VIEKIRAX 12.5mg / 75mg / 50mg film-coated tablets medication leaflet

Viekirax 12.5 mg/75 mg/50 mg film-coated tablets

Each film-coated tablet contains 12.5 mg of ombitasvir, 75 mg of paritaprevir and 50 mg of ritonavir.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Pink, oblong, biconvex, film-coated tablets of dimensions 18.8 mm x 10.0 mm, debossed on one side with‘AV1’.

Viekirax is indicated in combination with other medicinal products for the treatment of chronic hepatitis 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 Viekirax should be initiated and monitored by a physician experienced in the managementof chronic hepatitis C.

The recommended oral dose of Viekirax is two 12.5 mg/75 mg/50 mg tablets once daily with food.

Viekirax should be used in combination with other medicinal products for the treatment of HCV (see

Table 1).

Medicinal product no longer authorised

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

Patient population Treatment* Duration12 weeks8 weeks may be considered in

Genotype 1b, without cirrhosis or

Viekirax + dasabuvir previously untreated genotype 1b-with compensated cirrhosisinfected patients with minimal tomoderate fibrosis** (see section 5.1,

GARNET study)

Genotype 1a,

Viekirax + dasabuvir + ribavirin* 12 weekswithout cirrhosis

Genotype 1a,

Viekirax + dasabuvir + ribavirin* 24 weeks (see section 5.1.)with compensated cirrhosis

Genotype 4, without cirrhosis or

Viekirax + ribavirin 12 weekswith compensated cirrhosis

*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.

For specific dosage instructions for dasabuvir and ribavirin, including dose modification, refer to therespective Summaries of Product Characteristics.

In case a dose of Viekirax is missed, the prescribed dose can be taken within 12 hours. If more than 12hours have passed since Viekirax is usually taken, the missed dose should NOT be taken and the patientshould take the next dose per the usual dosing schedule. Patients should be instructed not to take a doubledose.

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.

Viekirax and dasabuvir in combination with ribavirin is recommended for 24 weeks in liver transplantrecipients with genotype 1 HCV infection. Viekirax in combination with ribavirin is recommended ingenotype 4 infection. Lower ribavirin dose at initiation may be appropriate. In the post-liver transplantstudy, ribavirin dosing was individualized and most subjects received 600 to 800 mg per day (see section5.1). For dosing recommendations with calcineurin inhibitors see section 4.5.

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

Medicinal prodct no longer authorised

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

No dose adjustment of Viekirax is required in patients with mild hepatic impairment (Child-Pugh A).

Viekirax is contraindicated in patients with moderate to severe hepatic impairment (Child-Pugh B or C)(see sections 4.3 and 5.2).

The safety and efficacy of Viekirax in children less than 18 years of age have not been established. Nodata 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, Viekirax tablets should betaken with food, without regard to fat and calorie content (see section 5.2).

Hypersensitivity to the active substances 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).

Medicinal products that are highly dependent on CYP3A for clearance and for which elevated plasmalevels are associated with serious events must not be co-administered with Viekirax (see section 4.5).

Examples are provided below.

- alfuzosin hydrochloride

- amiodarone, disopyramide, dronedarone, quinidine, ranolazine

- astemizole, terfenadine

- cisapride

- colchicine in patients with renal or hepatic impairment

- ergotamine, dihydroergotamine, ergonovine, methylergometrine

- fusidic acid

- lomitapide

- lovastatin, simvastatin, atorvastatin

- lurasidone

- oral midazolam, triazolam

- pimozide

- quetiapine

- salmeterol

- sildenafil (when used for the treatment of pulmonary arterial hypertension)

- ticagrelor

Medicinal prouct no longer authorised

Co-administration of Viekirax with or without dasabuvir with medicinal products that are strong ormoderate enzyme inducers is expected to decrease ombitasvir, paritaprevir, and ritonavir plasmaconcentrations and reduce their therapeutic effect and must not be co-administered (see section 4.5).

Examples of contraindicated strong or moderate enzyme inducers are provided below.

Enzyme inducers:

- carbamazepine, phenytoin, phenobarbital

- efavirenz, nevirapine, etravirine

- apalutamide,enzalutamide

- mitotane

- rifampicin

- St. John’s Wort (Hypericum perforatum)

Co-administration of Viekirax with or without dasabuvir with medicinal products that are strong inhibitorsof CYP3A4 is expected to increase paritaprevir plasma concentrations and must not be co-administeredwith Viekirax (see section 4.5). Examples of contraindicated strong CYP3A4 inhibitors are providedbelow.

- cobicistat

- indinavir, lopinavir/ritonavir, saquinavir, tipranavir,

- itraconazole, ketoconazole, posaconazole, voriconazole

- clarithromycin, telithromycin

- conivaptan

Viekirax is not recommended for administration as monotherapy and must be used in combination withother medicinal products for the treatment of hepatitis C infection (see sections 4.2 and 5.1).

Risk of hepatic decompensation and hepatic failure in patients with cirrhosis

Hepatic decompensation and hepatic failure, including liver transplantation or fatal outcomes, have beenreported postmarketing in patients treated with Viekirax with and without dasabuvir and with and withoutribavirin. Most patients with these severe outcomes had evidence of advanced or decompensated cirrhosisprior to initiating therapy. Although causality is difficult to establish due to background advanced liverdisease, a potential risk cannot be excluded.

Viekirax is contraindicated in patients with moderate to severe hepatic impairment (Child-Pugh B or 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 (suchas ascites, hepatic encephalopathy, variceal haemorrhage).

* Hepatic laboratory testing including direct bilirubin levels should be performed at baseline, duringthe first 4 weeks of starting treatment and as clinically indicated thereafter.

* Treatment should be discontinued in patients who develop evidence of hepatic decompensation.

Medicinal product no longer authorised

During clinical trials with Viekirax and dasabuvir with or without ribavirin, transient elevations of ALT togreater than 5 times the upper limit of normal occurred in approximately 1% of subjects (35 of 3,039).

ALT elevations were asymptomatic and generally occurred during the first 4 weeks of treatment, withoutconcomitant elevations of bilirubin, and declined within approximately two weeks of onset with continueddosing of Viekirax and dasabuvir 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 or contraceptivevaginal rings (6 of 25 subjects); (see section 4.3). In contrast, the rate of ALT elevations in subjects usingother types of oestrogens as typically used in hormonal replacement therapy (i.e., oral and topicaloestradiol and conjugated oestrogens) was similar to the rate observed in subjects who were not usingoestrogen-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 Viekirax with or withoutdasabuvir therapy (see sections 4.3 and 4.5).

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

Pregnancy and concomitant use with ribavirin

Also see section 4.6.

Extreme caution must be taken to avoid pregnancy in female patients and female partners of male patientswhen Viekirax 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 Viekirax and dasabuvir with systemic tacrolimus, sirolimus or everolimus increasesthe concentrations of the immunosuppressant due to CYP3A inhibition by ritonavir (see section 4.5).

Serious and/or life threatening events have been observed with co-administration of Viekirax anddasabuvir with systemic tacrolimus, and a similar risk can be expected with sirolimus and everolimus.

Avoid concomitant use of tacrolimus or sirolimus with Viekirax and dasabuvir unless the benefitsoutweigh the risks. If tacrolimus or sirolimus are used together with Viekirax and dasabuvir, caution isadvised, and recommended doses and monitoring strategies can be found in section 4.5. Everolimuscannot be used due to lack of suitable dose strengths for dose adjustments.

Tacrolimus or sirolimus whole blood concentrations should be monitored upon initiation and throughoutco-administration with Viekirax and dasabuvir and the dose and/or dosing frequency should be adjusted asneeded. Patients should be monitored frequently for any changes in renal function or tacrolimus or

Medicinal product no longer authorisedsirolimus associated adverse reactions. Refer to the tacrolimus or sirolimus Summary of Product

Characteristics for additional dosing and monitoring instructions.

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

The efficacy of Viekirax has not been established in patients with HCV genotypes 2, 3, 5 and 6; therefore

Viekirax should not be used to treat patients infected with these genotypes.

Co-administration with other direct-acting antivirals against HCV

Viekirax safety and efficacy have been established in combination with dasabuvir and/or ribavirin. Co-administration of Viekirax with other antivirals has not been studied and, therefore, cannot berecommended.

The efficacy of Viekirax in patients previously exposed to Viekirax, or to medicinal products of the sameclasses as those of Viekirax (NS3/4A inhibitors or NS5A inhibitors), has not been demonstrated.

Concerning cross-resistance, see also section 5.1.

Use with glucocorticoids metabolised by CYP3A (e.g. fluticasone)

Caution should be used when administering Viekirax with fluticasone or other glucocorticoids that aremetabolised by CYP3A4. Concomitant use of inhaled glucocorticoids metabolised with CYP3A canincrease systemic exposures of the glucocorticoids, and cases of Cushing’s syndrome and subsequentadrenal suppression have been reported with ritonavir-containing regimens. Concomitant use of Viekiraxand glucocorticoids, particularly long-term use, should only be initiated if the potential benefit oftreatment outweighs the risk of systemic corticosteroid effects (see section 4.5).

Use with colchicine

The interaction between Viekirax with or without dasabuvir and colchicine has not been evaluated. Areduction in colchicine dosage or an interruption of colchicine treatment is recommended in patients withnormal renal or hepatic function if treatment with Viekirax with or without dasabuvir is required (seesection 4.5). In patients with renal or hepatic impairment, use of colchicine with Viekirax with or withoutdasabuvir is contraindicated (see sections 4.3 and 4.5).

Use with statins

Simvastatin, lovastatin and atorvastatin are contraindicated (see sections 4.3 and 4.5).

Viekirax with dasabuvir is expected to increase the exposure to rosuvastatin more than 3-fold. Ifrosuvastatin treatment is required during the treatment period, the maximum daily dose of rosuvastatinshould be 5 mg (see section 4.5, Table 2).The increase in rosuvastatin when combined with Viekiraxwithout dasabuvir is less pronounced. In this combination, the maximum daily dose of rosuvastatin shouldbe 10 mg (see section 4.5, Table 2).

Medicinal product no longer authorised

Pitavastatin and fluvastatin

The interactions between pitavastatin and fluvastatin and Viekirax have not been investigated.

Theoretically, Viekirax with and without dasabuvir is expected to increase the exposure to pitavastatin andfluvastatin. A temporary suspension of pitavastatin/fluvastatin is recommended for the duration oftreatment with Viekirax. If statin treatment is required during the treatment period, a switch to a reduceddose of pravastatin/rosuvastatin is possible (see section 4.5, Table 2).

Treatment of patients with HIV co-infection

Low dose ritonavir, which is part of the fixed dose combination Viekirax, may select for PI resistance in

HIV co-infected patients without ongoing antiretroviral therapy. HIV co-infected patients withoutsuppressive antiretroviral therapy should not be treated with Viekirax.

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

Atazanavir can be used in combination with Viekirax and dasabuvir, if administered at the same time. Tobe noted, atazanavir should be taken without ritonavir, since ritonavir 100 mg once daily is provided aspart of Viekirax. 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 as Viekirax and dasabuvir, can beused in the absence of extensive PI resistance (darunavir exposure lowered). To be noted, darunavirshould be taken without ritonavir, since ritonavir 100 mg once daily is provided as part of Viekirax.

HIV protease inhibitors other than atazanavir and darunavir (e.g., indinavir, saquinavir, tipranavir,lopinavir/ritonavir) are contraindicated (see section 4.3).

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

Rilpivirine exposure is substantially increased (3-fold) when rilpivirine is given in combination with

Viekirax and dasabuvir, with a consequent potential for QT-prolongation. If an HIV protease inhibitor isadded (atazanavir, darunavir), rilpivirine exposure may increase even further and is, therefore, notrecommended. Rilpivirine should be used cautiously, in the setting of repeated ECG monitoring.

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

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

Depression or psychiatric illness

Cases of depression and more rarely of suicidal ideation and suicide attempt have been reported with

Viekirax with or without dasabuvir treatment in combination with ribavirin in the majority of the cases.

Although some cases had previous history of depression, psychiatric illness and/or substance abuse, acausal relation with Viekirax with or without dasabuvir treatment cannot be excluded. Caution should beused in patients with a pre-existing history of depression or psychiatric illness. Patients and caregivers

Medicinal product no longer authrisedshould be instructed to notify the prescriber of any changes in behaviour or mood and of any suicidalideation.

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

Viekirax may be administered with or without dasabuvir. When co-administered, they exert mutual effectson each other (see section 5.2). Therefore, the interaction profile of the compounds must be considered asa combination.

Coadministration with enzyme inducers may increase the risk of adverse reactions and ALT elevations(see Table 2). Coadministration with ethinyloestradiol may increase the risk of ALT elevations (seesections 4.3 and 4.4). Examples of contraindicated enzyme inducers are provided in section 4.3.

Potential for Viekirax to affect the pharmacokinetics of other medicinal products

In vivo drug interaction studies evaluated the net effect of the combination treatment, including ritonavir.

The following section describes the specific transporters and metabolizing enzymes that are affected by

Viekirax with or without dasabuvir. See Table 2 for guidance regarding potential interactions with othermedicinal products and dosing recommendations.

Ritonavir is a strong inhibitor of CYP3A. Co-administration of Viekirax with or without dasabuvir withmedicinal products primarily metabolized by CYP3A may result in increased plasma concentrations ofthese medicinal products. Medicinal products that are highly dependent on CYP3A for clearance and forwhich elevated plasma levels are associated with serious events are contraindicated (see section 4.3 and

Table 2).

CYP3A substrates evaluated in drug interaction studies which may require dose adjustment and/or clinicalmonitoring include (see Table 2) ciclosporin, sirolimus, tacrolimus, amlodipine, rilpivirine andalprazolam. Examples of other CYP3A4 substrates which may require dose adjustment and/or clinicalmonitoring include calcium channel blockers (e.g. nifedipine), and trazodone. Although buprenorphineand zolpidem are also metabolized by CYP3A, drug interaction studies indicate that no dose adjustment isneeded when co-administering these medicinal products with Viekirax with or without dasabuvir (see

Table 2).

Medicinal products transported by the OATP family and OCT1

Paritaprevir is an inhibitor of the hepatic uptake transporters OATP1B1 and OATP1B3, and paritaprevirand ritonavir are inhibitors of OATP2B1. Ritonavir is an in vitro inhibitor of OCT1, but the clinicalrelevance is unknown. Co-administration of Viekirax with or without dasabuvir with medicinal products

Medicinal product no longer authorisedthat are substrates of OATP1B1, OATP1B3, OATP2B1 or OCT1 may increase plasma concentrations ofthese transporter substrates, potentially requiring dose adjustment/clinical monitoring. Such medicinalproducts include some statins (see Table 2), fexofenadine, repaglinide and angiotensin II receptorantagonists (e.g., valsartan).

OATP1B1/3 substrates evaluated in drug interaction studies include pravastatin and rosuvastatin (see

Table 2).

Medicinal products transported by BCRP

Paritaprevir, ritonavir and dasabuvir are inhibitors of BCRP in vivo. Co-administration of Viekirax with orwithout dasabuvir together with medicinal products that are substrates of BCRP may increase plasmaconcentrations of these transporter substrates, potentially requiring dose adjustment/clinical monitoring.

Such medicinal products include sulfasalazine, imatinib and some of the statins (see Table 2).

BCRP substrates evaluated in drug interaction studies include rosuvastatin (see Table 2).

Medicinal products transported by P-gp in the intestine

While paritaprevir, ritonavir and dasabuvir are in vitro inhibitors of P-gp, no significant change wasobserved in the exposure of the P-gp substrate digoxin when administered with Viekirax and dasabuvir.

However, co-administration of digoxin with Viekirax without dasabuvir may result in increased plasmaconcentrations (see Table 2). Viekirax may increase the plasma exposure to medicinal products that aresensitive for changed intestinal P-gp activity (such as dabigatran etexilate).

Medicinal products metabolised by glucuronidation (UGT1A1)

Paritaprevir, ombitasvir and dasabuvir are inhibitors of UGT1A1. Co-administration of Viekirax with orwithout dasabuvir with medicinal products that are primarily metabolized by UGT1A1 result in increasedplasma concentrations of such medicinal products; routine clinical monitoring is recommended for narrowtherapeutic index medicinal products (i.e. levothyroxine). See also Table 2 for specific advice onraltegravir and buprenorphine, which have been evaluated in drug interaction studies.

