dasabuvir retained full activity against replicons containing substitutions S282T in thenucleoside binding site, M423T in the lower thumb site, and P495A/S, P496S or V499A in the upperthumb 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 toexplore the association between baseline NS3/4A, NS5A or NS5B substitutions/polymorphisms andtreatment outcome in these recommended regimens.

In the greater than 500 genotype 1a baseline samples in this analysis, the most frequently observedresistance-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 toparitaprevir. Resistance-associated variants at amino acid positions R155 and D168 in NS3 were rarelyobserved (less than 1%) at baseline. In the greater than 200 genotype 1b baseline samples in thisanalysis, 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 observedwith recommended treatment regimens for HCV genotype 1a- and 1b-infected subjects, the presenceof baseline variants appears to have little impact on the likelihood of achieving SVR.

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 clinicaltrials, 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, NS5Avariants 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 3drug targets.

Medicinal product no longer authorised

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

Genotype 1a Genotype 1b

N=67b N=7

Target Emergent amino acid substitutionsa % (n) % (n)

NS3 V55Ic 6 (4) --

Y56Hc 9 (6) 42.9 (3)d

I132Vc 6 (4) --

R155K 13.4 (9) --

D168A 6 (4) --

D168V 50.7 (34) 42.9 (3)d

D168Y 7.5 (5) --

V36Ac, V36Mc, F43Lc, D168H, E357Kc < 5% --

NS5A M28T 20.9 (14) --

M28Ve 9 (6) --

Q30Re 40.3 (27) --

Y93H 28.6 (2)

H58D, H58P, Y93N < 5% --

NS5B A553T 6.1 (4) --

S556G 33.3 (22) --

C316Y, M414T, G554S, S556R, G558R, < 5% --

D559G, D559N, Y561H

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 Y448Hin genotype 1a, and M414T and Y448H in genotype 1b.

The persistence of dasabuvir, ombitasvir and paritaprevir resistance-associated amino acidsubstitutions 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/Nin 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 post-treatment Week 48, whereas NS3 variant D168V and all other NS5B variants were not observed atpost-treatment Week 48. All treatment-emergent variants in NS5A remained detectable at post-treatment Week 48. Due to high SVR rates in genotype 1b, trends in persistence of treatment-emergentvariants in this genotype could not be established.

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

Mdicinal product no longer authorised

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 treatmentexperience on the efficacy of other NS5A inhibitors, NS3/4A protease inhibitors, or NS5B inhibitorshas not been studied.

The efficacy and safety of dasabuvir in combination with ombitasvir/paritaprevir/ritonavir with andwithout ribavirin was evaluated in eight Phase 3 clinical trials, including two trials exclusively insubjects with compensated cirrhosis (Child-Pugh A), in over 2,360 subjects with genotype 1 chronichepatitis C infection as summarised in Table 6.

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

Number of HCV genotype

Trial Summary of study designsubjects treated (GT)

Treatment-naïve, without cirrhosis

Arm A: dasabuvir and

SAPPHIRE I 631 GT1 ombitasvir/paritaprevir/ritonavir + RBV

Arm B: Placebo

Arm A: dasabuvir andombitasvir/paritaprevir/ritonavir + RBV

PEARL III 419 GT1b

Arm B: dasabuvir andombitasvir/paritaprevir/ritonavir

Arm A: dasabuvir andombitasvir/paritaprevir/ritonavir + RBV

PEARL IV 305 GT1a

Arm B: dasabuvir andombitasvir/paritaprevir/ritonavir

GARNET dasabuvir and166 GT1b(open-label) ombitasvir/paritaprevir/ritonavir (8 weeks)

Peginteferon+ribavirin-experienced, without cirrhosis

Arm A: dasabuvir and

SAPPHIRE II 394 GT1 ombitasvir/paritaprevir/ritonavir + RBV

Arm B: Placebo

Arm A: dasabuvir and

PEARL II ombitasvir/paritaprevir/ritonavir + RBV179 GT1b(open-label) Arm B: dasabuvir andombitasvir/paritaprevir/ritonavir

