4.1. Therapeutic indications

Harvoni is indicated for the treatment of chronic hepatitis C (CHC) in adult 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

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

Posology

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

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

Patient population

(including HIV co-infected patients)

Treatment and duration

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

Patients without cirrhosis

Harvoni for 12 weeks.

- Harvoni for 8 weeks may be considered in previously untreated genotype 1-infected patients (see section 5.1, ION-3 study).

Patients with compensated cirrhosis

Harvoni + ribavirinb,c for 12 weeks

or

Harvoni (without ribavirin) for 24 weeks.

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

Patients who are post-liver transplant without cirrhosis or with compensated cirrhosis

Harvoni + ribavirinb,c for 12 weeks (see section 5.1).

- Harvoni (without ribavirin) for 12 weeks (in patients without cirrhosis) or 24 weeks (in patients with cirrhosis) may be considered for patients who are ineligible for or intolerant to ribavirin.

Patients with decompensated cirrhosis irrespective of transplant status

Harvoni + ribavirind for 12 weeks (see section 5.1)

- Harvoni (without ribavirin) for 24 weeks may be considered in patients who are ineligible for or intolerant to ribavirin.

Adult and paediatric patients aged 3 years and abovea with genotype 3 CHC

Patients with compensated cirrhosis and/or prior treatment failure

Harvoni + ribavirinb for 24 weeks (see sections 4.4 and 5.1).

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

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

c Paediatric patients: for ribavirin dosing recommendations see Table 4 below.

d For ribavirin dosing recommendations in adult patients with decompensated cirrhosis, see Table 3 below.

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

Body Weight (kg)

Dosing of Oral Granules in Sachet

Ledipasvir/Sofosbuvir Daily Dose

≥ 35

two 45 mg/200 mg sachets of granules once daily

90 mg/400 mg/day

17 to < 35

one 45 mg/200 mg sachet of granules once daily

45 mg/200 mg/day

< 17

one 33.75 mg/150 mg sachet of granules once daily

33.75 mg/150 mg/day

* Harvoni is also available as 45 mg/200 mg and 90 mg/400 mg film-coated tablets (see section 5.1). Please refer to the Summaries of Product Characteristics for Harvoni film-coated tablets.

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

Patient

Ribavirin dose*

Child-Pugh-Turcotte (CPT) Class B cirrhosis pre-transplant

1,000 mg per day for patients < 75 kg and 1,200 mg for those weighing ≥ 75 kg

CPT Class C cirrhosis pre-transplant

CPT Class B or C cirrhosis post- transplant

Starting dose of 600 mg, which can be titrated up to a maximum of 1,000/1,200 mg (1,000 mg for patients weighing < 75 kg and 1,200 mg for patients weighing ≥ 75 kg) if well tolerated. If the starting dose is not well tolerated, the dose should be reduced as clinically indicated based on haemoglobin levels

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

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

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

Body weight kg

Ribavirin Dose*

< 47

15 mg/kg/day

47-49

600 mg/day

50-65

800 mg/day

66-74

1000 mg/day

> or = 75

1200 mg/day

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

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

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

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

Laboratory values

Reduce ribavirin dose to 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 originally assigned dose (1,000 mg to 1,200 mg daily).

Paediatric population aged < 3 years

The safety and efficacy of Harvoni in paediatric patients aged < 3 years have not been established. No data are available.

Missed dose

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

If a dose is missed and it is within 18 hours of the normal time, patients should be instructed to take the additional 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.

Elderly

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

Renal impairment

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

Safety data are limited in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m2) and end stage renal disease (ESRD) requiring dialysis. Harvoni can 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 Harvoni is required for patients with mild, moderate or severe hepatic impairment (Child-Pugh-Turcotte [CPT] class A, B or C) (see section 5.2). Safety and efficacy of ledipasvir/sofosbuvir have been established in patients with decompensated cirrhosis (see section 5.1).

Method of administration

For oral use.

Harvoni can be taken either with or without food.

To help with swallowing of the Harvoni oral granules you can use food or water as detailed below. Alternatively, Harvoni can be swallowed without food or water.

Taking Harvoni granules with food to aid swallowing

To administer with food to aid swallowability of the granules, patients should be instructed to sprinkle the granules on one or more spoonfuls of non-acidic soft food at or below room temperature. Patients should be instructed to take the Harvoni granules within 30 minutes of gently mixing with food and to swallow the entire contents without chewing to avoid a bitter taste. Examples of non-acidic foods include chocolate syrup, mashed potato, and ice-cream.

Taking Harvoni granules with water to aid swallowing

To administer with water, patients should be instructed that the granules can be taken directly into the mouth and swallowed with water.