Medicinal products metabolised by CYP2C19

Co-administration of Viekirax with or without dasabuvir can decrease exposures of medicinal productsthat are metabolized by CYP2C19 (e.g. lansoprazole, esomeprazole, s-mephenytoin), which may requiredose adjustment/clinical monitoring. CYP2C19 substrates evaluated in drug interaction studies includeomeprazole and escitalopram (see Table 2).

Viekirax administered with or without dasabuvir 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

Viekirax administered with or without dasabuvir did not affect the exposures of the CYP2D6/CYP1A2substrate, duloxetine. Exposures of cyclobenzaprine, a CYP1A2 substrate, were decreased. Clinicalmonitoring and dose adjustment may be needed for other CYP1A2 substrates (e.g. ciprofloxacin,cyclobenzaprine, theophylline and caffeine). CYP2D6 substrates (e.g. desipramine, metoprolol anddextromethorphan) are not expected to require dose adjustments.

Medicinal products renally excreted via transport proteins

Ombitasvir, paritaprevir, and ritonavir do not inhibit organic anion transporter (OAT1) in vivo as shownby the lack of interaction with tenofovir (OAT1 substrate). In vitro studies show that ombitasvir,paritaprevir, and ritonavir are not inhibitors of organic cation transporters (OCT2), organic anion

Medicinal product no longer authorisedtransporters (OAT3), or multidrug and toxin extrusion proteins (MATE1 and MATE2K) at clinicallyrelevant concentrations.

Therefore, Viekirax with or without dasabuvir is not expected to affect medicinal products which areprimarily excreted by the renal route via these transporters (see section 5.2).

Potential for other medicinal products to affect the pharmacokinetics of ombitasvir, paritaprevir, anddasabuvir

Co-administration of Viekirax with or without dasabuvir with strong inhibitors of CYP3A may increaseparitaprevir concentrations (see section 4.3 and Table 2).

Enzyme inducers

Co-administration of Viekirax and dasabuvir with medicinal products that are moderate or strong enzymeinducers is expected to decrease ombitasvir, paritaprevir, ritonavir and dasabuvir plasma concentrationsand reduce their therapeutic effect. Contraindicated enzyme inducers are provided in section 4.3 and Table2.

Medicinal products that inhibit CYP3A4 and transport proteins

Paritaprevir is eliminated via CYP3A4 mediated metabolism and biliary excretion (substrate of the hepatictransporters OATP1B1, P-gp and BCRP). Caution is advised if co-administering Viekirax with medicinalproducts that are both moderate inhibitors of CYP3A4 and inhibitors of multiple transporters (P-gp, BCRPand/or OATP1B1/ OATP1B3). These medicinal products may show clinically relevant increases inexposures of paritaprevir (e.g., ritonavir with atazanavir, erythromycin, diltiazem or verapamil).

Medicinal products that inhibit transport proteins

Potent inhibitors of P-gp, BCRP, OATP1B1 and/or OATP1B3 have the potential to increase the exposureto paritaprevir. Inhibition of these transporters is not expected to show clinically relevant increases inexposures of ombitasvir and dasabuvir.

As liver function may change during treatment with Viekirax administered with or without dasabuvir, aclose monitoring of International Normalised Ratio (INR) values is recommended.

Recommendations for co-administration of Viekirax with and without dasabuvir for a number ofmedicinal products are provided in Table 2.

If a patient is already taking medicinal product(s) or initiating a medicinal product while receiving

Viekirax with or without dasabuvir for which potential for drug interaction is expected, dose adjustment ofthe concomitant medicinal product(s) or appropriate clinical monitoring should be considered (Table 2).

If dose adjustments of concomitant medicinal products are made due to treatment with Viekirax or

Viekirax with dasabuvir, doses should be re-adjusted after administration of Viekirax or Viekirax withdasabuvir is completed.

Table 2 provides the Least Squares Means Ratio (90% Confidence Interval) effect on concentration of

Viekirax with or without dasabuvir and concomitant medicinal products.

Medicinal product no loger authorised

The magnitude of interaction when administered with medicinal products listed in Table 2 are similar(≤25% difference in the Least Square Means ratio) for Viekirax with or without dasabuvir, unlessotherwise noted. Drug interactions were evaluated for the Viekirax and dasabuvir regimen, but not for the

Viekirax without dasabuvir, with carbamazepine, furosemide, zolpidem, darunavir twice daily, darunavir(evening administration), atazanavir (evening administration), rilpivirine, abacavir/lamivudine,dolutegravir, metformin, sulfamethoxazole/trimethoprim, cyclobenzaprine, carisoprodol, hydrocodone/paracetamol or diazepam. Thus, for these medicinal products, results and dosing recommendations of the

Viekirax and dasabuvir regimen can be extrapolated to Viekirax without dasabuvir.

The direction of the arrow indicates the direction of the change in exposures (Cmax, and AUC) inparitaprevir, ombitasvir, dasabuvir and the co-administered medicinal product (↑ = increase (more than20%), ↓ = decrease (of more than 20%), ↔ = no change or change less than 20%). This is not anexclusive list.

Table 2. Interactions between Viekirax with or without dasabuvir and other medicinal products

Medicinal GIVEN EFFECT Cmax AUC Ctrough Clinical Comments

Product/Poss WITHible

Mechanismof

Interaction

ALPHA 1-ADRENORECEPTOR ANTAGONIST

Alfuzosin Viekirax Not studied. Expected Concomitant use iswith or contraindicated (see section

Mechanism: without ↑ alfuzosin 4.3).

CYP3A dasabuvirinhibition byritonavir

AMINOSALICYLATE

Sulfasalazine Viekirax Not Studied. Expected: Caution should be usedwith or when sulfasalazine is co-

Mechanism: without ↑ sulfasalazine administered with Viekirax

BCRP dasabuvir with or without dasabuvir.

inhibition byparitaprevir, .

ritonavir anddasabuvir.

ANGIOTENSIN RECEPTOR BLOCKER

Valsartan Viekirax Not Studied. Expected: Clinical monitoring and

Losartan with or dose reduction is

Candesartan without ↑ valsartan recommended fordasabuvir ↑ losartan angiotensin receptor

Mechanism: ↑ candesartan blockers when co-

CYP3A4 administered with Viekiraxand/or with or without dasabuvir.

OATP1Binhibition byparitaprevir.

ANTIANGINA/ANTIARRYTHMICS

Medicinal product no longer authorised

Medicinal GIVEN EFFECT Cmax AUC Ctrough Clinical Comments

Product/Poss WITHible

Mechanismof

Interaction

Amiodarone Viekirax Not studied. Expected: Concomitant use is

Disopyramide with or contraindicated (see section

Dronedarone without ↑ amiodarone 4.3).dasabuvir ↑ disopyramide

Quinidine↑ dronedarone

Ranolazine↑ quinidine

Mechanism:↑ ranolazine

CYP3A4inhibition byritonavir.

Digoxin Viekirax + ↔ digoxin 1.15 1.16 1.01 While no dose adjustmentdasabuvir (1.04-1.27) (1.09-1.23) (0.97-1.05) is necessary for digoxin,0.5 mg single ↔ 1.03 1.00 0.99 appropriate monitoring ofombitasvir (0.97-1.10) (0.98-1.03) (0.96-1.02)dose serum digoxin levels is↔ 0.92 0.94 0.92recommended.paritaprevir (0.80-1.06) (0.81-1.08) (0.82-1.02)

Mechanism: ↔ dasabuvir 0.99 0.97 0.99

P-gp (0.92-1.07) (0.91-1.02) (0.92-1.07)inhibition by Viekirax ↑ digoxin 1.58 1.36 1.24 Decrease digoxin dose byparitaprevir, without (1.43-1.73) (1.21-1.54) (1.07-1.43) 30-50%. Appropriateritonavir and dasabuvir ↔ The magnitude of interaction was similar monitoring of serumdasabuvir. ombitasvir to that observed with Viekirax + dasabuvir. digoxin levels is↔recommended.

paritaprevir

ANTIBIOTICS (SYSTEMIC ADMINISTRATION)

Clarithromycin Viekirax Not Studied. Expected: Concomitant use iswith or contraindicated (see

Telithromycin without ↑ clarithromycin section 4.3).dasabuvir ↑ telithromycin

Mechanism:

CYP3A4/P- ↑ paritaprevirgp inhibition ↑ dasabuvirbyclarithromycin andritonavir.

Erythromycin Viekirax Not Studied. Expected: Administration of Viekiraxwith or with or without dasabuvir

Mechanism: without ↑ erythromycin with erythromycin maydasabuvir

CYP3A4/P- result in increased↑ paritaprevirgp inhibition concentrations of↑ dasabuvirby erythromycin anderythromycin, paritaprevir. Caution isparitaprevir, advised.

ritonavir anddasabuvir.

Fusidic Acid Viekirax Not studied. Expected: Concomitant use iswith or contraindicated (seewithout ↑ fusidic acid section 4.3).dasabuvir

Medicinal product no longer authorised

Medicinal GIVEN EFFECT Cmax AUC Ctrough Clinical Comments

Product/Poss WITHible

Mechanismof

Interaction

Mechanism:

CYP3A4inhibition byritonavir.

Sulfameth- Viekirax + ↑ Sulfameth- 1.21 1.17 1.15 No dose adjustment neededoxazole, dasabuvir oxazole, (1.15-1.28) (1.14-1.20) (1.10-1.20) for Viekirax with or

Trimethoprim ↑ trimetho- 1.17 1.22 1.25 without dasabuvir.prim (1.12-1.22) (1.18-1.26) (1.19-1.31)↔ 0.88 0.85 NA800/160 mgombitasvir (0.83-0.94) (0.80-0.90)twice daily ↓ 0.78 0.87 NAparitaprevir (0.61-1.01) (0.72-1.06)

Mechanism: ↑ dasabuvir 1.15 1.33 NAincrease in (1.02-1.31) (1.23-1.44)dasabuvir Viekirax Not studied:

possibly due without Similar effect is expected as observed with Viekirax +to CYP2C8 dasabuvir dasabuvir.

inhibition bytrimethoprim

ANTICANCER AGENTS/KINASE INHIBITORS

Encorafenib Viekirax Not studied. Expected: Co-administration maywith or result in increased risk for

Mechanism: without ↑ encorafenib adverse events. Refer to

CYP3A4 dasabuvir the prescribing informationinhibition by of encorafenib for detailsritonavir. on co-administration withstrong CYP3A inhibitors.

Apalutamide Viekirax Not studied. Expected: Concomitant use iswith or contraindicated (see

Enzalutamide without ↓ombitasvir section 4.3).

dasabuvir ↓ paritaprevir

Mitotane ↓ dasabuvir

Mechanism:

CYP3A4inductionapalutamideenzalutamideor mitotane.

Fostamatinib Viekirax Not Studied. Expected Co-administration maywith or result in increased risk for

Mechanism: without ↑ fostamatinib adverse events. Refer to

CYP3A4 dasabuvirthe prescribing informationinhibition by of fostamatinib for detailsritonavir.

on co-administration withstrong CYP3A inhibitors.

Ibrutinib Viekirax Not studied. Expected: Co-administration maywith or result in increased risk for↑ ibrutinib adverse events. Refer to

Medicinal product no longer authorised

Medicinal GIVEN EFFECT Cmax AUC Ctrough Clinical Comments

Product/Poss WITHible

Mechanismof

Interaction

Mechanism: without the prescribing information

CYP3A4 dasabuvir of ibrutinib for details oninhibition by co-administration withritonavir.

strong CYP3A inhibitors.

Imatinib Viekirax Not Studied. Expected: Clinical monitoring andwith or lower doses of imatinib are

Mechanism: without ↑ imatinib recommended.

BCRP dasabuvirinhibition byparitaprevir,ritonavir anddasabuvir.

ANTICOAGULANTS

Warfarin Viekirax + ↔ 1.05 0.88 0.94 While no change to thedasabuvir R-warfarin (0.95-1.17) (0.81-0.95) (0.84-1.05) pharmacokinetics of5 mg single ↔ 0.96 0.88 0.95 warfarin is expected, close

S-warfarin (0.85-1.08) (0.81-0.96) (0.88-1.02)dose and monitoring of INR is↔ 0.94 0.96 0.98other vitamin recommended with allombitasvir (0.89-1.00) (0.93-1.00) (0.95-1.02)

K antagonists ↔ 0.98 1.07 0.96 vitamin K antagonists. Thisparitaprevir (0.82-1.18) (0.89-1.27) (0.85-1.09) is due to liver function↔ 0.97 0.98 1.03 changes during treatmentdasabuvir (0.89-1.06) (0.91-1.06) (0.94-1.13) with Viekirax ± dasabuvir.

Viekirax ↔ The magnitude of interaction was similarwithout R-warfarin to that observed with Viekirax + dasabuvir.

dasabuvir ↔

S-warfarin↔paritaprevir↔ombitasvir

Dabigatran Viekirax Not Studied. Expected: Viekirax without dasabuviretexilate with or may increase the plasma

Mechanism: without ↑ dabigatran etexilate concentrations of dabigatran

Intestinal P- dasabuvir etexilate. Use with caution.

gp inhibitionbyparitaprevirand ritonavir.

ANTICONVULSANTS

Carbamaze- Viekirax + ↔ carba- 1.10 1.17 1.35 Concomitant use ispine dasabuvir mazepine (1.07-1.14) (1.13-1.22) (1.27-1.45) contraindicated (see↓ carbamaze 0.84 0.75 0.57 section 4.3).pine 10, 11- (0.82-0.87) (0.73-0.77) (0.54-0.61)200 mg onceepoxidedaily followed ↓ 0.69 0.69 NAby 200 mg ombitasvir (0.61-0.78) (0.64-0.74)twice daily ↓ 0.34 0.30 NAparitaprevir (0.25-0.48) (0.23-0.38)

Medicinal product no longer authori ed

Medicinal GIVEN EFFECT Cmax AUC Ctrough Clinical Comments

Product/Poss WITHible

Mechanismof

Interaction↓ 0.45 0.30 NA

Mechanism: dasabuvir (0.41-0.50) (0.28-0.33)

CYP3A4 Viekirax Not studied: similar effect expected as observed withinduction by without Viekirax + dasabuvir.

carbamazepine dasabuvir

Phenobarbital Viekirax Not Studied. Expected: Concomitant use iswith or contraindicated (see

Mechanism: without ↓ ombitasvir section 4.3).

CYP3A4 dasabuvir ↓ paritaprevirinduction by ↓ dasabuvirphenobarbital.

Phenytoin Viekirax Not Studied. Expected: Concomitant use iswith or contraindicated (see

Mechanism: without ↓ ombitasvir section 4.3).

CYP3A4 dasabuvir ↓ paritaprevirinduction by ↓ dasabuvirphenytoin.

S- Viekirax Not studied. Expected: Clinical monitoring andmephenytoin with or dose adjustment maybewithout ↓ S-mephenytoin needed for s-mephenytoin.

Mechanism: dasabuvir

CYP2C19induction byritonavir.

ANTIDEPRESSANTS

Escitalopram Viekirax + ↔ es- 1.00 0.87 NA No dose adjustment isdasabuvir citalopram (0.96-1.05) (0.80-0.95) necessary for escitalopram.10 mg single ↑ S- 1.15 1.36 NAdose Desmethyl (1.10-1.21) (1.03-1.80)citalopram↔ 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)↔ 1.10 1.01 0.89dasabuvir (0.95-1.27) (0.93-1.10) (0.79-1.00)

Viekirax ↓ es- The magnitude of interaction was similarwithout citalopram to that observed with Viekirax + dasabuvir.dasabuvir↔ S- 1.17 1.07 NA

Desmethyl (1.08-1.26) (1.01-1.13)citalopram↔ The magnitude of interaction was similarombitasvir to that observed with Viekirax + dasabuvir.↔paritaprevir

Duloxetine Viekirax + ↓ 0.79 0.75 NA No dose adjustment isdasabuvir duloxetine (0.67-0.94) (0.67-0.83) necessary for duloxetine.

