SOVALDI 400mg film-coated tablets medication leaflet

Sovaldi 400 mg film-coated tablets

Sovaldi 200 mg film-coated tablets

Sovaldi 400 mg film-coated tablets

Each film-coated tablet contains 400 mg of sofosbuvir.

Sovaldi 200 mg film-coated tablets

Each film-coated tablet contains 200 mg of sofosbuvir.

For the full list of excipients, see section 6.1.

Film-coated tablet.

Sovaldi 400 mg film-coated tablets

Yellow, capsule-shaped, film-coated tablet of dimensions of approximately 20 mm x 9 mm, debossedon one side with “GSI” and “7977” on the other side.

Sovaldi 200 mg film-coated tablets

Yellow, oval-shaped, film-coated tablet of dimensions of approximately 15 mm x 8 mm, debossed onone side with “GSI” and “200” on the other side.

Sovaldi is indicated in combination with other medicinal products for the treatment of chronichepatitis C (CHC) in adults and paediatric patients aged 3 years and above (see sections 4.2, pct. 4.4 and5.1).

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

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

The recommended dose of Sovaldi in adults is one 400 mg tablet, taken orally, once daily with food(see section 5.2).

The recommended dose of Sovaldi in paediatric patients aged 3 years and above is based on weight (asdetailed in Table 2). Sovaldi should be taken with food (see section 5.2).

Sovaldi oral granules are available for the treatment of chronic HCV-infection in paediatric patientsaged 3 years and above having difficulty in swallowing film-coated tablets. Please refer to the

Summary of Product Characteristics for Sovaldi 150 mg or 200 mg granules.

Sovaldi should be used in combination with other medicinal products. Monotherapy of Sovaldi is notrecommended (see section 5.1). Refer also to the Summary of Product Characteristics of the medicinalproducts that are used in combination with Sovaldi. The recommended co-administered medicinalproduct(s) and treatment duration for Sovaldi combination therapy are provided in Table 1.

Table 1: Recommended co-administered medicinal product(s) and treatment duration for adultsand paediatric patients treated with Sovaldi combination therapy

Patient population* Treatment Duration

Adult patients with Sovaldi + ribavirinc + peginterferon alfa 12 weeksa,bgenotype 1, 4, 5 or 6 CHC Sovaldi + ribavirinc 24 weeks

Only for use in patients ineligible or intolerantto peginterferon alfa (see section 4.4)

Adult and paediatric patients Sovaldid + ribavirinc, e 12 weeksbaged 3 years and above withgenotype 2 CHC

Adult patients with Sovaldi + ribavirinc + peginterferon alfa 12 weeksbgenotype 3 CHC Sovaldi + ribavirinc 24 weeks

Paediatric patients aged3 years and above with Sovaldid + ribavirine 24 weeksgenotype 3 CHC

Adult patients with CHC Sovaldi + ribavirinc Until liver transplantationfawaiting liver transplantation

* Includes patients co-infected with human immunodeficiency virus (HIV).

a. For previously treated patients with HCV genotype 1 infection, no data exists with the combination of Sovaldi, ribavirinand peginterferon alfa (see section 4.4).

b. Consideration should be given to potentially extending the duration of therapy beyond 12 weeks and up to 24 weeks;especially for those subgroups who have one or more factors historically associated with lower response rates tointerferon-based therapies (e.g. advanced fibrosis/cirrhosis, high baseline viral concentrations, black race, IL28B non

CC genotype, prior null response to peginterferon alfa and ribavirin therapy).

c. Adults: weight-based ribavirin (< 75 kg = 1,000 mg and ≥ 75 kg = 1,200 mg); administered orally in two divided doseswith food.

d. See Table 2 for weight-based Sovaldi dosing recommendations for paediatric patients aged 3 years and above.

e. See Table 3 for weight-based ribavirin dosing recommendations for paediatric patients aged 3 years and above.

f. See Special patient populations - Patients awaiting liver transplantation below.

Table 2: Dosing for paediatric patients aged 3 years and above using Sovaldi tablets*

Body Weight (kg) Dosing of Sovaldi Tablets Sofosbuvir Daily Dose≥ 35 one 400 mg tablet once daily 400 mg/dayortwo 200 mg tablets once daily17 to < 35 one 200 mg tablet once daily 200 mg/day

* Sovaldi 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 Sovaldi 150 mg or 200 mg granules.

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 3: Guidance for ribavirin dosing when administered in combination with Sovaldi to HCV-infected paediatric patients aged 3 years and above

Body weight kg (lbs) RBV daily dose*< 47 (< 103) 15 mg/kg/day47-49 (103-108) 600 mg/day50-65 (110-143) 800 mg/day66-80 (145-176) 1000 mg/day> 81 (178) 1200 mg/day

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

Concerning co-administration with other direct-acting antivirals against HCV, see section 4.4.

Dose modification in adults

Dose reduction of Sovaldi is not recommended.

If sofosbuvir is used in combination with peginterferon alfa, and a patient has a serious adversereaction potentially related to this medicinal product, the peginterferon alfa dose should be reduced ordiscontinued. Refer to the peginterferon alfa Summary of Product Characteristics for additionalinformation about how to reduce and/or discontinue the peginterferon alfa dose.

If a patient has a serious adverse reaction potentially related to ribavirin, the ribavirin dose should bemodified or discontinued, if appropriate, until the adverse reaction abates or decreases in severity.

Table 4 provides guidelines for dose modifications and discontinuation based on the patient’shaemoglobin concentration and cardiac status.

Table 4: Ribavirin dose modification guideline for co-administration with Sovaldi 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 period reduced dose

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 original assigned dose (1,000 mg to1,200 mg daily).

Dose modification in paediatric patients aged 3 years and above

Dose reduction of Sovaldi is not recommended.

If a patient has a serious adverse reaction potentially related to ribavirin, the ribavirin dose should bemodified or discontinued, if appropriate, until the adverse reaction abates or decreases in severity.

Refer to the ribavirin prescribing information for guidance on dose modification or discontinuation.

Discontinuation of dosing

If the other medicinal products used in combination with Sovaldi are permanently discontinued,

Sovaldi should also be discontinued (see section 4.4).

Vomiting and missed doses

Patients should be instructed that if vomiting occurs within 2 hours of dosing an additional doseshould be taken. If vomiting occurs more than 2 hours after dosing, no further dose is needed. Theserecommendations are based on the absorption kinetics of sofosbuvir and GS-331007 suggesting thatthe majority of the dose is absorbed within 2 hours after dosing.

If a dose is missed and it is within 18 hours of the normal time, patients should be instructed to takethe dose 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 Sovaldi 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 haemodialysis. Sovaldican be used in these patients with no dose adjustment when no other relevant treatment options areavailable (see section 4.4, pct. 4.8, 5.1 and 5.2).

No dose adjustment of Sovaldi is required for patients with mild, moderate or severe hepaticimpairment (Child-Pugh-Turcotte [CPT] class A, B or C) (see section 5.2). The safety and efficacy of

Sovaldi have not been established in patients with decompensated cirrhosis.

Patients awaiting liver transplantation

The duration of administration of Sovaldi in patients awaiting liver transplantation should be guidedby an assessment of the potential benefits and risks for the individual patient (see section 5.1).

Adult liver transplant recipients

Sovaldi in combination with ribavirin is recommended for 24 weeks in liver transplant recipients. Inadults a starting ribavirin dose of 400 mg administered orally in two divided doses with food isrecommended. If the starting dose of ribavirin is well-tolerated, the dose can be titrated up to amaximum of 1,000-1,200 mg daily (1,000 mg for patients weighing <75 kg and 1,200 mg for patientsweighing ≥75 kg). If the starting dose of ribavirin is not well-tolerated, the dose should be reduced asclinically indicated based on haemoglobin levels (see section 5.1).

Paediatric population aged < 3 years

The safety and efficacy of Sovaldi in children aged <3 years have not yet been established. No data areavailable.

Oral use.

Patients should be instructed to swallow the tablet(s) whole. The film-coated tablet(s) should not bechewed or crushed, due to the bitter taste of the active substance. The tablet(s) should be taken withfood (see section 5.2).

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

Medicinal products that are strong P-glycoprotein (P-gp) inducers in the intestine (carbamazepine,phenobarbital, phenytoin, rifampicin and St. John’s wort). Co-administration will significantlydecrease sofosbuvir plasma concentration and could result in loss of efficacy of Sovaldi (seesection 4.5).

Sovaldi is not recommended for administration as monotherapy and should be prescribed incombination with other medicinal products for the treatment of hepatitis C infection. If the othermedicinal products used in combination with Sovaldi are permanently discontinued, Sovaldi shouldalso be discontinued (see section 4.2). Consult the Summary of Product Characteristics forco-prescribed medicinal products before starting therapy with Sovaldi.

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 Sovaldi 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 Sovaldi.

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.

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-experienced patients with genotype 1, 4, 5 and 6 HCV infection

Sovaldi has not been studied in a Phase 3 study in treatment-experienced patients with genotype 1, 4, 5and 6 HCV infection. Thus, the optimal treatment duration in this population has not been established(see also sections 4.2 and 5.1).

Consideration should be given to treating these patients, and potentially extending the duration oftherapy with sofosbuvir, peginterferon alfa and ribavirin beyond 12 weeks and up to 24 weeks;especially for those subgroups who have one or more factors historically associated with lowerresponse rates to interferon-based therapies (advanced fibrosis/cirrhosis, high baseline viralconcentrations, black race, IL28B non CC genotype).

