HARVONI 90mg / 400mg tablets medication leaflet

Harvoni 90 mg/400 mg film-coated tablets

Harvoni 45 mg/200 mg film-coated tablets

Harvoni 90 mg/400 mg film-coated tablets

Each film-coated tablet contains 90 mg ledipasvir and 400 mg sofosbuvir.

Each film-coated tablet contains 157 mg of lactose (as monohydrate) and 47 micrograms of sunsetyellow FCF.

Harvoni 45 mg/200 mg film-coated tablets

Each film-coated tablet contains 45 mg ledipasvir and 200 mg sofosbuvir.

Each film-coated tablet contains 78 mg of lactose (as monohydrate).

For the full list of excipients, see section 6.1.

Film-coated tablet.

Harvoni 90 mg/400 mg film-coated tablets

Orange, diamond-shaped, film-coated tablet of dimensions of approximately 19 mm x 10 mm,debossed with “GSI” on one side and “7985” on the other side.

Harvoni 45 mg/200 mg film-coated tablets

White, capsule-shaped, film-coated tablet of dimensions of approximately 14 mm x 7 mm, debossedwith “GSI” on one side and “HRV” on the other side.

Harvoni is indicated for the treatment of chronic hepatitis C (CHC) in adult and paediatric patientsaged 3 years and above (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.

Harvoni treatment should be initiated and monitored by a physician experienced in the management ofpatients with CHC.

The recommended dose of Harvoni in adults is 90 mg/400 mg once daily with or without food (seesection 5.2).

The recommended dose of Harvoni in paediatric patients aged 3 years and above is based on weight(as detailed in Table 2) and can be taken with or without food (see section 5.2).

A granule formulation of Harvoni is available for the treatment of chronic HCV-infection in paediatricpatients aged 3 years and above having difficulty swallowing film-coated tablets. Please refer to the

Summary of Product Characteristics for Harvoni 33.75 mg/150 mg or 45 mg/200 mg granules.

Table 1: Recommended treatment duration for Harvoni and the recommended use ofco-administered ribavirin for certain subgroups

Patient population Treatment and duration(including HIV co-infected patients)

Adult and paediatric patients aged 3 years and abovea with genotype 1, 4, 5 or 6 CHC

Patients without cirrhosis Harvoni for 12 weeks.

- Harvoni for 8 weeks may be considered in previouslyuntreated genotype 1-infected patients (see section 5.1,

ION-3 study).

Patients with compensated cirrhosis Harvoni + ribavirinb,c for 12 weeksor

Harvoni (without ribavirin) for 24 weeks.

- Harvoni (without ribavirin) for 12 weeks may be consideredfor patients deemed at low risk for clinical diseaseprogression and who have subsequent retreatment options(see section 4.4).

Patients who are post-liver transplant Harvoni + ribavirinb,c for 12 weeks (see section 5.1).without cirrhosis or with compensated - Harvoni (without ribavirin) for 12 weeks (in patientscirrhosis without cirrhosis) or 24 weeks (in patients with cirrhosis)may be considered for patients who are ineligible for orintolerant to ribavirin.

Patients with decompensated cirrhosis Harvoni + ribavirind for 12 weeks (see section 5.1)irrespective of transplant status - Harvoni (without ribavirin) for 24 weeks may be consideredin patients who are ineligible for or intolerant to ribavirin.

Adult and paediatric patients 3 years of ageand abovea with genotype 3 CHC

Patients with compensated cirrhosis and/or Harvoni + ribavirinb for 24 weeks (see sections 4.4 and 5.1).prior treatment failurea See Table 2 for weight-based Harvoni dosing recommendations for paediatric patients aged 3 years and above..b Adults: weight based ribavirin (< 75 kg = 1,000 mg and ≥ 75 kg = 1,200 mg), administered orally in two divided doseswith food.c Paediatric patients: for ribavirin dosing recommendations see table 4 below.d For ribavirin dosing recommendations in adult patients with decompensated cirrhosis, see table 3 below.

Table 2: Dosing for paediatric patients aged 3 years and above using Harvoni Tablets*

Body Weight (kg) Dosing of Harvoni Tablets Ledipasvir/Sofosbuvir Daily

Dose≥ 35 one 90 mg/400 mg tablet once daily 90 mg/400 mg/dayortwo 45 mg/200 mg tablets oncedaily17 to < 35 one 45 mg/200 mg tablet once daily 45 mg/200 mg/day

* Harvoni is also available as granules for use in paediatric patients with CHC aged 3 years and above (see section 5.1).

Patients that weigh < 17 kg are not recommended to take tablets. Please refer to the Summary of Product Characteristicsfor Harvoni 33.75 mg/150 mg or 45 mg/200 mg granules.

Table 3: Guidance for ribavirin dosing when administered with Harvoni to adult patients withdecompensated cirrhosis

Patient Ribavirin dose*

Child-Pugh-Turcotte (CPT) Class B 1,000 mg per day for patients < 75 kg and 1,200 mg for thosecirrhosis pre-transplant weighing ≥ 75 kg

CPT Class C cirrhosis pre-transplant Starting dose of 600 mg, which can be titrated up to a maximumof 1,000/1,200 mg (1,000 mg for patients weighing < 75 kg and

CPT Class B or C cirrhosis post- 1,200 mg for patients weighing ≥ 75 kg) if well tolerated. If thetransplant starting dose is not well tolerated, the dose should be reduced asclinically indicated based on haemoglobin levels

* If a more normalized dose of ribavirin (by weight and renal function) cannot be reached for reasons of tolerability,24 weeks of Harvoni + ribavirin should be considered in order to minimize the risk for relapse.

For adults when ribavirin is added to Harvoni, refer also to the Summary of Product Characteristics ofribavirin.

In paediatric patients aged 3 years and above the following ribavirin dosing is recommended whereribavirin is divided into two daily doses and given with food:

Table 4: Guidance for ribavirin dosing when administered with Harvoni to paediatric patientsaged 3 years and above.

Body weight kg Ribavirin Dose*< 47 15 mg/kg/day47-49 600 mg/day50-65 800 mg/day66-74 1000 mg/day> or = 75 1200 mg/day

* The daily dosage of ribavirin is weight-based and administered orally in two divided doses with food.

Dose modification of ribavirin in adults taking 1,000-1,200 mg daily

If Harvoni is used in combination with ribavirin and a patient has a serious adverse reaction potentiallyrelated to ribavirin, the ribavirin dose should be modified or discontinued, if appropriate, until theadverse reaction abates or decreases in severity. Table 5 provides guidelines for dose modificationsand discontinuation based on the patient’s haemoglobin concentration and cardiac status.

Table 5: Ribavirin dose modification guideline for co-administration with Harvoni in adults

Laboratory values Reduce ribavirin dose to Discontinue ribavirin if:600 mg/day if:

Haemoglobin in patients with no < 10 g/dL < 8.5 g/dLcardiac disease

Haemoglobin in patients with ≥ 2 g/dL decrease in haemoglobin < 12 g/dL despite 4 weeks athistory of stable cardiac disease during any 4-week treatment reduced doseperiod

Once ribavirin has been withheld due to either a laboratory abnormality or clinical manifestation, anattempt may be made to restart ribavirin at 600 mg daily and further increase the dose to 800 mg daily.

However, it is not recommended that ribavirin be increased to the originally assigned dose (1,000 mgto 1,200 mg daily).

Paediatric population aged < 3 years

The safety and efficacy of Harvoni in paediatric patients aged < 3 years have not been established. Nodata are available.

Patients should be instructed that if vomiting occurs within 5 hours of dosing an additional tabletshould be taken. If vomiting occurs more than 5 hours after dosing, no further dose is needed (seesection 5.1).

If a dose is missed and it is within 18 hours of the normal time, patients should be instructed to takethe tablet as soon as possible and then patients should take the next dose at the usual time. If it is after18 hours then patients should be instructed to wait and take the next dose at the usual time. Patientsshould be instructed not to take a double dose.

No dose adjustment is warranted for elderly patients (see section 5.2).

No dose adjustment of Harvoni is required for patients with mild or moderate renal impairment.

Safety data are limited in patients with severe renal impairment (estimated glomerular filtration rate[eGFR] < 30 mL/min/1.73 m2) and end stage renal disease (ESRD) requiring dialysis. Harvoni can beused in these patients with no dose adjustment when no other relevant treatment options are available(see section 4.4, pct. 4.8, 5.1 and 5.2).

No dose adjustment of Harvoni is required for patients with mild, moderate or severe hepaticimpairment (Child-Pugh-Turcotte [CPT] class A, B or C) (see section 5.2). Safety and efficacy ofledipasvir/sofosbuvir have been established in patients with decompensated cirrhosis (see section 5.1).

For oral use.

Patients should be instructed to swallow the tablet(s) whole with or without food. Due to the bittertaste, it is recommended that film-coated tablets are not chewed or crushed (see section 5.2).

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

Co-administration with rosuvastatin (see section 4.5).

Use with strong P-gp inducers

Medicinal products that are strong P-glycoprotein (P-gp) inducers in the intestine (carbamazepine,phenobarbital, phenytoin, rifampicin, rifabutin and St. John’s wort). Co-administration willsignificantly decrease ledipasvir and sofosbuvir plasma concentrations and could result in loss ofefficacy of Harvoni (see section 4.5).

Harvoni should not be administered concomitantly with other medicinal products containingsofosbuvir.

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

The clinical data to support the use of Harvoni in adults infected with HCV genotype 3 are limited (seesection 5.1). The relative efficacy of a 12-week regimen consisting of ledipasvir/sofosbuvir+ ribavirin, compared to a 24-week regimen of sofosbuvir + ribavirin has not been investigated. Aconservative 24 weeks of therapy is advised in all treatment-experienced genotype 3 patients and thosetreatment-naïve genotype 3 patients with cirrhosis (see section 4.2). In genotype 3-infection, the use of

Harvoni (always in combination with ribavirin) should only be considered for patients who aredeemed at high risk for clinical disease progression and who do not have alternative treatment options.

The clinical data to support the use of Harvoni in adults infected with HCV genotype 2 and 6 arelimited (see section 5.1).

Life-threatening cases of severe bradycardia and heart block have been observed when sofosbuvir-containing regimens are used in combination with amiodarone. Bradycardia has generally occurredwithin hours to days, but cases with a longer time to onset have been observed mostly up to 2 weeksafter initiating HCV treatment.

Amiodarone should only be used in patients on Harvoni when other alternative anti-arrhythmictreatments are not tolerated or are contraindicated.

Should concomitant use of amiodarone be considered necessary it is recommended that patientsundergo cardiac monitoring in an in-patient setting for the first 48 hours of coadministration, afterwhich outpatient or self-monitoring of the heart rate should occur on a daily basis through at least thefirst 2 weeks of treatment.

Due to the long half-life of amiodarone, cardiac monitoring as outlined above should also be carriedout for patients who have discontinued amiodarone within the past few months and are to be initiatedon Harvoni.

All patients with concurrent or recent use of amiodarone should be warned of the symptoms ofbradycardia and heart block and should be advised to seek medical advice urgently should theyexperience them.

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

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

Treatment of patients with prior exposure to HCV direct-acting antivirals

In patients who fail treatment with ledipasvir/sofosbuvir, selection of NS5A resistance mutations thatsubstantially reduce the susceptibility to ledipasvir is seen in the majority of cases (see section 5.1).

Limited data indicate that such NS5A mutations do not revert on long-term follow-up. There arepresently no data to support the effectiveness of retreatment of patients who have failedledipasvir/sofosbuvir with a subsequent regimen that contains an NS5A inhibitor. Similarly, there arepresently no data to support the effectiveness of NS3/4A protease inhibitors in patients who previouslyfailed prior therapy that included an NS3/4A protease inhibitor. Such patients may therefore bedependent on other classes of medicinal products for clearance of HCV infection. Consequently,consideration should be given to longer treatment for patients with uncertain subsequent retreatmentoptions.

Safety data are limited in patients with severe renal impairment (estimated glomerular filtration rate[eGFR] < 30 mL/min/1.73 m2) and ESRD requiring haemodialysis. Harvoni can be used in thesepatients with no dose adjustment when no other relevant treatment options are available (seesections 4.8, 5.1 and 5.2). When Harvoni is used in combination with ribavirin refer also to the

Summary of Product Characteristics for ribavirin for patients with creatinine clearance (CrCl)< 50 mL/min (see section 5.2).

Adults with decompensated cirrhosis and/or who are awaiting liver transplant or post-liver transplant

The efficacy of ledipasvir/sofosbuvir in genotype 5 and genotype 6 HCV-infected patients withdecompensated cirrhosis and/or who are awaiting liver transplant or post-liver transplant has not beeninvestigated. Treatment with Harvoni should be guided by an assessment of the potential benefits andrisks for the individual patient.

Use with moderate P-gp inducers

Medicinal products that are moderate P-gp inducers in the intestine (e.g. oxcarbazepine) may decreaseledipasvir and sofosbuvir plasma concentrations leading to reduced therapeutic effect of Harvoni.

Co-administration of such medicinal products is not recommended with Harvoni (see section 4.5).

Harvoni has been shown to increase tenofovir exposure, especially when used together with an HIVregimen containing tenofovir disoproxil fumarate and a pharmacokinetic enhancer (ritonavir orcobicistat). The safety of tenofovir disoproxil fumarate in the setting of Harvoni and apharmacokinetic enhancer has not been established. The potential risks and benefits associated withco-administration of Harvoni with the fixed-dose combination tablet containingelvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate or tenofovir disoproxil fumarategiven in conjunction with a boosted HIV protease inhibitor (e.g. atazanavir or darunavir) should beconsidered, particularly in patients at increased risk of renal dysfunction. Patients receiving Harvoniconcomitantly with elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate or withtenofovir disoproxil fumarate and a boosted HIV protease inhibitor should be monitored for tenofovir-associated adverse reactions. Refer to tenofovir disoproxil fumarate, emtricitabine/tenofovir disoproxilfumarate, or elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate Summary of Product

Characteristics for recommendations on renal monitoring.