Medicinal product no longer authorised

Medicinal GIVEN EFFECT Cmax AUC Ctrough Clinical Comments

Product/Poss WITHible

Mechanismof

Interaction60 mg single ↔ 0.98 1.00 1.01dose ombitasvir (0.88-1.08) (0.95-1.06) (0.96-1.06) No dose adjustment needed↓ 0.79 0.83 0.77 for Viekirax with orparitaprevir (0.53-1.16) (0.62-1.10) (0.65-0.91)without dasabuvir.↔ 0.94 0.92 0.88dasabuvir (0.81-1.09) (0.81-1.04) (0.76-1.01)

Viekirax ↔ The magnitude of interaction was similarwithout duloxetine to that observed with Viekirax + dasabuvir.dasabuvir ↔ The magnitude of interaction was similarombitasvir to that observed with Viekirax + dasabuvir.↔ 1.07 0.96 0.93paritaprevir (0.63-1.81) (0.70-1.32) (0.76-1.14)

Trazodone Viekirax Trazodone should be used

Mechanism: with or Not studied. Expected: with caution and a lower

CYP3A4 without dose of trazodone may be↑ trazodoneinhibition by dasabuvir considered.

ritonavir.

ANTI-DIURETIC HORMONE

Conivaptan Viekirax Not studied. Expected: Concomitant use iswith or contraindicated (see section

Mechanism: without ↑conivaptan 4.3).

CYP3A4/P- dasabuvir ↑ paritaprevirgp inhibition ↑ dasabuvirby conivaptanandparitaprevir/ritonavir/ombitasvir

ANTIFUNGALS

Ketoconazole Viekirax ↑ keto- 1.15 2.17 NA Concomitant use is400 mg once with conazole (1.09-1.21) (2.05-2.29) contraindicated (seedaily dasabuvir ↔ 0.98 1.17 NA section 4.3).ombitasvir (0.90-1.06) (1.11-1.24)

Mechanism: ↑ 1.37 1.98 NAparitaprevir (1.11-1.69) (1.63-2.42)

CYP3A4/P-↑ 1.16 1.42 NAgp inhibition dasabuvir (1.03-1.32) (1.26-1.59)by Viekirax ↑ keto- The magnitude of interaction was similarketoconazole without conazole to that observed with Viekirax + dasabuvir.and dasabuvir ↑ The magnitude of interaction was similarparitaprevir/ ombitasvir to that observed with Viekirax + dasabuvir.

ritonavir/ ↑ 1.72 2.16 NAombitasvir paritaprevir (1.32-2.26) (1.76-2.66)

Medicinal product no longer authorised

Medicinal GIVEN EFFECT Cmax AUC Ctrough Clinical Comments

Product/Poss WITHible

Mechanismof

Interaction

Itraconazole Viekirax + Not Studied. Expected: Concomitant use is

Posaconazole dasabuvir contraindicated (see↑ itraconazole section 4.3).

Mechanism: ↑ posaconazole

CYP3A4 Viekirax ↑ paritaprevirand/or P-gp without ↑ dasabuvirinhibition by dasabuviritraconazole,posaconazoleandparitaprevir/ritonavir/ombitasvir

Voriconazole Viekirax Not studied. Expected in CYP2C19 Extensive Concomitant use iswith or Metabolisers: contraindicated (see section

Mechanism: without 4.3).

CYP2C19 dasabuvir ↓ voriconazoleinduction and ↑ paritaprevir

CYP3A4 ↑ dasabuvirinhibition byritonavir Not studied. Expected in CYP2C19 Poor Metabolisers:

↑ voriconazole↑ dasabuvir↑ paritaprevir

ANTI-GOUT

Colchicine Viekirax Not Studied. Expected: A reduction in colchicine

Mechanism: with or dosage or an interruption of

CYP3A4 without ↑ colchicine colchicine treatment isinhibition by dasabuvir recommended in patientsritonavir. with normal renal or hepaticfunction if treatment with

Viekirax with or withoutdasabuvir is required. Use ofcolchicine is contraindicatedwith Viekirax with orwithout dasabuvir inpatients with renal orhepatic impairment (seesections 4.3 and 4.4).

ANTIHISTAMINES

Astemizole Viekirax Not Studied. Expected: Concomitant use is

Terfenadine with or contraindicated (see section

Mechanism: without ↑ astemizole/terfenadine 4.3).

CYP3A4 dasabuvir

Medicinal product no longer authorised

Medicinal GIVEN EFFECT Cmax AUC Ctrough Clinical Comments

Product/Poss WITHible

Mechanismof

Interactioninhibition byritonavir.

Fexofenadine Viekirax Not Studied. Expected: Caution should be usedwith or when Viekirax with or

Mechanism: without ↑ fexofenadine without dasabuvir is

OATP1B1 dasabuvir coadministered withinhibition by fexofenadine.

paritaprevir.

ANTIHYPERLIPIDAEMICS

Gemfibrozil Paritaprevir/ ↑ 1.21 1.38 NA Concomitant use of600 mg twice ritonavir + paritaprevir (0.94-1.57) (1.18-1.61) Viekirax with dasabuvir isdasabuvirdaily ↑ dasabuvir 2.01 11.25 NA contraindicated (see(1.71-2.38) (9.05-13.99) section 4.3).

Mechanism:

Increase in Viekirax Not studied; No dose adjustment ofdasabuvir without No interaction expected when gemfibrozil is used in gemfibrozil is necessary.

exposure is dasabuvir combination with Viekirax without dasabuvir.

possibly due No dose adjustmentto CYP2C8 needed for Viekirax.inhibition andincrease inparitaprevirpossibly dueto OATP1B1inhibition bygemfibrozil.

Lomitapide Viekirax Not Studied. Expected: Concomitant use iswith or contraindicated (see

Mechanism: without lomitapide section 4.3).

CYP3A4 dasabuvirinhibition byritonavir.

ANTIMYCOBACTERIALS

Rifampicin Viekirax Not Studied. Expected: Concomitant use iswith or contraindicated (see section

Mechanism: without ↓ ombitasvir 4.3).

CYP3A4 dasabuvir ↓ paritaprevirinduction by ↓ dasabuvirrifampicin.

ANTIPSYCHOTICS

Lurasidone Viekirax Not Studied. Expected: Concomitant use is

Pimozide with or contraindicated (see section

Quetiapine without ↑ pimozide 4.3).

dasabuvir ↑ quetiapine

Mechanism: ↑ lurasidone

Medicinal product no longer authorised

Medicinal GIVEN EFFECT Cmax AUC Ctrough Clinical Comments

Product/Poss WITHible

Mechanismof

Interactioninhibition byritonavir.

ANTITPLATELET AGENTS

Ticagrelor Viekirax Not studied. Expected: Concomitant use iswith or contraindicated (see section

Mechanism: without ↑ ticagrelor 4.3).

CYP3A4dasabuvirinhibition byritonavir

BIGUANIDE ORAL ANTIHYPERGLYCEMICS

Metformin Viekirax + ↓ metformin 0.77 0.90 No dose adjustmentdasabuvir (0.71-0.83) (0.84-0.97) NA needed for metformin500 mg single ↔ ombitasvir 0.92 1.01 1.01 when co-administered withdose (0.87-0.98) (0.97-1.05) (0.98-1.04) Viekirax with and without↓ paritaprevir 0.63 0.80 1.22dasabuvir.

(0.44-0.91) (0.61-1.03) (1.13-1.31)↔ dasabuvir 0.83 0.86 0.95(0.74-0.93) (0.78-0.94) (0.84-1.07)

Viekirax Not studied.without Similar effect expected as observed with Viekirax +dasabuvir dasabuvir.

CALCIUM CHANNEL BLOCKERS

Amlodipine Viekirax + ↑ 1.26 2.57 Decrease amlodipine dose

NAdasabuvir amlodipine (1.11-1.44) (2.31-2.86) by 50% and monitor5 mg single ↔ 1.00 1.00 1.00 patients for clinical effects.

dose ombitasvir (0.95-1.06) (0.97-1.04) (0.97-1.04)↓ 0.77 0.78 0.88

Mechanism: paritaprevir (0.64-0.94) (0.68-0.88) (0.80-0.95)

CYP3A4 ↔ dasabuvir 1.05 1.01 0.95inhibition by (0.97-1.14) (0.96-1.06) (0.89-1.01)ritonavir. Viekirax Not studied:without Similar effect expected as observed with Viekirax +dasabuvir dasabuvir.

Diltiazem Viekirax Not studied. Expected: Caution is advised due to

Verapamil with or the expected increase inwithout ↑ diltiazem, verapamil paritaprevir exposures.

Mechanism: dasabuvir

CYP3A4/P- ↑ paritaprevir

Dose decrease and clinicalgp inhibition. ↑/↔ dasabuvirmonitoring of calciumchannel blockers isrecommended when co-administered with Viekiraxwith and withoutdasabuvir.

Nifedipine Viekirax Not studied. Expected: Dose decrease and clinicalwith or monitoring of calcium

Mechanism: without ↑ nifedipine channel blockers is

CYP3A4dasabuvir recommended when co-inhibition

Medicinal product no longer authorised

Medicinal GIVEN EFFECT Cmax AUC Ctrough Clinical Comments

Product/Poss WITHible

Mechanismof

Interactionadministered with Viekiraxwith and withoutdasabuvir.

CONTRACEPTIVES

Ethinyloestra Viekirax ↔ 1.16 1.06 1.12 Ethinyloestradiol-diol/ with or ethinyloestra (0.90-1.50) (0.96-1.17) (0.94-1.33) containing oralnorgestimate without diol contraceptives aredasabuvir Norgestimate metabolites: contraindicated (see0.035/0.25 mg ↑ norgestrel 2.26 2.54 2.93 section 4.3).

once daily (1.91-2.67) (2.09-3.09) (2.39-3.57)↑ nor- 2.01 2.60 3.11

Mechanism: elgestromine (1.77-2.29) (2.30-2.95) (2.51-3.85)possibly due ↔ 1.05 0.97 1.00to UGT ombitasvir (0.81-1.35) (0.81-1.15) (0.88-inhibition by 1.12)paritaprevir, ↓ 0.70 0.66 0.87ombitasvir paritaprevir (0.40-1.21) (0.42-1.04) (0.67-1.14)and ↓ dasabuvir 0.51 0.48 0.53dasabuvir. (0.22-1.18) (0.23-1.02) (0.30-0.95)

Nor- Viekirax + ↔ nor- 0.83 0.91 0.85 No dose adjustment isethindrone dasabuvir ethindrone (0.69-1.01) (0.76-1.09) (0.64-1.13) necessary for(progestin ↔ 1.00 0.99 0.97 norethindrone or Viekiraxonly pill) ombitasvir (0.93-1.08) (0.94-1.04) (0.90-1.03) with or without dasabuvir.0.35 mg once ↑ 1.24 1.23 1.43daily paritaprevir (0.95-1.62) (0.96-1.57) (1.13-1.80)↔ dasabuvir 1.01 0.96 0.95(0.90-1.14) (0.85-1.09) (0.80-1.13)

Viekirax Not studied.without Similar effect expected as observed with Viekirax +dasabuvir dasabuvir.

DIURETICS

Furosemide Viekirax + ↑ 1.42 1.08 NA Patients should bedasabuvir furosemide (1.17-1.72) (1.00-1.17) monitored for clinical20 mg single ↔ 1.14 1.07 1.12 effects; a decrease inombitasvir (1.03-1.26) (1.01-1.12) (1.08-1.16) furosemide dose of up todose↔ 0.93 0.92 1.26 50% may be required.

paritaprevir (0.63-1.36) (0.70-1.21) (1.16-1.38)

Mechanism: ↔ dasabuvir 1.12 1.09 1.06possibly due (0.96-1.31) (0.96-1.23) (0.98-1.14) No dose adjustmentto UGT1A1 Viekirax Not studied. needed for Viekirax withinhibition by without Similar effect expected as observed with Viekirax + or without dasabuvir.paritaprevir, dasabuvir dasabuvir.

ombitasviranddasabuvir.

ERGOT ALKALOIDS

Meicinal product no longer authori ed

Medicinal GIVEN EFFECT Cmax AUC Ctrough Clinical Comments

Product/Poss WITHible

Mechanismof

Interaction

Ergotamine Viekirax Not studied. Expected: Concomitant use is

Dihydroergot with or contraindicated (see sectionamine without ↑ ergot derivatives 4.3).

Ergonovine dasabuvir

Methylergometrine

Mechanism:

CYP3A4inhibition byritonavir.

GLUCOCORTICOIDS (INHALED)

Fluticasone Viekirax Not studied. Expected: Concomitant use ofwith or fluticasone can increase

Mechanism: without ↑ fluticasone systemic exposures of

CYP3A4 dasabuvir fluticasone. Concomitantinhibition by use of Viekirax andritonavir. fluticasone particularlylong-term use, should onlybe initiated if the potentialbenefit of treatmentoutweighs the risk ofsystemic corticosteroideffects (see section 4.4).

GASTROINTESTINAL PRODUCTS (PROPULSIVE)

Cisapride Viekirax Not studied. Expected: Concomitant use is

Mechanism: with or contraindicated (see section

CYP3A4 without ↑ cisapride 4.3).

inhibition by dasabuvirritonavir.

HCV ANTIVIRALS

Sofosbuvir Viekirax + ↑ sofosbuvir 1.61 2.12 NA No dose adjustmentdasabuvir (1.38-1.88) (1.91-2.37) needed for sofosbuvir400 mg once ↑ GS-331007 1.02 1.27 NA when administered with(0.90-1.16) (1.14-1.42)daily Viekirax with or without↔ ombitasvir 0.93 0.93 0.92dasabuvir.(0.84-1.03) (0.87-0.99) (0.88-0.96)

Mechanism: ↔ 0.81 0.85 0.82

BCRP and P- paritaprevir (0.65-1.01) (0.71-1.01) (0.67-1.01)gp inhibition ↔ dasabuvir 1.09 1.02 0.85by (0.98-1.22) (0.95-1.10) (0.76-0.95)paritaprevir, Viekirax The magnitude of interaction was similar to that observedritonavir and without with Viekirax + dasabuvir.

dasabuvir dasabuvir

HERBAL PRODUCTS

Medicinal prouct no longer authorised

Medicinal GIVEN EFFECT Cmax AUC Ctrough Clinical Comments

Product/Poss WITHible

Mechanismof

Interaction

St. John's Wort (hypericum Viekirax with or without Not studied. Expected: Concomitant use isperforatum) dasabuvir contraindicated (see section↓ dasabuvir 4.3).

Mechanism: ↓ ombitasvir

CYP3A4 induction by St. ↓ paritaprevir

John's Wort

HIV ANTIVIRALS: PROTEASE INHIBITORS

For a general comment on treatment of HIV co-infected patients, including a discussion on different antiretroviralregimens that may be used, please see section 4.4 (Treatment of HIV co-infected patients).

Atazanavir Viekirax + ↔ 0.91 1.01 0.90 The recommended dose ofdasabuvir atazanavir (0.84-0.99) (0.93-1.10) (0.81-1.01) atazanavir is 300 mg,300 mg once without ritonavir, indaily (given at combination with Viekiraxthe same with dasabuvir. Atazanavirtime) must be administered atthe same time as Viekirax

Mechanism: with dasabuvir. Ritonavir

Increase in dose in Viekirax willparitaprevir provide atazanavirexposures pharmacokineticmay be due to enhancement).

inhibition of

OATP1B1/B3 No dose adjustmentand CYP3A needed for Viekirax withby atazanavir. dasabuvir.

Treatment with atazanavir+ Viekirax withoutdasabuvir is notrecommended-(↑↓ ombitasvir 0.77 0.83 0.89 paritaprevir).

(0.70-0.85) (0.74-0.94) (0.78-1.02)↑ 1.46 1.94 3.26 The combination ofparitaprevir (1.06-1.99) (1.34-2.81) (2.06-5.16) atazanavir and Viekirax +↔ dasabuvir 0.83 0.82 0.79 dasabuvir increase(0.71-0.96) (0.71-0.94) (0.66-0.94) bilirubin levels, inparticular when ribavirin ispart of the hepatitis Cregimen (see sections 4.4and 4.8).↔ The magnitude of interaction was similaratazanavir to that observed with Viekirax + dasabuvir.