Taking Harvoni granules without food or water

To administer without food or water, patients should be instructed that the granules can be taken directly into the mouth and swallowed. Patients should be instructed to swallow the entire contents without chewing (see section 5.2).

4.3. Contraindications

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

Co-administration with rosuvastatin (see section 4.5).

Use with strong P-gp inducers

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

4.4. Special warnings and precautions for use

Harvoni should not be administered concomitantly with other medicinal products containing sofosbuvir.

Genotype-specific activity

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

The clinical data to support the use of Harvoni in adults infected with HCV genotype 3 are limited (see section 5.1). The relative efficacy of a 12-week regimen consisting of ledipasvir/sofosbuvir + ribavirin, compared to a 24-week regimen of sofosbuvir + ribavirin has not been investigated. A conservative 24 weeks of therapy is advised in all treatment-experienced genotype 3 patients and those treatment-naïve genotype 3 patients with cirrhosis (see section 4.2). In genotype 3-infection, the use of Harvoni (always in combination with ribavirin) should only be considered for patients who are deemed at high risk for clinical disease progression and who do not have alternative treatment options.

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

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 Harvoni 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 Harvoni.

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.

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.

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 of patients with prior exposure to HCV direct-acting antivirals

In patients who fail treatment with ledipasvir/sofosbuvir, selection of NS5A resistance mutations that substantially reduce the susceptibility to ledipasvir is seen in the majority of cases (see section 5.1). Limited data indicate that such NS5A mutations do not revert on long-term follow-up. There are presently no data to support the effectiveness of retreatment of patients who have failed ledipasvir/sofosbuvir with a subsequent regimen that contains an NS5A inhibitor. Similarly, there are presently no data to support the effectiveness of NS3/4A protease inhibitors in patients who previously failed prior therapy that included an NS3/4A protease inhibitor. Such patients may therefore be dependent on other classes of medicinal products for clearance of HCV infection. Consequently, consideration should be given to longer treatment for patients with uncertain subsequent retreatment options.

Renal impairment

Safety data are limited in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m2) and ESRD requiring haemodialysis. Harvoni can be used in these patients with no dose adjustment when no other relevant treatment options are available (see sections 4.8, 5.1 and 5.2). When Harvoni is used in combination with ribavirin refer also to the Summary of Product Characteristics for ribavirin for patients with creatinine clearance (CrCl) < 50 mL/min (see section 5.2).

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

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

Use with moderate P-gp inducers

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

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

Use with certain HIV antiretroviral regimens

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

Use with HMG-CoA reductase inhibitors

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

Paediatric population

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

Excipients

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

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

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

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

Potential for Harvoni to affect other medicinal products

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

Potential for other medicinal products to affect Harvoni

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

Medicinal products that are strong P-gp inducers (carbamazepine, phenobarbital, phenytoin, rifampicin, rifabutin and St. John's wort) may significantly decrease ledipasvir and sofosbuvir plasma concentrations leading to reduced therapeutic effect of ledipasvir/sofosbuvir and thus are contraindicated with Harvoni (see section 4.3). Medicinal products that are moderate P-gp inducers in the intestine (e.g. oxcarbazepine) may decrease ledipasvir and sofosbuvir plasma concentrations leading to reduced therapeutic effect of Harvoni. Co-administration with such medicinal products is not recommended with Harvoni (see section 4.4). Co-administration with medicinal products that inhibit P-gp and/or BCRP may increase ledipasvir and sofosbuvir plasma concentrations without increasing GS-331007 plasma concentration; Harvoni may be co-administered with P-gp and/or BCRP inhibitors. Clinically significant medicinal product interactions with ledipasvir/sofosbuvir mediated by CYP450s or UGT1A1 enzymes are not expected.

Patients treated with vitamin K antagonists

As liver function may change during treatment with Harvoni, 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 virus.

Interactions between Harvoni and other medicinal products

Table 6 provides a listing of established or potentially clinically significant medicinal product interactions (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 medicinal product interactions described are based on studies conducted with either ledipasvir/sofosbuvir or ledipasvir and sofosbuvir as individual agents, or are predicted medicinal product interactions that may occur with ledipasvir/sofosbuvir. The table is not all-inclusive.

Table 6: Interactions between Harvoni and other medicinal products

Medicinal product by therapeutic areas

Effects on medicinal product levels.

Mean ratio (90% confidence interval) for AUC, Cmax, Cmin a, b

Recommendation concerning co-administration with Harvoni

ACID REDUCING AGENTS

Ledipasvir solubility decreases as pH increases. Medicinal products that increase gastric pH are expected to decrease concentration of ledipasvir.