Use with HMG-CoA reductase inhibitors

Co-administration of Harvoni and HMG-CoA reductase inhibitors (statins) can significantly increasethe concentration of the statin, which increases the risk of myopathy and rhabdomyolysis (seesection 4.5).

Harvoni is not recommended for use in paediatric patients aged < 3 years because the safety andefficacy have not been established in this population.

Harvoni contains the azo colouring agent sunset yellow FCF (E110), which may cause allergicreactions. It also contains lactose. Patients with rare hereditary problems of galactose intolerance, totallactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially‘sodium-free’.

As Harvoni contains ledipasvir and sofosbuvir, any interactions that have been identified with theseactive substances individually may occur with Harvoni.

Potential for Harvoni to affect other medicinal products

Ledipasvir is an in vitro inhibitor of drug transporter P-gp and breast cancer resistance protein (BCRP)and may increase intestinal absorption of co-administered substrates for these transporters.

Potential for other medicinal products to affect Harvoni

Ledipasvir and sofosbuvir are substrates of drug transporter P-gp and BCRP while GS-331007 is not.

Medicinal products that are strong P-gp inducers (carbamazepine, phenobarbital, phenytoin,rifampicin, rifabutin and St. John’s wort) may significantly decrease ledipasvir and sofosbuvir plasmaconcentrations leading to reduced therapeutic effect of ledipasvir/sofosbuvir and thus arecontraindicated with Harvoni (see section 4.3). Medicinal products that are moderate P-gp inducers inthe intestine (e.g. oxcarbazepine) may decrease ledipasvir and sofosbuvir plasma concentrationsleading to reduced therapeutic effect of Harvoni. Co-administration with such medicinal products isnot recommended with Harvoni (see section 4.4). Co-administration with medicinal products thatinhibit P-gp and/or BCRP may increase ledipasvir and sofosbuvir plasma concentrations withoutincreasing GS-331007 plasma concentration; Harvoni may be co-administered with P-gp and/or

BCRP inhibitors. Clinically significant medicinal product interactions with ledipasvir/sofosbuvirmediated by CYP450s or UGT1A1 enzymes are not expected.

As liver function may change during treatment with Harvoni, a close monitoring of International

Normalised Ratio (INR) values is recommended.

The pharmacokinetics of drugs that are metabolized by the liver (e.g. immunosuppressive agents suchas calcineurin inhibitors) may be impacted by changes in liver function during DAA therapy, related toclearance of HCV virus.

Interactions between Harvoni and other medicinal products

Table 6 provides a listing of established or potentially clinically significant medicinal productinteractions (where 90% confidence interval [CI] of the geometric least-squares mean [GLSM] ratiowere within “↔”, extended above “↑”, or extended below “↓” the predetermined equivalenceboundaries). The medicinal product interactions described are based on studies conducted with eitherledipasvir/sofosbuvir or ledipasvir and sofosbuvir as individual agents, or are predicted medicinalproduct interactions that may occur with ledipasvir/sofosbuvir. The table is not all-inclusive.

Table 6: Interactions between Harvoni and other medicinal products

Medicinal product by Effects on medicinal Recommendation concerning co-administrationtherapeutic areas product levels. with Harvoni

Mean ratio (90%confidence interval) for

AUC, Cmax, Cmina, b

ACID REDUCING AGENTS

Ledipasvir solubility decreases as pH increases.

Medicinal products that increase gastric pH areexpected to decrease concentration of ledipasvir.

Antacidse.g. Aluminium or Interaction not studied. It is recommended to separate antacid and Harvonimagnesium hydroxide; Expected: administration by 4 hours.calcium carbonate ↓ Ledipasvir↔ Sofosbuvir↔ GS-331007(Increase in gastric pH)

H2-receptor antagonists

Famotidine Ledipasvir H2-receptor antagonists may be administered(40 mg single dose)/ ↓ Cmax 0.80 (0.69, 0.93) simultaneously with or staggered from Harvoni at aledipasvir (90 mg single ↔ AUC 0.89 (0.76, 1.06) dose that does not exceed doses comparable todose)c/ sofosbuvir (400 mg famotidine 40 mg twice daily.single dose)c, d Sofosbuvir↑ Cmax 1.15 (0.88, 1.50)

Famotidine dosed ↔ AUC 1.11 (1.00, 1.24)simultaneously with

Harvonid GS-331007↔ Cmax 1.06 (0.97, 1.14)↔ AUC 1.06 (1.02, 1.11)

Cimetidinee

Nizatidinee (Increase in gastric pH)

Ranitidinee

Famotidine Ledipasvir(40 mg single dose)/ ↓ Cmax 0.83 (0.69, 1.00)ledipasvir (90 mg single ↔ AUC 0.98 (0.80, 1.20)dose)c/ sofosbuvir (400 mgsingle dose)c, d Sofosbuvir↔ Cmax 1.00 (0.76, 1.32)

Famotidine dosed 12 hours ↔ AUC 0.95 (0.82, 1.10)prior to Harvonid

GS-331007↔ Cmax 1.13 (1.07, 1.20)↔ AUC 1.06 (1.01, 1.12)(Increase in gastric pH)

Omeprazole Ledipasvir Proton pump inhibitor doses comparable to(20 mg once daily)/ ↓ Cmax 0.89 (0.61, 1.30) omeprazole 20 mg can be administeredledipasvir (90 mg single ↓ AUC 0.96 (0.66, 1.39) simultaneously with Harvoni. Proton pumpdose)c/ sofosbuvir (400 mg inhibitors should not be taken before Harvoni.single dose)c Sofosbuvir↔ Cmax 1.12 (0.88, 1.42)

Omeprazole dosed ↔ AUC 1.00 (0.80, 1.25)simultaneously with Harvoni

GS-331007

Lansoprazolee ↔ Cmax 1.14 (1.01, 1.29)

Rabeprazolee ↔ AUC 1.03 (0.96, 1.12)

Pantoprazolee

Esomeprazolee (Increase in gastric pH)

Medicinal product by Effects on medicinal Recommendation concerning co-administrationtherapeutic areas product levels. with Harvoni

Mean ratio (90%confidence interval) for

AUC, C , Cmina, bmax

ANTIARRHYTHMICS

Amiodarone Effect on amiodarone, Coadministration of amiodarone with a sofosbuvir-sofosbuvir and ledipasvir containing regimen may result in seriousconcentrations unknown. symptomatic bradycardia.

Use only if no other alternative is available. Closemonitoring is recommended if this medicinalproduct is administered with Harvoni (seesections 4.4 and 4.8).

Digoxin Interaction not studied. Co-administration of Harvoni with digoxin may

Expected: increase the concentration of digoxin. Caution is↑ Digoxin warranted and therapeutic concentration monitoring↔ Ledipasvir of digoxin is recommended when co-administered↔ Sofosbuvir with Harvoni.↔ GS-331007(Inhibition of P-gp)

ANTICOAGULANTS

Dabigatran etexilate Interaction not studied. Clinical monitoring, looking for signs of bleeding

Expected: and anaemia, is recommended when dabigatran↑ Dabigatran etexilate is co-administered with Harvoni. A↔ Ledipasvir coagulation test helps to identify patients with an↔ Sofosbuvir increased bleeding risk due to increased dabigatran↔ GS-331007 exposure.

(Inhibition of P-gp)

Vitamin K antagonists Interaction not studied. Close monitoring of INR is recommended with allvitamin K antagonists. This is due to liver functionchanges during treatment with Harvoni.

ANTICONVULSANTS

Phenobarbital Interaction not studied. Harvoni is contraindicated with phenobarbital and

Phenytoin Expected: phenytoin (see section 4.3).

↓ Ledipasvir↓ Sofosbuvir↔ GS-331007(Induction of P-gp)

Carbamazepine Interaction not studied Harvoni is contraindicated with carbamazepine (see

Expected: section 4.3).↓ Ledipasvir

Observed:

Sofosbuvir↓ Cmax 0.52 (0.43, 0.62)↓ AUC 0.52 (0.46, 0.59)

Cmin (NA)

GS-331007↔ Cmax 1.04 (0.97, 1.11)↔ AUC 0.99 (0.94, 1.04)

Cmin (NA)(Induction of P-gp)

Medicinal product by Effects on medicinal Recommendation concerning co-administrationtherapeutic areas product levels. with Harvoni

Mean ratio (90%confidence interval) for

AUC, C , Cmina, bmax

Oxcarbazepine Interaction not studied. Co-administration of Harvoni with oxcarbazepine is

Expected: expected to decrease the concentration of ledipasvir↓ Ledipasvir and sofosbuvir leading to reduced therapeutic effect↓ Sofosbuvir of Harvoni. Such co-administration is not↔ GS-331007 recommended (see section 4.4).

(Induction of P-gp)

ANTIMYCOBACTERIALS

Rifampicin (600 mg once Interaction not studied. Harvoni is contraindicated with rifampicin (seedaily)/ ledipasvir (90 mg Expected: section 4.3).single dose)d Rifampicin↔ Cmax↔ AUC↔ Cmin

Observed:

Ledipasvir↓ Cmax 0.65 (0.56, 0.76)↓ AUC 0.41 (0.36, 0.48)(Induction of P-gp)

Rifampicin (600 mg once Interaction not studied.daily)/ sofosbuvir (400 mg Expected:single dose)d Rifampicin↔ Cmax↔ AUC↔ Cmin

Observed:

Sofosbuvir↓ Cmax 0.23 (0.19, 0.29)↓ AUC 0.28 (0.24, 0.32)

GS-331007↔ Cmax 1.23 (1.14, 1.34)↔ AUC 0.95 (0.88, 1.03)(Induction of P-gp)

Rifabutin Interaction not studied. Harvoni is contraindicated with rifabutin (see

Expected: section 4.3).↓ Ledipasvir

Observed:

Sofosbuvir↓ Cmax 0.64 (0.53, 0.77)↓ AUC 0.76 (0.63, 0.91)

Cmin (NA)

GS-331007↔ Cmax 1.15 (1.03, 1.27)↔ AUC 1.03 (0.95, 1.12)

Cmin (NA)(Induction of P-gp)

Medicinal product by Effects on medicinal Recommendation concerning co-administrationtherapeutic areas product levels. with Harvoni

Mean ratio (90%confidence interval) for

AUC, Cmax, Cmina, b

Rifapentine Interaction not studied. Co-administration of Harvoni with rifapentine is

Expected: expected to decrease the concentration of ledipasvir↓ Ledipasvir and sofosbuvir, leading to reduced therapeutic effect↓ Sofosbuvir of Harvoni. Such co-administration is not↔ GS-331007 recommended.(Induction of P-gp)

SEDATIVES/HYPNOTICS

Midazolam (2.5 mg single Observed: No dose adjustment of Harvoni or midazolam isdose)/ ledipasvir (90 mg Midazolam required.single dose) ↔ Cmax 1.07 (1.00, 1.14)↔ AUC 0.99 (0.95, 1.04)(Inhibition of CYP3A)

Ledipasvir (90 mg once Midazolamdaily) ↔ Cmax 0.95 (0.87, 1.04)↔ AUC 0.89 (0.84, 0.95)(Induction of CYP3A)

Expected:↔ Sofosbuvir↔ GS-331007

HIV ANTIVIRAL AGENTS: REVERSE TRANSCRIPTASE INHIBITORS

Efavirenz/ emtricitabine/ Efavirenz No dose adjustment of Harvoni or efavirenz/tenofovir disoproxil ↔ Cmax 0.87 (0.79, 0.97) emtricitabine/ tenofovir disoproxil fumarate isfumarate ↔ AUC 0.90 (0.84, 0.96) required.(600 mg/ 200 mg/ 300 mg/ ↔ Cmin 0.91 (0.83, 0.99)once daily)/ ledipasvir(90 mg once daily)c/ Emtricitabinesofosbuvir (400 mg once ↔ Cmax 1.08 (0.97, 1.21)daily)c, d ↔ AUC 1.05 (0.98, 1.11)↔ Cmin 1.04 (0.98, 1.11)

Tenofovir↑ Cmax 1.79 (1.56, 2.04)↑ AUC 1.98 (1.77, 2.23)↑ Cmin 2.63 (2.32, 2.97)

Ledipasvir↓ Cmax 0.66 (0.59, 0.75)↓ AUC 0.66 (0.59, 0.75)↓ Cmin 0.66 (0.57, 0.76)

Sofosbuvir↔ Cmax 1.03 (0.87, 1.23)↔ AUC 0.94 (0.81, 1.10)

GS-331007↔ Cmax 0.86 (0.76, 0.96)↔ AUC 0.90 (0.83, 0.97)↔ Cmin 1.07 (1.02, 1.13)

Medicinal product by Effects on medicinal Recommendation concerning co-administrationtherapeutic areas product levels. with Harvoni

Mean ratio (90%confidence interval) for

AUC, Cmax, Cmina, b

Emtricitabine/ rilpivirine/ Emtricitabine No dose adjustment of Harvoni or emtricitabine/tenofovir disoproxil ↔ Cmax 1.02 (0.98, 1.06) rilpivirine/ tenofovir disoproxil fumarate isfumarate ↔ AUC 1.05 (1.02, 1.08) required.(200 mg/ 25 mg/ 300 mg ↔ Cmin 1.06 (0.97, 1.15)once daily)/ ledipasvir(90 mg once daily)c/ Rilpivirinesofosbuvir (400 mg once ↔ Cmax 0.97 (0.88, 1.07)daily)c, d ↔ AUC 1.02 (0.94, 1.11)↔ Cmin 1.12 (1.03, 1.21)

Tenofovir↔ Cmax 1.32 (1.25, 1.39)↑ AUC 1.40 (1.31, 1.50)↑ Cmin 1.91 (1.74, 2.10)

Ledipasvir↔ Cmax 1.01 (0.95, 1.07)↔ AUC 1.08 (1.02, 1.15)↔ Cmin 1.16 (1.08, 1.25)

Sofosbuvir↔ Cmax 1.05 (0.93, 1.20)↔ AUC 1.10 (1.01, 1.21)

GS-331007↔ Cmax 1.06 (1.01, 1.11)↔ AUC 1.15 (1.11, 1.19)↔ Cmin 1.18 (1.13, 1.24)