Treatment-naïve and peginterferon+ribavirin-experienced, with compensated cirrhosis

Arm A: dasabuvir andombitasvir/paritaprevir/ritonavir + RBV

TURQUOISE II (12 weeks)380 GT1(open-label) Arm B: dasabuvir andombitasvir/paritaprevir/ritonavir + RBV(24 weeks)dasabuvir and

TURQUOISE III60 GT1b ombitasvir/paritaprevir/ritonavir (12(open-label)weeks)

In all eight trials, the dasabuvir dose was 250 mg twice daily and the ombitasvir/paritaprevir/ritonavirdose was 25 mg/150 mg/100 mg once daily. For subjects who received ribavirin, the ribavirin dose

Medicinal product no longer uthorisedwas 1000 mg per day for subjects weighing less than 75 kg or 1200 mg per day for subjects weighinggreater 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 endof 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 duringthe 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-naïve 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 12weeks

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 RNAlevels 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-Idasabuvir andombitasvir/paritaprevir/ritonavir with RBV

Treatment outcomefor 12 weeksn/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 IU/mL after HCV RNA < 25 IU/mL during treatment, confirmed 1 log10 IU/mLincrease in HCV RNA from nadir, or HCV RNA persistently ≥ 25 IU/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 onesubject with HCV genotype 1b infection experienced relapse.

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

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

Treatment: dasabuvir and ombitasvir/paritaprevir/ritonavir without ribavirin or with weight-basedribavirin 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 atleast 800,000 IU/mL; 20.3% had portal fibrosis (F2) and 10.0% had bridging fibrosis (F3).

Medicinal product no longer authorised

Table 8. SVR12 for genotype 1b-infected treatment-naïve subjects in PEARL IIIdasabuvir and ombitasvir/paritaprevir/ritonavir for 12 weeks

Treatment outcome With RBV Without RBVn/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-basedribavirin 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 RNAlevels 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-naïve subjects in PEARL IVdasabuvir and ombitasvir/paritaprevir/ritonavir for 12 weeks

With RBV Without RBV

Treatment outcomen/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 1/100 1.0 6/205 2.9

Relapse 1/98 1.0 10/194 5.2

Other 1/100 1.0 4/205 2.0

GARNET - Genotype 1b, Treatment-Naïve 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 hadgenotype 1a, 1d, and 6 infection).

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

Medicinal product no longer authoriseddasabuvir and ombitasvir/paritaprevir/ritonavir for 8 weeksn/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 IU/mL post-treatment before or during SVR12 windowamong 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, pegIFN+RBV-experienced, without cirrhosis

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

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

Treated subjects (N=394) had a median age of 54 years (range: 19 to 71); 49.0% were priorpegIFN/RBV null responders; 21.8/% were prior pegIFN/RBV partial responders; and 29.2% wereprior pegIFN/RBV relapsers; 57.6% were male; 8.1% were Black; 20.6% had a history of depressionor bipolar disorder; 87.1% had baseline HCV RNA levels of at least 800,000 IU per mL; 17.8% hadportal 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-IIdasabuvir andombitasvir/paritaprevir/ritonavir with RBV for12 weeks

Treatment outcome 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 pegIFN/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 subjectswith HCV genotype 1b infection experienced relapse.

Medicinal product no longer authorised

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-basedribavirin for 12 weeks

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

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

PEARL IIdasabuvir and ombitasvir/paritaprevir/ritonavir for 12weeks

Treatment outcome

With RBV Without RBVn/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, 100.0responder

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 or pegIFN + RBV-experienced with compensated cirrhosis

Design: randomised, global multicentre, open-label

Treatment: dasabuvir and ombitasvir/paritaprevir/ritonavir with weight-based ribavirin for 12 or24 weeks

Treated subjects (N=380) had a median age of 58 years (range: 21 to 71); 42.1% were treatment-naïve,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 plateletcounts of less than 90 x 109/L; 49.7% had albumin less than 40 g/L; 86.1% had baseline HCV RNAlevels 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.