Antacids

e.g. Aluminium or magnesium hydroxide; calcium carbonate

Interaction not studied.

Expected:

↓ Ledipasvir

↔ Sofosbuvir

↔ GS-331007

(Increase in gastric pH)

It is recommended to separate antacid and Harvoni administration by 4 hours.

H2-receptor antagonists

Famotidine

(40 mg single dose)/ ledipasvir (90 mg single dose)c/ sofosbuvir (400 mg single dose)c, d

Famotidine dosed simultaneously with Harvonid

Cimetidinee

Nizatidinee

Ranitidinee

Ledipasvir

↓ Cmax 0.80 (0.69, 0.93)

↔ AUC 0.89 (0.76, 1.06)

Sofosbuvir

↑ Cmax 1.15 (0.88, 1.50)

↔ AUC 1.11 (1.00, 1.24)

GS-331007

↔ Cmax 1.06 (0.97, 1.14)

↔ AUC 1.06 (1.02, 1.11)

(Increase in gastric pH)

H2-receptor antagonists may be administered simultaneously with or staggered from Harvoni at a dose that does not exceed doses comparable to famotidine 40 mg twice daily.

Famotidine

(40 mg single dose)/ ledipasvir (90 mg single dose)c/ sofosbuvir (400 mg single dose)c, d

Famotidine dosed 12 hours prior to Harvonid

Ledipasvir

↓ Cmax 0.83 (0.69, 1.00)

↔ AUC 0.98 (0.80, 1.20)

Sofosbuvir

↔ Cmax 1.00 (0.76, 1.32)

↔ AUC 0.95 (0.82, 1.10)

GS-331007

↔ Cmax 1.13 (1.07, 1.20)

↔ AUC 1.06 (1.01, 1.12)

(Increase in gastric pH)

Proton pump inhibitors

Omeprazole

(20 mg once daily)/ ledipasvir (90 mg single dose)c/ sofosbuvir (400 mg single dose)c

Omeprazole dosed simultaneously with Harvoni

Lansoprazolee

Rabeprazolee

Pantoprazolee

Esomeprazolee

Ledipasvir

↓ Cmax 0.89 (0.61, 1.30)

↓ AUC 0.96 (0.66, 1.39)

Sofosbuvir

↔ Cmax 1.12 (0.88, 1.42)

↔ AUC 1.00 (0.80, 1.25)

GS-331007

↔ Cmax 1.14 (1.01, 1.29)

↔ AUC 1.03 (0.96, 1.12)

(Increase in gastric pH)

Proton pump inhibitor doses comparable to omeprazole 20 mg can be administered simultaneously with Harvoni. Proton pump inhibitors should not be taken before Harvoni.

ANTIARRHYTHMICS

Amiodarone

Effect on amiodarone, sofosbuvir and ledipasvir 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 Harvoni (see sections 4.4 and 4.8).

Digoxin

Interaction not studied.

Expected:

↑ Digoxin

↔ Ledipasvir

↔ Sofosbuvir

↔ GS-331007

(Inhibition of P-gp)

Co-administration of Harvoni with digoxin may increase the concentration of digoxin. Caution is warranted and therapeutic concentration monitoring of digoxin is recommended when co-administered with Harvoni.

ANTICOAGULANTS

Dabigatran etexilate

Interaction not studied.

Expected:

↑ Dabigatran

↔ Ledipasvir

↔ Sofosbuvir

↔ GS-331007

(Inhibition of P-gp)

Clinical monitoring, looking for signs of bleeding and anaemia, is recommended when dabigatran etexilate is co-administered with Harvoni. A coagulation test helps to identify patients with an increased bleeding risk due to increased dabigatran exposure.

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 Harvoni.

ANTICONVULSANTS

Phenobarbital

Phenytoin

Interaction not studied.

Expected:

↓ Ledipasvir

↓ Sofosbuvir

↔ GS-331007

(Inhibition of P-gp)

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

Carbamazepine

Interaction not studied

Expected:

↓ Ledipasvir

Observed:

Sofosbuvir

↓ Cmax 0.52 (0.43, 0.62)

↓ AUC 0.52 (0.46, 0.59)

Cmin (NA)

GS 331007

↔ Cmax 1.04 (0.97, 1.11)

↔ AUC 0.99 (0.94, 1.04)

Cmin (NA)

(Induction of P-gp)

Harvoni is contraindicated with carbamazepine (see section 4.3).

Oxcarbazepine

Interaction not studied.

