SOVALDI 400 MG FILM-COATED TABLETS - summary of medicine characteristics

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

Sovaldi 400 mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Sovaldi 400 mg film-coated tablets

Each film-coated tablet contains 400 mg of sofosbuvir.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet.

Sovaldi 400 mg film-coated tablets

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

4 CLINICAL PARTICULARS

Sovaldi is indicated in combination with other medicinal products for the treatment of chronic hepatitis C (CHC) in adults and paediatric patients aged 3 years and above (see sections 4.2, 4.4 and 5.1).

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

4.2 Posology and method of administration

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

Posology

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 (as detailed 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 patients aged 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 not recommended (see section 5.1). Refer also to the Summary of Product Characteristics of the medicinal products that are used in combination with Sovaldi. The recommended co-administered medicinal product(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 adults and paediatric patients treated with Sovaldi combination therapy

* 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, ribavirin and 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 to interferon-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 doses with 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*

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 Characteristics for Sovaldi 150 mg or 200 mg granules.

In paediatric patients aged 3 years and above the following ribavirin dosing is recommended where ribavirin 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

* 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 adverse reaction potentially related to this medicinal product, the peginterferon alfa dose should be reduced or discontinued. Refer to the peginterferon alfa Summary of Product Characteristics for additional information 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 be modified 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’s hae­moglobin concentration and cardiac status.

Table 4: Ribavirin dose modification guideline for co-administration with Sovaldi in adults

Once ribavirin has been withheld due to either a laboratory abnormality or clinical manifestation, an attempt 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 to 1,200 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 be modified 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 dose should be taken. If vomiting occurs more than 2 hours after dosing, no further dose is needed. These recommendations are based on the absorption kinetics of sofosbuvir and GS-331007 suggesting that the 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 take the dose as soon as possible and then patients should take the next dose at the usual time. If it is after 18 hours then patients should be instructed to wait and take the next dose at the usual time. Patients should be instructed not to take a double dose.

Special patient populations

Elderly

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

Renal impairment

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. Sovaldi can be used in these patients with no dose adjustment when no other relevant treatment options are available (see section 4.4, 4.8, 5.1 and 5.2).

Hepatic impairment

No dose adjustment of Sovaldi is required for patients with mild, moderate or severe hepatic impairment (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 guided by 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. In adults a starting ribavirin dose of 400 mg administered orally in two divided doses with food is recommended. If the starting dose of ribavirin is well-tolerated, the dose can be titrated up to a maximum of 1,000–1,200 mg daily (1,000 mg for patients weighing <75 kg and 1,200 mg for patients weighing >75 kg). If the starting dose of ribavirin is not well-tolerated, the dose should be reduced as clinically 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 are available.

Method of administration

Oral use.

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

4.3 Contraindi­cations

HCV/HBV (hepatitis B virus) co-infection

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

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, 5 and 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 of therapy 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 lower response rates to interferon-based therapies (advanced fibrosis/cirrhosis, high baseline viral concentrations, 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 very limited (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 not been investigated in Phase 3 studies (see section 5.1). The optimal regimen and treatment duration have not been established. Such regimens should only be used for patients that are intolerant to or ineligible 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 the benefit is considered to outweigh the risks based upon available data. There are no data to support the co-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 of childbearing potential or their male partners must use an effective form of contraception during the treatment and for a period of time after the treatment as recommended in the Summary of

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 concentration leading to reduced therapeutic effect of Sovaldi and thus are contraindicated with Sovaldi (see section 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 reduced therapeutic effect of Sovaldi. Co-administration with such medicinal products is not recommended with Sovaldi (see section 4.4). Co-administration of Sovaldi with medicinal products that inhibit P-gp and/or BCRP may increase sofosbuvir plasma concentration without increasing GS-331007 plasma concentration, 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 of medicinal products that are substrates of these transporters.

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

Patients treated with vitamin K antagonists

As liver function may change during treatment with Sovaldi, a close monitoring of International Normalised Ratio (INR) values is recommended.

Impact of DAA therapy on drugs metabolized by the liver

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

Other interactions

Drug interaction information for Sovaldi with potential concomitant medicinal products is summarised in Table 5 below (where 90% confidence interval (CI) of the geometric least-squares mean (GLSM) ratio were within “->”, extended above “f”, or extended below “j” the predetermined equivalence boundaries). The table is not all-inclusive.