↑ 2.74 2.87 3.71paritaprevir (1.76-4.27) (2.08-3.97) (2.87-4.79)

Medicinal product no longer authorised

Medicinal GIVEN EFFECT Cmax AUC Ctrough Clinical Comments

Product/Poss WITHible

Mechanismof

Interaction

Viekirax ↔ The magnitude of interaction was similarwithout ombitasvir to that observed with Viekirax + dasabuvir.

dasabuvir

Atazanavir/ Viekirax + ↔ 1.02 1.19 1.68ritonavir dasabuvir atazanavir (0.92-1.13) (1.11-1.28) (1.44-1.95)↔ 0.83 0.90 1.00ombitasvir (0.72-0.96) (0.78-1.02) (0.89-1.13)300/100 mg↑ 2.19 3.16 11.95once daily paritaprevir (1.61-2.98) (2.40-4.17) (8.94-(administered 15.98)12 hours ↔ dasabuvir 0.81 0.81 0.80apart) (0.73-0.91) (0.71-0.92) (0.65-0.98)

Viekirax Not studied:

Mechanism: without Similar effect expected as observed with Viekirax +

Increase in dasabuvir dasabuvir.

paritaprevirexposuresmay be due toinhibition of

OATP1B1/B3and CYP3Aby atazanavirand CYP3Aby theadditionaldose ofritonavir.

Darunavir Viekirax + ↓ darunavir 0.92 0.76 0.52 The recommended dose ofdasabuvir (0.87-0.98) (0.71-0.82) (0.47-0.58) darunavir is 800 mg once800 mg once ↔ 0.86 0.86 0.87 daily, without ritonavir,ombitasvir (0.77-0.95) (0.79-0.94) (0.82-0.92)daily (given at when administered at the↑ 1.54 1.29 1.30the same same time as Viekirax +paritaprevir (1.14-2.09) (1.04-1.61) (1.09-1.54)time) ↔ dasabuvir 1.10 0.94 0.90 dasabuvir (ritonavir dose(0.88-1.37) (0.78-1.14) (0.76-1.06) in Viekirax will provide

Mechanism: Viekirax ↔ darunavir 0.99 0. 92 0.74 darunavir pharmacokinetic

Unknown without (0.92-1.08) (0.84-1.00) (0.63-0.88) enhancement). Thisdasabuvir regimen can be used in the↔ The magnitude of interaction was similar absence of extensive PIombitasvir to that observed with Viekirax + dasabuvir. resistance (i.e. lack of↑ 2.09 1.94 1.85 darunavir associatedparitaprevir (1.35-3.24) (1.36-2.75) (1.41-2.42)

RAMs), see also section4.4.

Medicinal product no longer authorised

Medicinal GIVEN EFFECT Cmax AUC Ctrough Clinical Comments

Product/Poss WITHible

Mechanismof

Interaction

No dose adjustmentneeded for Viekirax withdasabuvir.

Darunavir combined with

Viekirax + dasabuvir is notrecommended in patientswith extensive PIresistance.

Treatment with darunavir+ Viekirax withoutdasabuvir is notrecommended-(↑paritaprevir).

Darunavir/ Viekirax + ↔ darunavir 0.87 0.80 0.57ritonavir dasabuvir (0.79-0.96) (0.74-0.86) (0.48-0.67)↓ ombitasvir 0.76 0.73 0.73(0.65-0.88) (0.66-0.80) (0.64-0.83)600/100 mg↓ 0.70 0.59 0.83twice daily paritaprevir (0.43-1.12) (0.44-0.79) (0.69-1.01)↓ dasabuvir 0.84 0.73 0.54

Mechanism: (0.67-1.05) (0.62-0.86) (0.49-0.61)

Unknown Viekirax Not studied.

without Similar effect expected as observed with Viekirax +dasabuvir dasabuvir.

darunavir/ Viekirax + ↑ darunavir 0.79 1.34 0.54ritonavir dasabuvir (0.70-0.90) (1.25-1.43) (0.48-0.62)↔ 0.87 0.87 0.87ombitasvir (0.82-0.93) (0.81-0.93) (0.80-0.95)800/100 mg↓ 0.70 0.81 1.59once daily paritaprevir (0.50-0.99) (0.60-1.09) (1.23-2.05)↓ dasabuvir 0.75 0.72 0.65(administered (0.64-0.88) (0.64-0.82) (0.58-0.72)12 hours Viekirax Not studied:apart) without Similar effect expected as observed with Viekirax +dasabuvir dasabuvir.

Mechanism:

Unknown

Lopinavir/Viekirax + ↔ lopinavir 0.87 0.94 1.15 Concomitant use isritonavir dasabuvir (0.76-0.99) (0.81-1.10) (0.93-1.42) contraindicated (see↔ 1.14 1.17 1.24 section 4.3).

ombitasvir (1.01-1.28) (1.07-1.28) (1.14-1.34)400/100 mg↑ 2.04 2.17 2.36twice daily1paritaprevir (1.30-3.20) (1.63-2.89) (1.00-5.55)

Medicinal product no longer authori ed

Medicinal GIVEN EFFECT Cmax AUC Ctrough Clinical Comments

Product/Poss WITHible

Mechanismof

Interaction↔ 0.99 0.93 0.68

Mechanism: dasabuvir (0.75-1.31) (0.75-1.15) (0.57-0.80)

Increase in Viekirax ↔ lopinavir The magnitude of interaction was similar toparitaprevir without that observed with Viekirax + dasabuvir.

dasabuvir ↑ The magnitude of interaction was similar toexposuresombitasvir that observed with Viekirax + dasabuvir.may be due to ↑ 4.76 6.10 12.33inhibition of paritaprevir (3.54-6.39) (4.30-8.67) (7.30-20.84)

CYP3A/efflux transportersby lopinavirand higherdose ofritonavir

Indinavir Viekirax Not studied. Expected Concomitant use is

Saquinavir with or contraindicated (see

Tipranavir without ↑ paritaprevir section 4.3).

dasabuvir

Mechanism:

CYP3A4inhibition byproteaseinhibitors.

HIV ANTIVIRALS: NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS

Rilpivirine2 Viekirax + ↑ rilpivirine 2.55 3.25 3.62 Co-administration ofdasabuvir (2.08-3.12) (2.80-3.77) (3.12-4.21) Viekirax with rilpivirine25 mg once ↔ 1.11 1.09 1.05 once daily should only beombitasvir (1.02-1.20) (1.04-1.14) (1.01-1.08)daily considered in patients↑ 1.30 1.23 0.95administered without known QT-paritaprevir (0.94-1.81) (0.93-1.64) (0.84-1.07)in the prolongation, and withoutmorning, with ↔ dasabuvir 1.18 1.17 1.10 other QT-prolongation co-food (1.02-1.37) (0.99-1.38) (0.89-1.37) medications. If the Viekirax Not studied: combination is used,

Mechanism: without Similar effect expected as observed with Viekirax + repeated ECG-monitoring

CYP3A4 dasabuvir dasabuvir. should be done, see sectioninhibition by 4.4. No dose adjustmentritonavir. needed for Viekirax withor without dasabuvir.

Efavirenz/ Viekirax Co-administration of efavirenz (enzyme inducer) based Concomitant use withemtricitabine/ with or regimens with paritaprevir /ritonavir + dasabuvir resulted efavirenz istenofovir without in ALT elevations and therefore, early discontinuation of contraindicated (seethe study.

disoproxil dasabuvir section 4.3).

fumarate600/300/200mg once daily

Mdicinal product no longer authorised

Medicinal GIVEN EFFECT Cmax AUC Ctrough Clinical Comments

Product/Poss WITHible

Mechanismof

Interaction

Mechanism:

possible

CYP3A4induction byefavirenz.

Nevirapine Viekirax Not Studied. Expected: Concomitant use is contra-etravirine with or indicated (see section 4.3).

without ↓ ombitasvirdasabuvir ↓ paritaprevir↓ dasabuvir

HIV ANTIVIRALS: INTEGRASE STRAND TRANSFER INHIBITOR

Dolutegravir Viekirax + ↑ 1.22 1.38 1.36 No dose adjustmentdasabuvir dolutegravir (1.15-1.29) (1.30-1.47) (1.19-1.55) needed for dolutegravir50 mg once ↔ 0.96 0.95 0.92 when coadministered withdaily ombitasvir (0.89-1.03) (0.90-1.00) (0.87-0.98) Viekirax with or withoutdasabuvir.↔ 0.89 0.84 0.66

Mechanism:paritaprevir (0.69-1.14) (0.67-1.04) (0.59-0.75)possibly dueto UGT1A1 ↔ dasabuvir 1.01 0.98 0.92inhibition by (0.92-1.11) (0.92-1.05) (0.85-0.99)paritaprevir, Viekirax Not studied.dasabuvir and without Similar effect expected as observed with Viekirax +ombitasvir dasabuvir dasabuvir.

and CYP3A4inhibition byritonavir

Raltegravir Viekirax + ↑ raltegravir 2.33 2.34 2.00 No dose adjustment isdasabuvir (1.66-3.27) (1.70-3.24) (1.17-3.42) necessary for raltegravir or400 mg twice No clinically relevant changes in dasabuvir, paritaprevir Viekirax with or withoutand ombitasvir exposures (based on comparison withdaily dasabuvir.historical data) were observed during co-administration.

Viekirax ↑ raltegravir 1.22 1.20 1.13

Mechanism:

without (0.78-1.89) (0.74-1.95) (0.51-2.51)

Increase indasabuvirraltegravir No clinically relevant changes in dasabuvir, paritaprevirexposures and ombitasvir exposures (based on comparison withmay be due to historical data) were observed during co-administration.

UGT1A1inhibition byparitaprevir,ombitasvir.

and dasabuvir

Medicinal product no longer authorised

Medicinal GIVEN EFFECT Cmax AUC Ctrough Clinical Comments

Product/Poss WITHible

Mechanismof

Interaction

HIV ANTIVIRALS: NUCLEOSIDE INHIBITORS

Abacavir/ Viekirax + ↔ abacavir 0.87 0.94 NA No dose adjustmentlamivudine dasabuvir (0.78-0.98) (0.90-0.99) needed for abacavir orlamivudine when co-↓ 0.78 0.88 1.29600/300 mg administered with Viekiraxlamivudine (0.72-0.84) (0.82-0.93) (1.05-1.58)once daily with or without dasabuvir.↔ 0.82 0.91 0.92ombitasvir (0.76-0.89) (0.87-0.95) (0.88-0.96)↔ 0.84 0.82 0.73paritaprevir (0.69-1.02) (0.70-0.97) (0.63-0.85)↔ dasabuvir 0.94 0.91 0.95(0.86-1.03) (0.86-0.96) (0.88-1.02)

Viekirax Not studied.

without Similar effect expected as observed with Viekirax +dasabuvir dasabuvir.

Em- Viekirax + ↔ em- 1.05 1.07 1.09 No dose adjustment istricitabine/ dasabuvir tricitabine (1.00-1.12) (1.00-1.14) (1.01-1.17) necessary fortenofovir ↔ tenofovir 1.07 1.13 1.24 emtricitabine/tenofovir and(0.93-1.24) (1.07-1.20) (1.13-1.36) Viekirax with or without↔ 0.89 0.99 0.97200 mg once dasabuvir.

ombitasvir (0.81-0.97) (0.93-1.05) (0.90-1.04)daily/300 mg ↓ 0.68 0.84 1.06once daily paritaprevir (0.42-1.11) (0.59-1.17) (0.83-1.35)↔ dasabuvir 0.85 0.85 0.85(0.74-0.98) (0.75-0.96) (0.73-0.98)

Viekirax ↔ em- The magnitude of interaction was similarwithout tricitabine to that observed with Viekirax + dasabuvir.

dasabuvir ↔ tenofovir 0.80 1.01 1.13(0.71-0.90) (0.96-1.07) (1.06-1.21)↔ The magnitude of interaction was similarombitasvir to that observed with Viekirax + dasabuvir.

↔ 1.02 1.04 1.09paritaprevir (0.63-1.64) (0.74-1.47) (0.88-1.35)

HIV ANTIVIRALS: PHARMACOKINETIC ENHANCER

Cobicistat- Viekirax Not Studied. Expected: Concomitant use iscontaining with or contraindicated (See sectionregimens without ↑ ombitasvir 4.3).

Mechanism: dasabuvir ↑ paritaprevir

CYP3A4 ↑ dasabuvirinhibition bycobicistat

HMG CoA REDUCTASE INHIBITOR

Viekirax + ↑ 7.13 2.59 0.59dasabuvir rosuvastatin (5.11-9.96) (2.09-3.21) (0.51-0.69)↔ 0.92 0.89 0.88ombitasvir (0.82-1.04) (0.83-0.95) (0.83-0.94)

Medicinal product no longer authorised

Medicinal GIVEN EFFECT Cmax AUC Ctrough Clinical Comments

Product/Poss WITHible

Mechanismof

Interaction

Rosuvastatin ↑ 1.59 1.52 1.43 The maximum daily doseparitaprevir (1.13-2.23) (1.23-1.90) (1.22-1.68) of rosuvastatin should be5 mg once ↔ dasabuvir 1.07 1.08 1.15 5 mg (see section 4.4).(0.92-1.24) (0.92-1.26) (1.05-1.25)daily

No dose adjustmentneeded for Viekirax with

Mechanism: dasabuvir

OATP1Binhibition byparitaprevir Viekirax ↑ 2.61 1.33 0.65 The maximum daily doseand BCRP without rosuvastatin (2.01-3.39) (1.14-1.56) (0.57-0.74) of rosuvastatin should beinhibition by dasabuvir 10 mg (see section 4.4).paritaprevir, ↔ The magnitude of interaction was similarombitasvir to that observed with Viekirax + dasabuvir.ritonavir or No dose adjustmentdasabuvir. ↑ 1.40 1.22 1.06 needed for Viekirax.

paritaprevir (1.12-1.74) (1.05-1.41) (0.85-1.32)

Pravastatin Viekirax+ ↑ pravastatin 1.37 1.82 NA Reduce pravastatin dose bydasabuvir (1.11-1.69) (1.60-2.08) 50%.

10 mg once ↔ 0.95 0.89 0.94ombitasvir (0.89-1.02) (0.83-0.95) (0.89-0.99)daily No dose adjustment↔ dasabuvir 1.00 0.96 1.03(0.87-1.14) (0.85-1.09) (0.91-1.15) needed for Viekirax with↔ 0.96 1.13 1.39 or without dasabuvir.

Mechanism: paritaprevir (0.69-1.32) (0.92-1.38) (1.21-1.59)

OATP1B1inhibition by Viekirax ↑ pravastatin The magnitude of interaction was similarparitaprevir. without to that observed with Viekirax + dasabuvir.

dasabuvir ↔ The magnitude of interaction was similarombitasvir to that observed with Viekirax + dasabuvir.

↑ 1.44 1.33 1.28paritaprevir (1.15-1.81) (1.09-1.62) (0.83-1.96)

Fluvastatin Viekirax Not studied. Expected: Concomitant use withwith or fluvastatin and pitavastatin

Mechanism: without ↑ fluvastatin is not recommended (see

OATP1B/BC dasabuvir section 4.4).

RP inhibition ↑ pitavastatin A temporary suspension ofby fluvastatin and pitavastatinparitaprevir is recommended for theduration of treatment with

Pitavastatin Viekirax. If statin

Mechanism: treatment is required

OATP1B during the treatmentinhibition by period, a switch to doseparitaprevir reduced pravastatin orrosuvastatin is possible.

Medicinal product no longer authorised

Medicinal GIVEN EFFECT Cmax AUC Ctrough Clinical Comments

Product/Poss WITHible

Mechanismof

Interaction

Lovastatin Viekirax Not studied. Expected: Concomitant use is

Simvastatin with or contraindicated (seeatorvastatin without ↑ lovastatin, simvastatin, atorvastatin section 4.3).

dasabuvir

Mechanism:

CYP3A4/OA

TP1Binhibition

IMMUNOSUPPRESSANTS

Ciclosporin Viekirax + ↑ 1.01 5.82 15.8 When starting co-dasabuvir ciclosporin (0.85-1.20) (4.73-7.14) (13.8- administration with30 mg once 18.09) Viekirax, give one fifth of↔ 0.99 1.08 1.15 the total daily dose ofdaily singleombitasvir (0.92-1.07) (1.05-1.11) (1.08-1.23) ciclosporin once daily withdose3↑ 1.44 1.72 1.85 Viekirax. Monitorparitaprevir (1.16-1.78) (1.49-1.99) (1.58-2.18) ciclosporin levels and

Mechanism: ↓ dasabuvir 0.66 0.70 0.76 adjust dose and/or dosing

Effect on (0.58-0.75) (0.65-0.76) (0.71-0.82) frequency as needed.

ciclosporin is Viekirax ↑ 0.83 4.28 12.8due to without ciclosporin (0.72-0.94) (3.66-5.01) (10.6-15.6) No dose adjustmentneeded for Viekirax with

CYP3A4 dasabuvir↔ The magnitude of interaction was similar or without dasabuvir.

inhibition byombitasvir to that observed with Viekirax + dasabuvir.

ritonavir and ↑ 1.39 1.46 1.18increase in paritaprevir (1.10-1.75) (1.29-1.64) (1.08-1.30)paritaprevirexposuresmay be due to

OATP/BCRP/

P-gpinhibition byciclosporin.