Treatment of patients with genotype 5 or 6 HCV infection

The clinical data to support the use of Sovaldi in patients with genotype 5 and 6 HCV infection is verylimited (see section 5.1).

Interferon-free therapy for genotype 1, 4, 5 and 6 HCV infection

Interferon-free regimens for patients with genotype 1, 4, 5 and 6 HCV infection with Sovaldi have notbeen investigated in Phase 3 studies (see section 5.1). The optimal regimen and treatment durationhave not been established. Such regimens should only be used for patients that are intolerant to orineligible for interferon therapy, and are in urgent need of treatment.

Co-administration with other direct-acting antivirals against HCV

Sovaldi should only be co-administered with other direct-acting antiviral medicinal products if thebenefit is considered to outweigh the risks based upon available data. There are no data to support theco-administration of Sovaldi and telaprevir or boceprevir. Such co-administration is not recommended(see also section 4.5).

Pregnancy and concomitant use with ribavirin

When Sovaldi is used in combination with ribavirin or peginterferon alfa/ribavirin, women ofchildbearing potential or their male partners must use an effective form of contraception during thetreatment and for a period of time after the treatment as recommended in the Summary of Product

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

Use with moderate P-gp inducers

Medicinal products that are moderate P-gp inducers in the intestine (e.g. modafinil, oxcarbazepine andrifapentine) may decrease sofosbuvir plasma concentration leading to reduced therapeutic effect of

Sovaldi. Co-administration of such medicinal products is not recommended with Sovaldi (seesection 4.5).

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.

Safety data are limited in patients with severe renal impairment (eGFR <30 mL/min/1.73 m2) and

ESRD requiring haemodialysis. Sovaldi can be used in these patients with no dose adjustment whenno other relevant treatment options are available (see sections 4.8, 5.1 and 5.2). When Sovaldi is usedin combination with ribavirin or peginterferon alfa/ribavirin, refer also to the Summary of Product

Characteristics for ribavirin for patients with creatinine clearance (CrCl) <50 mL/min (see alsosection 5.2).

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

Sofosbuvir is a nucleotide prodrug. After oral administration of Sovaldi, sofosbuvir is rapidlyabsorbed and subject to extensive first-pass hepatic and intestinal metabolism. Intracellular hydrolyticprodrug cleavage catalysed by enzymes including carboxylesterase 1 and sequential phosphorylationsteps catalysed by nucleotide kinases result in formation of the pharmacologically active uridinenucleoside analogue triphosphate. The predominant inactive circulating metabolite GS-331007 thataccounts for greater than 90% of drug-related material systemic exposure is formed through pathwayssequential and parallel to formation of active metabolite. The parent sofosbuvir accounts forapproximately 4% of drug-related material systemic exposure (see section 5.2). In clinicalpharmacology studies, both sofosbuvir and GS-331007 were monitored for purposes ofpharmacokinetic analyses.

Sofosbuvir is a substrate of drug transporter P-gp and breast cancer resistance protein (BCRP) while

GS-331007 is not.

Medicinal products that are strong P-gp inducers in the intestine (carbamazepine, phenobarbital,phenytoin, rifampicin and St. John’s wort) may significantly decrease sofosbuvir plasma concentrationleading to reduced therapeutic effect of Sovaldi and thus are contraindicated with Sovaldi (seesection 4.3). Medicinal products that are moderate P-gp inducers in the intestine (e.g. modafinil,oxcarbazepine and rifapentine) may decrease sofosbuvir plasma concentration leading to reducedtherapeutic effect of Sovaldi. Co-administration with such medicinal products is not recommendedwith Sovaldi (see section 4.4). Co-administration of Sovaldi with medicinal products that inhibit P-gpand/or BCRP may increase sofosbuvir plasma concentration without increasing GS-331007 plasmaconcentration, thus Sovaldi may be co-administered with P-gp and/or BCRP inhibitors. Sofosbuvir and

GS-331007 are not inhibitors of P-gp and BCRP and thus are not expected to increase exposures ofmedicinal products that are substrates of these transporters.

The intracellular metabolic activation pathway of sofosbuvir is mediated by generally low affinity andhigh capacity hydrolase and nucleotide phosphorylation pathways that are unlikely to be affected byconcomitant medicinal products (see section 5.2).

As liver function may change during treatment with Sovaldi, 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.

Drug interaction information for Sovaldi with potential concomitant medicinal products is summarisedin Table 5 below (where 90% confidence interval (CI) of the geometric least-squares mean (GLSM)ratio were within “↔”, extended above “↑”, or extended below “↓” the predetermined equivalenceboundaries). The table is not all-inclusive.

Table 5: Interactions between Sovaldi and other medicinal products

Medicinal product by Effects on drug levels. Recommendation concerning co-administrationtherapeutic areas Mean ratio (90% with Sovaldiconfidence interval) for

AUC, Cmax, Cmina,b

ANALEPTICS

Modafinil Interaction not studied. Co-administration of Sovaldi with modafinil is

Expected: expected to decrease the concentration of↓ Sofosbuvir sofosbuvir, leading to reduced therapeutic effect of↔ GS-331007 Sovaldi. Such co-administration is notrecommended.(Induction of P-gp)

ANTIARRHYTHMICS

Amiodarone Effect on amiodarone and Coadministration of amiodarone with a sofosbuvir-sofosbuvir concentrations containing regimen may result in seriousunknown. symptomatic bradycardia.

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

ANTICOAGULANTS

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 Sovaldi.

ANTICONVULSANTS

Phenobarbital Interaction not studied. Sovaldi is contraindicated with phenobarbital and

Phenytoin Expected: phenytoin (see section 4.3).

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

Carbamazepine Sofosbuvir Sovaldi is contraindicated with carbamazepine (see↓ Cmax 0.52 (0.43, 0.62) section 4.3).↓ 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)

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

Expected: expected to decrease the concentration of↓ Sofosbuvir sofosbuvir, leading to reduced therapeutic effect of↔ GS-331007 Sovaldi. Such co-administration is notrecommended (see section 4.4).(Induction of P-gp)

ANTIMYCOBACTERIALS

Rifampicinf Sofosbuvir Sovaldi is contraindicated with rifampicin (see(600 mg single dose) ↓ Cmax 0.23 (0.19, 0.29) section 4.3).

↓ AUC 0.28 (0.24, 0.32)

Cmin (NA)

GS-331007↔ Cmax 1.23 (1.14, 1.34)↔ AUC 0.95 (0.88, 1.03)

Cmin (NA)(Induction of P-gp)

Medicinal product by Effects on drug levels. Recommendation concerning co-administrationtherapeutic areas Mean ratio (90% with Sovaldiconfidence interval) for

AUC, Cmax, Cmina,b

Rifabutin Sofosbuvir No dose adjustment of Sovaldi is required when↓ Cmax 0.64 (0.53, 0.77) concomitantly used with rifabutin.↓ 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)

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

Expected: expected to decrease the concentration of↓ Sofosbuvir sofosbuvir, leading to reduced therapeutic effect of↔ GS-331007 Sovaldi. Such co-administration is notrecommended (see section 4.4).(Induction of P-gp)

HERBAL SUPPLEMENTS

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

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

HCV ANITIVIRAL AGENTS: HCV PROTEASE INHIBITORS

Boceprevir (BOC) Interaction not studied. No drug-drug interaction data exists regarding the

Telaprevir (TPV) Expected: co-administration of Sovaldi with boceprevir or↑ Sofosbuvir (TPV) telaprevir.↔ Sofosbuvir (BOC)↔ GS-331007 (TPV or

BOC)

NARCOTIC ANALGESICS

Methadonef R-methadone No dose adjustment of sofosbuvir or methadone is(Methadone ↔ Cmax 0.99 (0.85, 1.16) required when sofosbuvir and methadone are usedmaintenance therapy ↔ AUC 1.01 (0.85, 1.21) concomitantly.[30 to 130 mg/daily]) ↔ Cmin 0.94 (0.77, 1.14)

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 0.95c (0.68, 1.33)↑ AUC 1.30c (1.00, 1.69)

Cmin (NA)

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

Cmin (NA)

Medicinal product by Effects on drug levels. Recommendation concerning co-administrationtherapeutic areas Mean ratio (90% with Sovaldiconfidence interval) for

AUC, Cmax, Cmina,b

IMMUNOSUPPRESSANTS

Ciclosporine Ciclosporin No dose adjustment of sofosbuvir or ciclosporin is(600 mg single dose) ↔ Cmax 1.06 (0.94, 1.18) required at initiation of co-administration.

↔ AUC 0.98 (0.85, 1.14) Afterwards, close monitoring and potential dose

Cmin (NA) adjustment of ciclosporin may be required.

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

Cmin (NA)

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

Cmin (NA)

Tacrolimuse Tacrolimus No dose adjustment of sofosbuvir or tacrolimus is(5 mg single dose) ↓ Cmax 0.73 (0.59, 0.90) required at initiation of co-administration.

↔ AUC 1.09 (0.84, 1.40) Afterwards, close monitoring and potential dose

Cmin (NA) adjustment of tacrolimus may be required.