Expected:

↓ Ledipasvir

↓ Sofosbuvir

↔ GS-331007

(Induction of P-gp)

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

ANTIMYCOBACTERIALS

Rifampicin (600 mg once daily)/ ledipasvir (90 mg single dose)d

Interaction not studied.

Expected:

Rifampicin

↔ Cmax

↔ AUC

↔ Cmin

Observed:

Ledipasvir

↓ Cmax 0.65 (0.56, 0.76)

↓ AUC 0.41 (0.36, 0.48)

(Induction of P-gp)

Harvoni is contraindicated with rifampicin (see section 4.3).

Rifampicin (600 mg once daily)/ sofosbuvir (400 mg single dose)d

Interaction not studied.

Expected:

Rifampicin

↔ Cmax

↔ AUC

↔ Cmin

Observed:

Sofosbuvir

↓ Cmax 0.23 (0.19, 0.29)

↓ AUC 0.28 (0.24, 0.32)

GS-331007

↔ Cmax 1.23 (1.14, 1.34)

↔ AUC 0.95 (0.88, 1.03)

(Induction of P-gp)

Rifabutin

Interaction not studied.

Expected:

↓ Ledipasvir

Observed:

Sofosbuvir

↓ Cmax 0.64 (0.53, 0.77)

↓ AUC 0.76 (0.63, 0.91)

Cmin (NA)

GS 331007

↔ Cmax 1.15 (1.03, 1.27)

↔ AUC 1.03 (0.95, 1.12)

Cmin (NA)

(Induction of P-gp)

Harvoni is contraindicated with rifabutin (see section 4.3).

Rifapentine

Interaction not studied.

Expected:

↓ Ledipasvir

↓ Sofosbuvir

↔ GS-331007

(Induction of P-gp)

Co-administration of Harvoni with rifapentine is expected to decrease the concentration of ledipasvir and sofosbuvir, leading to reduced therapeutic effect of Harvoni. Such co-administration is not recommended.

SEDATIVES/HYPNOTICS

Midazolam (2.5 mg single dose)/ ledipasvir (90 mg single dose)

Ledipasvir (90 mg once daily)

Observed:

Midazolam

↔ Cmax 1.07 (1.00, 1.14)

↔ AUC 0.99 (0.95, 1.04)

(Inhibition of CYP3A)

Midazolam

↔ Cmax 0.95 (0.87, 1.04)

↔ AUC 0.89 (0.84, 0.95)

(Induction of CYP3A)

Expected:

↔ Sofosbuvir

↔ GS-331007

No dose adjustment of Harvoni or midazolam is required.

HIV ANTIVIRAL AGENTS: REVERSE TRANSCRIPTASE INHIBITORS

Efavirenz/ emtricitabine/ tenofovir disoproxil fumarate (600 mg/ 200 mg/ 300 mg/ once daily)/ ledipasvir (90 mg once daily)c/ sofosbuvir (400 mg once daily)c, d

Efavirenz

↔ Cmax 0.87 (0.79, 0.97)

↔ AUC 0.90 (0.84, 0.96)

↔ Cmin 0.91 (0.83, 0.99)

Emtricitabine

↔ Cmax 1.08 (0.97, 1.21)

↔ AUC 1.05 (0.98, 1.11)

↔ Cmin 1.04 (0.98, 1.11)

Tenofovir

↑ Cmax 1.79 (1.56, 2.04)

↑ AUC 1.98 (1.77, 2.23)

↑ Cmin 2.63 (2.32, 2.97)

Ledipasvir

↓ Cmax 0.66 (0.59, 0.75)

↓ AUC 0.66 (0.59, 0.75)

↓ Cmin 0.66 (0.57, 0.76)

Sofosbuvir

↔ Cmax 1.03 (0.87, 1.23)

↔ AUC 0.94 (0.81, 1.10)

GS-331007

↔ Cmax 0.86 (0.76, 0.96)

↔ AUC 0.90 (0.83, 0.97)

↔ Cmin 1.07 (1.02, 1.13)

No dose adjustment of Harvoni or efavirenz/ emtricitabine/ tenofovir disoproxil fumarate is required.