Everolimus Viekirax + ↑ 4.74 27.1 16.1 Co-administration ofdasabuvir everolimus (4.29-5.25) (24.5-30.1) (14.5- Viekirax with everolimus0.75 mg 17.9) is not recommended↔ 0.99 1.02 1.02single dose because of a significantombitasvir (0.95-1.03) (0.99-1.05) (0.99-1.06)increase in everolimus↔ 1.22 1.26 1.06

Mechanism: paritaprevir (1.03-1.43) (1.07-1.49) (0.97-1.16) exposures which cannot be

Effect on ↔ 1.03 1.08 1.14 properly dose adjustedeverolimus is dasabuvir (0.90-1.18) (0.98-1.20) (1.05-1.23) with available dosedue to Viekirax Not studied: strengths (see section 4.4).

CYP3A4 without Similar effect is expected as observed with Viekirax +inhibition by dasabuvir dasabuvir.

ritonavir

Sirolimus Viekirax + ↑ sirolimus 6.40 38.0 19.6 Concomitant use ofdasabuvir (5.34-7.68) (31.5-45.8) (16.7- sirolimus with Viekirax22.9)6 and dasabuvir is not

Medicinal product no longer authorised

Medicinal GIVEN EFFECT Cmax AUC Ctrough Clinical Comments

Product/Poss WITHible

Mechanismof

Interaction0.5 mg single ↔ 1.03 1.02 1.05 recommended unless thedose5 ombitasvir (0.93-1.15) (0.96-1.09) (0.98-1.12) benefits outweigh the risks↔ 1.18 1.19 1.16

Mechanism: paritaprevir (0.91-1.54) (0.97-1.46) (1.00-1.34) (see section 4.4). If

Effect on ↔ dasabuvir 1.04 1.07 1.13 sirolimus is used togethersirolimus is (0.89-1.22) (0.95-1.22) (1.01-1.25) with Viekirax + dasabuvir,due to administer sirolimus

CYP3A4 Viekirax Not studied: 0.2 mg twice a weekinhibition by without Similar effect is expected as observed with Viekirax + (every 3 or 4 days on theritonavir dasabuvir dasabuvir same two days each week).

Sirolimus bloodconcentrations should bemonitored every 4 to 7days until 3 consecutivetrough levels have shownstable concentrations ofsirolimus. Sirolimus doseand/or dosing frequencyshould be adjusted asneeded.

5 days after completion of

Viekirax + dasabuvirtreatment, the sirolimusdose and dosing frequencyprior to receiving Viekiraxshould be resumed, alongwith routine monitoring ofsirolimus bloodconcentrations.

Tacrolimus Viekirax + ↑ tacrolimus 3.99 57.1 16.6 Concomitant use ofdasabuvir (3.21-4.97) (45.5-71.7) (13.0-21.2) tacrolimus with Viekirax2 mg single ↔ 0.93 0.94 0.94 and dasabuvir is not7 ombitasvir (0.88-0.99) (0.89-0.98) (0.91-0.96)dose recommended unless the↓ 0.57 0.66 0.73 benefits outweigh the risksparitaprevir (0.42-0.78) (0.54-0.81) (0.66-0.80)

Mechanism: (see section 4.4).

↔ dasabuvir 0.85 0.90 1.01

Effect on (0.73-0.98) (0.80-1.02) (0.91-1.11) If tacrolimus with Viekiraxtacrolimus is Viekirax ↑ tacrolimus 4.27 85.8 24.6 and dasabuvir are useddue to without (3.49-5.22) (67.9-108) (19.7-30.8) concomitantly, tacrolimus

CYP3A4 dasabuvir ↔ The magnitude of interaction was similar should not be administeredinhibition by ombitasvir to that observed with Viekirax + dasabuvir. on the day Viekirax andritonavir. ↓ dasabuvir are initiated.paritaprevir Beginning the day after

Viekirax and dasabuvir are

Medicinal product no longer authorised

Medicinal GIVEN EFFECT Cmax AUC Ctrough Clinical Comments

Product/Poss WITHible

Mechanismof

Interactioninitiated; reinitiatetacrolimus at a reduceddose based on tacrolimusblood concentrations. Therecommended tacrolimusdosing is 0.5 mg every 7days.

Tacrolimus whole bloodconcentrations should bemonitored upon initiationand throughout co-administration with

Viekirax and dasabuvirand the dose and/or dosingfrequency should beadjusted as needed. Uponcompletion of Viekiraxand dasabuvir treatment,the appropriate dose anddosing frequency oftacrolimus should beguided by assessment oftacrolimus bloodconcentrations.

INHALED BETA AGONISTS

Salmeterol Viekirax Not studied. Expected: Concomitant use is

Mechanism: with or contraindicated (see section

CYP3A4 without ↑ salmeterol 4.3).

inhibition by dasabuvirritonavir.

INSULIN SECRETAGOGUES

Repaglinide Viekirax Not Studied. Expected: Caution should be used and

Mechanism: with or dose decrease maybe

OATP1B1 without ↑ repaglinide needed for repaglinideinhibition by dasabuvir when administered withparitaprevir. Viekirax with or withoutdasabuvir.

MUSCLE RELAXANTS

Carisoprodol Viekirax ↓ 0.54 0.62 NA No dose adjustment250 mg single with Carisoprodol (0.47-0.63) (0.55-0.70) required for carisoprodol;dose dasabuvir increase dose if clinically↔ ombitasvir 0.98 0.95 0.96 indicated.

(0.92-1.04) (0.92-0.97) (0.92-0.99)↔ 0.88 0.96 1.14paritaprevir (0.75-1.03) (0.85-1.08) (1.02-1.27)edicinal product no longer authorised

Medicinal GIVEN EFFECT Cmax AUC Ctrough Clinical Comments

Product/Poss WITHible

Mechanismof

Interaction

Mechanism: ↔ dasabuvir 0.96 1.02 1.00

CYP2C19 (0.91-1.01) (0.97-1.07) (0.92-1.10)induction byritonavir

Viekirax Not studied.

without Similar effect expected as observed with Viekirax +dasabuvir dasabuvir.

Cyclobenzapr Viekirax ↓ cycloben- 0.68 0.60 NA No dose adjustmentine 5 mg with zaprine (0.61-0.75) (0.53-0.68) required forsingle dose dasabuvir cyclobenzaprine; increase↔ ombitasvir 0.98 1.00 1.01 dose if clinically indicated.

(0.92-1.04) (0.97-1.03) (0.98-1.04)

Mechanism: ↔ paritaprevir 1.14 1.13 1.13decrease (0.99-1.32) (1.00-1.28) (1.01-1.25)possibly due ↔ dasabuvir 0.98 1.01 1.13to CYP1A2 (0.90-1.07) (0.96-1.06) (1.07-1.18)induction byritonavir

Viekirax Not studied.

without Similar effect expected as observed with Viekirax +dasabuvir dasabuvir.

NARCOTIC ANALGESICS

Paracetamol Viekirax ↔ 1.02 1.17 NA No dose adjustment(as given in a + paracetamol (0.89-1.18) (1.09-1.26) necessary for paracetamolfixed-dose dasabuvir ↔ ombitasvir 1.01 0.97 0.93 when administered withhydrocodone/ (0.93-1.10) (0.93-1.02) (0.90-0.97) Viekirax with or withoutparacetamol) ↔ paritaprevir 1.01 1.03 1.10 dasabuvir.(0.80-1.27) (0.89-1.18) (0.97-1.26)300 mg single ↔ dasabuvir 1.13 1.12 1.16dose (1.01-1.26) (1.05-1.19) (1.08-1.25)

Viekirax Not studied.

without Similar effect expected as observed with Viekirax +dasabuvir dasabuvir.

Hydrocodone Viekirax ↑ hydrocodo 1.27 1.90 NA A reduction of(as given in a + ne (1.14-1.40) (1.72-2.10) hydrocodone dose by 50%fixed-dose dasabuvir Changes for ombitasvir, paritaprevir and dasabuvir the and/or clinical monitoringhydrocodone/ same as shown for paracetamol above should be considered whenparacetamol) Viekirax Not studied. administered with Viekiraxwithout Similar effect expected as observed with Viekirax +with or without dasabuvir .dasabuvir.

5 mg single dasabuvirdose

Mechanism:

CYP3A4inhibition byritonavir

Meicinal product nlonger authorised

Medicinal GIVEN EFFECT Cmax AUC Ctrough Clinical Comments

Product/Poss WITHible

Mechanismof

Interaction

OPIOIDS

Methadone Viekirax + ↔ R- 1.04 1.05 0.94 No dose adjustment isdasabuvir Methadone (0.98-1.11) (0.98-1.11) (0.87-1.01) necessary for methadone20-120 mg ↔ S- 0.99 0.99 0.86 and Viekirax with or8 Methadone (0.91-1.08) (0.89-1.09) (0.76-0.96)once daily without dasabuvir.↔ paritaprevir /ombitasvir/dasabuvir (based on the cross-study comparison)

Viekiraxwithout The magnitude of interaction was similar to that observeddasabuvir with Viekirax + dasabuvir.

Buprenorphine Viekirax + ↑ bu- 2.18 2.07 3.12 No dose adjustment is/ naloxone dasabuvir prenorphine (1.78-2.68) (1.78-2.40) (2.29-4.27) necessary forbuprenorphine/naloxone4-24 mg/1- and Viekirax with or↑ norbu- 2.07 1.84 2.106 mg once without dasabuvir.prenorphine (1.42-3.01) (1.30-2.60) (1.49-2.97)daily8↑ naloxone 1.18 1.28 NA(0.81-1.73) (0.92-1.79)

Mechanism: ↔ ombitasvir/paritaprevir/dasabuvir (based on the cross-

CYP3A4 study comparison)inhibition by Viekirax ↑ bu- 1.19 1.51 1.65ritonavir and without prenorphine (1.01-1.40) (1.27-1.78) (1.30-2.08)

UGT dasabuvir ↑ norbu- The magnitude of interaction was similarprenorphine to that observed with Viekirax + dasabuvir.

inhibition by↔ naloxoneparitaprevir, ↔ ombitasvir/paritaprevir (based on the cross-studyombitasvir comparison)anddasabuvir.

PHOSPHODIESTERASE-(PDE-5) INHIBITORS

Sildenafil Viekirax Not studied. Expected: Concomitant use is(when used with and contraindicated (see sectionfor treatment without ↑ sildenafil 4.3).

of pulmonary dasabuvirhypertension)

Mechanism:

CYP3A4inhibition byritonavir.

PROTON PUMP INHIBITORS

Viekirax + ↓ 0.62 0.62 NA If clinically indicateddasabuvir omeprazole (0.48-0.80) (0.51-0.75) higher doses of↔ 1.02 1.05 1.04ombitasvir (0.95-1.09) (0.98-1.12) (0.98-1.11)↔ 1.19 1.18 0.92paritaprevir (1.04-1.36) (1.03-1.37) (0.76-1.12)↔ dasabuvir 1.13 1.08 1.05(1.03-1.25) (0.98-1.20) (0.93-1.19)

Medicinal product no longer authorised

Medicinal GIVEN EFFECT Cmax AUC Ctrough Clinical Comments

Product/Poss WITHible

Mechanismof

Interaction

Omeprazole Viekirax ↓ 0.48 0.46 NA omeprazole should bewithout omeprazole (0.29-0.78) (0.27-0.77) used.

40 mg once dasabuvir ↔ The magnitude of interaction was similarombitasvir to that observed with Viekirax + dasabuvir.

daily No dose adjustment↔paritaprevir needed for Viekirax withor without dasabuvir.

Mechanism:

CYP2C19induction byritonavir.

Esomeprazole Viekirax Not studied. Expected: If clinically indicated,

Lansoprazole with and ↓ esomeprazole, lansoprazole higher doses of

Mechanism: without esomeprazole/lansoprazole

CYP2C19 dasabuvir may be needed.

induction byritonavir.

SEDATIVES/HYPNOTICS

Zolpidem Viekirax + ↔ zolpidem 0.94 0.95 NA No dose adjustment isdasabuvir (0.76-1.16) (0.74-1.23) necessary for zolpidem.

5 mg single ↔ 1.07 1.03 1.04ombitasvir (1.00-1.15) (1.00-1.07) (1.00-1.08)dose No dose adjustment↓ 0.63 0.68 1.23paritaprevir (0.46-0.86) (0.55-0.85) (1.10-1.38) needed for Viekirax with↔ dasabuvir 0.93 0.95 0.92 or without dasabuvir.

(0.84-1.03) (0.84-1.08) (0.83-1.01)

Viekirax Not studied.

without Similar effect expected as observed with Viekirax +dasabuvir dasabuvir.

Alprazolam Viekirax + ↑ 1.09 1.34 NA Clinical monitoring ofdasabuvir alprazolam (1.03-1.15) (1.15-1.55) patients is recommended.

0.5 mg single ↔ 0.98 1.00 0.98 A decrease in alprazolamombitasvir (0.93-1.04) (0.96-1.04) (0.93-1.04)dose dose can be considered↔ 0.91 0.96 1.12based on clinical response.paritaprevir (0.64-1.31) (0.73-1.27) (1.02-1.23)↔ dasabuvir 0.93 0.98 1.00

Mechanism: (0.83-1.04) (0.87-1.11) (0.87-1.15) No dose adjustment

CYP3A4 Viekirax Not studied. needed for Viekirax withinhibition by without Similar effect expected as observed with Viekirax + or without dasabuvir.

ritonavir dasabuvir dasabuvir.

Oral Viekirax Not studied. Expected: Concomitant use ismidazolam with or contraindicated (see

Triazolam without ↑ midazolam or triazolam section 4.3).

dasabuvir

If parenteral midazolam is

Mechanism:co-administered with

Viekirax with or withoutinhibition bydasabuvir, close clinicalritonavir.

Medicinal prodct no longer authorised

Medicinal GIVEN EFFECT Cmax AUC Ctrough Clinical Comments

Product/Poss WITHible

Mechanismof

Interactionmonitoring for respiratorydepression and/orprolonged sedation shouldbe exercised and dosageadjustment should beconsidered.

Diazepam Viekirax + ↓diazepam 1.18 0.78 NA No dose adjustmentdasabuvir (1.07-1.30) (0.73-0.82) required for diazepam;2 mg single ↓ 1.10 0.56 NA increase dose if clinicallydose nordiazepam (1.03-1.19) (0.45-0.70) indicated.

↔ ombitasvir 1.00 0.98 0.93

Mechanism: (0.93-1.08) (0.93-1.03) (0.88-0.98)

CYP2C19 ↔ 0.95 0.91 0.92induction by paritaprevir (0.77-1.18) (0.78-1.07) (0.82-1.03)ritonavir ↔ dasabuvir 1.05 1.01 1.05(0.98-1.13) (0.94-1.08) (0.98-1.12)

Viekirax Not studied.

without Similar effect expected as observed with Viekirax +dasabuvir dasabuvir.

THYROID HORMONES

Levothyroxine Viekirax Not studied. Expected: Clinical monitoring andwith or dose adjustment may be

Mechanism: without ↑ levothyroxine required for levothyroxine

UGT1A1 dasabuvirinhibition byparitaprevir,ombitasviranddasabuvir.

1. Lopinavir/ritonavir 800/200 mg once daily (administered in the evening) was also administered with

Viekirax with or without dasabuvir. The effect on Cmax and AUC of DAAs and lopinavir was similarto that observed when lopinavir/ritonavir 400/100 mg twice daily was administered with Viekiraxwith or without dasabuvir.

2. Rilpivirine was also administered in the evening with food and at night 4 hours after dinner with

Viekirax + dasabuvir in other two arms in the study. The effect on rilpivirine exposures was similarto that observed when rilpivirine was administered in the morning with food with Viekirax +dasabuvir (shown in the table above).