Medicinal product no longer authorised

Table 13. SVR12 for genotype 1-infected subjects with compensated cirrhosis who weretreatment-naïve or previously treated with pegIFN/RBV

Treatment outcome dasabuvir and ombitasvir/paritaprevir/ritonavir with RBV12 weeks 24 weeksn/N % CIa n/N % CIa

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 40/50 80.0 39/42 92.9responders

Prior pegIFN/RBV partial 11/11 100 10/10 100responders

Prior pegIFN/RBV Prior 14/15 93.3 13/13 100relapsers

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 25/25 100 20/20 100responders

Prior pegIFN/RBV partial 6/7 85.7 3/3 100responders

Prior pegIFN/RBV Prior 14/14 100 10/10 100relapsers

Outcome for subjectswithout 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 and1b-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 oftreatment in subjects with genotype 1a infection and compensated cirrhosisdasabuvir and dasabuvir andombitasvir/paritaprevir/ritonavir ombitasvir/paritaprevir/ritonavirwith RBV with RBV12-week arm 24-week arm

Number of Responders at 135 113the End of Treatment

AFP* < 20 ng/mL, platelets ≥ 90 x 109/L, AND albumin ≥ 35 g/L prior to treatment

Yes (for all three 1/87 (1%) 0/68 (0%)parameters listed above)

No (for any parameter 10/48 (21%) 1/45 (2%)listed above)

*AFP= serum alpha fetoprotein

In subjects with all three favourable baseline laboratory values (AFP < 20 ng/mL, platelets ≥ 90 x109/L, and albumin ≥ 35 g/L), relapse rates were similar in subjects treated for 12 or 24 weeks.

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

Mdicinal product no longer authorised

Design: global multicentre, open-label

Treatment: dasabuvir and ombitasvir/paritaprevir/ritonavir without ribavirin for 12 weeks60 patients were randomized and treated, and 60/60 (100%) achieved SVR12. Main characteristics areshown 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:

naïve, 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 ( 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 was99.8%.

Pooled efficacy analysis

In Phase 3 clinical trials, 1075 subjects (including 181 with compensated cirrhosis) received therecommended 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 181subjects with compensated cirrhosis achieved 97% SVR), while 0.5% experienced virologicbreakthrough and 1.2% experienced post-treatment relapse.

Medicinal pduct no longer authorised

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

HCV Genotype 1b HCV Genotype 1adasabuvir and dasabuvir andombitasvir/paritaprevir/ritonavir ombitasvir/paritaprevir/ritonavirwith RBV

Without With Without Withcirrhosis compensated cirrhosis compensatedcirrhosis cirrhosis

Treatment duration 12 weeks 12 weeks 12 weeks 24 weeks

Treatment-naïve 100% (210/210) 100% (27/27) 96% (403/420) 95% (53/56)pegIFN + RBV- 100% (91/91) 100% (33/33) 96% (166/173) 95% (62/65)experienced

Prior relapse 100% (33/33) 100% (3/3) 94% (47/50) 100% (13/13)

Prior partial 100% (26/26) 100% (5/5) 100% (36/36) 100% (10/10)response

Prior null response 100% (32/32) 100% (7/7) 95% (83/87) 93% (39/42)

Other pegIFN/RBV0 100% (18/18)+ 0 0failures

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 otherpegIFN 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%) wascomparable to subjects who maintained their starting ribavirin dose throughout treatment.

TURQUOISE-I: treatment-naïve or pegIFN + RBV-experienced with HCV GT1 or GT4/HIV-1 co-infection, without cirrhosis or with compensated cirrhosis

Design: randomised, global multicentre, open-label

Treatment: ombitasvir/paritaprevir/ritonavir with or without dasabuvir coadminstered with orwithout 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 astable HIV-1 antiretroviral therapy (ART) regimen that included ritonavir-boosted atazanavir orraltegravir, dolutegravir (Part 2 only), or darunavir (Part 1b and Part 2 GT4 only)-, co-administeredwith a backbone of tenofovir plus emtricitabine or lamivudine. Part 1 of the study was a Phase 2 pilotcohort consisting of 2 parts, Part 1a (63 subjects) and Part 1b (22 subjects). Part 2 was a Phase 3cohort consisting of 233 subjects.