Emtricitabine/ rilpivirine/ tenofovir disoproxil fumarate (200 mg/ 25 mg/ 300 mg once daily)/ ledipasvir (90 mg once daily)c/ sofosbuvir (400 mg once daily)c, d

Emtricitabine

↔ Cmax 1.02 (0.98, 1.06)

↔ AUC 1.05 (1.02, 1.08)

↔ Cmin 1.06 (0.97, 1.15)

Rilpivirine

↔ Cmax 0.97 (0.88, 1.07)

↔ AUC 1.02 (0.94, 1.11)

↔ Cmin 1.12 (1.03, 1.21)

Tenofovir

↔ Cmax 1.32 (1.25, 1.39)

↑ AUC 1.40 (1.31, 1.50)

↑ Cmin 1.91 (1.74, 2.10)

Ledipasvir

↔ Cmax 1.01 (0.95, 1.07)

↔ AUC 1.08 (1.02, 1.15)

↔ Cmin 1.16 (1.08, 1.25)

Sofosbuvir

↔ Cmax 1.05 (0.93, 1.20)

↔ AUC 1.10 (1.01, 1.21)

GS-331007

↔ Cmax 1.06 (1.01, 1.11)

↔ AUC 1.15 (1.11, 1.19)

↔ Cmin 1.18 (1.13, 1.24)

No dose adjustment of Harvoni or emtricitabine/ rilpivirine/ tenofovir disoproxil fumarate is required.

Abacavir/ lamivudine

(600 mg/ 300 mg once daily)/ ledipasvir (90 mg once daily)c/ sofosbuvir (400 mg once daily)c, d

Abacavir

↔ Cmax 0.92 (0.87, 0.97)

↔ AUC 0.90 (0.85, 0.94)

Lamivudine

↔ Cmax 0.93 (0.87, 1.00)

↔ AUC 0.94 (0.90, 0.98)

↔ Cmin 1.12 (1.05, 1.20)

Ledipasvir

↔ Cmax 1.10 (1.01, 1.19)

↔ AUC 1.18 (1.10, 1.28)

↔ Cmin 1.26 (1.17, 1.36)

Sofosbuvir

↔ Cmax 1.08 (0.85, 1.35)

↔ AUC 1.21 (1.09, 1.35)

GS-331007

↔ Cmax 1.00 (0.94, 1.07)

↔ AUC 1.05 (1.01, 1.09)

↔ Cmin 1.08 (1.01, 1.14)

No dose adjustment of Harvoni or abacavir/ lamivudine is required.

HIV ANTIVIRAL AGENTS: HIV PROTEASE INHIBITORS

Atazanavir boosted with ritonavir (300 mg/ 100 mg once daily)/ ledipasvir (90 mg once daily)c/ sofosbuvir (400 mg once daily)c, d

Atazanavir

↔ Cmax 1.07 (1.00, 1.15)

↔ AUC 1.33 (1.25, 1.42)

↑ Cmin 1.75 (1.58, 1.93)

Ledipasvir

↑ Cmax 1.98 (1.78, 2.20)

↑ AUC 2.13 (1.89, 2.40)

↑ Cmin 2.36 (2.08, 2.67)

Sofosbuvir

↔ Cmax 0.96 (0.88, 1.05)

↔ AUC 1.08 (1.02, 1.15)

GS-331007

↔ Cmax 1.13 (1.08, 1.19)

↔ AUC 1.23 (1.18, 1.29)

↔ Cmin 1.28 (1.21, 1.36)

No dose adjustment of Harvoni or atazanavir (ritonavir boosted) is required.

For the combination of tenofovir/emtricitabine + atazanavir/ritonavir, please see below.

Atazanavir boosted with ritonavir (300 mg/ 100 mg once daily) + emtricitabine/ tenofovir disoproxil fumarate (200 mg/ 300 mg once daily)/ ledipasvir (90 mg once daily)c/ sofosbuvir (400 mg once daily)c, d

Dosed simultaneouslyf

Atazanavir

↔ Cmax 1.07 (0.99, 1.14)

↔ AUC 1.27 (1.18, 1.37)

↑ Cmin 1.63 (1.45, 1.84)

Ritonavir

↔ Cmax 0.86 (0.79, 0.93)

↔ AUC 0.97 (0.89, 1.05)

↑ Cmin 1.45 (1.27, 1.64)

Emtricitabine

↔ Cmax 0.98 (0.94, 1.02)

↔ AUC 1.00 (0.97, 1.04)

↔ Cmin 1.04 (0.96, 1.12)

Tenofovir

↑ Cmax 1.47 (1.37, 1.58)

↔ AUC 1.35 (1.29, 1.42)

↑ Cmin 1.47 (1.38, 1.57)

Ledipasvir

↑ Cmax 1.68 (1.54, 1.84)

↑ AUC 1.96 (1.74, 2.21)

↑ Cmin 2.18 (1.91, 2.50)

Sofosbuvir

↔ Cmax 1.01 (0.88, 1.15)

↔ AUC 1.11 (1.02, 1.21)

GS-331007

↔ Cmax 1.17 (1.12, 1.23)

↔ AUC 1.31 (1.25, 1.36)

↑ Cmin 1.42 (1.34, 1.49)

When given with tenofovir disoproxil fumarate used in conjunction with atazanavir/ritonavir, Harvoni increased the concentration of tenofovir.