Abacavir/ lamivudine Abacavir No dose adjustment of Harvoni or abacavir/(600 mg/ 300 mg once ↔ Cmax 0.92 (0.87, 0.97) lamivudine is required.daily)/ ledipasvir (90 mg ↔ AUC 0.90 (0.85, 0.94)once daily)c/ sofosbuvir(400 mg once daily)c, d Lamivudine↔ Cmax 0.93 (0.87, 1.00)↔ AUC 0.94 (0.90, 0.98)↔ Cmin 1.12 (1.05, 1.20)

Ledipasvir↔ Cmax 1.10 (1.01, 1.19)↔ AUC 1.18 (1.10, 1.28)↔ Cmin 1.26 (1.17, 1.36)

Sofosbuvir↔ Cmax 1.08 (0.85, 1.35)↔ AUC 1.21 (1.09, 1.35)

GS-331007↔ Cmax 1.00 (0.94, 1.07)↔ AUC 1.05 (1.01, 1.09)↔ Cmin 1.08 (1.01, 1.14)

Medicinal product by Effects on medicinal Recommendation concerning co-administrationtherapeutic areas product levels. with Harvoni

Mean ratio (90%confidence interval) for

AUC, C , Cmina, bmax

HIV ANTIVIRAL AGENTS: HIV PROTEASE INHIBITORS

Atazanavir boosted with Atazanavir No dose adjustment of Harvoni or atazanavirritonavir ↔ Cmax 1.07 (1.00, 1.15) (ritonavir boosted) is required.(300 mg/ 100 mg once ↔ AUC 1.33 (1.25, 1.42)daily)/ ledipasvir (90 mg ↑ Cmin 1.75 (1.58, 1.93) For the combination of tenofovir/emtricitabine +once daily)c/ sofosbuvir atazanavir/ritonavir, please see below.(400 mg once daily)c, d Ledipasvir↑ Cmax 1.98 (1.78, 2.20)↑ AUC 2.13 (1.89, 2.40)↑ Cmin 2.36 (2.08, 2.67)

Sofosbuvir↔ Cmax 0.96 (0.88, 1.05)↔ AUC 1.08 (1.02, 1.15)

GS-331007↔ Cmax 1.13 (1.08, 1.19)↔ AUC 1.23 (1.18, 1.29)↔ Cmin 1.28 (1.21, 1.36)

Atazanavir boosted with Atazanavir When given with tenofovir disoproxil fumarate usedritonavir (300 mg/ 100 mg ↔ Cmax 1.07 (0.99, 1.14) in conjunction with atazanavir/ritonavir, Harvonionce daily) + emtricitabine/ ↔ AUC 1.27 (1.18, 1.37) increased the concentration of tenofovir.tenofovir disoproxil ↑ Cmin 1.63 (1.45, 1.84)fumarate (200 mg/ 300 mg The safety of tenofovir disoproxil fumarate in theonce daily)/ ledipasvir Ritonavir setting of Harvoni and a pharmacokinetic enhancer(90 mg once daily)c/ ↔ Cmax 0.86 (0.79, 0.93) (e.g. ritonavir or cobicistat) has not beensofosbuvir (400 mg once ↔ AUC 0.97 (0.89, 1.05) established.daily)c, d ↑ Cmin 1.45 (1.27, 1.64)

The combination should be used with caution with

Dosed simultaneouslyf Emtricitabine frequent renal monitoring, if other alternatives are↔ Cmax 0.98 (0.94, 1.02) not available (see section 4.4).↔ AUC 1.00 (0.97, 1.04)↔ Cmin 1.04 (0.96, 1.12) Atazanavir concentrations are also increased, with arisk for an increase in bilirubin levels/icterus. That

Tenofovir risk is even higher if ribavirin is used as part of the↑ Cmax 1.47 (1.37, 1.58) HCV treatment.↔ AUC 1.35 (1.29, 1.42)↑ Cmin 1.47 (1.38, 1.57)

Ledipasvir↑ Cmax 1.68 (1.54, 1.84)↑ AUC 1.96 (1.74, 2.21)↑ Cmin 2.18 (1.91, 2.50)

Sofosbuvir↔ Cmax 1.01 (0.88, 1.15)↔ AUC 1.11 (1.02, 1.21)

GS-331007↔ Cmax 1.17 (1.12, 1.23)↔ AUC 1.31 (1.25, 1.36)↑ Cmin 1.42 (1.34, 1.49)

Medicinal product by Effects on medicinal Recommendation concerning co-administrationtherapeutic areas product levels. with Harvoni

Mean ratio (90%confidence interval) for

AUC, Cmax, Cmina, b

Darunavir boosted with Darunavir No dose adjustment of Harvoni or darunavirritonavir ↔ Cmax 1.02 (0.88, 1.19) (ritonavir boosted) is required.(800 mg/ 100 mg once ↔ AUC 0.96 (0.84, 1.11)daily)/ ledipasvir (90 mg ↔ Cmin 0.97 (0.86, 1.10) For the combination of tenofovir/emtricitabine +once daily)d darunavir/ritonavir, please see below.

Ledipasvir↑ Cmax 1.45 (1.34, 1.56)↑ AUC 1.39 (1.28, 1.49)↑ Cmin 1.39 (1.29, 1.51)

Darunavir boosted with Darunavirritonavir ↔ Cmax 0.97 (0.94, 1.01)(800 mg/ 100 mg once ↔ AUC 0.97 (0.94, 1.00)daily)/ sofosbuvir (400 mg ↔ Cmin 0.86 (0.78, 0.96)once daily)

Sofosbuvir↑ Cmax 1.45 (1.10, 1.92)↑ AUC 1.34 (1.12, 1.59)

GS-331007↔ Cmax 0.97 (0.90, 1.05)↔ AUC 1.24 (1.18, 1.30)

Darunavir boosted with Darunavir When given with darunavir/ritonavir used inritonavir (800 mg/ 100 mg ↔ Cmax 1.01 (0.96, 1.06) conjunction with tenofovir disoproxil fumarate,once daily) + emtricitabine/ ↔ AUC 1.04 (0.99, 1.08) Harvoni increased the concentration of tenofovir.tenofovir disoproxil ↔ Cmin 1.08 (0.98, 1.20)fumarate (200 mg/ 300 mg The safety of tenofovir disoproxil fumarate in theonce daily)/ ledipasvir Ritonavir setting of Harvoni and a pharmacokinetic enhancer(90 mg once daily)c/ ↔ Cmax 1.17 (1.01, 1.35) (e.g. ritonavir or cobicistat) has not beensofosbuvir (400 mg once ↔ AUC 1.25 (1.15, 1.36) established.daily)c, d ↑ Cmin 1.48 (1.34, 1.63)

The combination should be used with caution with

Dosed simultaneouslyf Emtricitabine frequent renal monitoring, if other alternatives are↔ Cmax 1.02 (0.96, 1.08) not available (see section 4.4).↔ AUC 1.04 (1.00, 1.08)↔ Cmin 1.03 (0.97, 1.10)

Tenofovir↑ Cmax 1.64 (1.54, 1.74)↑ AUC 1.50 (1.42, 1.59)↑ Cmin 1.59 (1.49, 1.70)

Ledipasvir↔ Cmax 1.11 (0.99, 1.24)↔ AUC 1.12 (1.00, 1.25)↔ Cmin 1.17 (1.04, 1.31)

Sofosbuvir↓ Cmax 0.63 (0.52, 0.75)↓ AUC 0.73 (0.65, 0.82)

GS-331007↔ Cmax 1.10 (1.04, 1.16)↔ AUC 1.20 (1.16, 1.24)↔ Cmin 1.26 (1.20, 1.32)

Medicinal product by Effects on medicinal Recommendation concerning co-administrationtherapeutic areas product levels. with Harvoni

Mean ratio (90%confidence interval) for

AUC, Cmax, Cmina, b

Lopinavir boosted with Interaction not studied. When given with lopinavir/ritonavir used inritonavir + emtricitabine/ Expected: conjunction with tenofovir disoproxil fumarate,tenofovir disoproxil ↑ Lopinavir Harvoni is expected to increase the concentration offumarate ↑ Ritonavir tenofovir.

↔ Emtricitabine The safety of tenofovir disoproxil fumarate in the↑ Tenofovir setting of Harvoni and a pharmacokinetic enhancer(e.g. ritonavir or cobicistat) has not been↑ Ledipasvir established.↔ Sofosbuvir↔ GS-331007 The combination should be used with caution withfrequent renal monitoring, if other alternatives arenot available (see section 4.4).

Tipranavir boosted with Interaction not studied. Co-administration of Harvoni with tipranavirritonavir Expected: (ritonavir boosted) is expected to decrease the↓ Ledipasvir concentration of ledipasvir, leading to reduced↓ Sofosbuvir therapeutic effect of Harvoni. Co-administration is↔ GS-331007 not recommended.

(Induction of P-gp)

HIV ANTIVIRAL AGENTS: INTEGRASE INHIBITORS

Raltegravir Raltegravir No dose adjustment of Harvoni or raltegravir is(400 mg twice daily)/ ↓ Cmax 0.82 (0.66, 1.02) required.ledipasvir (90 mg once ↔ AUC 0.85 (0.70, 1.02)daily)d ↑ Cmin 1.15 (0.90, 1.46)

Ledipasvir↔ Cmax 0.92 (0.85, 1.00)↔ AUC 0.91 (0.84, 1.00)↔ Cmin 0.89 (0.81, 0.98)

Raltegravir Raltegravir(400 mg twice daily)/ ↓ Cmax 0.57 (0.44, 0.75)sofosbuvir (400 mg once ↓ AUC 0.73 (0.59, 0.91)daily)d ↔ Cmin 0.95 (0.81, 1.12)

Sofosbuvir↔ Cmax 0.87 (0.71, 1.08)↔ AUC 0.95 (0.82, 1.09)

GS-331007↔ Cmax 1.09 (0.99, 1.19)↔ AUC 1.02 (0.97, 1.08)

Medicinal product by Effects on medicinal Recommendation concerning co-administrationtherapeutic areas product levels. with Harvoni

Mean ratio (90%confidence interval) for

AUC, Cmax, Cmina, b

Elvitegravir/ cobicistat/ Interaction not studied. When given with elvitegravir/ cobicistat/emtricitabine/ tenofovir Expected: emtricitabine/ tenofovir disoproxil fumarate,disoproxil fumarate ↔ Emtricitabine Harvoni is expected to increase the concentration of(150 mg/ 150 mg/ 200 mg/ ↑ Tenofovir tenofovir.300 mg once daily)/ledipasvir (90 mg once Observed: The safety of tenofovir disoproxil fumarate in thedaily)c/ sofosbuvir (400 mg Elvitegravir setting of Harvoni and a pharmacokinetic enhanceronce daily)c ↔ Cmax 0.88 (0.82, 0.95) (e.g. ritonavir or cobicistat) has not been↔ AUC 1.02 (0.95, 1.09) established.↑ Cmin 1.36 (1.23, 1.49)

The combination should be used with caution with

Cobicistat frequent renal monitoring, if other alternatives are↔ Cmax 1.25 (1.18, 1.32) not available (see section 4.4).↑ AUC 1.59 (1.49, 1.70)↑ Cmin 4.25 (3.47, pct. 5.22)

Ledipasvir↑ Cmax 1.63 (1.51, 1.75)↑ AUC 1.78 (1.64, 1.94)↑ Cmin 1.91 (1.76, 2.08)

Sofosbuvir↑ Cmax 1.33 (1.14, 1.56)↑ AUC 1.36 (1.21, 1.52)

GS-331007↑ Cmax 1.33 (1.22, 1.44)↑ AUC 1.44 (1.41, 1.48)↑ Cmin 1.53 (1.47, 1.59)

Dolutegravir Interaction not studied. No dose adjustment required.

Expected:↔ Dolutegravir↔ Ledipasvir↔ Sofosbuvir↔ GS-331007

HERBAL SUPPLEMENTS

St. John’s wort Interaction not studied. Harvoni is contraindicated with St. John’s wort (see

Expected: section 4.3).↓ Ledipasvir↓ Sofosbuvir↔ GS-331007(Induction of P-gp)

HMG-CoA REDUCTASE INHIBITORS

Rosuvastating ↑ Rosuvastatin Co-administration of Harvoni with rosuvastatin maysignificantly increase the concentration of(Inhibition of drug rosuvastatin (several fold-increase in AUC) whichtransporters OATP and is associated with increased risk of myopathy,

BCRP) including rhabdomyolysis. Co-administration of

Harvoni with rosuvastatin is contraindicated (seesection 4.3).

Pravastating ↑ Pravastatin Co-administration of Harvoni with pravastatin maysignificantly increase the concentration ofpravastatin which is associated with increased riskof myopathy. Clinical and biochemical control isrecommended in these patients and a doseadjustment may be needed (see section 4.4).

Medicinal product by Effects on medicinal Recommendation concerning co-administrationtherapeutic areas product levels. with Harvoni

Mean ratio (90%confidence interval) for

AUC, C , Cmina, bmax

Other statins Expected: Interactions cannot be excluded with other↑ Statins HMG-CoA reductase inhibitors. Whenco-administered with Harvoni, a reduced dose ofstatins should be considered and careful monitoringfor statin adverse reactions should be undertaken(see section 4.4).

NARCOTIC ANALGESICS

Methadone Interaction not studied. No dose adjustment of Harvoni or methadone is

Expected: required.↔ Ledipasvir

Methadone R-methadone(Methadone maintenance ↔ Cmax 0.99 (0.85, 1.16)therapy [30 to 130 mg/ ↔ AUC 1.01 (0.85, 1.21)daily])/ sofosbuvir (400 mg ↔ Cmin 0.94 (0.77, 1.14)once daily)d

S-methadone↔ Cmax 0.95 (0.79, 1.13)↔ AUC 0.95 (0.77, 1.17)↔ Cmin 0.95 (0.74, 1.22)

Sofosbuvir↓ Cmax 0.95 (0.68, 1.33)↑ AUC 1.30 (1.00, 1.69)

GS-331007↓ Cmax 0.73 (0.65, 0.83)↔ AUC 1.04 (0.89, 1.22)

IMMUNOSUPPRESSANTS

Ciclosporing Interaction not studied. No dose adjustment of Harvoni or ciclosporin is

Expected: required at initiation of co-administration.↑ Ledipasvir Afterwards, close monitoring and potential dose↔ Ciclosporin adjustment of ciclosporin may be required.