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

Cmin (NA)

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

Cmin (NA)

HIV ANTIVIRAL AGENTS: REVERSE TRANSCRIPTASE INHIBITORS

Efavirenzf Efavirenz No dose adjustment of sofosbuvir or efavirenz is(600 mg once daily)d ↔ Cmax 0.95 (0.85, 1.06) required when sofosbuvir and efavirenz are used↔ AUC 0.96 (0.91, 1.03) concomitantly.↔ Cmin 0.96 (0.93, 0.98)

Sofosbuvir↓ Cmax 0.81 (0.60, 1.10)↔ AUC 0.94 (0.76, 1.16)

Cmin (NA)

GS-331007↓ Cmax 0.77 (0.70, 0.84)↔ AUC 0.84 (0.76, 0.92)

Cmin (NA)

Emtricitabinef Emtricitabine No dose adjustment of sofosbuvir or emtricitabine(200 mg once daily)d ↔ Cmax 0.97 (0.88, 1.07) is required when sofosbuvir and emtricitabine are↔ AUC 0.99 (0.94, 1.05) used concomitantly.↔ Cmin 1.04 (0.98, 1.11)

Sofosbuvir↓ Cmax 0.81 (0.60, 1.10)↔ AUC 0.94 (0.76, 1.16)

Cmin (NA)

GS-331007↓ Cmax 0.77 (0.70, 0.84)↔ AUC 0.84 (0.76, 0.92)

Cmin (NA)

Medicinal product by Effects on drug levels. Recommendation concerning co-administrationtherapeutic areas Mean ratio (90% with Sovaldiconfidence interval) for

AUC, Cmax, Cmina,b

Tenofovir disoproxilf Tenofovir No dose adjustment of sofosbuvir or tenofovir(245 mg once daily)d ↑ Cmax 1.25 (1.08, 1.45) disoproxil is required when sofosbuvir and↔ AUC 0.98 (0.91, 1.05) tenofovir disoproxil are used concomitantly.↔ Cmin 0.99 (0.91, 1.07)

Sofosbuvir↓ Cmax 0.81 (0.60, 1.10)↔ AUC 0.94 (0.76, 1.16)

Cmin (NA)

GS-331007↓ Cmax 0.77 (0.70, 0.84)↔ AUC 0.84 (0.76, 0.92)

Cmin (NA)

Rilpivirinef Rilpivirine No dose adjustment of sofosbuvir or rilpivirine is(25 mg once daily) ↔ Cmax 1.05 (0.97, 1.15) required when sofosbuvir and rilpivirine are used↔ AUC 1.06 (1.02, 1.09) concomitantly.↔ Cmin 0.99 (0.94, 1.04)

Sofosbuvir↑ Cmax 1.21 (0.90, 1.62)↔ AUC 1.09 (0.94, 1.27)

Cmin (NA)

GS-331007↔ Cmax 1.06 (0.99, 1.14)↔ AUC 1.01 (0.97, 1.04)

Cmin (NA)

HIV ANTIVIRAL AGENTS: HIV PROTEASE INHIBITORS

Darunavir boosted with Darunavir No dose adjustment of sofosbuvir or darunavirritonavirf ↔ Cmax 0.97 (0.94, 1.01) (ritonavir boosted) is required when sofosbuvir and(800/100 mg once ↔ AUC 0.97 (0.94, 1.00) darunavir are used concomitantly.daily) ↔ Cmin 0.86 (0.78, 0.96)

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

Cmin (NA)

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

Cmin (NA)

HIV ANTIVIRAL AGENTS: INTEGRASE INHIBITORS

Raltegravirf Raltegravir No dose adjustment of sofosbuvir or raltegravir is(400 mg twice daily) ↓ Cmax 0.57 (0.44, 0.75) required when sofosbuvir and raltegravir are used↓ AUC 0.73 (0.59, 0.91) concomitantly.↔ Cmin 0.95 (0.81, 1.12)

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

Cmin (NA)

GS-331007↔ Cmax 1.09 (0.99, 1.20)↔ AUC 1.03 (0.97, 1.08)

Cmin (NA)

Medicinal product by Effects on drug levels. Recommendation concerning co-administrationtherapeutic areas Mean ratio (90% with Sovaldiconfidence interval) for

AUC, Cmax, Cmina,b

ORAL CONTRACEPTIVES

Norgestimate/ethinyl Norgestromin No dose adjustment of norgestimate/ethinylestradiol ↔ Cmax 1.06 (0.93, 1.22) estradiol is required when sofosbuvir and↔ AUC 1.05 (0.92, 1.20) norgestimate/ethinyl estradiol are used

Cmin (NA) concomitantly.

Norgestrel↔ Cmax 1.18 (0.99, 1.41)↔ AUC 1.19 (0.98, 1.44)

Cmin (NA)

Ethinyl estradiol↔ Cmax 1.14 (0.96, 1.36)↔ AUC 1.08 (0.93, 1.25)

Cmin (NA)

NA = not available/not applicable

a. Mean ratio (90% CI) of co-administered drug pharmacokinetics with/without sofosbuvir and mean ratio of sofosbuvir and

GS-331007 with/without co-administered drug. No effect = 1.00

b. All interaction studies conducted in healthy volunteers

c. Comparison based on historical control

d. Administered as Atripla

e. Bioequivalence boundary 80%-125%

f. Equivalence boundary 70%-143%

Women of childbearing potential/contraception in males and females

When Sovaldi is used in combination with ribavirin or peginterferon alfa/ribavirin, extreme care mustbe taken to avoid pregnancy in female patients and in female partners of male patients. Significantteratogenic and/or embryocidal effects have been demonstrated in all animal species exposed toribavirin (see section 4.4). Women of childbearing potential or their male partners must use aneffective form of contraception during treatment and for a period of time after the treatment hasconcluded as recommended in the Summary of Product Characteristics for ribavirin. Refer to the

Summary of Product Characteristics for ribavirin for additional information.

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of sofosbuvirin pregnant women.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity.

No effects on foetal development have been observed in rats and rabbits at the highest doses tested.

However, it has not been possible to fully estimate exposure margins achieved for sofosbuvir in the ratrelative 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 Sovaldi during pregnancy.

However, if ribavirin is co-administered with sofosbuvir, the contraindications regarding use ofribavirin during pregnancy apply (see also the Summary of Product Characteristics for ribavirin).

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

Available pharmacokinetic data in animals have shown excretion of metabolites in milk (for detailssee section 5.3).

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

No human data on the effect of Sovaldi on fertility are available. Animal studies do not indicateharmful effects on fertility.

Sovaldi has moderate influence on the ability to drive and use machines. Patients should be informedthat fatigue and disturbance in attention, dizziness and blurred vision have been reported duringtreatment with sofosbuvir in combination with peginterferon alfa and ribavirin (see section 4.8).

Summary of the safety profile in adults

Assessment of adverse reactions is based on pooled data from five Phase 3 clinical studies (bothcontrolled and uncontrolled).

Sovaldi has been studied in combination with ribavirin, with or without peginterferon alfa. In thiscontext, no adverse drug reactions specific to sofosbuvir have been identified. The most commonadverse drug reactions occurring in patients receiving sofosbuvir and ribavirin or sofosbuvir, ribavirinand peginterferon alfa were fatigue, headache, nausea and insomnia.

The following adverse drug reactions have been identified with sofosbuvir in combination withribavirin or in combination with peginterferon alfa and ribavirin (Table 6). The adverse reactions arelisted below by body system organ class and frequency. Frequencies are defined as follows: verycommon (≥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 6: Adverse drug reactions identified with sofosbuvir in combination with ribavirin orpeginterferon alfa and ribavirin

Frequency SOFa + RBVb SOF + PEGc + RBV

Common nasopharyngitis

Very common haemoglobin decreased anaemia, neutropenia, lymphocyte countdecreased, platelet count decreased

Common anaemia

Very common decreased appetited decreased appetite

Common weight decreased

Very common insomnia insomnia

Common depression depression, anxiety, agitation

Very common headache dizziness, headache

Common disturbance in attention migraine, memory impairment,disturbance in attention

Common vision blurred

Very common dyspnoea, cough

Common dyspnoea, dyspnoea dyspnoea exertionalexertional, cough

Very common nausea diarrhoea, nausea, vomiting

Common abdominal discomfort, constipation, dry mouth,constipation, dyspepsia gastroesophageal reflux

Very common blood bilirubin increased blood bilirubin increased

Very common rash, pruritus

Common alopecia, dry skin, pruritus alopecia, dry skin

Very common arthralgia, myalgia

Common arthralgia, back pain, back pain, muscle spasmsmuscle spasms, myalgia

Very common fatigue, irritability chills, fatigue, influenza-like illness,irritability, pain, pyrexia

Common pyrexia, asthenia chest pain, asthenia

a. SOF = sofosbuvir; b. RBV = ribavirin; c. PEG = peginterferon alfa; d. Decreased appetite was identified as an adversedrug reaction to Sovaldi in combination with ribavirin oral solution in paediatric patients aged 3 to < 12 years

Cases of severe bradycardia and heart block have been observed when sofosbuvir containing-regimesare used in combination with amiodarone and/or other medicinal products that lower heart rate (seesections 4.4 and 4.5).

Frequency not known: Stevens-Johnson syndrome

Other special population(s)

HIV/HCV co-infection

The safety profile of sofosbuvir and ribavirin in HCV/HIV co-infected adult patients was similar tothat observed in mono-infected HCV patients treated with sofosbuvir and ribavirin in Phase 3 clinicalstudies (see section 5.1).