The safety of tenofovir disoproxil fumarate in the setting of Harvoni and a pharmacokinetic enhancer (e.g. ritonavir or cobicistat) has not been established.

The combination should be used with caution with frequent renal monitoring, if other alternatives are not available (see section 4.4).

Atazanavir concentrations are also increased, with a risk for an increase in bilirubin levels/icterus. That risk is even higher if ribavirin is used as part of the HCV treatment.

Darunavir boosted with ritonavir (800 mg/ 100 mg once daily)/ ledipasvir (90 mg once daily)d

Darunavir

↔ Cmax 1.02 (0.88, 1.19)

↔ AUC 0.96 (0.84, 1.11)

↔ Cmin 0.97 (0.86, 1.10)

Ledipasvir

↑ Cmax 1.45 (1.34, 1.56)

↑ AUC 1.39 (1.28, 1.49)

↑ Cmin 1.39 (1.29, 1.51)

No dose adjustment of Harvoni or darunavir (ritonavir boosted) is required.

For the combination of tenofovir/emtricitabine + darunavir/ritonavir, please see below.

Darunavir boosted with ritonavir (800 mg/ 100 mg once daily)/ sofosbuvir (400 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)

GS-331007

↔ Cmax 0.97 (0.90, 1.05)

↔ AUC 1.24 (1.18, 1.30)

Darunavir boosted with ritonavir (800 mg/ 100 mg once daily) + emtricitabine/ tenofovir disoproxil fumarate (200 mg/ 300 mg once daily)/ ledipasvir (90 mg once daily)c/ sofosbuvir (400 mg once daily)c, d

Dosed simultaneouslyf

Darunavir

↔ Cmax 1.01 (0.96, 1.06)

↔ AUC 1.04 (0.99, 1.08)

↔ Cmin 1.08 (0.98, 1.20)

Ritonavir

↔ Cmax 1.17 (1.01, 1.35)

↔ AUC 1.25 (1.15, 1.36)

↑ Cmin 1.48 (1.34, 1.63)

Emtricitabine

↔ Cmax 1.02 (0.96, 1.08)

↔ AUC 1.04 (1.00, 1.08)

↔ Cmin 1.03 (0.97, 1.10)

Tenofovir

↑ Cmax 1.64 (1.54, 1.74)

↑ AUC 1.50 (1.42, 1.59)

↑ Cmin 1.59 (1.49, 1.70)

Ledipasvir

↔ Cmax 1.11 (0.99, 1.24)

↔ AUC 1.12 (1.00, 1.25)

↔ Cmin 1.17 (1.04, 1.31)

Sofosbuvir

↓ Cmax 0.63 (0.52, 0.75)

↓ AUC 0.73 (0.65, 0.82)

GS-331007

↔ Cmax 1.10 (1.04, 1.16)

↔ AUC 1.20 (1.16, 1.24)

↔ Cmin 1.26 (1.20, 1.32)

When given with darunavir/ritonavir used in conjunction with tenofovir disoproxil fumarate, Harvoni increased the concentration of tenofovir.

The safety of tenofovir disoproxil fumarate in the setting of Harvoni and a pharmacokinetic enhancer (e.g. ritonavir or cobicistat) has not been established.

The combination should be used with caution with frequent renal monitoring, if other alternatives are not available (see section 4.4).

Lopinavir boosted with ritonavir + emtricitabine/ tenofovir disoproxil fumarate

Interaction not studied.

Expected:

↑ Lopinavir

↑ Ritonavir

↔ Emtricitabine

↑ Tenofovir

↑ Ledipasvir

↔ Sofosbuvir

↔ GS-331007

When given with lopinavir/ritonavir used in conjunction with tenofovir disoproxil fumarate, Harvoni is expected to increase the concentration of tenofovir.

The safety of tenofovir disoproxil fumarate in the setting of Harvoni and a pharmacokinetic enhancer (e.g. ritonavir or cobicistat) has not been established.

The combination should be used with caution with frequent renal monitoring, if other alternatives are not available (see section 4.4).

Tipranavir boosted with ritonavir

Interaction not studied.

Expected:

↓ Ledipasvir

↓ Sofosbuvir

↔ GS-331007

(Induction of P-gp)

Co-administration of Harvoni with tipranavir (ritonavir boosted) is expected to decrease the concentration of ledipasvir, leading to reduced therapeutic effect of Harvoni. Co-administration is not recommended.