Ciclosporin Ciclosporin(600 mg single dose)/ ↔ Cmax 1.06 (0.94, 1.18)sofosbuvir (400 mg single ↔ AUC 0.98 (0.85, 1.14)dose)h

Sofosbuvir↑ Cmax 2.54 (1.87, 3.45)↑ AUC 4.53 (3.26, 6.30)

GS-331007↓ Cmax 0.60 (0.53, 0.69)↔ AUC 1.04 (0.90, 1.20)

Tacrolimus Interaction not studied. No dose adjustment of Harvoni or tacrolimus is

Expected: required at initiation of co-administration.↔ Ledipasvir Afterwards, close monitoring and potential dose

Tacrolimus Tacrolimus adjustment of tacrolimus may be required.(5 mg single dose)/ ↓ Cmax 0.73 (0.59, 0.90)sofosbuvir (400 mg single ↑ AUC 1.09 (0.84, 1.40)dose)h

Sofosbuvir↓ Cmax 0.97 (0.65, 1.43)↑ AUC 1.13 (0.81, 1.57)

GS-331007↔ Cmax 0.97 (0.83, 1.14)↔ AUC 1.00 (0.87, 1.13)

Medicinal product by Effects on medicinal Recommendation concerning co-administrationtherapeutic areas product levels. with Harvoni

Mean ratio (90%confidence interval) for

AUC, Cmax, Cmina, b

ORAL CONTRACEPTIVES

Norgestimate/ ethinyl Norelgestromin No dose adjustment of oral contraceptives isestradiol (norgestimate ↔ Cmax 1.02 (0.89, 1.16) required.0.180 mg/ 0.215 mg/ ↔ AUC 1.03 (0.90, 1.18)0.25 mg/ ethinyl estradiol ↔ Cmin 1.09 (0.91, 1.31)0.025 mg)/ ledipasvir(90 mg once daily)d Norgestrel↔ Cmax 1.03 (0.87, 1.23)↔ AUC 0.99 (0.82, 1.20)↔ Cmin 1.00 (0.81, 1.23)

Ethinyl estradiol↑ Cmax 1.40 (1.18, 1.66)↔ AUC 1.20 (1.04, 1.39)↔ Cmin 0.98 (0.79, 1.22)

Norgestimate/ ethinyl Norelgestrominestradiol (norgestimate ↔ Cmax 1.07 (0.94, 1.22)0.180 mg/ 0.215 mg/ ↔ AUC 1.06 (0.92, 1.21)0.25 mg/ ethinyl estradiol ↔ Cmin 1.07 (0.89, 1.28)0.025 mg)/ sofosbuvir(400 mg once daily)d Norgestrel↔ Cmax 1.18 (0.99, 1.41)↑ AUC 1.19 (0.98, 1.45)↑ Cmin 1.23 (1.00, 1.51)

Ethinyl estradiol↔ Cmax 1.15 (0.97, 1.36)↔ AUC 1.09 (0.94, 1.26)↔ Cmin 0.99 (0.80, 1.23)a Mean ratio (90% CI) of co-administered drug pharmacokinetics of study medicinal products alone or in combination. Noeffect = 1.00.

b All interaction studies conducted in healthy volunteers.c Administered as Harvoni.d Lack of pharmacokinetics interaction bounds 70-143%.e These are drugs within class where similar interactions could be predicted.f Staggered administration (12 hours apart) of atazanavir/ritonavir + emtricitabine/tenofovir disoproxil fumarate ordarunavir/ritonavir + emtricitabine/tenofovir disoproxil fumarate and Harvoni provided similar results.g This study was conducted in the presence of another two direct-acting antiviral agents.h Bioequivalence/Equivalence boundary 80-125%.

Women of childbearing potential/contraception in males and females

When Harvoni is used in combination with ribavirin, extreme care must be taken to avoid pregnancyin female patients and in female partners of male patients. Significant teratogenic and/or embryocidaleffects have been demonstrated in all animal species exposed to ribavirin. Women of childbearingpotential or their male partners must use an effective form of contraception during treatment and for aperiod of time after the treatment has concluded as recommended in the Summary of Product

Characteristics for ribavirin. Refer to the Summary of Product Characteristics for ribavirin foradditional information.

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of ledipasvir,sofosbuvir or Harvoni in pregnant women.

Animal studies do not indicate direct harmful effects with respect to reproductive toxicity. Nosignificant effects on foetal development have been observed with ledipasvir or sofosbuvir in rats andrabbits. However, it has not been possible to fully estimate exposure margins achieved for sofosbuvirin the rat relative to the exposure in humans at the recommended clinical dose (see section 5.3).

As a precautionary measure, it is preferable to avoid the use of Harvoni during pregnancy.

It is unknown whether ledipasvir or sofosbuvir and its metabolites are excreted in human milk.

Available pharmacokinetic data in animals has shown excretion of ledipasvir and metabolites ofsofosbuvir in milk (see section 5.3).

A risk to the newborns/infants cannot be excluded. Therefore, Harvoni should not be used duringbreast-feeding.

No human data on the effect of Harvoni on fertility are available. Animal studies do not indicateharmful effects of ledipasvir or sofosbuvir on fertility.

If ribavirin is co-administered with Harvoni, the contraindications regarding use of ribavirin duringpregnancy and breast-feeding apply (see also the Summary of Product Characteristics for ribavirin).

Harvoni (administered alone or in combination with ribavirin) has no or negligible influence on theability to drive and use machines. However, patients should be advised that fatigue was more commonin patients treated with ledipasvir/sofosbuvir compared to placebo.

Summary of the safety profile in adults

The safety assessment of Harvoni was mainly based on pooled Phase 3 clinical studies, without acontrol, in 1952 patients who received Harvoni for 8, 12 or 24 weeks, including 872 patients whoreceived Harvoni in combination with ribavirin.

The proportion of patients who permanently discontinued treatment due to adverse events was 0%,< 1% and 1% for patients receiving ledipasvir/sofosbuvir for 8, 12 and 24 weeks, respectively; and< 1%, 0%, and 2% for patients receiving ledipasvir/sofosbuvir + ribavirin combination therapy for 8,12 and 24 weeks, respectively.

In clinical studies, fatigue and headache were more common in patients treated withledipasvir/sofosbuvir compared to placebo. When ledipasvir/sofosbuvir was studied with ribavirin, themost frequent adverse drug reactions to ledipasvir/sofosbuvir + ribavirin combination therapy wereconsistent with the known safety profile of ribavirin, without increasing the frequency or severity ofthe expected adverse drug reactions.

Tabulated list of adverse events

The following adverse drug reactions have been identified with Harvoni (Table 7). The adversereactions are listed below by body 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).

Table 7: Adverse drug reactions identified with Harvoni

Frequency Adverse drug reaction

Very common headache

Common rash

Not known angioedema

General disorders:

Very common fatigue

Adults with decompensated cirrhosis and/or who are awaiting liver transplant or post-liver transplant

The safety profile of ledipasvir/sofosbuvir with ribavirin for 12 or 24 weeks in adults withdecompensated liver disease and/or those post-liver transplant was assessed in two open-label studies(SOLAR-1 and SOLAR-2). No new adverse drug reactions were detected among patients withdecompensated cirrhosis and/or who were post-liver transplant and who received ledipasvir/sofosbuvirwith ribavirin. Although adverse events, including serious adverse events, occurred more frequently inthis study compared to studies that excluded decompensated patients and/or patients who were post-liver transplantation, the adverse events observed were those expected as clinical sequelae of advancedliver disease and/or transplantation or were consistent with the known safety profile of ribavirin (seesection 5.1 for details of this study).

Decreases in haemoglobin to < 10 g/dL and < 8.5 g/dL during treatment were experienced by 39% and13% of patients treated with ledipasvir/sofosbuvir with ribavirin, respectively. Ribavirin wasdiscontinued in 15% of the patients.

7% of liver transplant recipients had a modification of their immunosuppressive agents.

Ledipasvir/sofosbuvir was administered for 12 weeks to 18 patients with genotype 1 CHC and severerenal impairment in an open-label study (Study 0154). In this limited clinical safety data set, the rateof adverse events was not clearly elevated from what is expected in patients with severe renalimpairment.

The safety of Harvoni has been evaluated in a 12-week non-controlled study including 95 patientswith ESRD requiring dialysis (Study 4063). In this setting, exposure of sofosbuvir metabolite GS-331007 is 20-fold increased, exceeding levels where adverse reactions have been observed inpreclinical trials. In this limited clinical safety data set, the rate of adverse events and deaths was notclearly elevated from what is expected in ESRD patients.

The safety and efficacy of Harvoni in paediatric patients aged 3 years and above are based on datafrom a Phase 2, open-label clinical study (Study 1116) that enrolled 226 patients who were treatedwith ledipasvir/sofosbuvir for 12 or 24 weeks or ledipasvir/sofosbuvir plus ribavirin for 24 weeks. Theadverse reactions observed were consistent with those observed in clinical studies ofledipasvir/sofosbuvir in adults (see Table 7).

Cases of severe bradycardia and heart block have been observed when Harvoni is used withamiodarone and/or other drugs that lower heart rate (see sections 4.4 and 4.5).

Frequency not known: Stevens-Johnson syndrome

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

The highest documented doses of ledipasvir and sofosbuvir were 120 mg twice daily for 10 days and asingle dose of 1,200 mg, respectively. In these healthy volunteer studies, there were no untowardeffects observed at these dose levels, and adverse reactions were similar in frequency and severity tothose reported in the placebo groups. The effects of higher doses are not known.

No specific antidote is available for overdose with Harvoni. If overdose occurs the patient must bemonitored for evidence of toxicity. Treatment of overdose with Harvoni consists of general supportivemeasures including monitoring of vital signs as well as observation of the clinical status of the patient.

Haemodialysis is unlikely to result in significant removal of ledipasvir as ledipasvir is highly bound toplasma protein. Haemodialysis can efficiently remove the predominant circulating metabolite ofsofosbuvir, GS-331007, with an extraction ratio of 53%.

Pharmacotherapeutic group: Direct-acting antiviral, ATC code: J05AP51

Ledipasvir is a HCV inhibitor targeting the HCV NS5A protein, which is essential for both RNAreplication and the assembly of HCV virions. Biochemical confirmation of NS5A inhibition byledipasvir is not currently possible as NS5A has no enzymatic function. In vitro resistance selectionand cross-resistance studies indicate ledipasvir targets NS5A as its mode of action.

Sofosbuvir is a pan-genotypic inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which isessential for viral replication. Sofosbuvir is a nucleotide prodrug that undergoes intracellularmetabolism to form the pharmacologically active uridine analogue triphosphate (GS-461203), whichcan be incorporated into HCV RNA by the NS5B polymerase and acts as a chain terminator.

GS-461203 (the active metabolite of sofosbuvir) is neither an inhibitor of human DNA and

RNA polymerases nor an inhibitor of mitochondrial RNA polymerase.

The EC50 values of ledipasvir and sofosbuvir against full-length or chimeric replicons encoding NS5Aand NS5B sequences from clinical isolates are detailed in Table 8. The presence of 40% human serumhad no effect on the anti-HCV activity of sofosbuvir but reduced the anti-HCV activity of ledipasvirby 12-fold against genotype 1a HCV replicons.

Table 8: Activity of ledipasvir and sofosbuvir against chimeric replicons

Genotype Ledipasvir activity (EC50, nM) Sofosbuvir activity (EC50, nM)replicons Stable replicons NS5A transient Stable replicons NS5B transientreplicons replicons

Median (range)a Median (range)a

Genotype 1a 0.031 0.018 (0.009-0.085) 40 62 (29-128)

Genotype Ledipasvir activity (EC50, nM) Sofosbuvir activity (EC50, nM)replicons Stable replicons NS5A transient Stable replicons NS5B transientreplicons replicons

Median (range)a Median (range)a

Genotype 1b 0.004 0.006 (0.004-0.007) 110 102 (45-170)

Genotype 2a 21-249 - 50 29 (14-81)

Genotype 2b 16-530b - 15b -

Genotype 3a 168 - 50 81 (24-181)

Genotype 4a 0.39 - 40 -

Genotype 4d 0.60 - - -

Genotype 5a 0.15b - 15b -

Genotype 6a 1.1b - 14b -

Genotype 6e 264b - - -a Transient replicons carrying NS5A or NS5B from patient isolates.b The chimeric replicons carrying NS5A genes from genotype 2b, 5a, 6a and 6e were used for testing ledipasvir while thechimeric replicons carrying NS5B genes from genotype 2b, 5a or 6a were used for testing sofosbuvir.

HCV replicons with reduced susceptibility to ledipasvir have been selected in cell culture forgenotype 1a and 1b. Reduced susceptibility to ledipasvir was associated with the primary NS5Asubstitution Y93H in both genotype 1a and 1b. Additionally a Q30E substitution developed ingenotype 1a replicons. Site-directed mutagenesis of NS5A RAVs showed that substitutions conferringa fold-change > 100 and ≤ 1,000 in ledipasvir susceptibility are Q30H/R, L31I/M/V, P32L and Y93Tin genotype 1a and P58D and Y93S in genotype 1b; and substitutions conferring a fold-change> 1,000 are M28A/G, Q30E/G/K, H58D, Y93C/H/N/S in genotype 1a and A92K and Y93H ingenotype 1b.

HCV replicons with reduced susceptibility to sofosbuvir have been selected in cell culture for multiplegenotypes including 1b, 2a, 2b, 3a, 4a, 5a and 6a. Reduced susceptibility to sofosbuvir was associatedwith the primary NS5B substitution S282T in all replicon genotypes examined. Site-directedmutagenesis of the S282T substitution in replicons of 8 genotypes conferred 2- to 18-fold reducedsusceptibility to sofosbuvir and reduced the viral replication capacity by 89% to 99% compared to thecorresponding wild-type.