Patients awaiting liver transplantation

The safety profile of sofosbuvir and ribavirin in HCV infected adult patients prior to livertransplantation was similar to that observed in patients treated with sofosbuvir and ribavirin in Phase 3clinical studies (see section 5.1).

Patients with Renal Impairment

Sofosbuvir in a fixed dose combination with ledipasvir was administered for 12 weeks to 18 patientswith genotype 1 CHC and severe renal impairment in an open-label study (Study 0154). The safety ofsofosbuvir in a fixed dose combination with either ledipasvir or velpatasvir has been studied in 154patients with ESRD requiring dialysis (Study 4062 and Study 4063). In this setting, exposure ofsofosbuvir metabolite GS-331007 is 20-fold increased, exceeding levels where adverse reactions havebeen observed in preclinical trials. In this limited clinical safety data set, the rate of adverse events anddeaths was not clearly elevated from what is expected in ESRD patients.

Adult liver transplant recipients

The safety profile of sofosbuvir and ribavirin in liver transplant adult recipients with chronichepatitis C was similar to that observed in patients treated with sofosbuvir and ribavirin in Phase 3clinical studies (see section 5.1). In study 0126, decreases in haemoglobin during treatment were verycommon with 32.5% (13/40 patients) experiencing a decline in haemoglobin to <10 g/dL, 1 of whomalso had a decline to <8.5 g/dL. Eight patients (20%) received epoetin and/or a blood product. In5 patients (12.5%), study drugs were discontinued, modified or interrupted due to adverse events.

The safety and efficacy of Sovaldi in paediatric patients aged 3 years and above are based on datafrom 106 patients who were treated with Sovaldi and ribavirin for 12 weeks (genotype 2 patients) andfor 24 weeks (genotype 3 patients) in a Phase 2, open-label clinical trial. No adverse drug reactionsspecific to Sovaldi have been identified. The adverse reactions observed were generally consistentwith those observed in clinical studies of Sovaldi plus ribavirin in adults (see Table 6). Decreasedappetite was observed as a very common adverse drug reaction to Sovaldi when given in combinationwith ribavirin oral solution in paediatric patients aged 3 to < 12 years.

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 dose of sofosbuvir was a single supratherapeutic dose of sofosbuvir 1,200 mgadministered to 59 healthy subjects. In that study, there were no untoward effects observed at this doselevel, and adverse reactions were similar in frequency and severity to those reported in the placebo andsofosbuvir 400 mg treatment groups. The effects of higher doses are unknown.

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

Haemodialysis can efficiently remove (53% extraction ratio) the predominant circulating metabolite

GS-331007. A 4-hour haemodialysis session removed 18% of the administered dose.

Pharmacotherapeutic group: Antivirals for systemic use, direct-acting antiviral; ATC code: J05AP08

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 analog triphosphate (GS-461203), which canbe incorporated into HCV RNA by the NS5B polymerase and acts as a chain terminator. In abiochemical assay, GS-461203 inhibited the polymerase activity of the recombinant NS5B from HCVgenotype 1b, 2a, 3a and 4a with a 50% inhibitory concentration (IC50) value ranging from 0.7 to2.6 μM. GS-461203 (the active metabolite of sofosbuvir) is not an inhibitor of human DNA and

RNA polymerases nor an inhibitor of mitochondrial RNA polymerase.

In HCV replicon assays, the effective concentration (EC50) values of sofosbuvir against full-lengthreplicons from genotype 1a, 1b, 2a, 3a and 4a were 0.04, 0.11, 0.05, 0.05 and 0.04 μM, respectively,and EC50 values of sofosbuvir against chimeric 1b replicons encoding NS5B from genotype 2b, 5a or6a were 0.014 to 0.015 μM. The mean ± SD EC50 of sofosbuvir against chimeric replicons encoding

NS5B sequences from clinical isolates was 0.068 ± 0.024 μM for genotype 1a (n = 67),0.11 ± 0.029 μM for genotype 1b (n = 29), 0.035 ± 0.018 μM for genotype 2 (n = 15) and0.085 ± 0.034 μM for genotype 3a (n = 106). In these assays, the in vitro antiviral activity ofsofosbuvir against the less common genotypes 4, 5 and 6 was similar to that observed for genotypes 1,2 and 3.

The presence of 40% human serum had no effect on the anti-HCV activity of sofosbuvir.

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 replication viral capacity by 89% to 99% compared to thecorresponding wild-type. In biochemical assays, recombinant NS5B polymerase from genotypes 1b,2a, 3a and 4a expressing the S282T substitution showed reduced susceptibility to GS-461203compared to respective wild-types.

In clinical studies - Adults

In a pooled analysis of 991 patients who received sofosbuvir in Phase 3 studies, 226 patients qualifiedfor resistance analysis due to virologic failure or early study drug discontinuation and having

HCV RNA >1,000 IU/mL. Post-baseline NS5B sequences were available for 225 of the 226 patients,with deep sequencing data (assay cutoff of 1%) from 221 of these patients. The sofosbuvir-associatedresistance substitution S282T was not detected in any of these patients by deep sequencing orpopulation sequencing. The S282T substitution in NS5B was detected in a single subject receiving

Sovaldi monotherapy in a Phase 2 study. This subject harboured <1% HCV S282T at baseline anddeveloped S282T (>99%) at 4 weeks post-treatment which resulted in a 13.5-fold change in sofosbuvir

EC50 and reduced viral replication capacity. The S282T substitution reverted to wild-type over the next8 weeks and was no longer detectable by deep sequencing at 12 weeks post-treatment.

Two NS5B substitutions, L159F and V321A, were detected in post-treatment relapse samples frommultiple genotype 3 HCV infected patients in the Phase 3 clinical studies. No shift in the phenotypicsusceptibility to sofosbuvir or ribavirin of subject isolates with these substitutions was detected. Inaddition, S282R and L320F substitutions were detected on treatment by deep sequencing in apre-transplant subject with a partial treatment response. The clinical significance of these findings isunknown.

Effect of baseline HCV polymorphisms on treatment outcome

Adult population

Baseline NS5B sequences were obtained for 1,292 patients from Phase 3 studies by populationsequencing and the S282T substitution was not detected in any subject with available baselinesequence. In an analysis evaluating the effect of baseline polymorphisms on treatment outcome, nostatistically significant association was observed between the presence of any HCV NS5B variant atbaseline and treatment outcome.

The presence of NS5B RAVs did not impact treatment outcome; all patients with baseline NS5Bnucleoside inhibitor RAVs achieved SVR following treatment with sofosbuvir.

HCV replicons expressing the sofosbuvir-associated resistance substitution S282T were fullysusceptible to other classes of anti-HCV agents. Sofosbuvir retained activity against the

NS5B substitutions L159F and L320F associated with resistance to other nucleoside inhibitors.

Sofosbuvir was fully active against substitutions associated with resistance to other direct-actingantivirals with different mechanisms of actions, such as NS5B non-nucleoside inhibitors, NS3 proteaseinhibitors and NS5A inhibitors.

The efficacy of sofosbuvir was evaluated in five Phase 3 studies in a total of 1,568 adult patients withgenotypes 1 to 6 chronic hepatitis C. One study was conducted in treatment-naïve patients withgenotype 1, 4, 5 or 6 chronic hepatitis C in combination with peginterferon alfa 2a and ribavirin andthe other four studies were conducted in patients with genotype 2 or 3 chronic hepatitis C incombination with ribavirin including one in treatment-naïve patients, one in interferon intolerant,ineligible or unwilling patients, one in patients previously treated with an interferon-based regimen,and one in all patients irrespective of prior treatment history or ability to receive treatment withinterferon. Patients in these studies had compensated liver disease including cirrhosis. Sofosbuvir wasadministered at a dose of 400 mg once daily. The ribavirin dose was weight-based at 1,000-1,200 mgdaily administered in two divided doses, and the peginterferon alfa 2a dose, where applicable, was180 μg per week. Treatment duration was fixed in each study and was not guided by patients’

HCV RNA levels (no response guided algorithm).

Plasma HCV RNA values were measured during the clinical studies using the COBAS TaqMan

HCV test (version 2.0), for use with the High Pure System. The assay had a lower limit ofquantification (LLOQ) of 25 IU/mL. Sustained virologic response (SVR) was the primary endpoint todetermine the HCV cure rate for all studies which was defined as HCV RNA less than LLOQ at12 weeks after the end of treatment (SVR12).

Clinical studies in patients with genotype 1, 4, 5 and 6 chronic hepatitis C

Treatment-naïve adult patients - NEUTRINO (study 110)

NEUTRINO was an open-label, single-arm study that evaluated 12 weeks of treatment with sofosbuvirin combination with peginterferon alfa 2a and ribavirin in treatment-naïve patients with genotype 1, 4,5 or 6 HCV infection.

Treated patients (n = 327) had a median age of 54 years (range: 19 to 70); 64% of the patients weremale; 79% were White; 17% were Black; 14% were Hispanic or Latino; mean body mass index was29 kg/m2 (range: 18 to 56 kg/m2); 78% had baseline HCV RNA greater than 6 log10 IU/mL; 17% hadcirrhosis; 89% had HCV genotype 1 and 11% had HCV genotype 4, 5 or 6. Table 7 presents theresponse rates for the treatment group of sofosbuvir + peginterferon alfa + ribavirin.