In Part 1a, all subjects received dasabuvir and ombitasvir/paritaprevir/ritonavir with ribavirin for 12 or24 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-naïve; 33% had failed prior treatment withpegIFN/RBV; 89% had HCV genotype 1a infection.

In Part 1b, all subjects received dasabuvir and ombitasvir/paritaprevir/ritonavir with ribavirin for 12weeks. 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-naïve; 14% had failed prior treatment withpegIFN/RBV; 68% had HCV genotype 1a infection.

Medicinal product no longer authorised

In Part 2, subjects with HCV GT1 received dasabuvir and ombitasvir/paritaprevir/ritonavir with orwithout ribavirin for 12 or 24 weeks. Subjects with HCV GT4 receivedombitasvir/paritaprevir/ritonavir with ribavirin for 12 or 24 Weeks. Treated subjects (N = 233) had amedian age of 49 years (range: 26 to 69); 10% were Black; 12% had compensated cirrhosis; 66% weretreatment-naïve; 32% had failed prior treatment with pegIFN/RBV; 2% had failed prior treatment withsofosbuvir.

Table 17 shows the primary efficacy analysis of SVR12 performed on subjects with HCV GT1/HIV-1co-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-Idasabuvir and ombitasvir/paritaprevir/ritonavir with orwithout ribavirin for12 or 24 Weeks

Endpoint 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

Otherb 4

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

b. Includes subjects who discontinued due to adverse event, lost to follow-up or subject withdrawal, andsubjects 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 1relapse 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 wasachieved by 27/28 (96.4%) subjects with HCV GT4/HIV-1 coinfection (95% CI: 82.3%, 99.4%) withno virologic failures.

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

CORAL-I: treatment-naïve or pegIFN + RBV-experienced, GT 1 or GT4 infected, at least 3 monthspost 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 withoutribavirin (investigator chosen dose) for GT1 and GT4 infection

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

Medici al product no longer authorised

A total of 129 subjects were treated, 84 with GT1a, 41 with GT1b, 1 with GT1 other, 3 with GT4infection. Overall, 61% had fibrosis stage F0-F1, 26% F2, 9% F3, and 4% F4. 61% had prior HCVtreatment experience before transplant. For immunosuppressive medication, most subjects were takingtacrolimus (81%), with the remainder taking cyclosporine.

Among all GT1 subjects who were post liver transplant, 111/114 (97.4%) achieved SVR12; with 2relapsing post treatment and 1 breakthrough on treatment. Among the GT1 subjects who were postrenal 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 treatmentexperienced, 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 incombination with ombitasvir/paritaprevir/ritonavir and ribavirin. Treated subjects had a median age of51 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 HCVtreatment.

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

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

Design: multicentre, open-label

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

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) hada median age of 58 years (range: 32-77 years); 83.8% were male; 58.8% were Black; 73.5% ofsubjects 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 orwithout 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.

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

Medicinal product no longer authorised

The pharmacokinetic properties of the combination of dasabuvir with ombitasvir/paritaprevir/ritonavirhave been evaluated in healthy adult subjects and in subjects with chronic hepatitis C. Table 18 showsmean Cmax and AUC of dasabuvir 250 mg twice daily with ombitasvir/paritaprevir/ritonavir25 mg/150 mg/100 mg once daily following multiple doses with food in healthy volunteers.

Table 18. Geometric mean Cmax, AUC of multiple doses of dasabuvir 250 mg twice daily andombitasvir/paritaprevir/ritonavir 25 mg/150 mg/100 mg once daily with food in healthyvolunteers

Cmax (ng/ml) (CV%) AUC (ng*hr/ml) (CV%)

Dasabuvir 1030 (31) 6840 (32)

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/ritonaviris achieved after approximately 12 days of dosing.