Table 5: Interactions between Sovaldi and other medicinal products

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%

4.6 Fertility, pregnancy and lactation

Women of childbearing potential / contraception in males and females

When Sovaldi is used in combination with ribavirin or peginterferon alfa/ribavirin, extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin (see section 4.4).

Women of childbearing potential or their male partners must use an effective form of contraception during treatment and for a period 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 for additional information.

Pregnancy

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of sofosbuvir in 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 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 Sovaldi during pregnancy.

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

Breast-feeding

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 details see section 5.3).

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

Fertility

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

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of the safety profile in adults

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

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

Tabulated summary of adverse reactions

The following adverse drug reactions have been identified with sofosbuvir in combination with ribavirin or in combination with peginterferon alfa and ribavirin (Table 6). The adverse reactions are listed below by body system organ class and frequency. Frequencies are defined as follows: very common (>1/10), common

(>1/100 to <1/10), uncommon (>1/1,000 to <1/100), rare (>1/10,000 to <1/1,000) or very rare (<1/10,000).

Table 6: Adverse drug reactions identified with sofosbuvir in combination with ribavirin or peginterferon alfa and ribavirin

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

Description of selected adverse reactions

Cardiac arrhythmias

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

Skin disorders

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 to that observed in mono-infected HCV patients treated with sofosbuvir and ribavirin in Phase 3 clinical studies (see section 5.1).

Patients awaiting liver transplantation

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

Patients with Renal Impairment

Sofosbuvir in a fixed dose combination with ledipasvir was administered for 12 weeks to 18 patients with genotype 1 CHC and severe renal impairment in an open-label study (Study 0154). The safety of sofosbuvir in a fixed dose combination with either ledipasvir or velpatasvir has been studied in 154 patients with ESRD requiring dialysis (Study 4062 and Study 4063). In this setting, exposure of sofosbuvir metabolite GS-331007 is 20-fold increased, exceeding levels where adverse reactions have been observed in preclinical trials. In this limited clinical safety data set, the rate of adverse events and deaths 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 chronic hepatitis C was similar to that observed in patients treated with sofosbuvir and ribavirin in Phase 3 clinical studies (see section 5.1). In study 0126, decreases in haemoglobin during treatment were very common with 32.5% (13/40 patients) experiencing a decline in haemoglobin to <10 g/dL, 1 of whom also had a decline to <8.5 g/dL. Eight patients (20%) received epoetin and/or a blood product. In 5 patients (12.5%), study drugs were discontinued, modified or interrupted due to adverse events.

Paediatric population

The safety and efficacy of Sovaldi in paediatric patients aged 3 years and above are based on data from 106 patients who were treated with Sovaldi and ribavirin for 12 weeks (genotype 2 patients) and for 24 weeks (genotype 3 patients) in a Phase 2, open-label clinical trial. No adverse drug reactions specific to Sovaldi have been identified. The adverse reactions observed were generally consistent with those observed in clinical studies of Sovaldi plus ribavirin in adults (see Table 6).

Decreased appetite was observed as a very common adverse drug reaction to Sovaldi when given in combination with ribavirin oral solution in paediatric patients aged 3 to < 12 years.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme,

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

The highest documented dose of sofosbuvir was a single supratherapeutic dose of sofosbuvir 1,200 mg administered to 59 healthy subjects. In that study, there were no untoward effects observed at this dose level, and adverse reactions were similar in frequency and severity to those reported in the placebo and sofosbuvir 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 be monitored for evidence of toxicity. Treatment of overdose with Sovaldi consists of general supportive measures 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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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

Mechanism of action

Sofosbuvir is a pan-genotypic inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is essential for viral replication. Sofosbuvir is a nucleotide prodrug that undergoes intracellular metabolism to form the pharmacologically active uridine analog triphosphate (GS-461203), which can be incorporated into HCV RNA by the NS5B polymerase and acts as a chain terminator. In a biochemical assay, GS-461203 inhibited the polymerase activity of the recombinant NS5B from HCV genotype 1b, 2a, 3a and 4a with a 50% inhibitory concentration (IC50) value ranging from 0.7 to 2.6 jiM. GS-461203 (the active metabolite of sofosbuvir) is not an inhibitor of human DNA and RNA polymerases nor an inhibitor of mitochondrial RNA polymerase.