Table 7: Response rates in study NEUTRINO

SOF+PEG+RBV12 weeks(n = 327)

Overall SVR12 91% (296/327)

Outcome for patients without SVR12

On-treatment virologic failure 0/327

Relapsea 9% (28/326)

Otherb 1% (3/327)

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 SVR12 and did not meet virologic failure criteria (e.g., lost to follow-up).

Response rates for selected subgroups are presented in Table 8.

Table 8: SVR12 rates for selected subgroups in NEUTRINO

SOF+PEG+RBV12 weeks(n = 327)

Genotype

Genotype 1 90% (262/292)

Genotype 4, 5 or 6 97% (34/35)

Cirrhosis

No 93% (253/273)

Yes 80% (43/54)

Black 87% (47/54)

Non-Black 91% (249/273)

SVR12 rates were similarly high in patients with baseline IL28B C/C allele [94/95 (99%)] andnon-C/C (C/T or T/T) allele [202/232 (87%)].

27/28 patients with genotype 4 HCV achieved SVR12. A single subject with genotype 5 and all6 patients with genotype 6 HCV infection in this study achieved SVR12.

Clinical studies in patients with genotype 2 and 3 chronic hepatitis C

Treatment-naïve adults - FISSION (study 1231)

FISSION was a randomised, open-label, active-controlled study that evaluated 12 weeks of treatmentwith sofosbuvir and ribavirin compared to 24 weeks of treatment with peginterferon alfa 2a andribavirin in treatment-naïve patients with genotype 2 or 3 HCV infection. The ribavirin doses used inthe sofosbuvir + ribavirin and peginterferon alfa 2a + ribavirin arms were weight-based1,000-1,200 mg/day and 800 mg/day regardless of weight, respectively. Patients were randomised in a1:1 ratio and stratified by cirrhosis (presence versus absence), HCV genotype (2 versus 3) and baseline

HCV RNA level (<6 log10 IU/mL versus ≥6 log10 IU/mL). Patients with genotype 2 or 3 HCV wereenrolled in an approximately 1:3 ratio.

Treated patients (n = 499) had a median age of 50 years (range: 19 to 77); 66% of the patients weremale; 87% were White; 3% were Black; 14% were Hispanic or Latino; mean body mass index was28 kg/m2 (range: 17 to 52 kg/m2); 57% had baseline HCV RNA levels greater than 6 log10 IU/mL;20% had cirrhosis; 72% had HCV genotype 3. Table 9 presents the response rates for the treatmentgroups of sofosbuvir + ribavirin and peginterferon alfa + ribavirin.

Table 9: Response rates in study FISSION

SOF+RBV PEG+RBV12 weeks 24 weeks(n = 256)a (n = 243)

Overall SVR12 67% (171/256) 67% (162/243)

Genotype 2 95% (69/73) 78% (52/67)

Genotype 3 56% (102/183) 63% (110/176)

Outcome for patients without

SVR12

On-treatment virologic failure < 1% (1/256) 7% (18/243)

Relapseb 30% (76/252) 21% (46/217)

Otherc 3% (8/256) 7% (17/243)

a. The efficacy analysis includes 3 patients with recombinant genotype 2/1 HCV infection.

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 SVR12 and did not meet virologic failure criteria (e.g., lost to follow-up).

The difference in the overall SVR12 rates between sofosbuvir + ribavirin and peginterferon alfa +ribavirin treatment groups was 0.3% (95% confidence interval: -7.5% to 8.0%) and the study met thepredefined non-inferiority criterion.

Response rates for patients with cirrhosis at baseline are presented in Table 10 by HCV genotype.

Table 10: SVR12 rates by cirrhosis and genotype in study FISSION

Genotype 2 Genotype 3

SOF+RBV PEG+RBV SOF+RBV PEG+RBV12 weeks 24 weeks 12 weeks 24 weeks(n = 73)a (n = 67) (n = 183) (n = 176)

Cirrhosis

No 97% (59/61) 81% (44/54) 61% (89/145) 71% (99/139)

Yes 83% (10/12) 62% (8/13) 34% (13/38) 30% (11/37)

a. The efficacy analysis includes 3 patients with recombinant genotype 2/1 HCV infection.

Interferon intolerant, ineligible or unwilling adults - POSITRON (study 107)

POSITRON was a randomised, double-blinded, placebo-controlled study that evaluated 12 weeks oftreatment with sofosbuvir and ribavirin (n = 207) compared to placebo (n = 71) in patients who areinterferon intolerant, ineligible or unwilling. Patients were randomised in 3:1 ratio and stratified bycirrhosis (presence versus absence).

Treated patients (n = 278) had a median age of 54 years (range: 21 to 75); 54% of the patients weremale; 91% were White; 5% were Black; 11% were Hispanic or Latino; mean body mass index was28 kg/m2 (range: 18 to 53 kg/m2); 70% had baseline HCV RNA levels greater than 6 log10 IU/mL;16% had cirrhosis; 49% had HCV genotype 3. The proportions of patients who were interferonintolerant, ineligible, or unwilling were 9%, 44%, and 47%, respectively. Most patients had no prior

HCV treatment (81.3%). Table 11 presents the response rates for the treatment groups of sofosbuvir +ribavirin and placebo.

Table 11: Response rates in study POSITRON

SOF+RBV Placebo12 weeks 12 weeks(n = 207) (n = 71)

Overall SVR12 78% (161/207) 0/71

Genotype 2 93% (101/109) 0/34

Genotype 3 61% (60/98) 0/37

Outcome for patients without

SVR12

On-treatment virologic failure 0/207 97% (69/71)

Relapsea 20% (42/205) 0/0

Otherb 2% (4/207) 3% (2/71)

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 SVR12 and did not meet virologic failure criteria (e.g., lost to follow-up).

The SVR12 rate in the sofosbuvir + ribavirin treatment group was statistically significant whencompared to placebo (p <0.001).

Table 12 presents the subgroup analysis by genotype for cirrhosis and interferon classification.

Table 12: SVR12 rates for selected subgroups by genotype in POSITRON

SOF+RBV12 weeks

Genotype 2 Genotype 3(n = 109) (n = 98)

Cirrhosis

No 92% (85/92) 68% (57/84)

Yes 94% (16/17) 21% (3/14)

Interferon classification

Ineligible 88% (36/41) 70% (33/47)

Intolerant 100% (9/9) 50% (4/8)

Unwilling 95% (56/59) 53% (23/43)

Previously treated adults - FUSION (study 108)

FUSION was a randomised, double-blinded study that evaluated 12 or 16 weeks of treatment withsofosbuvir and ribavirin in patients who did not achieve SVR with prior interferon-based treatment(relapsers and nonresponders). Patients were randomised in a 1:1 ratio and stratified by cirrhosis(presence versus absence) and HCV genotype (2 versus 3).

Treated patients (n = 201) had a median age of 56 years (range: 24 to 70); 70% of the patients weremale; 87% were White; 3% were Black; 9% were Hispanic or Latino; mean body mass index was29 kg/m2 (range: 19 to 44 kg/m2); 73% had baseline HCV RNA levels greater than 6 log10 IU/mL;34% had cirrhosis; 63% had HCV genotype 3; 75% were prior relapsers. Table 13 presents theresponse rates for the treatment groups of sofosbuvir + ribavirin for 12 weeks and 16 weeks.

Table 13: Response rates in study FUSION

SOF+RBV SOF+RBV12 weeks 16 weeks(n = 103)a (n = 98)a

Overall SVR12 50% (51/103) 71% (70/98)

Genotype 2 82% (32/39) 89% (31/35)

Genotype 3 30% (19/64) 62% (39/63)

Outcome for patients without

SVR12

On-treatment virologic failure 0/103 0/98

Relapseb 48% (49/103) 29% (28/98)

Otherc 3% (3/103) 0/98

a. The efficacy analysis includes 6 patients with recombinant genotype 2/1 HCV infection.

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 SVR12 and did not meet virologic failure criteria (e.g., lost to follow-up).

Table 14 presents the subgroup analysis by genotype for cirrhosis and response to prior

HCV treatment.

Table 14: SVR12 rates for selected subgroups by genotype in study FUSION

Genotype 2 Genotype 3

SOF+RBV SOF+RBV SOF+RBV SOF+RBV12 weeks 16 weeks 12 weeks 16 weeks(n = 39) (n = 35) (n = 64) (n = 63)

Cirrhosis

No 90% (26/29) 92% (24/26) 37% (14/38) 63% (25/40)

Yes 60% (6/10) 78% (7/9) 19% (5/26) 61% (14/23)

Response to prior

HCV treatment

Relapser 86% (25/29) 89% (24/27) 31% (15/49) 65% (30/46)

Nonresponder 70% (7/10) 88% (7/8) 27% (4/15) 53% (9/17)

Treatment-naïve and previously treated adults - VALENCE (study 133)

VALENCE was a Phase 3 study that evaluated sofosbuvir in combination with weight-based ribavirinfor the treatment of genotype 2 or 3 HCV infection in treatment-naïve patients or patients who did notachieve SVR with prior interferon-based treatment, including patients with compensated cirrhosis. Thestudy was designed as a direct comparison of sofosbuvir and ribavirin versus placebo for 12 weeks.

However, based on emerging data, the study was unblinded and all HCV genotype 2 patientscontinued to receive sofosbuvir and ribavirin for 12 weeks, whilst treatment for HCV genotype 3patients was extended to 24 weeks. Eleven HCV genotype 3 patients had already completed treatmentwith sofosbuvir and ribavirin for 12 weeks at the time of the amendment.