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

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

Dasabuvir is highly bound to plasma proteins. Plasma protein binding is not meaningfully altered inpatients with renal or hepatic impairment. The blood to plasma concentration ratios in human rangedfrom 0.5 to 0.7 indicating that dasabuvir was preferentially distributed in the plasma compartment ofwhole 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 g/mL. At steady-state theexposures ratio of M1 to dasabuvir is approximately 0.6. Taking into account the protein binding andin vitro activity of M1 against HCV genotype 1, its contribution to efficacy is expected to be similar tothat 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 thandasabuvir.

Dasabuvir is predominantly metabolised by CYP2C8 and to a lesser extent by CYP3A. Following a400 mg 14C-dasabuvir dose in humans, unchanged dasabuvir was the major component (approximately60%) of drug related radioactivity in plasma. Seven metabolites were identified in plasma. The mostabundant plasma metabolite was M1, which represented 21% of drug-related radioactivity (AUC) incirculation following single dose; it’s formed via oxidative metabolism predominantly by CYP2C8.

Medicinal product no longer authorised

Following dosing of dasabuvir with ombitasvir/ paritaprevir /ritonavir, mean plasma half-life ofdasabuvir was approximately 6 hours. Following a 400 mg 14C-dasabuvir dose, approximately 94% ofthe 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 mainlycleared through direct biliary excretion with the contribution of UGT-mediated glucuronidation and, toa small extent, oxidative metabolism.

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

Based on population pharmacokinetic analysis of data from Phase 3 clinical studies, a 10 year increaseor decrease in age from 54 years (median age in the Phase 3 studies) would results in <10% change indasabuvir 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 subjectswould have approximately 14 to 30% higher dasabuvir exposures than male subjects. A 10 kg changein body weight from 76 kg (median weight in the Phase 3 studies) would result in <10% change indasabuvir exposures.

Race or ethnicity

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

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: 60 to 89 ml/min), moderate (CrCl:30 to 59 ml/min) and severe (CrCl: 15 to 29 ml/min) renal impairment, relative to subjects withnormal 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 arenot considered to be clinically significant. Limited data in patients with end-stage renal diseaseindicate no clinically significant changes in exposure also in this patient group. No dose adjustment ofdasabuvir is required for patients with mild, moderate, or severe renal impairment, or end-stage-renaldisease on dialysis (see section 4.2).

Pharmacokinetics of the combination of dasabuvir 400 mg, with ombitasvir 25 mg, paritaprevir200 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 hepaticfunction.

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 wereunchanged, 57% lower, and 77% higher, respectively. Plasma protein binding of dasabuvir and its M1

Medicinal product nlonger authorisedmetabolite were not meaningfully different in subjects with hepatic impairment compared to normalcontrol subjects (see sections 4.2, pct. 4.4 and 4.8).

The pharmacokinetics of dasabuvir with ombitasvir/paritaprevir/ritonavir in paediatric patients has notbeen investigated (see section 4.2).

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 micronucleusassays.

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 inhumans 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 (800mg/kg/day), resulting in dasabuvir exposures approximately 19-fold higher than those in humans at500 mg.

Dasabuvir had no effects on embryo-foetal viability or on fertility in rodents and were not teratogenicin two species. No adverse effects on behaviour, reproduction or development of offspring werereported. 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 onnursing pups. Elimination half-life in rat milk was slightly shorter than in plasma, AUC was about 2fold of that in plasma. Since dasabuvir is a BCRP substrate, distribution to the milk may change if thistransporter is inhibited or induced by co-administration of other medicinal products. Dasabuvir-derived material was minimally transferred through the placenta in pregnant rats.

Microcrystalline cellulose (E 460(i))

Lactose monohydrate

Copovidone

Croscarmellose sodium

Colloidal anhydrous silica (E 551)

Magnesium stearate (E 470b)

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)

Medicinal product no longer aut orised

Not applicable.

3 years

This medicinal product does not require any special storage conditions.

PVC/PE/PCTFE aluminium foil blister packs.

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

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

AbbVie Deutschland GmbH & Co. KG

Knollstrasse67061 Ludwigshafen

Germany

EU/1/14/983/001

Date of first authorisation: 15 January 2015

Date of latest renewal: 26 September 2019

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.

Medicinal product no longer authorised