Antiviral activity

In HCV replicon assays, the effective concentration (EC50) values of sofosbuvir against full-length replicons from genotype 1a, 1b, 2a, 3a and 4a were 0.04, 0.11, 0.05, 0.05 and 0.04 jiM, respectively, and EC50 values of sofosbuvir against chimeric 1b replicons encoding NS5B from genotype 2b, 5a or 6a were 0.014 to 0.015 jiM. The mean ± SD EC50 of sofosbuvir against chimeric replicons encoding NS5B sequences from clinical isolates was 0.068 ± 0.024 jiM for genotype 1a (n = 67), 0.11 ± 0.029 jiM for genotype 1b (n = 29), 0.035 ± 0.018 jiM for genotype 2 (n = 15) and 0.085 ± 0.034 jiM for genotype 3a (n = 106). In these assays, the in vitro antiviral activity of sofosbuvir 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.

Resistance

In cell culture

HCV replicons with reduced susceptibility to sofosbuvir have been selected in cell culture for multiple genotypes including 1b, 2a, 2b, 3a, 4a, 5a and 6a. Reduced susceptibility to sofosbuvir was associated with the primary NS5B substitution S282T in all replicon genotypes examined. Site-directed mutagenesis of the S282T substitution in replicons of 8 genotypes conferred 2– to 18-fold reduced susceptibility to sofosbuvir and reduced the replication viral capacity by 89% to 99% compared to the corresponding wild-type. In biochemical assays, recombinant NS5B polymerase from genotypes 1b, 2a, 3a and 4a expressing the S282T substitution showed reduced susceptibility to GS-461203 compared to respective wild-types.

In clinical studies – Adults

In a pooled analysis of 991 patients who received sofosbuvir in Phase 3 studies, 226 patients qualified for 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-associated resistance substitution S282T was not detected in any of these patients by deep sequencing or population 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 and developed 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 next 8 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 from multiple genotype 3 HCV infected patients in the Phase 3 clinical studies. No shift in the phenotypic susceptibility to sofosbuvir or ribavirin of subject isolates with these substitutions was detected. In addition, S282R and

L320F substitutions were detected on treatment by deep sequencing in a pre-transplant subject with a partial treatment response. The clinical significance of these findings is unknown.

Effect of baseline HCV polymorphisms on treatment outcome

Adult population

Baseline NS5B sequences were obtained for 1,292 patients from Phase 3 studies by population sequencing and the S282T substitution was not detected in any subject with available baseline sequence. In an analysis evaluating the effect of baseline polymorphisms on treatment outcome, no statistically significant association was observed between the presence of any HCV NS5B variant at baseline and treatment outcome.

Paediatric population

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

Cross-resistance

HCV replicons expressing the sofosbuvir-associated resistance substitution S282T were fully susceptible 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-acting antivirals with different mechanisms of actions, such as NS5B non-nucleoside inhibitors, NS3 protease inhibitors and NS5A inhibitors.

Clinical efficacy and safety

The efficacy of sofosbuvir was evaluated in five Phase 3 studies in a total of 1,568 adult patients with genotypes 1 to 6 chronic hepatitis C. One study was conducted in treatment-naive patients with genotype 1, 4, 5 or 6 chronic hepatitis C in combination with peginterferon alfa 2a and ribavirin and the other four studies were conducted in patients with genotype 2 or 3 chronic hepatitis C in combination with ribavirin including one in treatment-naive 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 with interferon. Patients in these studies had compensated liver disease including cirrhosis. Sofosbuvir was administered at a dose of 400 mg once daily. The ribavirin dose was weight-based at 1,000–1,200 mg daily administered in two divided doses, and the peginterferon alfa 2a dose, where applicable, was 180 pg 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 of quantification (LLOQ) of 25 IU/mL. Sustained virologic response (SVR) was the primary endpoint to determine the HCV cure rate for all studies which was defined as HCV RNA less than LLOQ at 12 weeks after the end of treatment (SVR12).

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

Treatment-naive adult patients – NEUTRINO (study 110)

NEUTRINO was an open-label, single-arm study that evaluated 12 weeks of treatment with sofosbuvir in combination with peginterferon alfa 2a and ribavirin in treatment-naive 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 were male; 79% were White; 17% were Black; 14% were Hispanic or Latino; mean body mass index was 29 kg/m2 (range: 18 to 56 kg/m2); 78% had baseline HCV RNA greater than 6 log10 IU/mL; 17% had cirrhosis; 89% had HCV genotype 1 and 11% had HCV genotype 4, 5 or 6. Table 7 presents the response rates for the treatment group of sofosbuvir + peginterferon alfa + ribavirin.