Treated patients (n = 419) had a median age of 51 years (range: 19 to 74); 60% of the patients weremale; median body mass index was 25 kg/m2 (range: 17 to 44 kg/m2); the mean baseline HCV RNAlevel was 6.4 log10 IU/mL; 21% had cirrhosis; 78% had HCV genotype 3; 65% were prior relapsers.

Table 15 presents the response rates for the treatment groups of sofosbuvir + ribavirin for 12 weeksand 24 weeks.

Placebo recipients are not included in the tables since none achieved SVR12.

Table 15: Response rates in study VALENCE

Genotype 2 Genotype 3 Genotype 3

SOF+RBV 12 weeks SOF+RBV 12 weeks SOF+RBV 24 weeks(n = 73) (n = 11) (n = 250)

Overall SVR12 93% (68/73) 27% (3/11) 84% (210/250)

Outcome for patients without

SVR12

On-treatment virologic 0% (0/73) 0% (0/11) 0.4% (1/250)failure

Relapsea 7% (5/73) 55% (6/11) 14% (34/249)

Otherb 0% (0/73) 18% (2/11) 2% (5/250)

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 SVR12 and did not meet virologic failure criteria (e.g., lost to follow-up).

Table 16 presents the subgroup analysis by genotype for cirrhosis and exposure to prior

HCV treatment.

Table 16: SVR12 rates for selected subgroups by genotype in study VALENCE

Genotype 2 Genotype 3

SOF+RBV 12 weeks SOF+RBV 24 weeks(n = 73) (n = 250)

Treatment-naïve 97% (31/32) 93% (98/105)

Non-cirrhotic 97% (29/30) 93% (86/92)

Cirrhotic 100% (2/2) 92% (12/13)

Treatment-experienced 90% (37/41) 77% (112/145)

Non-cirrhotic 91% (30/33) 85% (85/100)

Cirrhotic 88% (7/8) 60% (27/45)

SVR12 to SVR24 concordance

The concordance between SVR12 and SVR24 (SVR 24 weeks after the end of the treatment)following treatment with sofosbuvir in combination with ribavirin or ribavirin and pegylated interferondemonstrates a positive predictive value of 99% and a negative predictive value of 99%.

Clinical efficacy and safety in special populations

HCV/HIV co-infected adult patients - PHOTON-1 (study 123)

Sofosbuvir was studied in an open-label clinical study evaluating the safety and efficacy of 12 or24 weeks of treatment with sofosbuvir and ribavirin in patients with genotype 1, 2 or 3 chronichepatitis C co-infected with HIV-1. Genotype 2 and 3 patients were either treatment-naïve orexperienced, whereas genotype 1 patients were naïve to prior treatment. Treatment duration was12 weeks in treatment-naïve patients with genotype 2 or 3 HCV infection, and 24 weeks intreatment-experienced patients with genotype 3 HCV infection, as well as patients with genotype 1

HCV infection. Patients received 400 mg sofosbuvir and weight-based ribavirin (1,000 mg for patientsweighing <75 kg or 1,200 mg for patients weighing ≥75 kg). Patients were either not on antiretroviraltherapy with a CD4+ cell count >500 cells/mm3 or had virologically suppressed HIV-1 with a CD4+cell count >200 cells/mm3. 95% of patients received antiretroviral therapy at the time of enrolment.

Preliminary SVR12 data are available for 210 patients.

Table 17 presents the response rates by genotype and exposure to prior HCV treatment.

Table 17: Response rates in study PHOTON-1

Genotype 2/3 Genotype 2/3 Genotype 1treatment-naïve treatment-experienced treatment-naïve

SOF+RBV SOF+RBV SOF+RBV12 weeks 24 weeks 24 weeks(n = 68) (n = 28) (n = 114)

Overall SVR12 75% (51/68) 93% (26/28) 76% (87/114)

Outcome for patientswithout SVR12

On-treatment 1% (1/68) 0/28 1% (1/114)virologic failure

Relapsea 18% (12/67) 7% (2/28) 22% (25/113)

Otherb 6% (4/68) 0/28 1% (1/114)

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 SVR12 and did not meet virologic failure criteria (e.g., lost to follow-up).

Table 18 presents the subgroup analysis by genotype for cirrhosis.

Table 18: SVR12 rates for selected subgroups by genotype in study PHOTON-1

HCV genotype 2 HCV genotype 3

SOF+RBV SOF+RBV SOF+RBV SOF+RBV12 weeks 24 weeks 12 weeks 24 weeks

TN (n = 26) TE (n = 15) TN (n = 42) TE (n = 13)

Overall 88% (23/26) 93% (14/15) 67% (28/42) 92% (12/13)

No cirrhosis 88% (22/25) 92% (12/13) 67% (24/36) 100% (8/8)

Cirrhosis 100% (1/1) 100% (2/2) 67% (4/6) 80% (4/5)

TN = treatment-naïve; TE = treatment-experienced.

Adult patients awaiting liver transplantation - Study 2025

Sofosbuvir was studied in HCV infected patients prior to undergoing liver transplantation in anopen-label clinical study evaluating the safety and efficacy of sofosbuvir and ribavirin administeredpre-transplant to prevent post-transplant HCV reinfection. The primary endpoint of the study waspost-transplant virologic response (pTVR, HCV RNA <LLOQ at 12 weeks post-transplant).

HCV infected patients, regardless of genotype, with hepatocellular carcinoma (HCC) meeting the

MILAN criteria received 400 mg sofosbuvir and 1,000-1,200 mg ribavirin daily for a maximum of24 weeks, subsequently amended to 48 weeks, or until the time of liver transplantation, whicheveroccurred first. An interim analysis was conducted on 61 patients who received sofosbuvir andribavirin; the majority of patients had HCV genotype 1, 44 patients were CPT class A and 17 patientswere CPT class B. Of these 61 patients, 44 patients underwent liver transplantation following up to48 weeks of treatment with sofosbuvir and ribavirin; 41 had HCV RNA <LLOQ at the time oftransplantation. The virologic response rates of the 41 patients transplanted with HCV RNA <LLOQ isdescribed in Table 19. Duration of viral suppression prior to transplantation was the most predictivefactor for pTVR in those who were HCV RNA <LLOQ at the time of transplantation.

Table 19: Virologic response post-transplant in patients with HCV RNA <LLOQ at the time ofliver transplantation

Week 12post-transplant(pTVR)b

Virologic response in 23/37 (62%)evaluable patientsa

a. Evaluable patients are defined as those who have reached the specified time point at the time of the interim analysis.

b. pTVR: post-transplant virologic response (HCV RNA <LLOQ at 12 weeks post-procedure).

In patients that discontinued therapy at 24 weeks, according to protocol, the relapse rate was 11/15.

Adult liver transplant recipients - Study 0126

Sofosbuvir was studied in an open-label clinical study evaluating the safety and efficacy of 24 weeksof treatment with sofosbuvir and ribavirin in liver transplant recipients with chronic hepatitis C.

Eligible patients were ≥18 years old and had undergone liver transplantation 6 to 150 months prior toscreening. Patients had HCV RNA ≥104 IU/mL at screening and documented evidence of chronic

HCV infection pre-transplantation. The starting dose of ribavirin was 400 mg given in a divided dailydose. If patients maintained haemoglobin levels ≥12 g/dL, ribavirin dose was increased at weeks 2, 4,and up to every 4 weeks until the appropriate weight-based dose was reached (1,000 mg daily inpatients <75 kg, 1,200 mg daily in patients ≥75 kg). The median ribavirin dose was 600 mg-800 mgdaily at weeks 4-24.

Forty patients (33 with HCV genotype 1 infection, 6 with HCV genotype 3 infection, and 1 with HCVgenotype 4 infection) were enrolled, 35 of whom had previously failed interferon-based treatment, and16 of whom had cirrhosis. 28 out of 40 (70%) patients achieved SVR12: 22/33 (73%) with HCVgenotype 1 infection, 6/6 (100%) with HCV genotype 3 infection, and 0/1 (0%) with HCV genotype 4infection. All patients who achieved SVR12 achieved SVR24 and SVR48.

Overview of outcomes by therapeutic regimen and treatment duration, a comparison across studies

The following tables (Table 20 to Table 23) present data from Phase 2 and Phase 3 studies relevant tothe dosing to help clinicians determine the best regimen for individual patients.