3. Ciclosporin 100 mg dosed alone, 10 mg administered with Viekirax and 30 mg administered with

Viekirax + dasabuvir. Dose normalized cyclosporine ratios are shown for interaction with Viekiraxwith or without dasabuvir.

4. C12:= concentration at 12 hours following single dose of everolimus.

Medicinal product no longer authorised

Medicinal GIVEN EFFECT Cmax AUC Ctrough Clinical Comments

Product/Poss WITHible

Mechanismof

Interaction5. Sirolimus 2 mg was dosed alone, 0.5 mg administered with Viekirax + dasabuvir. Dose normalizedsirolimus ratios are shown for interaction with Viekirax + dasabuvir.

6. C24:= concentration at 24 hours following single dose of cyclosporine, tacrolimus or sirolimus.

7. Tacrolimus 2 mg was dosed alone, 0.5 mg administered with Viekirax and 2 mg was administeredwith Viekirax + dasabuvir. Dose normalized tacrolimus ratios are shown for interaction with

Viekirax with or without dasabuvir.

8. Dose normalised parameters reported for methadone, buprenorphine and naloxone.

Note: Doses used for Viekirax and dasabuvir were: ombitasvir 25 mg, paritaprevir 150 mg, ritonavir 100 mg,once daily and dasabuvir 400 mg twice daily or 250 mg twice daily. The dasabuvir exposures obtained withthe 400 mg formulation and the 250 mg tablet are similar. Viekirax with or without dasabuvir wasadministered as multiple doses in all the drug interaction studies except the drug interaction studies withcarbamazepine, gemfibrozil, ketoconazole, and sulfamethoxazole/trimethoprim..

Drug interaction studies have only been performed in adults.

Women of childbearing potential/contraception in males and females

Extreme caution must be taken to avoid pregnancy in female patients and female partners of male patientswhen Viekirax is taken in combination with ribavirin. Significant teratogenic and/or embryocidal effectshave been 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 Summary of

Product Characteristics for ribavirin for additional information.

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

Ethinyloestradiol is contraindicated in combination with Viekirax (see sections 4.3 and 4.4).

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 months aftertreatment.

There are very limited data from the use of Viekirax in pregnant women. Studies with ombitasvir andparitaprevir/ritonavir in animals have shown malformations (see section 5.3). The potential risk forhumans is unknown. Viekirax should not be used during pregnancy or in women of childbearing potentialnot using effective contraception.

Medicinal product no longer authorised

If ribavirin is co-administered with Viekirax, the contraindications regarding use of ribavirin duringpregnancy apply (see also the Summary of Product Characteristics of ribavirin).

It is not known whether paritaprevir /ritonavir or ombitasvir and their metabolites are excreted in humanbreast milk. Available pharmacokinetic data in animals have shown excretion of active substance andmetabolite in milk (see section 5.3). Because of the potential for adverse reactions from the medicinalproduct in breastfed infants, a decision must be made whether to discontinue breast-feeding or discontinuetreatment with Viekirax, taking into account the importance of the therapy to the mother. For patients co-administered ribavirin refer to the Summary of Product Characteristics of ribavirin.

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

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

In subjects receiving Viekirax and dasabuvir with ribavirin, the most commonly reported adversereactions (greater than 20% of subjects) were fatigue and nausea. The proportion of subjects whopermanently discontinued treatment due to adverse reactions was 0.2% (5/2,044) and 4.8% (99/2,044) ofsubjects 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 received

Viekirax and dasabuvir with or without ribavirin. The majority of adverse reactions presented in Table 3were of grade 1 severity in Viekirax and dasabuvir-containing regimens.

The adverse reactions are listed below by system organ class and frequency. Frequencies are defined asfollows: 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).

Medicinal product no longer authorised

Table 3. Adverse drug reactions identified with Viekirax in combination with dasabuvir with andwithout ribavirin

Viekirax + dasabuvir +

Viekirax + dasabuvir

Frequency ribavirin*

N = 588

N = 2,044

Common Anaemia

Frequency unknown Anaphylactic reactions Anaphylactic reactions

Uncommon Dehydration

Very common Insomnia

Very common Nausea, Diarrhoea

Common Vomiting

Frequency unknown Hepatic decompensation Hepatic decompensationand hepatic failure and 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 withcirrhosis.

Note: For laboratory abnormalities, refer to Table 4

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

Changes in selected laboratory parameters are described in Table 4. A side-by-side tabulation is shown tosimplify presentation; direct comparison across trials should not be made due to differing trial designs.

Mdicinal product no longer authorised

Table 4. Selected treatment emergent laboratory abnormalities

SAPPHIRE I and II PEARL II, III, and IV TURQUOISE II(subjects with cirrhosis)

Viekirax and dasabuvir Viekirax and dasabuvir Viekirax and dasabuvir+ ribavirin + ribavirin

Laboratory Parameters12 weeks12 weeks N = 509 12 or 24 weeks

N = 770 n (%) N = 380n (%) 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 according to testing laboratory.

Serum ALT elevations

In a pooled analysis of clinical trials with Viekirax and dasabuvir with and without ribavirin, 1% ofsubjects experienced serum ALT levels greater than 5 times the upper limit of normal (ULN) after startingtreatment. As the incidence of such elevations was 26% among women taking a concomitantethinyloestradiol-containing medicinal product, such medicinal products are contraindicated with Viekiraxwith or without dasabuvir. No increase in incidence of ALT elevations was observed with other types ofestrogens commonly used for hormone replacement therapy (e.g. oestradiol and conjugated estrogens).

ALT elevations were typically asymptomatic, 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

Viekirax and dasabuvir due to elevated ALT, including one on ethinyloestradiol. Three interrupted

Viekirax and dasabuvir for one to seven days, including one on ethinyloestradiol. The majority of these

ALT elevations were transient and assessed as drug-related. Elevations in ALT were generally notassociated with bilirubin elevations. Cirrhosis was not a risk factor for elevated ALT (see section 4.4).

Transient elevations in serum bilirubin (predominantly indirect) were observed in subjects receiving

Viekirax and dasabuvir with ribavirin, related to the inhibition of the bilirubin transporters OATP1B1/1B3by paritaprevir and ribavirin-induced haemolysis. Bilirubin elevations occurred after initiation oftreatment, peaked by study Week 1, and generally resolved with ongoing therapy. Bilirubin elevationswere not associated with aminotransferase elevations. The frequency of indirect bilirubin elevations waslower among subjects who did not receive ribavirin.

The overall safety profile in HCV-infected transplant recipients who were administered Viekirax anddasabuvir and ribavirin (in addition to their immunosuppressant medications) was similar to subjects

Medicinal product no longer authorisedtreated with Viekirax and dasabuvir and ribavirin in phase 3 clinical trials, although some adversereactions were increased in frequency. 10 subjects (29.4%) had at least one post baseline haemoglobinvalue of less than 10 g/dL. 10 of 34 subjects (29.4%) dose modified ribavirin due to decrease inhaemoglobin and 2.9% (1/34) had an interruption of ribavirin. Ribavirin dose modification did not impact

SVR rates. 5 subjects required erythropoietin, all of whom initiated ribavirin at the starting dose of 1000 to1200 mg daily. No subject received a blood transfusion.

HIV/HCV co-infected patients

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

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

Viekirax and dasabuvir with or without ribavirin were assessed in 68 subjects with genotype 1 infectionwith or without cirrhosis who have severe renal impairment or ESRD (see Section 5.1). The overall safetyprofile in subjects with severe renal impairment was similar to that seen in prior Phase 3 studies insubjects without severe renal impairment, except that a greater proportion of subjects required interventiondue to ribavirin-associated decreases in serum haemoglobin. The mean baseline haemoglobin level was12.1 g/dL and the mean decline in haemoglobin at the end of treatment for subjects taking RBV was 1.2g/dL. Thirty-nine of the 50 subjects who received ribavirin required interruption of ribavirin, and 11 ofthese subjects were also treated with erythropoietin. Four subjects experienced a haemoglobin level < 8g/dL. Two subjects received a blood transfusion. Adverse events of anaemia were not seen in the 18

GT1b-infected subjects who did not receive ribavirin. Viekirax with or without dasabuvir was alsoevaluated without ribavirin in 18 GT1a- and GT4-infected patients; no adverse events of anaemia wereseen in these subjects.

The safety of Viekirax in children and adolescents aged < 18 years has not yet been established. No dataare available.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allowscontinued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals areasked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

The highest documented single dose administered to healthy volunteers was 400 mg for paritaprevir (with100 mg ritonavir), 200 mg for ritonavir (with 100 mg paritaprevir) and 350 mg for ombitasvir. No studyrelated adverse reactions with paritaprevir, ritonavir, or ombitasvir were observed. Transient increases inindirect bilirubin were observed at the highest doses of paritaprevir/ritonavir. In case of overdose, it isrecommended that the patient be monitored for any signs or symptoms of adverse reactions or effects andappropriate symptomatic treatment instituted immediately.

Medicinal product no l nger authorised

Pharmacotherapeutic group: Antivirals for systemic use; direct-acting antivirals, ATC code: J05AP53

Viekirax, when co-administered with dasabuvir, combines three direct-acting antiviral medicinal productswith distinct mechanisms of action and non-overlapping resistance profiles to target HCV at multiple stepsin the viral lifecycle. Refer to the Summary of Product Characteristics of dasabuvir for itspharmacological properties.

Ritonavir is not active against HCV. Ritonavir is a CYP3A inhibitor that increases the systemic exposureof the CYP3A substrate paritaprevir.

Ombitasvir

Ombitasvir is an inhibitor of HCV NS5A which is essential for viral replication.

Paritaprevir

Paritaprevir is an inhibitor of HCV NS3/4A protease which is necessary for the proteolytic cleavage of the

HCV encoded polyprotein (into mature forms of the NS3, NS4A, NS4B, NS5A, and NS5B proteins) andis essential for viral replication.

Activity in cell culture and/or biochemical studies

Ombitasvir

The EC50 of ombitasvir against genotype 1a-H77 and 1b-Con1 strains in HCV replicon cell culture assayswas 14.1 and 5 pM, respectively. The activity of ombitasvir was attenuated 11- to 13-fold in the presenceof 40% human plasma. The mean EC50 of ombitasvir against replicons containing NS5A from a panel oftreatment-naïve genotype 1a and 1b isolates in the HCV replicon cell culture assay was 0.66 pM (range0.35 to 0.88 pM; n=11) and 1.0 pM (range 0.74 to 1.5 pM; n=11), respectively. Ombitasvir has EC50values of 12, pct. 4.3, 19, 1.7, 3.2, and 366 pM against replicon cell lines constructed with NS5A from singleisolates representing genotypes 2a, 2b, 3a, 4a, 5a, and 6a, respectively.

Paritaprevir

The EC50 of paritaprevir against genotype 1a-H77 and 1b-Con1 strains in the HCV replicon cell cultureassay was 1.0 and 0.21 nM, respectively. The activity of paritaprevir was attenuated 24 to 27 -fold in thepresence of 40% human plasma. The mean EC50 of paritaprevir against replicons containing NS3 from apanel of treatment-naïve genotype 1a and 1b isolates in the HCV replicon cell culture assay was 0.86 nM(range 0.43 to 1.87 nM; n=11) and 0.06 nM (range 0.03 to 0.09 nM; n=9), respectively. Paritaprevir hadan EC50 value of 5.3 nM against the 2a-JFH-1 replicon cell line, and EC50 values of 19, 0.09, and 0.68 nMagainst replicon cell lines containing NS3 from a single isolate each of genotype 3a, 4a, and 6a,respectively

Ritonavir did not exhibit a direct antiviral effect on the replication of HCV subgenomic replicons, and thepresence of ritonavir did not affect the in vitro antiviral activity of paritaprevir.

Medicinal roduct no longer authorised

Genotype 1

Resistance to paritaprevir and ombitasvir conferred by variants in NS3 and NS5A respectively, selected incell culture or identified in Phase 2b and 3 clinical trials were phenotypically characterised in theappropriate genotype 1a or 1b replicons.

In genotype 1a, substitutions F43L, R155K, A156T, and D168A/F/H/V/Y in HCV NS3 reducedsusceptibility to paritaprevir. In the genotype 1a replicon, the activity of paritaprevir was reduced 20-, 37-,and 17-fold by the F43L, R155K and A156T substitutions, respectively. The activity of paritaprevir wasreduced 96-fold by D168V, and 50- to 219-fold by each of the other D168 substitutions. The activity ofparitaprevir in genotype 1a was not significantly affected (less than or equal to 3-fold) by singlesubstitutions V36A/M, V55I, Y56H, Q80K or E357K. Double variants including combinations of

V36LM, F43L, Y56H, Q80K or E357K with R155K or with a D168 substitution reduced the activity ofparitaprevir by an additional 2 to 3-fold relative to the single R155K or D168 substitution. In the genotype1b replicon, the activity of paritaprevir was reduced 76- and 159-and 337- fold by D168A, D168H,

D168V, and D168Y respectively. Y56H alone could not be evaluated due to poor replication capacity,however, the combination of Y56H and D168A/V/Y reduced the activity of paritaprevir by 700- to 4118-fold.

In genotype 1a, substitutions M28T/V, Q30E/R, L31V, H58D, Y93C/H/N, and M28V + Q30R in HCV

NS5A reduced susceptibility to ombitasvir. In the genotype 1a replicon, the activity of ombitasvir wasreduced by 896-, 58- and 243-fold against the M28T/V and H58D substitutions, respectively, and 1326-,800-, 155-foldand 1675- to 66740- fold by the Q30E/R, L31V and Y93C/H/N substitutions, respectively.

Y93H, Y93N or M28V in combination with Q30R reduced the activity of ombitasvir by more than42,802-fold. In genotype 1b, substitutions L28T, L31F/V, as well as Y93H alone or in combination with

L28M, R30Q, L31F/M/V or P58S in HCV NS5A reduced susceptibility to ombitasvir. In the genotype 1breplicon, the activity of ombitasvir was reduced by less than 10-fold by variants at amino acid positions 30and 31. The activity of ombitasvir was reduced by 661-, 77-, 284- and 142-fold against the genotype 1bsubstitutions L28T, Y93H, R30Q in combination with Y93H, and L31M in combination with Y93H,respectively. All other double substitutions of Y93H in combination with substitutions at positions 28, 31,or 58 reduced the activity of ombitasvir by more than 400-fold.

Genotype 4

In genotype 4a, resistance to paritaprevir or ombitasvir by variants in NS3 or NS5A, respectively, selectedin cell culture were phenotypically characterised. Substitutions R155C, A156T/V, and D168H/V in HCV

NS3 reduced susceptibility to paritaprevir by 40- to 323-fold. Substitution L28V in HCV NS5A reducedthe susceptibility to ombitasvir by 21-fold.

Effect of baseline HCV substitutions/polymorphisms on treatment outcome

A pooled analysis of subjects with genotype 1 HCV infection, who were treated with ombitasvir,paritaprevir, and dasabuvir (a non-nucleotide NS5B inhibitor) with or without ribavirin in the Phase 2band 3 clinical trials was conducted to explore the association between baseline NS3/4A, NS5A or NS5Bsubstitutions/polymorphisms and treatment outcome in 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 ahighly prevalent polymorphism in NS3 (41.2% of samples), confers minimal resistance to paritaprevir.

Medicinal product no longer authorised

Resistance-associated variants at amino acid positions R155 and D168 in NS3 were rarely observed (lessthan 1%) at baseline. In the greater than 200 genotype 1b baseline samples in this analysis, the mostfrequently observed resistance-associated variants observed were Y93H (7.5%) in NS5A, and C316N(17.0%) and S556G (15%) in NS5B. Given the low virologic failure rates observed with recommendedtreatment regimens for HCV genotype 1a- and 1b-infected subjects, the presence of baseline variantsappears 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 ombitasvir,paritaprevir, and dasabuvir 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 NS3and NS5A in 1 subject. No genotype 1b infected subjects had treatment-emergent variants in all 3 drugtargets.

Table 5. Treatment-emergent amino acid substitutions in the pooled analysis of Viekirax anddasabuvir with and without RBV regimens in Phase 2b and Phase 3 clinical 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, D559G, < 5% --

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: NS3variants A156T in genotype 1a, and R155Q and D168H in genotype 1b; NS5A variants Y93C/H in

Medicinal product no longer authorisedgenotype 1a, and L31F/V or Y93H in combination with L28M, L31F/V or P58S in genotype 1b; and

NS5B variants Y448H in genotype 1a, and M414T and Y448H in genotype 1b.