Table 7: Response rates in study NEUTRINO

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

SVR12 rates were similarly high in patients with baseline IL28B C/C allele [94/95 (99%)] and non-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 all 6 patients with genotype 6 HCV infection in this study achieved SVR12.

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

Treatment-naive adults – FISSION (study 1231)

FISSION was a randomised, open-label, active-controlled study that evaluated 12 weeks of treatment with sofosbuvir and ribavirin compared to 24 weeks of treatment with peginterferon alfa 2a and ribavirin in treatment-naive patients with genotype 2 or 3 HCV infection. The ribavirin doses used in the sofosbuvir + ribavirin and peginterferon alfa 2a + ribavirin arms were weight-based 1,000–1,200 mg/day and 800 mg/day regardless of weight, respectively. Patients were randomised in a 1:1 ratio and stratified by cirrhosis (presence versus absence), HCV genotype (2 versus 3) and baseline HCV RNA level (<6 log10 lU/mL versus >6 log10 lU/mL). Patients with genotype 2 or 3 HCV were enrolled 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 were male; 87% were White; 3% were Black; 14% were Hispanic or Latino; mean body mass index was 28 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 treatment groups of sofosbuvir + ribavirin and peginterferon alfa + ribavirin.

Table 9: Response rates in study FISSION

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 the predefined 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

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 of treatment with sofosbuvir and ribavirin (n = 207) compared to placebo (n = 71) in patients who are interferon intolerant, ineligible or unwilling. Patients were randomised in 3:1 ratio and stratified by cirrhosis (presence versus absence).

Treated patients (n = 278) had a median age of 54 years (range: 21 to 75); 54% of the patients were male; 91% were White; 5% were Black; 11% were Hispanic or Latino; mean body mass index was 28 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 interferon intolerant, 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

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 when compared 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

Previously treated adults – FUSION (study 108)

FUSION was a randomised, double-blinded study that evaluated 12 or 16 weeks of treatment with sofosbuvir 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 were male; 87% were White; 3% were Black; 9% were Hispanic or Latino; mean body mass index was 29 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 the response rates for the treatment groups of sofosbuvir + ribavirin for 12 weeks and 16 weeks.

Table 13: Response rates in study FUSION

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

Treatment-naive and previously treated adults – VALENCE (study 133)

VALENCE was a Phase 3 study that evaluated sofosbuvir in combination with weight-based ribavirin for the treatment of genotype 2 or 3 HCV infection in treatment-naive patients or patients who did not achieve SVR with prior interferon-based treatment, including patients with compensated cirrhosis. The study 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 patients continued to receive sofosbuvir and ribavirin for 12 weeks, whilst treatment for HCV genotype 3 patients was extended to 24 weeks. Eleven HCV genotype 3 patients had already completed treatment with 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 were male; median body mass index was 25 kg/m2 (range: 17 to 44 kg/m2); the mean baseline HCV RNA level 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 weeks and 24 weeks.

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

Table 15: Response rates in study VALENCE

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

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 interferon demonstrates 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 or 24 weeks of treatment with sofosbuvir and ribavirin in patients with genotype 1, 2 or 3 chronic hepatitis C co-infected with HIV-1. Genotype 2 and 3 patients were either treatment-naïve or experienced, whereas genotype 1 patients were naïve to prior treatment. Treatment duration was 12 weeks in treatment-naïve patients with genotype 2 or 3 HCV infection, and 24 weeks in treatment-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 patients weighing <75 kg or 1,200 mg for patients weighing >75 kg). Patients were either not on antiretroviral therapy 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

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

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 an open-label clinical study evaluating the safety and efficacy of sofosbuvir and ribavirin administered pre-transplant to prevent post-transplant HCV reinfection. The primary endpoint of the study was post-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 of 24 weeks, subsequently amended to 48 weeks, or until the time of liver transplantation, whichever occurred first. An interim analysis was conducted on 61 patients who received sofosbuvir and ribavirin; the majority of patients had HCV genotype 1, 44 patients were CPT class A and 17 patients were CPT class B. Of these 61 patients, 44 patients underwent liver transplantation following up to 48 weeks of treatment with sofosbuvir and ribavirin; 41 had HCV RNA <LLOQ at the time of transplantation. The virologic response rates of the 41 patients transplanted with HCV RNA <LLOQ is described in Table 19. Duration of viral suppression prior to transplantation was the most predictive factor 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 of liver transplantation

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 weeks of 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 to screening. Patients had

HCV RNA >104 lU/mL at screening and documented evidence of chronic HCV infection pre-transplantation. The starting dose of ribavirin was 400 mg given in a divided daily dose. 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 in patients <75 kg, 1,200 mg daily in patients >75 kg). The median ribavirin dose was 600 mg-800 mg daily at weeks 4–24.