Table 20: Outcomes by therapeutic regimen and treatment duration, a comparison acrossstudies in genotype 1 HCV infection

Patient population Regimen/Duration Subgroup SVR12 rate %(Study number/name) (n/N)

Treatment-naïvea SOF+PEG+RBV 12 weeks Overall 90% (262/292)(NEUTRINO) Genotype 1a 92% (206/225)

Genotype 1b 83% (55/66)

No cirrhosis 93% (253/273)

Cirrhosis 80% (43/54)

Treatment-naïve and SOF+RBV 24 weeks Overall 76% (87/114)co-infected with HIV Genotype 1a 82% (74/90)(PHOTON-1) Genotype 1b 54% (13/24)

No cirrhosis 77% (84/109)

Cirrhosis 60% (3/5)

Treatment-naïve SOF+RBV 24 weeks Overallc 65% (104/159)(QUANTUMb and Genotype 1ac 69% (84/121)11-1-0258b) Genotype 1bc 53% (20/38)

No cirrhosisc 68% (100/148)

Cirrhosisc 36% (4/11)n = number of patients with SVR12 response; N = total number of patients per group.

a. For previously treated patients with genotype 1 HCV infection, no data exists with the combination of sofosbuvir,peginterferon alfa and ribavirin. Consideration should be given to treating these patients, and potentially extending theduration of therapy with sofosbuvir, peginterferon alfa and ribavirin beyond 12 weeks and up to 24 weeks; especially forthose subgroups who have one or more factors historically associated with lower response rates to interferon-basedtherapies (prior null response to peginterferon alfa and ribavirin therapy, advanced fibrosis/cirrhosis, high baseline viralconcentrations, black race, IL28B non CC genotype).

b. These are exploratory or Phase 2 studies. The outcomes should be interpreted with caution, as subject numbers are smalland SVR rates may be impacted by the selection of patients.

c. Summary data from both studies.

Table 21: Outcomes by therapeutic regimen and treatment duration, a comparison acrossstudies in genotype 2 HCV infection

Patient population (Study Regimen/Duration Subgroup SVR12 rate % (n/N)number/name)

Treatment-naïve SOF+RBV 12 weeks Overall 95% (69/73)(FISSION) No cirrhosis 97% (59/61)

Cirrhosis 83% (10/12)

Interferon intolerant, ineligible SOF+RBV 12 weeks Overall 93% (101/109)or unwilling No cirrhosis 92% (85/92)(POSITRON) Cirrhosis 94% (16/17)

Treatment-experienced SOF+RBV 12 weeks Overall 82% (32/39)(FUSION) No cirrhosis 90% (26/29)

Cirrhosis 60% (6/10)

Treatment-naïve SOF+RBV 12 weeks Overall 97% (31/32)(VALENCE) No cirrhosis 97% (29/30)

Cirrhosis 100% (2/2)

Treatment-experienced SOF+RBV 12 weeks Overall 90% (37/41)(VALENCE) No cirrhosis 91% (30/33)

Cirrhosis 88% (7/8)

Treatment-experienced SOF+RBV 16 weeks Overall 89% (31/35)(FUSION) No cirrhosis 92% (24/26)

Cirrhosis 78% (7/9)

Patient population (Study Regimen/Duration Subgroup SVR12 rate % (n/N)number/name)

Treatment-naïve co-infected SOF+RBV 12 weeks Overall 88% (23/26)with HIV No cirrhosis 88% (22/25)(PHOTON-1) Cirrhosis 100% (1/1)

Treatment-experienced SOF+RBV 24 weeks Overalla 93% (14/15)co-infected with HIV No cirrhosisa 92% (12/13)(PHOTON-1) Cirrhosisa 100% (2/2)

Treatment-naïve SOF+PEG+RBV Overallc 96% (25/26)(ELECTRONb and PROTONb) 12 weeks

Treatment-experienced SOF+PEG+RBV Overall 96% (22/23)(LONESTAR-2b) 12 weeks No cirrhosis 100% (9/9)

Cirrhosis 93% (13/14)n = number of patients with SVR12 response; N = total number of patients per group.

a. These data are preliminary.

b. These are exploratory or Phase 2 studies. The outcomes should be interpreted with caution, as subject numbers are smalland SVR rates may be impacted by the selection of patients. In the ELECTRON study (N = 11), the duration ofpeginterferon alfa ranged from 4-12 weeks in combination with sofosbuvir + ribavirin.

c. All patients were non-cirrhotic in these two studies.

Table 22: Outcomes by therapeutic regimen and treatment duration, a comparison acrossstudies in genotype 3 HCV infection

Patient population (Study Regimen/Duration Subgroup SVR12 rate % (n/N)number/name)

Treatment-naïve SOF+RBV 12 weeks Overall 56% (102/183)(FISSION) No cirrhosis 61% (89/145)

Cirrhosis 34% (13/38)

Interferon intolerant, ineligible SOF+RBV 12 weeks Overall 61% (60/98)or unwilling No cirrhosis 68% (57/84)(POSITRON) Cirrhosis 21% (3/14)

Treatment-experienced SOF+RBV 12 weeks Overall 30% (19/64)(FUSION) No cirrhosis 37% (14/38)

Cirrhosis 19% (5/26)

Treatment-experienced SOF+RBV 16 weeks Overall 62% (39/63)(FUSION) No cirrhosis 63% (25/40)

Cirrhosis 61% (14/23)

Treatment-naïve SOF+RBV 24 weeks Overall 93% (98/105)(VALENCE) No cirrhosis 94% (86/92)

Cirrhosis 92% (12/13)

Treatment-experienced SOF+RBV 24 weeks Overall 77% (112/145)(VALENCE) No cirrhosis 85% (85/100)

Cirrhosis 60% (27/45)

Treatment-naïve co-infected SOF+RBV 12 weeks Overall 67% (28/42)with HIV No cirrhosis 67% (24/36)(PHOTON-1) Cirrhosis 67% (4/6)

Treatment-experienced SOF+RBV 24 weeks Overalla 92% (12/13)co-infected with HIV No cirrhosisa 100% (8/8)(PHOTON-1) Cirrhosisa 80% (4/5)

Treatment-naïve SOF+PEG+RBV 12 weeks Overallc 97% (38/39)(ELECTRONb and

PROTONb)

Treatment-experienced SOF+PEG+RBV 12 weeks Overall 83% (20/24)(LONESTAR-2b) No cirrhosis 83% (10/12)

Cirrhosis 83% (10/12)n = number of patients with SVR12 response; N = total number of patients per group.

a. These data are preliminary.

b. These are exploratory or Phase 2 studies. The outcomes should be interpreted with caution, as subject numbers are smalland SVR rates may be impacted by the selection of patients. In the ELECTRON study (N = 11), the duration ofpeginterferon alfa ranged from 4-12 weeks in combination with sofosbuvir + ribavirin.

c. All patients were non-cirrhotic in these two studies.

Table 23: Outcomes by therapeutic regimen and treatment duration, a comparison acrossstudies in genotype 4, 5 and 6 HCV infection

Patient population Regimen/Duration Subgroup SVR12 rate % (n/N)(Study number/name)

Treatment-naïve SOF+PEG+RBV Overall 97% (34/35)(NEUTRINO) 12 weeks No cirrhosis 100% (33/33)

Cirrhosis 50% (1/2)n = number of patients with SVR12 response; N = total number of patients per group.

Study 0154 was an open-label clinical study that evaluated the safety and efficacy of 24 weeks oftreatment with sofosbuvir in combination with ribavirin in 20 genotype 1 or 3 HCV-infected patientswith severe renal impairment not requiring dialysis. Following treatment with sofosbuvir 200 mg or400 mg in combination with ribavirin the SVR12 rate in patients with ESRD was 40% and 60%,respectively. The safety and efficacy of 12 weeks of treatment with ledipasvir/sofosbuvir in 18genotype 1 HCV-infected patients with severe renal impairment not requiring dialysis was also studiedin Study 0154. At baseline, two patients had cirrhosis and the mean eGFR was 24.9 mL/min (range:9.0-39.6). SVR12 was achieved in 100 % (18/18) of patients treated with ledipasvir/sofosbuvir.

Study 4063 was an open-label study that evaluated a fixed dose combination of sofosbuvir andledipasvir in 95 patients with HCV-infection and ESRD requiring dialysis. The SVR rates for the 8,12, and 24 week 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 virologicfailure or relapsed.

Study 4062 was an open-label study that evaluated a fixed dose combination of sofosbuvir andvelpatasvir in 59 HCV-infected patients with ESRD requiring dialysis. The SVR rate was 95%(56/59); of the three patients that did not achieve SVR12, one had completed sofosbuvir withvelpatasvir treatment and relapsed.

The efficacy of sofosbuvir in HCV-infected patients aged 3 years and above was evaluated in a

Phase 2, open label clinical trial that enrolled 106 patients with genotype 2 (n = 31) or genotype 3(n = 75) chronic HCV infection. Patients with HCV genotype 2 or 3 infection in the trial were treatedwith sofosbuvir with ribavirin for 12 or 24 weeks, respectively.

Patients aged 12 to < 18 Years:

Sofosbuvir was evaluated in 52 patients 12 to < 18 years with genotype 2 (n = 13) or genotype 3 (n =39) HCV infection. The median age was 15 years (range: 12 to 17); 40% of the patients were female;90% were White, 4% were Black, and 2% were Asian; 4% were Hispanic/Latino; mean weight was60.4 kg (range: 29.6 to 75.6 kg); 17% were treatment experienced; 65% had baseline HCV RNAlevels greater than or equal to 800,000 IU/mL; and no patients had known cirrhosis. The majority ofpatients (69%) had been infected through vertical transmission.

The SVR12 rate was 98% overall (100% [13/13] in genotype 2 patients and 97% [38/39]) ingenotype 3 patients. No patient experienced on-treatment virologic failure or relapse; one patient withgenotype 3 HCV infection achieved SVR4 but did not return for the SVR12 visit.

