4.1. Therapeutic indications

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

Patient population*

Treatment

Duration

Adult patients with genotype 1, 4, 5 or 6 CHC

Sovaldi + ribavirinc + peginterferon alfa

12 weeksa,b

Sovaldi + ribavirinc

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

24 weeks

Adult and paediatric patients aged 3 years and above with genotype 2 CHC

Sovaldid + ribavirinc, e

12 weeksb

Adult patients with genotype 3 CHC

Sovaldi + ribavirinc + peginterferon alfa

12 weeksb

Sovaldi + ribavirinc

24 weeks

Paediatric patients aged 3 years and above with genotype 3 CHC

Sovaldid + ribavirine

24 weeks

Adult patients with CHC awaiting liver transplantation

Sovaldi + ribavirinc

Until liver transplantationf

* 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*

Body Weight (kg)

Dosing of Sovaldi Tablets

Sofosbuvir Daily Dose

≥ 35

one 400 mg tablet once daily

or

two 200 mg tablets once daily

400 mg/day

17 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 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

Body weight kg (lbs)

RBV daily dose*

< 47 (< 103)

15 mg/kg/day

47-49 (103-108)

600 mg/day

50-65 (110-143)

800 mg/day

66-80 (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 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

Laboratory values

Reduce ribavirin dose to 600 mg/day if:

Discontinue ribavirin if:

Haemoglobin in patients with no cardiac disease

<10 g/dL

<8.5 g/dL

Haemoglobin in patients with history of stable cardiac disease

≥2 g/dL decrease in haemoglobin during any 4 week treatment period

<12 g/dL despite 4 weeks at reduced dose

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

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 significantly decrease sofosbuvir plasma concentration and could result in loss of efficacy of Sovaldi (see section 4.5).

4.4. Special warnings and precautions for use

General

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

Severe bradycardia and heart block

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 occurred within hours to days, but cases with a longer time to onset have been observed mostly up to 2 weeks after initiating HCV treatment.

Amiodarone should only be used in patients on Sovaldi when other alternative anti-arrhythmic treatments are not tolerated or are contraindicated.

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

Due to the long half-life of amiodarone, cardiac monitoring as outlined above should also be carried out for patients who have discontinued amiodarone within the past few months and are to be initiated on Sovaldi.

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

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

Use with moderate P-gp inducers

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 of such medicinal products is not recommended with Sovaldi (see section 4.5).

Use in diabetic patients

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

Renal impairment

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 when no other relevant treatment options are available (see sections 4.8, 5.1 and 5.2). When Sovaldi is used in 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 also section 5.2).

Excipients

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

4.5. Interaction with other medicinal products and other forms of interaction

Sofosbuvir is a nucleotide prodrug. After oral administration of Sovaldi, sofosbuvir is rapidly absorbed and subject to extensive first-pass hepatic and intestinal metabolism. Intracellular hydrolytic prodrug cleavage catalysed by enzymes including carboxylesterase 1 and sequential phosphorylation steps catalysed by nucleotide kinases result in formation of the pharmacologically active uridine nucleoside analogue triphosphate. The predominant inactive circulating metabolite GS-331007 that accounts for greater than 90% of drug-related material systemic exposure is formed through pathways sequential and parallel to formation of active metabolite. The parent sofosbuvir accounts for approximately 4% of drug-related material systemic exposure (see section 5.2). In clinical pharmacology studies, both sofosbuvir and GS-331007 were monitored for purposes of pharmacokinetic 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 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 “↑”, or extended below “↓” the predetermined equivalence boundaries). The table is not all-inclusive.

Table 5: Interactions between Sovaldi and other medicinal products

Medicinal product by therapeutic areas

Effects on drug levels. Mean ratio (90% confidence interval) for AUC, Cmax, Cmina,b

Recommendation concerning co-administration with Sovaldi

ANALEPTICS

Modafinil

Interaction not studied.

Expected:

↓ Sofosbuvir

↔ GS-331007

(Induction of P-gp)

Co-administration of Sovaldi with modafinil is expected to decrease the concentration of sofosbuvir, leading to reduced therapeutic effect of Sovaldi. Such co-administration is not recommended.

ANTIARRHYTHMICS

Amiodarone

Effect on amiodarone and sofosbuvir concentrations unknown.