HIV ANTIVIRAL AGENTS: INTEGRASE INHIBITORS

Raltegravir

(400 mg twice daily)/ ledipasvir (90 mg once daily)d

Raltegravir

↓ Cmax 0.82 (0.66, 1.02)

↔ AUC 0.85 (0.70, 1.02)

↑ Cmin 1.15 (0.90, 1.46)

Ledipasvir

↔ Cmax 0.92 (0.85, 1.00)

↔ AUC 0.91 (0.84, 1.00)

↔ Cmin 0.89 (0.81, 0.98)

No dose adjustment of Harvoni or raltegravir is required.

Raltegravir

(400 mg twice daily)/ sofosbuvir (400 mg once daily)d

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)

GS-331007

↔ Cmax 1.09 (0.99, 1.19)

↔ AUC 1.02 (0.97, 1.08)

Elvitegravir/ cobicistat/ emtricitabine/ tenofovir disoproxil fumarate

(150 mg/ 150 mg/ 200 mg/ 300 mg once daily)/ ledipasvir (90 mg once daily)c/ sofosbuvir (400 mg once daily)c

Interaction not studied.

Expected:

↔ Emtricitabine

↑ Tenofovir

Observed:

Elvitegravir

↔ Cmax 0.88 (0.82, 0.95)

↔ AUC 1.02 (0.95, 1.09)

↑ Cmin 1.36 (1.23, 1.49)

Cobicistat

↔ Cmax 1.25 (1.18, 1.32)

↑ AUC 1.59 (1.49, 1.70)

↑ Cmin 4.25 (3.47, 5.22)

Ledipasvir

↑ Cmax 1.63 (1.51, 1.75)

↑ AUC 1.78 (1.64, 1.94)

↑ Cmin 1.91 (1.76, 2.08)

Sofosbuvir

↑ Cmax 1.33 (1.14, 1.56)

↑ AUC 1.36 (1.21, 1.52)

GS-331007

↑ Cmax 1.33 (1.22, 1.44)

↑ AUC 1.44 (1.41, 1.48)

↑ Cmin 1.53 (1.47, 1.59)

When given with elvitegravir/ cobicistat/ emtricitabine/ tenofovir disoproxil fumarate, Harvoni is expected to increase the concentration of tenofovir.

The safety of tenofovir disoproxil fumarate in the setting of Harvoni and a pharmacokinetic enhancer (e.g. ritonavir or cobicistat) has not been established.

The combination should be used with caution with frequent renal monitoring, if other alternatives are not available (see section 4.4).

Dolutegravir

Interaction not studied.

Expected:

↔ Dolutegravir

↔ Ledipasvir

↔ Sofosbuvir

↔ GS-331007

No dose adjustment required.

HERBAL SUPPLEMENTS

St. John's wort

Interaction not studied.

Expected:

↓ Ledipasvir

↓ Sofosbuvir

↔ GS-331007

(Induction of P-gp)

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

HMG-CoA REDUCTASE INHIBITORS

Rosuvastating

↑ Rosuvastatin

(Inhibition of drug transporters OATP and BCRP)

Co-administration of Harvoni with rosuvastatin may significantly increase the concentration of rosuvastatin (several fold-increase in AUC) which is associated with increased risk of myopathy, including rhabdomyolysis. Co-administration of Harvoni with rosuvastatin is contraindicated (see section 4.3).

Pravastating

↑ Pravastatin

Co-administration of Harvoni with pravastatin may significantly increase the concentration of pravastatin which is associated with increased risk of myopathy. Clinical and biochemical control is recommended in these patients and a dose adjustment may be needed (see section 4.4).

Other statins

Expected:

↑ Statins

Interactions cannot be excluded with other HMG-CoA reductase inhibitors. When co-administered with Harvoni, a reduced dose of statins should be considered and careful monitoring for statin adverse reactions should be undertaken (see section 4.4).

NARCOTIC ANALGESICS

Methadone

Interaction not studied.

Expected:

↔ Ledipasvir

No dose adjustment of Harvoni or methadone is required.

Methadone

(Methadone maintenance therapy [30 to 130 mg/daily])/ sofosbuvir (400 mg once daily)d

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 0.95 (0.68, 1.33)

↑ AUC 1.30 (1.00, 1.69)

GS-331007

↓ Cmax 0.73 (0.65, 0.83)

↔ AUC 1.04 (0.89, 1.22)

IMMUNOSUPPRESSANTS

Ciclosporing

Interaction not studied.

Expected:

↑ Ledipasvir

↔ Ciclosporin

No dose adjustment of Harvoni or ciclosporin is required at initiation of co-administration.

Afterwards, close monitoring and potential dose adjustment of ciclosporin may be required.