In clinical studies - Adults-Genotype 1

In a pooled analysis of patients who received ledipasvir/sofosbuvir in Phase 3 studies (ION-3, ION-1and ION-2), 37 patients (29 with genotype 1a and 8 with genotype 1b) qualified for resistance analysisdue to virologic failure or early study drug discontinuation and having HCV RNA > 1,000 IU/mL.

Post-baseline NS5A and NS5B deep sequencing data (assay cut off of 1%) were available for 37/37and 36/37 patients, respectively.

NS5A resistance-associated variants (RAVs) were observed in post-baseline isolates from29/37 patients (22/29 genotype 1a and 7/8 genotype 1b) not achieving sustained virologic response(SVR). Of the 29 genotype 1a patients who qualified for resistance testing, 22/29 (76%) patientsharboured one or more NS5A RAVs at positions K24, M28, Q30, L31, S38 and Y93 at failure, whilethe remaining 7/29 patients had no NS5A RAVs detected at failure. The most common variants were

Q30R, Y93H and L31M. Of the 8 genotype 1b patients who qualified for resistance testing, 7/8 (88%)harboured one or more NS5A RAVs at positions L31 and Y93 at failure, while 1/8 patients had no

NS5A RAVs at failure. The most common variant was Y93H. Among the 8 patients who had no

NS5A RAVs at failure, 7 patients received 8 weeks of treatment (n = 3 with ledipasvir/sofosbuvir;n = 4 with ledipasvir/sofosbuvir + ribavirin) and 1 patient received ledipasvir/sofosbuvir for 12 weeks.

In phenotypic analyses, post-baseline isolates from patients who harboured NS5A RAVs at failureshowed 20- to at least a 243-fold (the highest dose tested) reduced susceptibility to ledipasvir.

Site-directed mutagenesis of the Y93H substitution in both genotype 1a and 1b as well as the Q30Rand L31M substitution in genotype 1a conferred high levels of reduced susceptibility to ledipasvir(fold-change in EC50 ranging from 544-fold to 1,677-fold).

Among post-transplant patients with compensated liver disease or patients with decompensated liverdisease either pre- or post-transplant (SOLAR-1 and SOLAR-2 studies), relapse was associated withthe detection of one or more of the following NS5A RAVs: K24R, M28T, Q30R/H/K, L31V, H58Dand Y93H/C in 12/14 genotype 1a patients, and L31M, Y93H/N in 6/6 genotype 1b patients.

A NS5B substitution E237G was detected in 3 patients (1 genotype 1b and 2 genotype 1a) in the

Phase 3 studies (ION-3, ION-1 and ION-2) and 3 patients with genotype 1a infection in the SOLAR-1and SOLAR-2 studies at the time of relapse. The E237G substitution showed a 1.3-fold reduction insusceptibility to sofosbuvir in the genotype 1a replicon assay. The clinical significance of thissubstitution is currently unknown.

The sofosbuvir resistance-associated substitution S282T in NS5B was not detected in any virologicfailure isolate from the Phase 3 studies. However, the NS5B S282T substitution in combination with

NS5A substitutions L31M, Y93H and Q30L were detected in one patient at failure following 8 weeksof treatment with ledipasvir/sofosbuvir from a Phase 2 study (LONESTAR). This patient wassubsequently retreated with ledipasvir/sofosbuvir + ribavirin for 24 weeks and achieved SVRfollowing retreatment.

In the SIRIUS study (see “Clinical efficacy and safety”, below) 5 patients with genotype 1 infectionrelapsed after treatment with ledipasvir/sofosbuvir with or without ribavirin. NS5A RAVs were seen atrelapse in 5/5 patients (for genotype 1a: Q30R/H + L31M/V [n = 1] and Q30R [n = 1]; forgenotype 1b: Y93H [n = 3]).

In clinical studies - Adults-Genotype 2, 3, 4, 5 and 6

NS5A RAVs: No genotype 2 infected patients experienced relapse in the clinical study and thereforethere are no data regarding NS5A RAVs at the time of failure.

In genotype 3 infected patients experiencing virologic failure, development of NS5A RAVs (includingenrichment of RAVs present at baseline) was typically not detected at the time of failure (n = 17).

In genotype 4, 5 and 6 infection, only small numbers of patients have been evaluated (total of5 patients with failure). The NS5A substitution Y93C emerged in the HCV of 1 patient (genotype 4),while NS5A RAVs present at baseline were observed at the time of failure in all patients. In the

SOLAR-2 study, one patient with genotype 4d developed NS5B substitution E237G at the time ofrelapse. The clinical significance of this substitution is currently unknown.

NS5B RAVs: The NS5B substitution S282T emerged in the HCV of 1/17 genotype 3-failures, and inthe HCV of 1/3, 1/1 and 1/1 of genotype 4-, 5- and 6-failures, respectively.

Adults-Genotype 1

Analyses were conducted to explore the association between pre-existing baseline NS5A RAVs andtreatment outcome. In the pooled analysis of the Phase 3 studies, 16% of patients had baseline

NS5A RAVs identified by population or deep sequencing irrespective of subtype. Baseline

NS5A RAVs were overrepresented in patients who experienced relapse in the Phase 3 studies (see“Clinical efficacy and safety”).

Following 12 weeks of treatment with ledipasvir/sofosbuvir (without ribavirin) in treatment-experienced patients (arm 1 of ION-2 study) 4/4 patients with baseline NS5A RAVs conferring aledipasvir fold-change of ≤ 100 achieved SVR. For the same treatment arm, patients with baseline

NS5A RAVs conferring a fold-change of > 100, relapse occurred in 4/13 (31%), as compared to 3/95(3%) in those without any baseline RAVs or RAVs conferring a fold-change of ≤ 100.

Following 12 weeks of treatment with ledipasvir/sofosbuvir with ribavirin in treatment-experiencedpatients with compensated cirrhosis (SIRIUS, n = 77), 8/8 patients with baseline NS5A RAVsconferring > 100-fold reduced susceptibility to ledipasvir achieved SVR12.

Among post-transplant patients with compensated liver disease (SOLAR-1 and SOLAR-2 studies), norelapse occurred in patients with baseline NS5A RAVs (n = 23) following 12 weeks of treatment withledipasvir/sofosbuvir + ribavirin. Among patients with decompensated liver disease (pre- and post-transplant), 4/16 (25%) patients with NS5A RAVs conferring > 100-fold resistance relapsed after12 weeks treatment with ledipasvir/sofosbuvir + ribavirin compared to 7/120 (6%) in those withoutany baseline NS5A RAVs or RAVs conferring a fold-change of ≤ 100.

The group of NS5A RAVs that conferred > 100-fold shift and was observed in patients were thefollowing substitutions in genotype 1a (M28A, Q30H/R/E, L31M/V/I, H58D, Y93H/N/C) or ingenotype 1b (Y93H). The proportion of such baseline NS5A RAVs seen with deep sequencing variedfrom very low (cut off for assay = 1%) to high (main part of the plasma population).

The sofosbuvir resistance-associated substitution S282T was not detected in the baseline NS5Bsequence of any patient in Phase 3 studies by population or deep sequencing. SVR was achieved in all24 patients (n = 20 with L159F+C316N; n = 1 with L159F; and n = 3 with N142T) who had baselinevariants associated with resistance to NS5B nucleoside inhibitors.

Adults-Genotype 2, 3, 4, 5 and 6

Due to the limited size of studies, the impact of baseline NS5A RAVs on treatment outcome forpatients with genotype 2, 3, 4, 5 or 6 CHC has not been fully evaluated. No major differences inoutcomes were observed by the presence or absence of baseline NS5A RAVs.

The presence of pre-treatment NS5A and/or NS5B RAVs did not impact treatment outcome as allsubjects with pre-treatment RAVs achieved SVR12 and SVR24. One 8-year-old subject infected withgenotype 1a HCV who failed to achieve SVR12 had no NS5A or NS5B nucleoside inhibitor RAVs atbaseline and had emergent NS5A RAV Y93H at relapse.

Ledipasvir was fully active against the sofosbuvir resistance-associated substitution S282T in NS5Bwhile all ledipasvir resistance-associated substitutions in NS5A were fully susceptible to sofosbuvir.

Both sofosbuvir and ledipasvir were fully active against substitutions associated with resistance toother classes of direct-acting antivirals with different mechanisms of actions, such as NS5Bnon-nucleoside inhibitors and NS3 protease inhibitors. NS5A substitutions conferring resistance toledipasvir may reduce the antiviral activity of other NS5A inhibitors.

The efficacy of ledipasvir [LDV]/sofosbuvir [SOF] was evaluated in three open-label Phase 3 studieswith data available for a total of 1,950 patients with genotype 1 CHC. The three Phase 3 studiesincluded one study conducted in non-cirrhotic treatment-naïve patients (ION-3); one study in cirrhoticand non-cirrhotic treatment-naïve patients (ION-1); and one study in cirrhotic and non-cirrhoticpatients who failed prior therapy with an interferon-based regimen, including regimens containing an

HCV protease inhibitor (ION-2). Patients in these studies had compensated liver disease. All three

Phase 3 studies evaluated the efficacy of ledipasvir/sofosbuvir with or without ribavirin.

Treatment duration was fixed in each study. Serum HCV RNA values were measured during theclinical studies using the COBAS TaqMan HCV test (version 2.0), for use with the High Pure System.

The assay had a lower limit of quantification (LLOQ) of 25 IU/mL. SVR was the primary endpoint todetermine the HCV cure rate which was defined as HCV RNA less than LLOQ at 12 weeks after thecessation of treatment.

Treatment-naïve adults without cirrhosis - ION-3 (study 0108) - Genotype 1

ION-3 evaluated 8 weeks of treatment with ledipasvir/sofosbuvir with or without ribavirin and12 weeks of treatment with ledipasvir/sofosbuvir in treatment-naïve non-cirrhotic patients withgenotype 1 CHC. Patients were randomised in a 1:1:1 ratio to one of the three treatment groups andstratified by HCV genotype (1a versus 1b).

Table 9: Demographics and baseline characteristics in study ION-3

Patient disposition LDV/SOF LDV/SOF+RBV LDV/SOF TOTAL8 weeks 8 weeks 12 weeks(n = 215) (n = 216) (n = 216) (n = 647)

Age (years): median (range) 53 (22-75) 51 (21-71) 53 (20-71) 52 (20-75)

Male gender 60% (130) 54% (117) 59% (128) 58% (375)

Race: Black/ African American 21% (45) 17% (36) 19% (42) 19% (123)

White 76% (164) 81% (176) 77% (167) 78% (507)

Genotype 1a 80% (171) 80% (172) 80% (172) 80% (515)a

IL28CC genotype 26% (56) 28% (60) 26% (56) 27% (172)

FibroTest-Determined Metavir scoreb

F0-F1 33% (72) 38% (81) 33% (72) 35% (225)

F2 30% (65) 28% (61) 30% (65) 30% (191)

F3-F4 36% (77) 33% (71) 37% (79) 35% (227)

Not interpretable < 1% (1) 1% (3) 0% (0) < 1% (4)a One patient in the LDV/SOF 8-week treatment arm did not have a confirmed genotype 1 subtype.b Non-missing FibroTest results are mapped to Metavir scores according to: 0-0.31 = F0-F1; 0.32-0.58 = F2;0.59-1.00 = F3-F4.

Table 10: Response rates in study ION-3

LDV/SOF LDV/SOF+RBV LDV/SOF8 weeks 8 weeks 12 weeks(n = 215) (n = 216) (n = 216)

SVR 94% (202/215) 93% (201/216) 96% (208/216)

Outcome for patients without SVR

On-treatment virologic failure 0/215 0/216 0/216

Relapsea 5% (11/215) 4% (9/214) 1% (3/216)

Otherb < 1% (2/215) 3% (6/216) 2% (5/216)

Genotype

Genotype 1a 93% (159/171) 92% (159/172) 96% (165/172)

Genotype 1b 98% (42/43) 95% (42/44) 98% (43/44)a The denominator for relapse is the number of patients with HCV RNA < LLOQ at their last on-treatment assessment.b Other includes patients who did not achieve SVR and did not meet virologic failure criteria (e.g. lost to follow-up).

The 8-week treatment of ledipasvir/sofosbuvir without ribavirin was non-inferior to the 8-weektreatment of ledipasvir/sofosbuvir with ribavirin (treatment difference 0.9%; 95% confidence interval:

- 3.9% to 5.7%) and the 12-week treatment of ledipasvir/sofosbuvir (treatment difference -2.3%; 97.5%confidence interval: -7.2% to 3.6%). Among patients with a baseline HCV RNA < 6 million IU/mL,the SVR was 97% (119/123) with 8-week treatment of ledipasvir/sofosbuvir and 96% (126/131) with12-week treatment of ledipasvir/sofosbuvir.

Table 11: Relapse rates by baseline characteristics in the ION-3 study, virological failurepopulation*

LDV/SOF LDV/SOF+RBV LDV/SOF8 weeks 8 weeks 12 weeks(n = 213) (n = 210) (n = 211)

Male 8% (10/129) 7% (8/114) 2% (3/127)

Female 1% (1/84) 1% (1/96) 0% (0/84)

IL28 genotype

CC 4% (2/56) 0% (0/57) 0% (0/54)

Non-CC 6% (9/157) 6% (9/153) 2% (3/157)

Baseline HCV RNAa

HCV RNA < 6 million IU/mL 2% (2/121) 2% (3/136) 2% (2/128)

HCV RNA ≥ 6 million IU/mL 10% (9/92) 8% (6/74) 1% (1/83)

* Patients lost to follow-up or who withdrew consent excluded.a HCV RNA values were determined using the Roche TaqMan Assay; a patient’s HCV RNA may vary from visit to visit.

Treatment-naïve adults with or without cirrhosis - ION-1 (study 0102) - Genotype 1

ION-1 was a randomised, open-label study that evaluated 12 and 24 weeks of treatment withledipasvir/sofosbuvir with or without ribavirin in 865 treatment-naïve patients with genotype 1 CHCincluding those with cirrhosis (randomised 1:1:1:1). Randomisation was stratified by the presence orabsence of cirrhosis and HCV genotype (1a versus 1b).