Coadministration of amiodarone with a sofosbuvir-containing regimen may result in serious symptomatic bradycardia.

Use only if no other alternative is available. Close monitoring is recommended if this medicinal product is administered with Sovaldi (see sections 4.4 and 4.8).

ANTICOAGULANTS

Vitamin K antagonists

Interaction not studied

Close monitoring of INR is recommended with all vitamin K antagonists. This is due to liver function changes during treatment with Sovaldi.

ANTICONVULSANTS

Phenobarbital

Phenytoin

Interaction not studied.

Expected:

↓ Sofosbuvir

↔ GS-331007

(Induction of P-gp)

Sovaldi is contraindicated with phenobarbital and phenytoin (see section 4.3).

Carbamazepine

Sofosbuvir

↓ Cmax 0.52 (0.43, 0.62)

↓ AUC 0.52 (0.46, 0.59)

Cmin (NA)

GS 331007

↔ Cmax 1.04 (0.97, 1.11)

↔ AUC 0.99 (0.94, 1.04)

Cmin (NA)

(Induction of P-gp)

Sovaldi is contraindicated with carbamazepine (see section 4.3).

Oxcarbazepine

Interaction not studied.

Expected:

↓ Sofosbuvir

↔ GS-331007

(Induction of P-gp)

Co-administration of Sovaldi with oxcarbazepine is expected to decrease the concentration of sofosbuvir, leading to reduced therapeutic effect of Sovaldi. Such co-administration is not recommended (see section 4.4).

ANTIMYCOBACTERIALS

Rifampicinf

(600 mg single dose)

Sofosbuvir

↓ Cmax 0.23 (0.19, 0.29)

↓ 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)

Sovaldi is contraindicated with rifampicin (see section 4.3).

Rifabutin

Sofosbuvir

↓ Cmax 0.64 (0.53, 0.77)

↓ AUC 0.76 (0.63, 0.91)

Cmin (NA)

GS 331007

↔ Cmax 1.15 (1.03, 1.27)

↔ AUC 1.03 (0.95, 1.12)

Cmin (NA)

(Induction of P-gp)

No dose adjustment of Sovaldi is required when concomitantly used with rifabutin.

Rifapentine

Interaction not studied.

Expected:

↓ Sofosbuvir

↔ GS-331007

(Induction of P-gp)

Co-administration of Sovaldi with rifapentine is expected to decrease the concentration of sofosbuvir, leading to reduced therapeutic effect of Sovaldi. Such co-administration is not recommended (see section 4.4).

HERBAL SUPPLEMENTS

St. John's wort

Interaction not studied.

Expected:

↓ Sofosbuvir

↔ GS-331007

(Induction of P-gp)

Sovaldi is contraindicated with St. John's wort (see section 4.3).

HCV ANITIVIRAL AGENTS: HCV PROTEASE INHIBITORS

Boceprevir (BOC)

Telaprevir (TPV)

Interaction not studied.

Expected:

↑ Sofosbuvir (TPV)

↔ Sofosbuvir (BOC)

↔ GS-331007 (TPV or BOC)

No drug-drug interaction data exists regarding the co-administration of Sovaldi with boceprevir or telaprevir.

NARCOTIC ANALGESICS

Methadonef

(Methadone maintenance therapy [30 to 130 mg/daily])

R-methadone

↔ Cmax 0.99 (0.85, 1.16)

↔ AUC 1.01 (0.85, 1.21)

↔ 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)

No dose adjustment of sofosbuvir or methadone is required when sofosbuvir and methadone are used concomitantly.

IMMUNOSUPPRESSANTS

Ciclosporine

(600 mg single dose)

Ciclosporin

↔ Cmax 1.06 (0.94, 1.18)

↔ AUC 0.98 (0.85, 1.14)

Cmin (NA)

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)

No dose adjustment of sofosbuvir or ciclosporin is required at initiation of co-administration. Afterwards, close monitoring and potential dose adjustment of ciclosporin may be required.

Tacrolimuse

(5 mg single dose)

Tacrolimus

↓ Cmax 0.73 (0.59, 0.90)

↔ AUC 1.09 (0.84, 1.40)

Cmin (NA)

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)

No dose adjustment of sofosbuvir or tacrolimus is required at initiation of co-administration. Afterwards, close monitoring and potential dose adjustment of tacrolimus may be required.