Patients aged 6 to < 12 Years:

Sofosbuvir was evaluated in 41 patients 6 to < 12 years of age with genotype 2 (n = 13), or genotype 3(n = 28) HCV infection. The median age was 9 years (range: 6 to 11); 73% of the patients werefemale; 71% were White and 20% were Asian; 15% were Hispanic/Latino; mean weight was 33.7 kg(range: 15.1 to 80.0 kg); 98% were treatment naive; 46% had baseline HCV RNA levels greater thanor equal to 800,000 IU /mL; and no patients had known cirrhosis. The majority of patients (98%) hadbeen infected through vertical transmission.

The SVR12 rate was 100% (100% [13/13] in genotype 2 patients and 100% [28/28] in genotype 3patients). No patients experienced on-treatment virologic failure or relapse.

Patients aged 3 to < 6 Years:

Sofosbuvir was evaluated in 13 patients 3 to < 6 years with genotype 2 (n = 5) or genotype 3 (n = 8)

HCV infection. The median age was 4 years (range: 3 to 5); 77% of the patients were female; 69%were White, 8% were Black, and 8% were Asian; 8% were Hispanic/Latino; mean weight was 16.8 kg(range: 13.0 to 19.2 kg); 100% were treatment naive; 23% had baseline HCV RNA levels greater thanor equal to 800,000 IU/mL; and no patients had known cirrhosis. The majority of patients (85%) hadbeen infected through vertical transmission.

The SVR12 rate was 92% overall (80% [4/5] in genotype 2 patients and 100% [8/8] in genotype 3patients). No patients experienced on-treatment virologic failure or relapse; one patient withgenotype 2 HCV prematurely discontinued study treatment after three days due to abnormal taste ofthe medication and did not return for post-treatment Week 12.

Sofosbuvir is a nucleotide prodrug that is extensively metabolised. The active metabolite is formed inhepatocytes and not observed in plasma. The predominant (>90%) metabolite, GS-331007, is inactive.

It is formed through sequential and parallel pathways to the formation of active metabolite.

The pharmacokinetic properties of sofosbuvir and the predominant circulating metabolite GS-331007have been evaluated in healthy adult subjects and in patients with chronic hepatitis C. Following oraladministration, sofosbuvir was absorbed quickly and the peak plasma concentration was observed~0.5-2 hour post-dose, regardless of dose level. Peak plasma concentration of GS-331007 wasobserved between 2 to 4 hours post-dose. Based on population pharmacokinetic analysis in patientswith genotypes 1 to 6 HCV infection (n = 986), steady-state AUC0-24 for sofosbuvir and GS-331007was 1,010 ng*h/mL and 7,200 ng*h/mL, respectively. Relative to healthy subjects (n = 284), thesofosbuvir and GS-331007 AUC0-24 was 57% higher and 39% lower, respectively in HCV infectedpatients.

Relative to fasting conditions, the administration of a single dose of sofosbuvir with a standardisedhigh fat meal slowed the rate of absorption of sofosbuvir. The extent of absorption of sofosbuvir wasincreased approximately 1.8-fold, with little effect on peak concentration. The exposure to GS-331007was not altered in the presence of a high-fat meal.

Sofosbuvir is not a substrate for hepatic uptake transporters, organic anion-transporting polypeptide(OATP) 1B1 or 1B3, and organic cation transporter (OCT) 1. While subject to active tubular secretion,

GS-331007 is not a substrate for renal transporters including organic anion transporter (OAT) 1 or 3,

OCT2, MRP2, P-gp, BCRP or MATE1. Sofosbuvir and GS-331007 are not inhibitors of drugtransporters P-gp, BCRP, MRP2, BSEP, OATP1B1, OATP1B3 and OCT1. GS-331007 is not aninhibitor of OAT1, OCT2, and MATE1.

Sofosbuvir is approximately 85% bound to human plasma proteins (ex vivo data) and the binding isindependent of drug concentration over the range of 1 μg/mL to 20 μg/mL. Protein binding of

GS-331007 was minimal in human plasma. After a single 400 mg dose of [14C]-sofosbuvir in healthysubjects, the blood to plasma ratio of 14C-radioactivity was approximately 0.7.

Sofosbuvir is extensively metabolised in the liver to form the pharmacologically active nucleosideanalog triphosphate GS-461203. The metabolic activation pathway involves sequential hydrolysis ofthe carboxyl ester moiety catalysed by human cathepsin A (CatA) or carboxylesterase 1 (CES1) andphosphoramidate cleavage by histidine triad nucleotide-binding protein 1 (HINT1) followed byphosphorylation by the pyrimidine nucleotide biosynthesis pathway. Dephosphorylation results in theformation of nucleoside metabolite GS-331007 that cannot be efficiently rephosphorylated and lacksanti-HCV activity in vitro. Sofosbuvir and GS-331007 are not substrates or inhibitors of UGT1A1 or

CYP3A4, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6 enzymes.

After a single 400 mg oral dose of [14C]-sofosbuvir, sofosbuvir and GS-331007 accounted forapproximately 4% and >90% of drug-related material (sum of molecular weight-adjusted AUC ofsofosbuvir and its metabolites) systemic exposure, respectively.

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 were 0.4 and 27 hours respectively.

The dose linearity of sofosbuvir and its primary metabolite, GS-331007, was evaluated in fastedhealthy subjects. Sofosbuvir and GS-331007 AUCs are near dose proportional over the dose range of200 mg to 400 mg.

No clinically relevant pharmacokinetic differences due to gender or race have been identified forsofosbuvir and GS-331007.

Population pharmacokinetic analysis in HCV infected patients showed that within the age range (19 to75 years) analysed, age did not have a clinically relevant effect on the exposure to sofosbuvir and

GS-331007. Clinical studies of sofosbuvir included 65 patients aged 65 and over. The response ratesobserved for patients over 65 years of age were similar to that of younger patients across treatmentgroups.

A summary of the effect of varying degrees of renal impairment (RI) on the exposures of sofosbuvirand GS-331007 compared to subjects with normal renal function, as described in the text below, areprovided in Table 24.

Table 24: Effect of varying degrees of renal impairment on exposures (AUC) of sofosbuvir and

GS-331007 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 (eGFR (eGFR Dialysis (eGFR Requiring≥50 and ≥30 and <30 mL/min/ Dosed Dosed <30 mL/min/ Dialysis<80 mL/min/ <50 mL/min/ 1.73m2) 1 hr 1 hr 1.73m2)1.73m2) 1.73m2) Before After

Dialysis 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↑ ~7-fold↑ 21-fold↑

The pharmacokinetics of sofosbuvir were studied in adult HCV negative 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 following asingle 400 mg dose of sofosbuvir, relative to adult 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 sofosbuvir 200 mg withribavirin (n=10) or sofosbuvir 400 mg with ribavirin (n=10) for 24 weeks or ledipasvir/sofosbuvir90/400 mg (n=18) for 12 weeks, the pharmacokinetics of sofosbuvir and GS-331007 were consistentwith that observed in HCV negative adult patients with severe renal impairment.

The pharmacokinetics of sofosbuvir, and GS-331007 were studied in HCV-infected adult patients with

ESRD requiring dialysis treated with ledipasvir/sofosbuvir (n = 94) for 8, 12, or 24 weeks orsofosbuvir/velpatasvir (n = 59) for 12 weeks, and compared to patients without renal impairment in theledipasvir/sofosbuvir and sofosbuvir/velpatasvir Phase 2/3 trials (see section 4.4).

The pharmacokinetics of sofosbuvir were studied following 7-day dosing of 400 mg sofosbuvir inadult HCV-infected 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 adult HCV-infected patients indicated thatcirrhosis had no clinically relevant effect on the exposure to sofosbuvir and GS-331007. No doseadjustment of sofosbuvir is recommended for patients with mild, moderate and severe hepaticimpairment (see section 4.2).

Sofosbuvir and GS-331007 exposures in paediatric patients aged 3 years and above were similar tothose in adults from Phase 2/3 studies following administration of sofosbuvir. The pharmacokineticsof sofosbuvir and GS-331007 have not been established in paediatric patients aged < 3 years (seesection 4.2).

Efficacy, in terms of rapid virologic response, has been shown to correlate with exposure to sofosbuviras well as GS 331007. However, neither of these entities has been evidenced to be a general surrogatemarker for efficacy (SVR12) at the therapeutic 400 mg dose.

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 the adverse dose was 29 times (rat) and 123 times (dog) higher thanthe clinical exposure at 400 mg sofosbuvir. No liver or heart findings were observed in chronictoxicity studies at exposures 9 times (rat) and 27 times (dog) 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 30 times (mouse) and 15 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 9 times the expectedclinical exposure. In the rat studies, exposure to sofosbuvir could not be determined but exposuremargins based on the major human metabolite ranged from 8 to 28 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.

Mannitol (E421)

Microcrystalline cellulose

Croscarmellose sodium

Colloidal anhydrous silica

Magnesium stearate

Polyvinyl alcohol

Titanium dioxide

Macrogol

Talc

Iron oxide yellow

Not applicable.

6 years.

This medicinal product does not require any special storage conditions.

Sovaldi 400 mg 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.

Sovaldi 200 mg tablets are supplied in high density polyethylene (HDPE) bottles with a polypropylenechild-resistant closure containing 28 film-coated tablets and a polyester coil.

The following pack sizes are available:

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

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

Not all pack sizes may be marketed.

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

Gilead Sciences Ireland UC

Carrigtohill

County Cork, T45 DP77

Ireland

EU/1/13/894/001

EU/1/13/894/002

EU/1/13/894/003

Date of first authorisation: 16 January 2014

Date of latest renewal: 17 September 2018

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

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