Forty patients (33 with HCV genotype 1 infection, 6 with HCV genotype 3 infection, and 1 with HCV genotype 4 infection) were enrolled, 35 of whom had previously failed interferon-based treatment, and 16 of whom had cirrhosis. 28 out of 40 (70%) patients achieved SVR12: 22/33 (73%) with HCV genotype 1 infection, 6/6 (100%) with HCV genotype 3 infection, and 0/1 (0%) with HCV genotype 4 infection. 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 to the dosing to help clinicians determine the best regimen for individual patients.

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

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 the duration of therapy 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 lower response rates to interferon-based therapies (prior null response to peginterferon alfa and ribavirin therapy, advanced fibrosis/cirrhosis, high baseline viral concentrations, 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 small and 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 across studies in genotype 2 HCV infection

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 small and SVR rates may be impacted by the selection of patients. In the ELECTRON study (N = 11), the duration of peginterferon 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 across studies in genotype 3 HCV infection

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 small and SVR rates may be impacted by the selection of patients. In the ELECTRON study (N = 11), the duration of peginterferon 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 across studies in genotype 4, 5 and 6 HCV infection

n = number of patients with SVR12 response; N = total number of patients per group.

Patients with renal impairment

Study 0154 was an open-label clinical study that evaluated the safety and efficacy of 24 weeks of treatment with sofosbuvir in combination with ribavirin in 20 genotype 1 or 3 HCV-infected patients with severe renal impairment not requiring dialysis.

Following treatment with sofosbuvir 200 mg or 400 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 18 genotype 1 HCV-infected patients with severe renal impairment not requiring dialysis was also studied in 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 and ledipasvir 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 virologic failure or relapsed.

Study 4062 was an open-label study that evaluated a fixed dose combination of sofosbuvir and velpatasvir 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 with velpatasvir treatment and relapsed.

Paediatric population

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 treated with 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 was 60.4 kg (range: 29.6 to 75.6 kg); 17% were treatment experienced; 65% had baseline HCV RNA levels greater than or equal to 800,000 IU/mL; and no patients had known cirrhosis. The majority of patients (69%) had been infected through vertical transmission.

The SVR12 rate was 98% overall (100% [13/13] in genotype 2 patients and 97% [38/39]) in genotype 3 patients. No patient experienced on-treatment virologic failure or relapse; one patient with genotype 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 were female; 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 than or equal to 800,000 IU /mL; and no patients had known cirrhosis. The majority of patients (98%) had been infected through vertical transmission.

The SVR12 rate was 100% (100% [13/13] in genotype 2 patients and 100% [28/28] in genotype 3 patients). 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 than or equal to 800,000 IU/mL; and no patients had known cirrhosis. The majority of patients (85%) had been infected through vertical transmission.

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

5.2 Pharmacokinetic properties

Sofosbuvir is a nucleotide prodrug that is extensively metabolised. The active metabolite is formed in hepatocytes 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.

Absorption

The pharmacokinetic properties of sofosbuvir and the predominant circulating metabolite GS-331007 have been evaluated in healthy adult subjects and in patients with chronic hepatitis C. Following oral administration, 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 was observed between 2 to 4 hours post-dose. Based on population pharmacokinetic analysis in patients with genotypes 1 to 6 HCV infection (n = 986), steady-state AUC0–24 for sofosbuvir and GS-331007 was 1,010 ng^h/mL and 7,200 ng^h/mL, respectively.

Relative to healthy subjects (n = 284), the sofosbuvir and GS-331007 AUC0–24 was 57% higher and 39% lower, respectively in HCV infected patients.

Effects of food

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

Distribution

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 drug transporters P-gp, BCRP, MRP2, BSEP, OATP1B1, OATP1B3 and OCT1. GS-331007 is not an inhibitor of OAT1, OCT2, and MATE1.