HIV ANTIVIRAL AGENTS: REVERSE TRANSCRIPTASE INHIBITORS

Efavirenzf

(600 mg once daily)d

Efavirenz

↔ Cmax 0.95 (0.85, 1.06)

↔ AUC 0.96 (0.91, 1.03)

↔ 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)

No dose adjustment of sofosbuvir or efavirenz is required when sofosbuvir and efavirenz are used concomitantly.

Emtricitabinef

(200 mg once daily)d

Emtricitabine

↔ Cmax 0.97 (0.88, 1.07)

↔ AUC 0.99 (0.94, 1.05)

↔ 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)

No dose adjustment of sofosbuvir or emtricitabine is required when sofosbuvir and emtricitabine are used concomitantly.

Tenofovir disoproxilf

(245 mg once daily)d

Tenofovir

↑ Cmax 1.25 (1.08, 1.45)

↔ AUC 0.98 (0.91, 1.05)

↔ 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)

No dose adjustment of sofosbuvir or tenofovir disoproxil is required when sofosbuvir and tenofovir disoproxil are used concomitantly.

Rilpivirinef

(25 mg once daily)

Rilpivirine

↔ Cmax 1.05 (0.97, 1.15)

↔ AUC 1.06 (1.02, 1.09)

↔ 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)

No dose adjustment of sofosbuvir or rilpivirine is required when sofosbuvir and rilpivirine are used concomitantly.

HIV ANTIVIRAL AGENTS: HIV PROTEASE INHIBITORS

Darunavir boosted with ritonavirf

(800/100 mg once daily)

Darunavir

↔ Cmax 0.97 (0.94, 1.01)

↔ AUC 0.97 (0.94, 1.00)

↔ 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)

No dose adjustment of sofosbuvir or darunavir (ritonavir boosted) is required when sofosbuvir and darunavir are used concomitantly.

HIV ANTIVIRAL AGENTS: INTEGRASE INHIBITORS

Raltegravirf

(400 mg twice daily)

Raltegravir

↓ Cmax 0.57 (0.44, 0.75)

↓ AUC 0.73 (0.59, 0.91)

↔ 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)

No dose adjustment of sofosbuvir or raltegravir is required when sofosbuvir and raltegravir are used concomitantly.

ORAL CONTRACEPTIVES

Norgestimate/ethinyl estradiol

Norgestromin

↔ Cmax 1.06 (0.93, 1.22)

↔ AUC 1.05 (0.92, 1.20)

Cmin (NA)

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)

No dose adjustment of norgestimate/ethinyl estradiol is required when sofosbuvir and norgestimate/ethinyl estradiol are used concomitantly.

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

Frequency

SOFa + RBVb

SOF + PEGc + RBV

Infections and infestations:

Common

nasopharyngitis

Blood and lymphatic system disorders:

Very common

haemoglobin decreased

anaemia, neutropenia, lymphocyte count decreased, platelet count decreased

Common

anaemia

Metabolism and nutrition disorders:

Very common

decreased appetited

decreased appetite

Common

weight decreased

Psychiatric disorders:

Very common

insomnia

insomnia

Common

depression

depression, anxiety, agitation

Nervous system disorders:

Very common

headache

dizziness, headache

Common

disturbance in attention

migraine, memory impairment, disturbance in attention

Eye disorders:

Common

vision blurred

Respiratory, thoracic and mediastinal disorders:

Very common

dyspnoea, cough

Common

dyspnoea, dyspnoea exertional, cough

dyspnoea exertional

Gastrointestinal disorders:

Very common

nausea

diarrhoea, nausea, vomiting

Common

abdominal discomfort, constipation, dyspepsia

constipation, dry mouth, gastroesophageal reflux

Hepatobiliary disorders:

Very common

blood bilirubin increased

blood bilirubin increased

Skin and subcutaneous tissue disorders:

Very common

rash, pruritus

Common

alopecia, dry skin, pruritus

alopecia, dry skin

Musculoskeletal and connective tissue disorders:

Very common

arthralgia, myalgia

Common

arthralgia, back pain, muscle spasms, myalgia

back pain, muscle spasms

General disorders and administration site conditions:

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 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.