Table 12: Demographics and baseline characteristics in study ION-1

Patient disposition LDV/SOF LDV/SOF+ LDV/SOF LDV/SOF+ TOTAL12 weeks RBV 24 weeks RBV(n = 214) 12 weeks (n = 217) 24 weeks (n = 865)(n = 217) (n = 217)

Age (years): median (range) 52 (18-75) 52 (18-78) 53 (22-80) 53 (24-77) 52 (18-80)

Male gender 59% (127) 59% (128) 64% (139) 55% (119) 59% (513)

Race: Black/ African 11% (24) 12% (26) 15% (32) 12% (26) 12% (108)

American

White 87% (187) 87% (188) 82% (177) 84% (183) 85% (735)

Genotype 1aa 68% (145) 68% (148) 67% (146) 66% (143) 67% (582)

IL28CC genotype 26% (55) 35% (76) 24% (52) 34% (73) 30% (256)

FibroTest-Determined Metavir scoreb

F0-F1 27% (57) 26% (56) 29% (62) 30% (66) 28% (241)

F2 26% (56) 25% (55) 22% (47) 28% (60) 25% (218)

F3-F4 47% (100) 48% (104) 49% (107) 42% (91) 46% (402)

Not interpretable < 1% (1) 1% (2) < 1% (1) 0% (0) < 1% (4)a Two patients in the LDV/SOF 12-week treatment arm, one patient in the LDV/SOF+RBV 12-week treatment arm, twopatients in the LDV/SOF 24-week treatment arm, and two patients in the LDV/SOF+RBV 24-week treatment arm did nothave a confirmed genotype 1 subtype.

b Non-missing FibroTest results are mapped to Metavir scores according to: 0-0.31 = F0-F1; 0.32-0.58 = F2;0.59-1.00 = F3-F4.

Table 13: Response rates in study ION-1

LDV/SOF LDV/SOF+RBV LDV/SOF LDV/SOF+RBV12 weeks 12 weeks 24 weeks 24 weeks(n = 214) (n = 217) (n = 217) (n = 217)

SVR 99% (210/213) 97% (211/217) 98% (213/217) 99% (215/217)

Outcome for patients without SVR

On-treatment virologic 0/213a 0/217 < 1% (1/217) 0/216failure

Relapseb < 1% (1/212) 0/217 < 1% (1/215) 0/216

Otherc < 1% (2/213) 3% (6/217) < 1% (2/217) < 1% (2/217)

SVR rates for selected subgroups

Genotype

Genotype 1a 98% (142/145) 97% (143/148) 99% (144/146) 99% (141/143)

Genotype 1b 100% (67/67) 99% (67/68) 97% (67/69) 100% (72/72)

Cirrhosisd

No 99% (176/177) 97% (177/183) 98% (181/184) 99% (178/180)

Yes 94% (32/34) 100% (33/33) 97% (32/33) 100% (36/36)a One patient was excluded from the LDV/SOF 12-week treatment arm and one patient was excluded from the

LDV/SOF+RBV 24-week treatment arm as both patients were infected with genotype 4 CHC.b The denominator for relapse is the number of patients with HCV RNA < LLOQ at their last on-treatment assessment.c Other includes patients who did not achieve SVR and did not meet virologic failure criteria (e.g. lost to follow-up).d Patients with missing cirrhosis status were excluded from this subgroup analysis.

Previously treated adults with or without cirrhosis - ION-2 (study 0109) - Genotype 1

ION-2 was a randomised, open-label study that evaluated 12 and 24 weeks of treatment withledipasvir/sofosbuvir with or without ribavirin (randomised 1:1:1:1) in genotype 1 HCV-infectedpatients with or without cirrhosis who failed prior therapy with an interferon-based regimen, includingregimens containing an HCV protease inhibitor. Randomisation was stratified by the presence orabsence of cirrhosis, HCV genotype (1a versus 1b) and response to prior HCV therapy(relapse/breakthrough versus non-response).

Table 14: Demographics and baseline characteristics in study ION-2

Patient disposition LDV/SOF LDV/SOF+ LDV/SOF LDV/SOF+ TOTAL12 weeks RBV 24 weeks RBV(n = 109) 12 weeks (n = 109) 24 weeks (n = 440)(n = 111) (n = 111)

Age (years): median 56 (24-67) 57 (27-75) 56 (25-68) 55 (28-70) 56 (24-75)(range)

Male gender 68% (74) 64% (71) 68% (74) 61% (68) 65% (287)

Race: Black/ African 22% (24) 14% (16) 16% (17) 18% (20) 18% (77)

American

White 77% (84) 85% (94) 83% (91) 80% (89) 81% (358)

Genotype 1a 79% (86) 79% (88) 78% (85) 79% (88) 79% (347)

Prior HCV therapy

PEG-IFN+RBV 39% (43) 42% (47) 53% (58) 53% (59) 47% (207)a

HCV protease 61% (66) 58% (64) 46% (50) 46% (51) 53% (231)ainhibitor +

PEG-IFN+RBV

IL28CC genotype 9% (10) 10% (11) 14% (16) 16% (18) 13% (55)

FibroTest-Determined Metavir scoreb

F0-F1 14% (15) 10% (11) 12% (13) 16% (18) 13% (57)

F2 28% (31) 26% (29) 28% (31) 30% (33) 28% (124)

F3-F4 58% (63) 64% (71) 58% (63) 54% (60) 58% (257)

Not interpretable 0% (0) 0% (0) 2% (2) 0% (0) < 1% (2)a One patient in the LDV/SOF 24-week treatment arms and one patient in the LDV/SOF+RBV 24-week treatment armwere prior treatment failures of a non-pegylated interferon-based regimen.b Non-missing FibroTest results are mapped to Metavir scores according to: 0-0.31 = F0-F1; 0.32-0.58 = F2;0.59-1.00 = F3-F4.

Table 15: Response rates in study ION-2

LDV/SOF LDV/SOF+RBV LDV/SOF LDV/SOF+RBV12 weeks 12 weeks 24 weeks 24 weeks(n = 109) (n = 111) (n = 109) (n = 111)

SVR 94% (102/109) 96% (107/111) 99% (108/109) 99% (110/111)

Outcome for patients without SVR

On-treatment virologic 0/109 0/111 0/109 < 1% (1/111)failure

Relapsea 6% (7/108) 4% (4/111) 0/109 0/110

Otherb 0/109 0/111 < 1% (1/109) 0/111

SVR rates for selected subgroups

Genotype

Genotype 1a 95% (82/86) 95% (84/88) 99% (84/85) 99% (87/88)

Genotype 1b 87% (20/23) 100% (23/23) 100% (24/24) 100% (23/23)

Cirrhosis

No 95% (83/87) 100% (88/88)c 99% (85/86)c 99% (88/89)

Yesd 86% (19/22) 82% (18/22) 100% (22/22) 100% (22/22)

Prior HCV therapy

PEG-IFN+RBV 93% (40/43) 96% (45/47) 100% (58/58) 98% (58/59)

HCV protease inhibitor 94% (62/66) 97% (62/64) 98% (49/50) 100% (51/51)+ PEG-IFN+RBVa The denominator for relapse is the number of patients with HCV RNA < LLOQ at their last on-treatment assessment.b Other includes patients who did not achieve SVR and did not meet virologic failure criteria (e.g. lost to follow-up).c Patients with missing cirrhosis status were excluded from this subgroup analysis.d Metavir score = 4 or Ishak score ≥ 5 by liver biopsy, or FibroTest score of > 0.75 and (APRI) of > 2.

Table 16 presents relapse rates with the 12-week regimens (with or without ribavirin) for selectedsubgroups (see also previous section “Effect of baseline HCV resistance-associated variants ontreatment outcome”). In non-cirrhotic patients relapses only occurred in the presence of baseline

NS5A RAVs, and during therapy with ledipasvir/sofosbuvir without ribavirin. In cirrhotic patientsrelapses occurred with both regimens, and in the absence and presence of baseline NS5A RAVs.

Table 16: Relapse rates for selected subgroups in study ION-2

LDV/SOF LDV/SOF+RBV LDV/SOF LDV/SOF+RBV12 weeks 12 weeks 24 weeks 24 weeks(n = 109) (n = 111) (n = 109) (n = 111)

Number of responders at end of 108 111 109 110treatment

Cirrhosis

No 5% (4/86)a 0% (0/88)b 0% (0/86)b 0% (0/88)

Yes 14% (3/22) 18% (4/22) 0% (0/22) 0% (0/22)

Presence of baseline NS5A resistance-associated substitutionsc

No 3% (3/91)d 2% (2/94) 0% (0/96) 0% (0/95)f

Yes 24% (4/17)e 12% (2/17) 0% (0/13) 0% (0/14)a These 4 non-cirrhotic relapsers all had baseline NS5A resistance-associated polymorphisms.b Patients with missing cirrhosis status were excluded from this subgroup analysis.c Analysis (by deep sequencing) included NS5A resistance-associated polymorphisms that conferred > 2.5-fold change in

EC50 (K24G/N/R, M28A/G/T, Q30E/G/H/L/K/R/T, L31I/F/M/V, P32L, S38F, H58D, A92K/T, and Y93C/F/H/N/S forgenotype 1a and L31I/F/M/V, P32L, P58D, A92K, and Y93C/H/N/S for genotype 1b HCV infection).

d 3/3 of these patients had cirrhosis.e 0/4 of these patients had cirrhosis.f One patient who achieved a viral load < LLOQ at end of treatment had missing baseline NS5A data and was excludedfrom the analysis.

Previously treated adults with cirrhosis - SIRIUS - Genotype 1

SIRIUS included patients with compensated cirrhosis who first failed therapy with pegylatedinterferon (PEG-IFN) + ribavirin, and then failed a regimen consisting of a pegylatedinterferon + ribavirin + an NS3/4A protease inhibitor. Cirrhosis was defined by biopsy, Fibroscan(> 12.5 kPa) or FibroTest > 0.75 and an AST:platelet ratio index (APRI) of > 2.

The study (double-blind and placebo-controlled) evaluated 24 weeks of treatmentledipasvir/sofosbuvir (with ribavirin placebo) versus 12 weeks of treatment with ledipasvir/sofosbuvirwith ribavirin. Patients in the latter treatment arm received placebo (for ledipasvir/sofosbuvir andribavirin) during the first 12 weeks, followed by active blinded therapy during the subsequent12 weeks. Patients were stratified by HCV genotype (1a versus 1b) and prior treatment response(whether HCV RNA < LLOQ had been achieved).

Demographics and baseline characteristics were balanced across the two treatment groups. Themedian age was 56 years (range: 23 to 77); 74% of patients were male; 97% were white; 63% hadgenotype 1a HCV infection; 94% had non-CC IL28B alleles (CT or TT).

Of the 155 patients enrolled, 1 patient discontinued treatment whilst on placebo. Of the remaining154 patients, a total of 149 achieved SVR12 across both treatment groups; 96% (74/77) of patients inthe ledipasvir/sofosbuvir with ribavirin 12-week group and 97% (75/77) of patients in theledipasvir/sofosbuvir 24-week group. All 5 patients who did not achieve SVR12 relapsed after havingend-of-treatment response (see section “Resistance” - “In clinical studies” above).

Previously treated adults who have failed on sofosbuvir + ribavirin ± PEG-IFN

The efficacy of ledipasvir/sofosbuvir in patients who had previously failed treatment with sofosbuvir +ribavirin ± PEG-IFN is supported by two clinical studies. In study 1118, 44 patients with genotype 1infection, including 12 cirrhotic patients, who had previously failed treatment with sofosbuvir +ribavirin + PEG-IFN or with sofosbuvir + ribavirin were treated with ledipasvir/sofosbuvir + ribavirinfor 12 weeks; the SVR was 100% (44/44). In study ION-4, 13 HCV/HIV-1 co-infected patients withgenotype 1, including 1 cirrhotic patient, who had failed a sofosbuvir + ribavirin regimen wereenrolled; the SVR was 100% (13/13) after 12 weeks of treatment with ledipasvir/sofosbuvir.

HCV/HIV co-infected adults - ION-4

ION-4 was an open-label clinical study that evaluated the safety and efficacy of 12 weeks of treatmentwith ledipasvir/sofosbuvir without ribavirin in HCV treatment-naïve and treatment-experiencedpatients with genotype 1 or 4 CHC who were co-infected with HIV-1. Treatment-experienced patientshad failed prior treatment with PEG-IFN + ribavirin ± an HCV protease inhibitor or sofosbuvir +ribavirin ± PEG-IFN. Patients were on a stable HIV-1 antiretroviral therapy that includedemtricitabine/tenofovir disoproxil fumarate, administered with efavirenz, rilpivirine or raltegravir.

The median age was 52 years (range: 26 to 72); 82% of the patients were male; 61% were white; 34%were black; 75% had genotype 1a HCV infection; 2% had genotype 4 infection; 76% had non-CC

IL28B alleles (CT or TT); and 20% had compensated cirrhosis. Fifty-five percent (55%) of thepatients were treatment-experienced.

Table 17: Response rates in study ION-4

LDV/SOF12 weeks(n = 335)

SVR 96% (321/335)a

Outcome for patients without SVR

On-treatment virologic failure < 1% (2/335)

Relapseb 3% (10/333)

Otherc < 1% (2/335)

SVR rates for selected subgroups

Patients with cirrhosis 94% (63/67)

Previously treated patients with cirrhosis 98% (46/47)a 8 patients with genotype 4 HCV infection were enrolled in the study with 8/8 achieving SVR12.b The denominator for relapse is the number of patients with HCV RNA < LLOQ at their last on-treatment assessment.c Other includes patients who did not achieve SVR and did not meet virologic failure criteria (e.g. lost to follow-up).

HCV/HIV co-infected adults - ERADICATE

ERADICATE was an open-label study to evaluate 12 weeks of treatment with ledipasvir/sofosbuvir in50 patients with genotype 1 CHC co-infected with HIV. All patients were treatment-naïve to HCVtherapy without cirrhosis, 26% (13/50) of patients were HIV antiretroviral naïve and 74% (37/50) ofpatients were receiving concomitant HIV antiretroviral therapy. At the time of the interim analysis40 patients have reached 12 weeks post treatment and SVR12 was 98% (39/40).