The persistence of paritaprevir, ombitasvir, and dasabuvir resistance-associated amino acid substitutions in

NS3, NS5A, and NS5B, respectively, was assessed in genotype 1a-infected subjects in Phase 2b trials.

Paritaprevir treatment-emergent variants V36A/M, R155K or D168V were observed in NS3 in 47subjects. Ombitasvir treatment-emergent variants M28T, M28V or Q30R in NS5A were observed in 32subjects. Dasabuvir treatment-emergent variants M414T, G554S, S556G, G558R or D559G/N in NS5Bwere observed in 34 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 at post-treatment Week 48. All treatment-emergent variants in NS5A remained detectable at post-treatment Week48. Due to high SVR rates in genotype 1b, trends in persistence of treatment-emergent variants in thisgenotype 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 Viekirax- and dasabuvir-resistance-associated substitutionson future treatment is unknown.

Cross-resistance is expected among NS5A inhibitors, NS3/4A protease inhibitors, and non-nucleoside

NS5B inhibitors by class. The impact of prior ombitasvir, paritaprevir or dasabuvir treatment experienceon the efficacy of other NS5A inhibitors, NS3/4A protease inhibitors, or NS5B inhibitors has not beenstudied.

Clinical studies in subjects with genotype 1 hepatitis C infection

The efficacy and safety of Viekirax in combination with dasabuvir with and without ribavirin wasevaluated in eight Phase 3 clinical trials, including two trials exclusively in subjects with cirrhosis (Child-

Pugh A), in over 2,360 subjects with genotype 1 chronic hepatitis C infection as summarised in Table 6.

Medicinal product no longer authorised

Table 6. Phase 3 global multicentre studies conducted with Viekirax and dasabuvir with or withoutribavirin (RBV).

Number of HCV

Trial subjects genotype Summary of study designtreated (GT)

Treatment-naïve, without cirrhosis

Arm A: Viekirax and dasabuvir + RBV

SAPPHIRE I 631 GT1

Arm B: Placebo

Arm A: Viekirax and dasabuvir + RBV

PEARL III 419 GT1b

Arm B: Viekirax and dasabuvir

Arm A: Viekirax and dasabuvir + RBV

PEARL IV 305 GT1a

Arm B: Viekirax and dasabuvir

GARNET166 GT1b Viekirax and dasabuvir (8 weeks)(open-label)

Peginterferon+ribavirin experienced -, without cirrhosis

Arm A: Viekirax and dasabuvir + RBV

SAPPHIRE II 394 GT1

Arm B: Placebo

PEARL II Arm A: Viekirax and dasabuvir + RBV179 GT1b(open-label) Arm B: Viekirax and dasabuvir

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

Arm A: Viekirax and dasabuvir + RBV (12

TURQUOISE II weeks)380 GT1(open-label) Arm B: Viekirax and dasabuvir + RBV (24weeks)

TURQUOISE III60 GT1b Viekirax and dasabuvir (12 weeks)(open-label)

In all eight trials, the Viekirax dose was 25 mg/150 mg/100 mg once daily and the dasabuvir dose was250 mg twice daily. For subjects who received ribavirin, the ribavirin dose was 1000 mg per day forsubjects weighing less than 75 kg or 1200 mg per day for subjects weighing greater than or equal to 75 kg.

Sustained virologic response (SVR) was the primary endpoint to determine the HCV cure rate in the Phase3 studies and was defined as unquantifiable or undetectable HCV RNA 12 weeks after the end oftreatment (SVR12). Treatment duration was fixed in each trial and was not guided by subjects’ HCV RNAlevels (no response guided algorithm). Plasma HCV RNA values were measured during the clinical trialsusing the COBAS TaqMan HCV test (version 2.0), for use with the High Pure System (except GARNETwhich used COBAS AmpliPrep/COBAS TaqMan HCV Test v2.0). The High Pure system assay had alower limit of quantification (LLOQ) of 25 IU per mL and the AmpliPrep assay had a LLOQ of 15 IU permL.

Clinical trials in treatment-naïve adults

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

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

Treatment: Viekirax and dasabuvir with weight-based ribavirin for 12 weeks

Medicinal product no longr authorised

Treated subjects (N=631) had a median age of 52 years (range: 18 to 70); 54.5% were male; 5.4% were

Black; 15.2% had a history of depression or bipolar disorder; 79.1% had baseline HCV RNA levels of atleast 800,000 IU/mL; 15.4% had portal fibrosis (F2) and 8.7% had bridging fibrosis (F3); 67.7% had HCVgenotype 1a infection; 32.3% had HCV genotype 1b infection.

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

Viekirax and dasabuvir with RBV for 12

Treatment outcome 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/mL increase 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 missing HCV RNA values in the SVR12window.

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

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

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

Treatment: Viekirax and dasabuvir without ribavirin or with weight-based ribavirin for 12 weeks

Treated subjects (N=419) had a median age of 50 years (range: 19 to 70), 45.8% were male; 4.8% were

Black; 9.3% had a history of depression or bipolar disorder; 73.3% had baseline HCV RNA of at least800,000 IU/mL; 20.3% had portal fibrosis (F2) and 10.0% had bridging fibrosis (F3).

Table 8. SVR12 for genotype 1b-infected treatment-naïve subjects in PEARL III

Viekirax and dasabuvir for 12 weeks

Treatment outcome With RBV Without RBVn/N % 95% CI n/N % 95% CI

Overall SVR12 20209/210 99.5 98.6, 100.0 100 98.2, 100.09/209

Outcome for subjectswithout 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

Medicinal p out no longer authorised

Treatment: Viekirax and dasabuvir without ribavirin or with weight-based ribavirin for 12 weeks

Treated subjects (N=305) had a median age of 54 years (range: 19 to 70); 65.2% were male; 11.8% were

Black; 20.7% had a history of depression or bipolar disorder; 86.6% had baseline HCV RNA levels of atleast 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 IV

Viekirax and dasabuvir 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 subjectswithout 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: Viekirax and dasabuvir 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% hadadvanced fibrosis (F3) and 98.2% had HCV genotype 1b infection (one subject each had genotype 1a, 1d,and 6 infection).

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

Viekirax and dasabuvir 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: Viekirax and dasabuvir with weight-based ribavirin for 12 weeks

Medicinal product no longer authorised

Treated subjects (N=394) had a median age of 54 years (range: 19 to 71); 49.0% were prior pegIFN/RBVnull responders; 21.8/% were prior pegIFN/RBV partial responders, and 29.2% were prior pegIFN/RBVrelapsers; 57.6% were male; 8.1% were Black; 20.6% had a history of depression or bipolar disorder;87.1% had baseline HCV RNA levels of at least 800,000 IU per mL; 17.8% had portal fibrosis (F2) and14.5% had bridging fibrosis (F3); 58.4% had HCV genotype 1a infection; 41.4% had HCV genotype 1binfection.

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

SAPPHIRE-II

Viekirax and dasabuvir with RBV for 12 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.

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

Design: randomised, global multicentre, open-label

Treatment: Viekirax and dasabuvir without ribavirin or with weight-based ribavirin for 12 weeks

Treated subjects (N=179) had a median age of 57 years (range: 26 to 70); 35.2% were prior pegIFN/RBVnull responders; 28.5% were prior pegIFN/RBV partial responders, and 36.3% were prior pegIFN/RBVrelapsers; 54.2% were male; 3.9% were Black; 12.8% had a history of depression or bipolar disorder;87.7% had baseline HCV RNA levels of at least 800,000 IU/mL; 17.9% had portal fibrosis (F2) and14.0% had bridging fibrosis (F3).

Medic nal produt no longer authorised

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

II

Viekirax and dasabuvir for 12 weeks

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: Viekirax and dasabuvir with weight-based ribavirin for 12 or 24 weeks

Treated subjects (N=380) had a median age of 58 years (range: 21 to 71); 42.1% were treatment-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 platelet counts of lessthan 90 x 109/L; 49.7% had albumin less than 40 g/L; 86.1% had baseline HCV RNA levels of at least800,000 IU/mL; 24.7% had a history of depression or bipolar disorder; 68.7% had HCV genotype 1ainfection, 31.3% had HCV genotype 1b infection.

Medicinal product no longer authorised

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

Treatment outcome Viekirax and dasabuvir 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 of

Treatment in Subjects with Genotype 1a Infection and Compensated Cirrhosis

Viekirax and Viekirax anddasabuvir with RBV dasabuvir with RBV12-week arm 24-week arm

Number of Responders at the End of Treatment 135 113

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

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

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

*AFP= serum alpha fetoprotein

In subjects with all three favourable baseline laboratory values (AFP < 20 ng/mL, platelets ≥ 90 x 109/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

Medicinal product no longer authorised

Design: global multicentre, open-label

Treatment: Viekirax and dasabuvir 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 was 99.8%.

Pooled efficacy analysis

In Phase 3 clinical trials, 1075 subjects (including 181 with compensated cirrhosis) with genotype 1 HCVinfection received the recommended regimen (see section 4.2). Table 16 shows SVR rates for thesesubjects.

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

Medici al product no longer authorised

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

HCV Genotype 1b HCV Genotype 1a

Viekirax and dasabuvir Viekirax and dasabuvirwith 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 orother pegIFN failure.

Viekirax without ribavirin and without dasabuvir was also evaluated in genotype 1b infected subjects in

Phase 2 studies M13-393 (PEARL-I) and M12-536. PEARL I was conducted in the US and Europe, M12-536 in Japan. The treatment-experienced subjects studied were primarily pegIFN/RBV null responders.

The doses of ombitasvir, paritaprevir, ritonavir were 25 mg 150 mg, 100 mg once daily in PEARL-I, whilethe dose of paritaprevir was 100 mg or 150 mg in study M12-536. Treatment duration was 12 weeks fortreatment naïve subjects, 12-24 weeks for treatment experienced subjects and 24 weeks for subjects withcirrhosis. Overall, 107 of 113 subjects without cirrhosis and 147 of 155 subjects with cirrhosis achieved

SVR12 after 12-24 weeks of treatment.

Viekirax with ribavirin & without dasabuvir was evaluated for 12 weeks in genotype 1 treatment naiveand treatment experienced non-cirrhotic subjects in a phase 2 study M11-652 (AVIATOR). The doses ofparitaprevir were 100 mg and 200 mg and ombitasvir 25 mg. Ribavirin was dosed based on weight (1000mg - 1200 mg per day). Overall, 72 of 79 treatment-naive subjects (45 of 52 GT1a and 27 of 27 GT1b)and 40 of 45 treatment-experienced subjects (21 of 26 GT1a and 19 of 19 GT1b) achieved SVR12 after 12weeks of treatment.

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. Inthe 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.

Mdicinal product no longer autho ised

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: Viekirax with or without dasabuvir coadminstered with or without weight-based ribavirinfor 12 or 24 weeks

See section 4.2 for dosing recommendations in HCV/HIV-1 co-infected patients. HCV GT1- or 4-infectedsubjects with HIV-1 coinfection were on a stable HIV-1 antiretroviral therapy (ART) regimen thatincluded ritonavir-boosted atazanavir, raltegravir, dolutegravir (Part 2 only), or darunavir (Part 1b and Part2 GT4 only)-, co-administered with a backbone of tenofovir plus emtricitabine or lamivudine.

Part 1 of the study was a Phase 2 pilot cohort consisting of 2 parts, Part 1a (63 subjects) and Part 1b (22subjects). Part 2 was a Phase 3 cohort consisting of 233 subjects.

In Part 1a, all subjects received Viekirax and dasabuvir with ribavirin for 12 or 24 weeks.

Treated subjects (N = 63) had a median age of 51 years (range: 31 to 69); 24% were Black; 19% hadcompensated cirrhosis; 67% were treatment-naïve; 33% had failed prior treatment with pegIFN/RBV;89% had HCV genotype 1a infection.

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

In Part 2, subjects with HCV GT1 received Viekirax and dasabuvir with or without ribavirin for 12 or 24weeks. Subjects with HCV GT4 received Viekirax with ribavirin for 12 or 24 Weeks. Treated subjects(N = 233) had a median age of 49 years (range: 26 to 69); 10% were Black; 12% had compensatedcirrhosis; 66% were treatment-naïve; 32% had failed prior treatment with pegIFN/RBV; 2% had failedprior treatment with sofosbuvir.

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

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

TURQUOISE-I

Viekirax and dasabuvirwith/without 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.

Medicinal product no longer authorised

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

Efficacy analyses performed on other parts of the study demonstrated similarly high SVR12 rates. In Part1a, SVR12 was achieved by 29/31 (93.5%) subjects on the 12-week arm (95% CI: 79.3%, 98.2%) and by29/32 (90.6%) subjects on the 24-week arm (95% CI: 75.8% - 96.8%). There was 1 relapse in the 12-week arm and 1 on-treatment virologic failure in the 24-week arm. In Part 1b, SVR12 was achieved by22/22 (100%) subjects (95% CI: 85.1%, 100%). In Part 2, SVR12 was achieved by 27/28 (96.4%) subjectswith HCV GT4/HIV-1 coinfection (95% CI: 82.3%, 99.4%) with no virologic failures.

The SVR12 rates in HCV/HIV-1 co-infected subjects were thus consistent with SVR12 rates in the phase3 trials of HCV mono-infected subjects.

CORAL-I: treatment-naïve or pegIFN + RBV-experienced, at least 3 months post liver transplant or12 months post renal transplant

Design: randomised, global multicentre, open-label

Treatment: Viekirax and dasabuvir for 12 or 24 weeks with or without ribavirin ( investigator chosendose ) for GT1 and GT4 infection

In subjects with liver transplant, no cirrhosis and GT1 infection, patients were dosed with Viekirax anddasabuvir for 12-24 weeks, with and without RBV. Liver transplant subjects with cirrhosis were dosedwith Viekirax and dasabuvir with RBV (GT1a for 24 weeks [n=4], GT1b for 12 weeks [n=2]). Subjectswith renal transplant and no cirrhosis were dosed for 12 weeks (with RBV for GT1a [n=9], without RBVfor GT1b [n=3]). Subjects with liver transplant and GT4 infection were dosed with Viekirax with RBV(non-cirrhotic for 12 weeks [n=2] and cirrhotic for 24 weeks [n=1]. The dose of ribavirin was left to thediscretion of the investigator, with most subjects receiving 600 to 800 mg per day as a starting dose, andmost subjects also receiving 600 to 800 mg per day at the end of treatment.

A total of 129 subjects were treated, 84 with GT1a, 41 with GT1b, 1 with GT1 other, 3 with 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 post renaltransplant, 9/12 (75%) achieved SVR12; however, there were no virologic failures. All 3 (100%) subjectswith GT4 infection who were post liver transplant achieved SVR12.

Clinical trial in patients receiving 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 +/- naloxone (N=19) received 12 weeks of Viekirax and dasabuvir withribavirin. Treated subjects had a median age of 51 years (range: 26 to 64); 65.8% were male and 5.3%were Black. A majority (86.8%) had baseline HCV RNA levels of at least 800,000 IU/mL and a majority(84.2%) had genotype 1a infection; 15.8% had portal fibrosis (F2) and 5.3% had bridging fibrosis (F3);and 94.7% were naïve to prior HCV treatment.

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

Medicinal product no longer authorised

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

Design: multicentre, open-label

Treatment: Viekirax and dasabuvir with or without RBV for 12 or 24 weeks

Severe renal impairment or ESRD includes CKD Stage 4 defined as eGFR <30-15 mL/min/1.73 m2 or

CKD Stage 5 defined as <15 mL/min/1.73 m2 or requiring haemodialysis. Treated subjects (N=68) had amedian age of 58 years (range: 32-77 years); 83.8% were male; 58.8% were Black; 73.5% of subjectswere 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 Viekirax with or without dasabuvir andwithout 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 orrelapse.