Sofosbuvir is approximately 85% bound to human plasma proteins (ex vivo data) and the binding is independent of drug concentration over the range of 1 jig/mL to 20 jig/mL. Protein binding of GS-331007 was minimal in human plasma. After a single 400 mg dose of [14C]-sofosbuvir in healthy subjects, the blood to plasma ratio of 14C-radioactivity was approximately 0.7.

Biotransformation

Sofosbuvir is extensively metabolised in the liver to form the pharmacologically active nucleoside analog triphosphate GS-461203. The metabolic activation pathway involves sequential hydrolysis of the carboxyl ester moiety catalysed by human cathepsin A (CatA) or carboxylesterase 1 (CES1) and phosphoramidate cleavage by histidine triad nucleotide-binding protein 1 (HINT1) followed by phosphorylation by the pyrimidine nucleotide biosynthesis pathway. Dephosphorylation results in the formation of nucleoside metabolite GS-331007 that cannot be efficiently rephosphorylated and lacks anti-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 for approximately 4% and >90% of drug-related material (sum of molecular weight-adjusted AUC of sofosbuvir and its metabolites) systemic exposure, respectively.

Elimination

Following a single 400 mg oral dose of [14C]-sofosbuvir, mean total recovery of the dose was greater than 92%, consisting of approximately 80%, 14%, and 2.5% recovered in urine, faeces, and expired air, respectively. The majority of the sofosbuvir dose recovered in urine was GS-331007 (78%) while 3.5% was recovered as sofosbuvir. This data indicate that renal clearance is the major elimination pathway for GS-331007 with a large part actively secreted. The median terminal half-lives of sofosbuvir and GS-331007 were 0.4 and 27 hours respectively.

Linearity/non-linearity

The dose linearity of sofosbuvir and its primary metabolite, GS-331007, was evaluated in fasted healthy subjects. Sofosbuvir and GS-331007 AUCs are near dose proportional over the dose range of 200 mg to 400 mg.

Pharmacokinetics in special populations

Gender and race

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

Elderly

Population pharmacokinetic analysis in HCV infected patients showed that within the age range (19 to 75 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 rates observed for patients over 65 years of age were similar to that of younger patients across treatment groups.

Renal impairment

A summary of the effect of varying degrees of renal impairment (RI) on the exposures of sofosbuvir and GS-331007 compared to subjects with normal renal function, as described in the text below, are provided 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

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 renal impairment (eGFR <30 mL/min/1.73 m2) and patients with ESRD requiring haemodialysis following a single 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 extraction coefficient of approximately 53%. Following a single 400 mg dose of sofosbuvir, a 4 hour haemodialysis removed 18% of administered sofosbuvir dose.

In HCV-infected adult patients with severe renal impairment treated with sofosbuvir 200 mg with ribavirin (n=10) or sofosbuvir 400 mg with ribavirin (n=10) for 24 weeks or ledipasvir/so­fosbuvir 90/400 mg (n=18) for 12 weeks, the pharmacokinetics of sofosbuvir and GS-331007 were consistent with 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 or sofosbuvir/vel­patasvir (n = 59) for 12 weeks, and compared to patients without renal impairment in the ledipasvir/so­fosbuvir and sofosbuvir/vel­patasvir Phase 2/3 trials (see section 4.4).

Hepatic impairment

The pharmacokinetics of sofosbuvir were studied following 7-day dosing of 400 mg sofosbuvir in adult 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% higher in 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 that cirrhosis had no clinically relevant effect on the exposure to sofosbuvir and GS-331007. No dose adjustment of sofosbuvir is recommended for patients with mild, moderate and severe hepatic impairment (see section 4.2).

Paediatric population

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

Pharmacokinetic/phar­macodynamic relationship(s)

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

5.3 Preclinical safety data

6   PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core

Mannitol (E421)

Microcrystalline cellulose

Croscarmellose sodium

Colloidal anhydrous silica

Magnesium stearate

Film-coating

Polyvinyl alcohol

Titanium dioxide

Macrogol

Talc

Iron oxide yellow

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

6 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Sovaldi 400 mg tablets are supplied in high density polyethylene (HDPE) bottles with a polypropylene child-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 400 mg tablets only; outer cartons containing 84 (3 bottles of 28) film-coated tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

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

Gilead Sciences Ltd

280 High Holborn

London

WC1V 7EE

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PLGB 11972/0020

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

01/01/2021