Patients awaiting liver transplantation and post-liver transplant - SOLAR-1 and SOLAR-2

SOLAR-1 and SOLAR-2 were two open-label clinical studies that evaluated 12 and 24 weeks oftreatment with ledipasvir/sofosbuvir in combination with ribavirin in genotype 1 and 4 HCV-infectedpatients who have undergone liver transplantation and/or who have decompensated liver disease. Thetwo studies were identical in study design. Patients were enrolled in one of the seven groups based onliver transplantation status and severity of hepatic impairment (see Table 18). Patients with a CPTscore > 12 were excluded. Within each group, patients were randomized in a 1:1 ratio to receiveledipasvir/sofosbuvir + ribavirin for 12 or 24 weeks.

Demographics and baseline characteristics were balanced across the treatment groups. Of the 670treated patients, the median age was 59 years (range: 21 to 81 years); 77% of the patients were male;91% were White; mean body mass index was 28 kg/m2 (range: 18 to 49 kg/m2); 94% and 6% hadgenotype 1 and 4 HCV infection, respectively; 78% of the patients failed a prior HCV therapy. Amongthe patients who had decompensated cirrhosis (pre- or post-transplant), 64% and 36% were CPTclass B and C at screening, respectively, 24% had a baseline Model for End Stage Liver Disease(MELD) score greater than 15.

Table 18: Combined response rates (SVR12) in studies SOLAR-1 and SOLAR-2

LDV/SOF+RBV LDV/SOF+RBV12 weeks 24 weeks(n = 307)a,b (n = 307)a,b

SVR SVR

Pre-transplant

CPT B 87% (45/52) 92% (46/50)

CPT C 88% (35/40) 83% (38/46)

Post-transplant

Metavir score F0-F3 95% (94/99) 99% (99/100)

CPT Ac 98% (55/56) 96% (51/53)

CPT Bc 89% (41/46) 96% (43/45)

CPT Cc 57% (4/7) 78% (7/9)

FCH 100% (7/7) 100% (4/4)a Twelve patients transplanted prior to post-treatment Week 12 with HCV RNA< LLOQ at last measurement prior totransplant were excluded.

b Two patients who did not have decompensated cirrhosis and had also not received a liver transplant were excluded due tofailure to meet the inclusion criteria for any of the treatment groups.

c CPT = Child-Pugh-Turcotte, FCH = Fibrosing cholestatic hepatitis. CPT A = CPT score 5-6 (compensated),

CPT B = CPT score 7-9 (decompensated), CPT C = CPT score 10-12 (decompensated).

Forty patients with genotype 4 CHC were enrolled in SOLAR-1 and SOLAR-2 studies, SVR12 were92% (11/12) and 100% (10/10) in post-transplant patients without decompensated cirrhosis and 60%(6/10) and 75% (6/8) in patients with decompensated cirrhosis (pre- and post-liver transplantation)treated for 12 or 24 weeks, respectively. Of the 7 patients who failed to achieve SVR12, 3 relapsed, allhad decompensated cirrhosis and were treated with ledipasvir/sofosbuvir + ribavirin for 12 weeks.

Changes in MELD and CPT score from baseline to post-treatment Week 12 were analyzed for allpatients with decompensated cirrhosis (pre- or post-transplant) who achieved SVR12 and for whomdata were available (n = 123) to assess the effect of SVR12 on hepatic function.

Change in MELD score: Among those who achieved SVR12 with 12 weeks treatment withledipasvir/sofosbuvir + ribavirin, 57% (70/123) and 19% (23/123) had an improvement or no changein MELD score from baseline to post-treatment week 12, respectively; of the 32 patients whose

MELD score was ≥ 15 at baseline, 59% (19/32) had a MELD score < 15 at post-treatment Week 12.

The improvement in MELD scores observed was driven largely by improvements in total bilirubin.

Change in CPT score and class: Among those who achieved SVR12 with 12 weeks treatment withledipasvir/sofosbuvir with ribavirin, 60% (74/123) and 34% (42/123) had an improvement or nochange of CPT scores from baseline to post-treatment week 12, respectively; of the 32 patients whohad CPT C cirrhosis at baseline, 53% (17/32) had CPT B cirrhosis at post-treatment Week 12; of the88 patients who had CPT B cirrhosis at baseline, 25% (22/88) had CPT A cirrhosis at post-treatment

Week 12. The improvement in CPT scores observed was driven largely by improvements in totalbilirubin and albumin.

Clinical efficacy and safety in genotype 2, 3, 4, 5 and 6 (see also section 4.4)

Ledipasvir/sofosbuvir has been evaluated for the treatment of non-genotype 1 infection in small

Phase 2 studies, as summarised below.

The clinical studies enrolled patients with or without cirrhosis, who were treatment-naïve or with priortreatment failure after therapy with PEG-IFN + ribavirin +/- an HCV protease inhibitor.

For genotype 2, 4, 5 and 6 infection, therapy consisted of ledipasvir/sofosbuvir without ribavirin,given for 12 weeks (Table 19). For genotype 3 infection, ledipasvir/sofosbuvir was given with orwithout ribavirin, also for 12 weeks (Table 20).

Table 19: Response rates (SVR12) with ledipasvir/sofosbuvir for 12 weeks in patients withgenotype 2, 4, 5 and 6 HCV infection

Study GT n TEa SVR12 Relapseb

Overall Cirrhosis

Study 1468 (LEPTON) 2 26 19% (5/26) 96% (25/26) 100% (2/2) 0% (0/25)

Study 1119 4 44 50% (22/44) 93% (41/44) 100% (10/10) 7% (3/44)

Study 1119 5 41 49% (20/41) 93% (38/41) 89% (8/9) 5% (2/40)

Study 0122 (ELECTRON-2) 6 25 0% (0/25) 96% (24/25) 100% (2/2) 4% (1/25)a TE: number of treatment-experienced patients.b The denominator for relapse is the number of patients with HCV RNA < LLOQ at their last on-treatment assessment.

Table 20: Response rates (SVR12) in patients with genotype 3 infection (ELECTRON-2)

LDV/SOF+RBV LDV/SOF12 weeks 12 weeks

SVR Relapsea SVR Relapsea

Treatment-naïve 100% (26/26) 0% (0/26) 64% (16/25) 33% (8/24)

Patients without cirrhosis 100% (20/20) 0% (0/21) 71% (15/21) 25% (5/20)

Patients with cirrhosis 100% (6/6) 0% (0/5) 25% (1/4) 75% (3/4)

Treatment-experienced 82% (41/50) 16% (8/49) NS NS

Patients without cirrhosis 89% (25/28) 7% (2/27) NS NS

Patients with cirrhosis 73% (16/22) 27% (6/22) NS NS

NS: not studied.a The denominator for relapse is the number of patients with HCV RNA < LLOQ at their last on-treatment assessment.

Study 0154 was an open-label clinical study that evaluated the safety and efficacy of 12 weeks oftreatment with ledipasvir/sofosbuvir in 18 genotype 1 HCV-infected patients with severe renalimpairment not requiring dialysis. At baseline, two patients had cirrhosis and the mean eGFR was24.9 mL/min (range: 9.0-39.6). SVR12 was achieved in 18/18 patients.

Study 4063 was an open-label three-arm clinical study that evaluated 8, 12, and 24 weeks of treatmentwith ledipasvir/sofosbuvir in a total of 95 patients with genotype 1 (72%), 2 (22%), 4 (2%), 5 (1%), or6 (2%) CHC and ESRD requiring dialysis: 45 treatment-naïve genotype 1 HCV-infected patientswithout cirrhosis received ledipasvir/sofosbuvir for 8 weeks; 31 treatment-experienced genotype 1

HCV-infected patients and treatment-naïve or treatment-experienced patients with genotype 2, 5, and6 infection without cirrhosis received ledipasvir/sofosbuvir for 12 weeks; and 19 genotype 1, 2, and 4

HCV-infected patients with compensated cirrhosis received ledipasvir/sofosbuvir for 24 weeks. Of the95 total patients, at baseline, 20% of patients had cirrhosis, 22% were treatment experienced, 21% hadreceived a kidney transplant, 92% were on hemodialysis, and 8% were on peritoneal dialysis; meanduration on dialysis was 11.5 years (range: 0.2 to 43.0 years). The SVR rates for the 8, 12, and 24week ledipasvir/sofosbuvir treatment groups were 93% (42/45), 100% (31/31), and 79% (15/19),respectively. Of the seven patients who did not achieve SVR12, none experienced virologic failure orrelapsed.

The efficacy of ledipasvir/sofosbuvir in HCV infected patients aged 3 years and above was evaluatedin a Phase 2, open label clinical study that enrolled 226 patients: 221 patients with genotype 1, 2patients with genotype 3, and 3 patients with genotype 4 CHC (Study 1116) (see section 4.2 forinformation on paediatric use).

Patients aged 12 to < 18 Years:

Ledipasvir/sofosbuvir was evaluated in 100 patients aged 12 to < 18 years with genotype 1 HCVinfection. A total of 80 patients (n=80) were treatment-naïve, while 20 patients (n=20) weretreatment-experienced. All patients were treated with ledipasvir/sofosbuvir for 12 weeks.

Demographics and baseline characteristics were balanced across treatment-naïve andtreatment-experienced patients. The median age was 15 years (range: 12 to 17); 63% of the patientswere female; 91% were White, 7% were Black, and 2% were Asian; 13% were Hispanic/Latino; meanweight was 61.3 kg (range: 33.0 to 126.0 kg); 55% had baseline HCV RNA levels greater than orequal to 800,000 IU/mL; 81% had genotype 1a HCV infection; and 1 patient who was treatment naïvewas known to have cirrhosis. The majority of patients (84%) had been infected through verticaltransmission.

The SVR12 rate was 98% overall (98% [78/80] in treatment-naïve patients and 100% [20/20] intreatment experienced patients). A total of 2 out of 100 patients (2%), both treatment- naïve, did notachieve SVR12 (due to loss to follow-up). No patient experienced virologic failure.

Patients aged 6 to < 12 Years:

Ledipasvir/sofosbuvir was evaluated in 92 patients aged 6 to < 12 years with genotype 1, 3, or 4

HCV-infection. A total of 72 patients (78%) were treatment-naïve and 20 patients (22%) weretreatment-experienced. Eighty-nine of the patients (87 patients with genotype 1 HCV infection and 2patients with genotype 4 HCV infection) were treated with ledipasvir/sofosbuvir for 12 weeks, 1treatment experienced patient with genotype 1 HCV infection and cirrhosis was treated withledipasvir/sofosbuvir for 24 weeks, and 2 treatment experienced patients with genotype 3 HCVinfection were treated with ledipasvir/sofosbuvir plus ribavirin for 24 weeks.

The median age was 9 years (range: 6 to 11); 59% of the patients were male; 79% were White, 8%were Black, and 5% were Asian; 10% were Hispanic/Latino; mean weight was 32.8 kg (range: 17.5 to76.4 kg); 59% had baseline HCV RNA levels greater than or equal to 800,000 IU/ mL; 84% hadgenotype 1a HCV infection; 2 patients (1 treatment-naïve, 1 treatment-experienced) had knowncirrhosis. The majority of patients (97%) had been infected through vertical transmission.

The SVR rate was 99% overall (99% [88/89], 100% [1/1], and 100% [2/2] in patients treated withledipasvir/sofosbuvir for 12 weeks, ledipasvir/sofosbuvir for 24 weeks, and ledipasvir/sofosbuvir plusribavirin for 24 weeks, respectively). The one treatment-naïve patient with genotype 1 HCV infectionand cirrhosis who was treated with Harvoni for 12 weeks did not achieve SVR12 and relapsed.

Patients aged 3 to < 6 Years:

Ledipasvir/sofosbuvir was evaluated in 34 patients aged 3 to < 6 years with genotype 1 (n = 33) orgenotype 4 (n = 1) HCV-infection. All of the patients were treatment-naïve and treated withledipasvir/sofosbuvir for 12 weeks. The median age was 5 years (range: 3 to 5); 71% of the patientswere female; 79% were White, 3% were Black, and 6% were Asian; 18% were Hispanic/Latino; meanweight was 19.2 kg (range: 10.7 to 33.6 kg); 56% had baseline HCV RNA levels greater than or equalto 800,000 IU/ mL; 82% had genotype 1a HCV infection; no patients had known cirrhosis. All patients(100%) had been infected through vertical transmission.

The SVR rate was 97% overall (97% [32/33] in patients with genotype 1 HCV infection and 100%[1/1] in patients with genotype 4 HCV infection). One patient who prematurely discontinued studytreatment after five days due to abnormal taste of the medication did not achieve SVR.

Following oral administration of ledipasvir/sofosbuvir to HCV-infected patients, ledipasvir medianpeak plasma concentration was observed at 4.0 hours post-dose. Sofosbuvir was absorbed quickly andthe median peak plasma concentrations were observed ~ 1 hour post-dose. Median peak plasmaconcentration of GS-331007 was observed at 4 hours post-dose.

Based on the population pharmacokinetic analysis in HCV-infected patients, geometric meansteady-state AUC0-24 for ledipasvir (n = 2,113), sofosbuvir (n = 1,542), and GS-331007 (n = 2,113)were 7,290, 1,320 and 12,000 ng*h/mL, respectively. Steady-state Cmax for ledipasvir, sofosbuvir and

GS-331007 were 323, 618 and 707 ng/mL, respectively. Sofosbuvir and GS-331007 AUC0-24 and Cmaxwere similar in healthy adult subjects and patients with HCV infection. Relative to healthy subjects(n = 191), ledipasvir AUC0-24 and Cmax were 24% lower and 32% lower, respectively, in HCV-infectedpatients. Ledipasvir AUC is dose proportional over the dose range of 3 to 100 mg. Sofosbuvir and

GS-331007 AUCs are near dose proportional over the dose range of 200 mg to 400 mg.

Relative to fasting conditions, the administration of a single dose of ledipasvir/sofosbuvir with amoderate fat or high fat meal increased the sofosbuvir AUC0-inf by approximately 2-fold, but did notsignificantly affect the sofosbuvir Cmax. The exposures to GS-331007 and ledipasvir were not altered inthe presence of either meal type. Harvoni can be administered without regard to food.