Clinical trials in subjects with genotype 4 chronic hepatitis C

PEARL- I- genotype 4, treatment-naïve or pegIFN + RBV experienced without cirrhosis

Design: randomised, global multicentre, open-label

Treatment: treatment naïve: Viekirax without ribavirin or with weight-based ribavirin for 12 weekspegIFN + RBV experienced: Viekirax with weight-based ribavirin for 12 weeks

Subjects (N=135) had a median age of 51 years (range: 19 to 70); 63,7% were treatment-naïve, 17.0%were prior pegIFN/RBV null responders, 6.7% were prior pegIFN/RBV partial responders, 12.6% wereprior pegIFN/RBV relapsers; 65.2%were male; 8.9% were Black, 69.6% had baseline HCV RNA levelsat least 800,000 IU/mL; 6.7% had bridging fibrosis (F3).

Table 18. SVR12 for genotype 4-infected, subjects who were treatment-naïve or previously treatedwith pegIFN/RBV in PEARL I

Ombitasvir + paritaprevir + ritonavir* for 12 weeks

Treatment-naïve Treatment-naïve pegIFN + RBV-experienced

Treatment outcome

With RBV Without RBV

With RBVn/N % n/N % n/N %

Overall SVR12 42/42 100% 40/44 90.9% 49/49 100%

Outcome for subjects without SVR12

On-treatment VF 0/42 0 1/44 2.3% 0/49 0

Relapse 0/42 0 2/44 4.5% 0/49 0

Other 0/42 0 1/44 2.3% 0/49 0

* Ombitasvir tablets, paritaprevir tablets and ritonavir capsules administered separately.

Medicinal prouct no loner authrised

AGATE-1 -treatment-naïve or pegIFN +RBV experienced patients with compensated cirrhosis

Design: randomised, global multicentre, open-label

Treatment: Viekirax with weight-based ribavirin for 12 or 16 weeks

Subjects had a median age of 56 years (range: 32 to 81); 50% were treatment-naïve, 28% were priorpegIFN/RBV null responders; 10% were prior pegIFN/RBV partial responders, 13% were priorpegIFN/RBV relapsers; 70% were male; 17% were Black; 73% had baseline HCV RNA levels of at least800,000 IU per mL; 17% had platelet counts of less than 90 x 109 per L; and 4% had albumin less than3.5 mg per dL.

Table 19. SVR12 for HCV Genotype 4-Infected Subjects with Compensated Cirrhosis

Ombitasvir + Paritaprevir + Ritonavir with RBV12 Weeks 16 Weeks

SVR12 % (n/N) 97% (57/59) 98% (60/61)

Outcome for subjects without SVR12

On-treatment virologic failure 2 (1/59) 0 (0/61)

Post-treatment relapse 0 (0/57) 0 (0/59)

Other 2 (1/59) 2 (1/61)

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

The pharmacokinetic properties of the combination of Viekirax with dasabuvir have been evaluated inhealthy adult subjects and in subjects with chronic hepatitis C. Table 20 shows mean Cmax and AUC of

Viekirax 25 mg/150 mg/100 mg once daily with dasabuvir 250 mg twice daily following multiple doseswith food in healthy volunteers.

Table 20. Geometric mean Cmax, AUC of multiple doses of Viekirax 150 mg/100 mg/25 mg once dailywith dasabuvir 250 mg twice daily with food in healthy volunteers

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

Ombitasvir 127 (31) 1420 (36)

Paritaprevir 1470 (87) 6990 (96)

Ritonavir 1600 (40) 9470 (41)

Ombitasvir, paritaprevir and ritonavir were absorbed after oral administration with mean Tmax ofapproximately 4 to 5 hours. While ombitasvir exposures increased in a dose proportional manner,paritaprevir and ritonavir exposures increased in a more than dose proportional manner. Accumulation is

Medicinal pr ductlonger authorisedminimal for ombitasvir and approximately 1.5- to 2-fold for ritonavir and paritaprevir. Pharmacokineticsteady state for the combination is achieved after approximately 12 days of dosing.

The absolute bioavailability of ombitasvir and paritaprevir was approximately 50% when administeredwith food as Viekirax.

Effect of paritaprevir/ritonavir on ombitasvir and dasabuvir

In the presence of paritaprevir/ritonavir, dasabuvir exposures decreased by approximately 50% to 60%while ombitasvir exposures increased by 31-47%.

Effect of ombitasvir on paritaprevir/ritonavir and dasabuvir

In the presence of ombitasvir, paritaprevir exposures were minimally affected (5% to 27% change) whiledasabuvir exposures increase by approximately 30%.

Effect of dasabuvir on paritaprevir/ritonavir and ombitasvir

In the presence of dasabuvir, paritaprevir exposures increased by 50% to 65% while there was no changein ombitasvir exposures.

Ombitasvir, paritaprevir and ritonavir should be administered with food. All clinical trials with ombitasvir,paritaprevir and ritonavir have been conducted following administration with food.

Food increased the exposure (AUC) of ombitasvir, paritaprevir and ritonavir by up to 82%, 211% and49%, respectively relative to the fasting state. The increase in exposure was similar regardless of mealtype (e.g., high-fat versus moderate-fat) or calorie content (approximately 600 Kcal versus approximately1000 Kcal). To maximise absorption, Viekirax should be taken with food without regard to fat or caloriecontent.

Ombitasvir, paritaprevir and ritonavir are highly bound to plasma proteins. Plasma protein binding is notmeaningfully altered in subjects with renal or hepatic impairment. The blood to plasma concentrationratios in humans ranged from 0.6 to 0.8 indicating that ombitasvir and paritaprevir were preferentiallydistributed in the plasma compartment of whole blood. Ombitasvir was approximately 99.9% bound tohuman plasma proteins. Paritaprevir was approximately 97-98.6% bound to human plasma proteins.

Ritonavir was greater than 99% bound to human plasma proteins.

In vitro data indicate that paritaprevir is a substrate for the human hepatic uptake transporters, OATP1B1and OATP1B3.

Ombitasvir

Ombitasvir is metabolised via amide hydrolysis followed by oxidative metabolism. Following a 25 mgsingle dose of 14C-ombitasvir given alone, unchanged parent drug accounted for 8.9% of total radioactivityin human plasma; a total of 13 metabolites were identified in human plasma. These metabolites are notexpected to have antiviral activity or off-target pharmacologic activity.

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Paritaprevir

Paritaprevir is metabolised predominantly by CYP3A4 and to a lesser extent CYP3A5. Followingadministration of a single 200 mg/100 mg oral dose of 14C paritaprevir /ritonavir to humans, the parentdrug was the major circulating component, accounting for approximately 90% of the plasma radioactivity.

At least 5 minor metabolites of paritaprevir have been identified in circulation that accounted forapproximately 10% of plasma radioactivity. These metabolites are not expected to have antiviral activity.

Ritonavir is predominantly metabolised by CYP3A and to a lesser extent, by CYP2D6. Nearly the entireplasma radioactivity after a single 600 mg dose of 14C-ritonavir oral solution in humans was attributed tounchanged ritonavir.

Ombitasvir

Following dosing of ombitasvir/paritaprevir/ritonavir with or without dasabuvir, mean plasma half-life ofombitasvir was approximately 21 to 25 hours. Following a single 25 mg dose of 14C- ombitasvirapproximately 90% of the radioactivity was recovered in faeces and 2% in urine. Unchanged parent drugaccounted for 88% of total radioactivity recovered in faeces, indicating that biliary excretion is a majorelimination pathway for ombitasvir.

Paritaprevir

Following dosing of ombitasvir/paritaprevir /ritonavir with or without dasabuvir, mean plasma half-life ofparitaprevir was approximately 5.5 hours. Following a 200 mg 14C -paritaprevir dose with 100 mgritonavir, approximately 88% of the radioactivity was recovered in faeces with limited radioactivity(8.8%) in urine. Metabolism as well as biliary excretion of parent drug contribute to the elimination ofparitaprevir.

Following dosing of ombitasvir/paritaprevir /ritonavir, mean plasma half-life of ritonavir wasapproximately 4 hours. Following a 600 mg dose of 14C -ritonavir oral solution, 86.4% of the radioactivitywas recovered in the faeces and 11.3% of the dose was excreted in the urine.

In vitro interaction data

Ombitasvir and paritaprevir do not inhibit organic anion transporter (OAT1) in vivo and are not expectedto inhibit organic cation transporters (OCT1 and OCT2), organic anion transporters (OAT3), or multidrugand toxin extrusion proteins (MATE1 and MATE2K) at clinically relevant concentrations. Ritonavir doesnot inhibit OAT1 and is not expected to inhibit OCT2, OAT3, MATE1 and MATE2K at clinicallyrelevant concentrations.

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Based on population pharmacokinetic analysis of data from Phase 3 clinical studies, a 10 year increase ordecrease in age from 54 years (median age in the Phase 3 studies) would result in approximately 10%change in ombitasvir exposures, and ≤20% change in paritaprevir exposures. There is no pharmacokineticinformation in patients >75 years.

Sex or body weight

Based on population pharmacokinetic analysis of data from Phase 3 clinical studies, female subjectswould have approximately 55% higher, 100% higher and 15% higher ombitasvir, paritaprevir andritonavir exposures than male subjects. However, no dose-adjustment based on gender is warranted. A10 kg change in body weight from 76 kg (median weight in the Phase 3 studies) would results in <10%change in ombitasvir exposures, and no change in paritaprevir exposures. Body weight is not a significantpredictor of ritonavir exposures.

Race or ethnicity

Based on population pharmacokinetic analysis of data from Phase 3 clinical studies, Asian subjects had18% to 21% higher ombitasvir exposures, and 37% to 39% higher paritaprevir exposures than non-Asiansubjects. The ritonavir exposures were comparable between Asians and non-Asians.

The changes in ombitasvir, paritaprevir, and ritonavir exposures in subjects with mild, moderate andsevere renal impairment are not considered to be clinically significant. Limited data in patients with end-stage renal disease indicate no clinically significant changes in exposure also in this patient group. Nodose adjustment of Viekirax with and without dasabuvir is required for patients with mild, moderate orsevere renal impairment , or end-stage-renal disease on dialysis (see section 4.2).

Pharmacokinetics of the combination of ombitasvir 25 mg, paritaprevir 150 mg, and ritonavir 100 mg,with or without dasabuvir 400 mg were evaluated in subjects with mild (CrCl: 60 to 89 ml/min), moderate(CrCl: 30 to 59 ml/min) and severe (CrCl: 15 to 29 ml/min) renal impairment.

Following administration of Viekirax and dasabuvir

Compared to the subjects with normal renal function, ombitasvir exposures were comparable in subjectswith mild, moderate and severe renal impairment. Compared to the subjects with normal renal function,paritaprevir Cmax values were comparable, but AUC values were 19%, 33% and 45% higher in mild,moderate and severe renal impairment, respectively. Ritonavir plasma concentrations increased whenrenal function was reduced: Cmax and AUC values were 26% to 42% higher, 48% to 80% higher and 66%to 114% higher in subjects with mild, moderate and severe renal impairment, respectively.

Following administration of Viekirax

Following administration of Viekirax, the changes in ombitasvir, paritaprevir, and ritonavir exposures insubjects with mild, moderate and severe renal impairment were similar to those observed when Viekiraxwas administered with dasabuvir, and are not considered to be clinically significant.

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Following administration of Viekirax and dasabuvir

Pharmacokinetics of the combination of ombitasvir 25 mg, paritaprevir 200 mg, and ritonavir 100 mg,with dasabuvir 400 mg were evaluated in non-HCV infected subjects with mild (Child-Pugh A), moderate(Child-Pugh B) and severe (Child-Pugh C) hepatic impairment.

In subjects with mild hepatic impairment, paritaprevir, ritonavir and ombitasvir mean Cmax and AUCvalues decreased by 29% to 48%, 34% to 38% and up to 8%, respectively, compared to subjects withnormal hepatic function.

In subjects with moderate hepatic impairment, ombitasvir and ritonavir mean Cmax and AUC valuesdecreased by 29% to 30% and 30 to 33%, respectively, while paritaprevir mean Cmax and AUC valuesincreased by 26% to 62% compared to subjects with normal hepatic function. (see sections 4.2, pct. 4.4, and4.8).

In subjects with severe hepatic impairment, paritaprevir mean Cmax and AUC values increased by 3.2-to9.5-fold; ritonavir mean Cmax values were 35% lower and AUC values were 13% higher and ombitasvirmean Cmax and AUC values decreased by 68% and 54%, respectively, compared to subjects with normalhepatic function, therefore, Viekirax must not be used in patients with severe hepatic impairment (seesections 4.2 and 4.4).

In HCV-infected subjects, in comparison to those without cirrhosis, paritaprevir AUC increased to 2.2- to2.4-fold for those with compensated cirrhosis (Child-Pugh A) and 3- to 4-fold for those with Child-Pugh Bcirrhosis.

Following administration of Viekirax

Pharmacokinetics of the combination of ombitasvir 25 mg, paritaprevir 200 mg, and ritonavir 100 mgwere not evaluated in subjects with mild (Child-Pugh A), moderate (Child-Pugh B) and severe (Child-

Pugh C) hepatic impairment. Results from the pharmacokinetic evaluation of the combination ofombitasvir 25 mg, paritaprevir 200 mg, and ritonavir 100 mg, with dasabuvir 400 mg can be extrapolatedto the combination of ombitasvir 25 mg, paritaprevir 200 mg, and ritonavir 100 mg.

The pharmacokinetics of Viekirax in paediatric patients has not been established (see section 4.2).

Ombitasvir

Ombitasvir and its major inactive human metabolites (M29, M36) were not genotoxic in a battery of invitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheralblood lymphocytes and in vivo mouse micronucleus assays.

Ombitasvir was not carcinogenic in a 6-month transgenic mouse study up to the highest dosage tested(150 mg/kg/day), resulting in ombitasvir AUC exposures approximately 26-fold higher than those inhumans at the recommended clinical dose of 25 mg.

Similarly, ombitasvir was not carcinogenic in a 2-year rat study up to the highest dose tested (30 mg perkg per day), resulting in ombitasvir exposures approximately 16-fold higher than those in humans at 25mg.

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Ombitasvir has shown malformations in rabbits at maximal feasible exposures 4-fold higher than the AUCexposure at recommended clinical dose. Malformations at low incidence were observed mainly in the eyes(microphthalmia) and teeth (absent incisors). In mice, an increased incidence of open eye lid was presentin foetuses of dams administered ombitasvir; however, the relationship to treatment with ombitasvir isuncertain. The major, inactive human metabolites of ombitasvir were not teratogenic in mice at exposuresapproximately 26 times higher than in humans at the recommended clinical dose. Ombitasvir had no effecton fertility when evaluated in mice.

Unchanged ombitasvir was the predominant component observed in the milk of lactating rats, withouteffect on nursing pups. Ombitasvir-derived material was minimally transferred through the placenta inpregnant rats.

Paritaprevir/ritonavir

Paritaprevir was positive in an in vitro human chromosome aberration test. Paritaprevir was negative in abacterial mutation assay, and in two in vivo genetic toxicology assays (rat bone marrow micronucleus andrat liver Comet tests).

Paritaprevir /ritonavir was not carcinogenic in a 6-month transgenic mouse study up to the highest dosagetested (300 mg/30 mg/kg/day), resulting in paritaprevir AUC exposures approximately 38-fold higher thanthose in humans at the recommended dose of 150 mg. Similarly, paritaprevir/ritonavir was notcarcinogenic in a 2-year rat study up to the highest dosage tested (300 mg/30 mg/kg/day), resulting inparitaprevir AUC exposures approximately 8-fold higher than those in humans at 150 mg.

Paritaprevir/ritonavir has shown malformations (open eye lids) at a low incidence in mice at exposures32/8-fold higher than the exposure in humans at the recommended clinical dose. Paritaprevir/ritonavir hadno effects on embryo-foetal viability or on fertility when evaluated in rats at exposures 2- to 8-fold higherthan the exposure in humans at the recommended clinical dose.

Paritaprevir and its hydrolysis product M13 were the predominant components observed in the milk oflactating rats, without effect on nursing pups. Paritaprevir -derived material was minimally transferredthrough the placenta in pregnant rats.

Copovidone

Tocofersolan

Propylene glycol monolaurate

Sorbitan monolaurate

Colloidal anhydrous silica (E 551)

Sodium stearyl fumarate

Poly(vinyl alcohol) (E 1203)

Macrogol (3350)

Talc (E 553b)

Titanium dioxide (E 171)

Medicinal product no longer authorised

Iron oxide red (E 172)

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/1/14/982/001

Date of first authorisation: 15 January 2015

Date of latest renewal: 19 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