Ledipasvir is > 99.8% bound to human plasma proteins. After a single 90 mg dose of [14C]-ledipasvirin healthy subjects, the blood to plasma ratio of [14C]-radioactivity ranged between 0.51 and 0.66.

Sofosbuvir is approximately 61-65% bound to human plasma proteins and the binding is independentof drug concentration over the range of 1 µg/mL to 20 µg/mL. Protein binding of GS-331007 wasminimal in human plasma. After a single 400 mg dose of [14C]-sofosbuvir in healthy subjects, theblood to plasma ratio of [14C]-radioactivity was approximately 0.7.

In vitro, no detectable metabolism of ledipasvir was observed by human CYP1A2, CYP2C8,

CYP2C9, CYP2C19, CYP2D6 and CYP3A4. Evidence of slow oxidative metabolism via an unknownmechanism has been observed. Following a single dose of 90 mg [14C]-ledipasvir, systemic exposurewas almost exclusively due to the parent drug (> 98%). Unchanged ledipasvir is also the major speciespresent in faeces.

Sofosbuvir is extensively metabolised in the liver to form the pharmacologically active nucleosideanalogue triphosphate GS-461203. The active metabolite is not observed. The metabolic activationpathway involves sequential hydrolysis of the carboxyl ester moiety catalysed by human cathepsin Aor carboxylesterase 1 and phosphoramidate cleavage by histidine triad nucleotide-binding protein 1followed by phosphorylation by the pyrimidine nucleotide biosynthesis pathway. Dephosphorylationresults in the formation of nucleoside metabolite GS-331007 that cannot be efficientlyrephosphorylated and lacks anti-HCV activity in vitro. Within ledipasvir/sofosbuvir, GS-331007accounts for approximately 85% of total systemic exposure.

Following a single 90 mg oral dose of [14C]-ledipasvir, mean total recovery of the [14C]-radioactivityin faeces and urine was 87%, with most of the radioactive dose recovered from faeces (86%).

Unchanged ledipasvir excreted in faeces accounted for a mean of 70% of the administered dose andthe oxidative metabolite M19 accounted for 2.2% of the dose. These data suggest that biliary excretionof unchanged ledipasvir is a major route of elimination with renal excretion being a minor pathway(approximately 1%). The median terminal half-life of ledipasvir in healthy volunteers followingadministration of ledipasvir/sofosbuvir in the fasted state was 47 hours.

Following a single 400 mg oral dose of [14C]-sofosbuvir, mean total recovery of the dose was greaterthan 92%, consisting of approximately 80%, 14%, and 2.5% recovered in urine, faeces, and expiredair, respectively. The majority of the sofosbuvir dose recovered in urine was GS-331007 (78%) while3.5% was recovered as sofosbuvir. This data indicate that renal clearance is the major eliminationpathway for GS-331007 with a large part actively secreted. The median terminal half-lives ofsofosbuvir and GS-331007 following administration of ledipasvir/sofosbuvir were 0.5 and 27 hours,respectively.

Neither ledipasvir nor sofosbuvir are substrates for hepatic uptake transporters, organic cationtransporter (OCT) 1, organic anion-transporting polypeptide (OATP) 1B1 or OATP1B3. GS-331007 isnot a substrate for renal transporters including organic anion transporter (OAT) 1 or OAT3, or OCT2.

In vitro potential for ledipasvir/sofosbuvir to affect other medicinal products

At concentrations achieved in the clinic, ledipasvir is not an inhibitor of hepatic transporters includingthe OATP 1B1 or 1B3, BSEP, OCT1, OCT2, OAT1, OAT3, multidrug and toxic compound extrusion(MATE) 1 transporter, multidrug resistance protein (MRP) 2 or MRP4. Sofosbuvir and GS-331007 arenot inhibitors of drug transporters P-gp, BCRP, MRP2, BSEP, OATP1B1, OATP1B3, OCT1 and

GS-331007 is not an inhibitor of OAT1, OCT2 and MATE1.

Sofosbuvir and GS-331007 are not inhibitors or inducers of CYP or uridine diphosphateglucuronosyltransferase (UGT) 1A1 enzymes.

No clinically relevant pharmacokinetic differences due to race have been identified for ledipasvir,sofosbuvir or GS-331007. No clinically relevant pharmacokinetic differences due to gender have beenidentified for sofosbuvir or GS-331007. AUC and Cmax of ledipasvir were 77% and 58% higher,respectively, in females than males; however, the relationship between gender and ledipasvirexposures was not considered clinically relevant.

Population pharmacokinetic analysis in HCV-infected patients showed that within the age range (18 to80 years) analysed, age did not have a clinically relevant effect on the exposure to ledipasvir,sofosbuvir or GS-331007. Clinical studies of ledipasvir/sofosbuvir included 235 patients (8.6% of totalnumber of patients) aged 65 years and over.

A summary of the effect of varying degrees of renal impairment (RI) on the exposures of thecomponents of Harvoni compared to subjects with normal renal function, as described in the textbelow, are provided in Table 21.

Table 21: Effect of Varying Degrees of Renal Impairment on Exposures (AUC) of Sofosbuvir,

GS-331007, and Ledipasvir Compared to Subjects with Normal Renal Function

HCV-Negative Subjects HCV-Infected

Subjects

Mild RI Moderate RI Severe RI ESRD Requiring Severe RI ESRD(eGFR ≥50 (eGFR ≥30 (eGFR Dialysis (eGFR Requiringand and <50 mL/ <30 mL/ Dosed Dosed <30 mL/ Dialysis<80 mL/ min/ min/ 1 hr 1 hr After min/min/ 1.73m2) 1.73m2) Before Dialysis 1.73m2)1.73m2) Dialysis

Sofosbuvir 1.6-fold↑ 2.1-fold↑ 2.7-fold↑ 1.3-fold↑ 1.6-fold↑ ~2-fold↑ 1.9-fold↑

GS-331007 1.6-fold↑ 1.9-fold↑ 5.5-fold↑ ≥10-fold↑ ≥20-fold↑ ~6-fold↑ 23-fold↑

Ledipasvir - - ↔ - - - 1.6-fold↑↔ indicates no clinically relevant change in the exposure of Ledipasvir.

The pharmacokinetics of ledipasvir were studied with a single dose of 90 mg ledipasvir in

HCV negative adult patients with severe renal impairment (eGFR < 30 mL/min by Cockcroft-Gault,median [range] CrCl 22 [17-29] mL/min).

The pharmacokinetics of sofosbuvir were studied in HCV negative adult patients with mild (eGFR≥ 50 and < 80 mL/min/1.73 m2), moderate (eGFR ≥ 30 and < 50 mL/min/1.73 m2), severe renalimpairment (eGFR < 30 mL/min/1.73 m2) and patients with ESRD requiring haemodialysis followinga single 400 mg dose of sofosbuvir,relative to patients with normal renal function (eGFR> 80 mL/min/1.73 m2). GS-331007 is efficiently removed by haemodialysis with an extractioncoefficient of approximately 53%. Following a single 400 mg dose of sofosbuvir, a 4 hourhaemodialysis removed 18% of administered sofosbuvir dose.

In HCV-infected adult patients with severe renal impairment treated with ledipasvir/sofosbuvir for12 weeks (n = 18), the pharmacokinetics of ledipasvir, sofosbuvir, and GS-331007 were consistentwith that observed in HCV negative patients with severe renal impairment.

The pharmacokinetics of ledipasvir, sofosbuvir, and GS-331007 were studied in HCV-infected adultpatients with ESRD requiring dialysis treated with ledipasvir/sofosbuvir (n=94) for 8, 12, or 24 weeks,and compared to patients without renal impairment in the ledipasvir/sofosbuvir Phase 2/3 trials.

The pharmacokinetics of ledipasvir were studied with a single dose of 90 mg ledipasvir in

HCV negative adult patients with severe hepatic impairment (CPT class C). Ledipasvir plasmaexposure (AUCinf) was similar in patients with severe hepatic impairment and control patients withnormal hepatic function. Population pharmacokinetics analysis in HCV-infected adult patientsindicated that cirrhosis (including decompensated cirrhosis) had no clinically relevant effect on theexposure to ledipasvir.

The pharmacokinetics of sofosbuvir were studied following 7-day dosing of 400 mg sofosbuvir in

HCV-infected adult patients with moderate and severe hepatic impairment (CPT class B and C).

Relative to patients with normal hepatic function, the sofosbuvir AUC0-24 was 126% and 143% higherin moderate and severe hepatic impairment, while the GS-331007 AUC0-24 was 18% and 9% higher,respectively. Population pharmacokinetics analysis in HCV-infected patients indicated that cirrhosis(including decompensated cirrhosis) had no clinically relevant effect on the exposure to sofosbuvirand GS-331007.

Body weight did not have a significant effect on sofosbuvir exposure according to a populationpharmacokinetic analysis. Exposure to ledipasvir decreases with increasing body weight but the effectis not considered to be clinically relevant.

Ledipasvir, sofosbuvir, and GS-331007 exposures in paediatric patients aged 3 years and above weresimilar to those in adults from Phase 2/3 studies, following administration of ledipasvir/sofosbuvir.

The 90% confidence intervals of geometric least-squares mean ratios for all PK parameters of interestwere contained within the predetermined similarity bounds of less than 2-fold (50% to 200%) with theexception of ledipasvir Ctau in paediatric patients 12 years and above which was 84% higher (90%CI:168% to 203%) and was not considered clinically relevant.

The pharmacokinetics of ledipasvir, sofosbuvir, and GS-331007 have not been established inpaediatric patients aged < 3 years (see section 4.2).

Ledipasvir

No target organs of toxicity were identified in rat and dog studies with ledipasvir at AUC exposuresapproximately 7 times the human exposure at the recommended clinical dose.

Ledipasvir was not genotoxic in a battery of in vitro or in vivo assays, including bacterialmutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo ratmicronucleus assays.

Ledipasvir was not carcinogenic in the 26-week rasH2 transgenic mouse and the 2-year ratcarcinogenicity studies at exposures up to 26-times in mice and 8-times in rats higher than humanexposure.

Ledipasvir had no adverse effects on mating and fertility. In female rats, the mean number of corporalutea and implantation sites were slightly reduced at maternal exposures 6-fold the exposure in humansat the recommended clinical dose. At the no observed effect level, AUC exposure to ledipasvir wasapproximately 7- and 3-fold, in males and females, respectively, the human exposure at therecommended clinical dose.

No teratogenic effects were observed in rat and rabbit developmental toxicity studies with ledipasvir.

In a rat pre- and postnatal study, at a maternally toxic dose, the developing rat offspring exhibitedmean decreased body weight and body weight gain when exposed in utero (via maternal dosing) andduring lactation (via maternal milk) at a maternal exposure 4 times the exposure in humans at therecommended clinical dose. There were no effects on survival, physical and behavioural developmentand reproductive performance in the offspring at maternal exposures similar to the exposure in humansat the recommended clinical dose.

When administered to lactating rats, ledipasvir was detected in plasma of suckling rats likely due toexcretion of ledipasvir via milk.

Environmental risk assessment studies have shown that ledipasvir has the potential to be verypersistent and very bioaccumulative (vPvB) in the environment (see section 6.6).

In repeat dose toxicology studies in rat and dog, high doses of the 1:1 diastereomeric mixture causedadverse liver (dog) and heart (rat) effects and gastrointestinal reactions (dog). Exposure to sofosbuvirin rodent studies could not be detected likely due to high esterase activity; however, exposure to themajor metabolite GS-331007 at doses which cause adverse effects was 16 times (rat) and 71 times(dog) higher than the clinical exposure at 400 mg sofosbuvir. No liver or heart findings were observedin chronic toxicity studies at exposures 5 times (rat) and 16 times (dog) higher than the clinicalexposure. No liver or heart findings were observed in the 2-year carcinogenicity studies at exposures17 times (mouse) and 9 times (rat) higher than the clinical exposure.

Sofosbuvir was not genotoxic in a battery of in vitro or in vivo assays, including bacterialmutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo mousemicronucleus assays.

Carcinogenicity studies in mice and rats do not indicate any carcinogenicity potential of sofosbuviradministered at doses up to 600 mg/kg/day in mouse and 750 mg/kg/day in rat. Exposure to

GS-331007 in these studies was up to 17 times (mouse) and 9 times (rat) higher than the clinicalexposure at 400 mg sofosbuvir.

Sofosbuvir had no effects on embryo-foetal viability or on fertility in rat and was not teratogenic in ratand rabbit development studies. No adverse effects on behaviour, reproduction or development ofoffspring in rat were reported. In rabbit studies exposure to sofosbuvir was 6 times the expectedclinical exposure. In the rat studies, exposure to sofosbuvir could not be determined but exposuremargins based on the major human metabolite was approximately 5 times higher than the clinicalexposure at 400 mg sofosbuvir.

Sofosbuvir-derived material was transferred through the placenta in pregnant rats and into the milk oflactating rats.

Copovidone

Lactose monohydrate

Microcrystalline cellulose

Croscarmellose sodium

Colloidal anhydrous silica

Magnesium stearate

Polyvinyl alcohol partially hydrolyzed

Titanium dioxide

Macrogol

Talc

Sunset yellow FCF (E110) (Harvoni 90 mg/400 mg film-coated tablet only)

Not applicable.

6 years.

This medicinal product does not require any special storage conditions.

Harvoni tablets are supplied in high density polyethylene (HDPE) bottles with a polypropylenechild-resistant closure containing 28 film-coated tablets with a silica gel desiccant and polyester coil.

The following pack sizes are available:

* outer cartons containing 1 bottle of 28 film-coated tablets

* and for the 90 mg/400 mg tablets only; outer cartons containing 84 (3 bottles of 28) film-coatedtablets.

Not all pack sizes may be marketed.

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

This medicinal product may pose a risk to the environment (see section 5.3).

Gilead Sciences Ireland UC

Carrigtohill

County Cork, T45 DP77

Ireland

EU/1/14/958/001

EU/1/14/958/002

EU/1/14/958/003

Date of first authorisation: 17 November 2014

Date of latest renewal: 01 August 2019

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

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