Ciclosporin

(600 mg single dose)/ sofosbuvir (400 mg single dose)h

Ciclosporin

↔ Cmax 1.06 (0.94, 1.18)

↔ AUC 0.98 (0.85, 1.14)

Sofosbuvir

↑ Cmax 2.54 (1.87, 3.45)

↑ AUC 4.53 (3.26, 6.30)

GS-331007

↓ Cmax 0.60 (0.53, 0.69)

↔ AUC 1.04 (0.90, 1.20)

Tacrolimus

Interaction not studied.

Expected:

↔ Ledipasvir

No dose adjustment of Harvoni or tacrolimus is required at initiation of co-administration.

Afterwards, close monitoring and potential dose adjustment of tacrolimus may be required.

Tacrolimus

(5 mg single dose)/ sofosbuvir (400 mg single dose)h

Tacrolimus

↓ Cmax 0.73 (0.59, 0.90)

↑ AUC 1.09 (0.84, 1.40)

Sofosbuvir

↓ Cmax 0.97 (0.65, 1.43)

↑ AUC 1.13 (0.81, 1.57)

GS-331007

↔ Cmax 0.97 (0.83, 1.14)

↔ AUC 1.00 (0.87, 1.13)

ORAL CONTRACEPTIVES

Norgestimate/ ethinyl estradiol (norgestimate 0.180 mg/ 0.215 mg/ 0.25 mg/ ethinyl estradiol 0.025 mg)/ ledipasvir (90 mg once daily)d

Norelgestromin

↔ Cmax 1.02 (0.89, 1.16)

↔ AUC 1.03 (0.90, 1.18)

↔ Cmin 1.09 (0.91, 1.31)

Norgestrel

↔ Cmax 1.03 (0.87, 1.23)

↔ AUC 0.99 (0.82, 1.20)

↔ Cmin 1.00 (0.81, 1.23)

Ethinyl estradiol

↑ Cmax 1.40 (1.18, 1.66)

↔ AUC 1.20 (1.04, 1.39)

↔ Cmin 0.98 (0.79, 1.22)

No dose adjustment of oral contraceptives is required.

Norgestimate/ ethinyl estradiol (norgestimate 0.180 mg/ 0.215 mg/ 0.25 mg/ ethinyl estradiol 0.025 mg)/ sofosbuvir (400 mg once daily)d

Norelgestromin

↔ Cmax 1.07 (0.94, 1.22)

↔ AUC 1.06 (0.92, 1.21)

↔ Cmin 1.07 (0.89, 1.28)

Norgestrel

↔ Cmax 1.18 (0.99, 1.41)

↑ AUC 1.19 (0.98, 1.45)

↑ Cmin 1.23 (1.00, 1.51)

Ethinyl estradiol

↔ Cmax 1.15 (0.97, 1.36)

↔ AUC 1.09 (0.94, 1.26)

↔ Cmin 0.99 (0.80, 1.23)

a Mean ratio (90% CI) of co-administered drug pharmacokinetics of study medicinal products alone or in combination. No effect = 1.00.

b All interaction studies conducted in healthy volunteers. c Administered as Harvoni.

d Lack of pharmacokinetics interaction bounds 70-143%.

e These are drugs within class where similar interactions could be predicted.

f Staggered administration (12 hours apart) of atazanavir/ritonavir + emtricitabine/tenofovir disoproxil fumarate or darunavir/ritonavir + emtricitabine/tenofovir disoproxil fumarate and Harvoni provided similar results.

g This study was conducted in the presence of another two direct-acting antiviral agents.

h Bioequivalence/Equivalence boundary 80-125%.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential / contraception in males and females

When Harvoni is used in combination with 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. 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 ledipasvir, sofosbuvir or Harvoni in pregnant women.

Animal studies do not indicate direct harmful effects with respect to reproductive toxicity. No significant effects on foetal development have been observed with ledipasvir or sofosbuvir in rats and rabbits. 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 Harvoni during pregnancy.

Breast-feeding

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

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

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

Fertility

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

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

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile in adults

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

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

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

Tabulated list of adverse events

The following adverse drug reactions have been identified with Harvoni (Table 7). 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 7: Adverse drug reactions identified with Harvoni

Frequency

Adverse drug reaction

Nervous system disorders:

Very common

headache

Skin and subcutaneous tissue disorders:

Common

rash

Not known

angioedema

General disorders:

Very common

fatigue

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

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

Decreases in haemoglobin to < 10 g/dL and < 8.5 g/dL during treatment were experienced by 39% and 13% of patients treated with ledipasvir/sofosbuvir with ribavirin, respectively. Ribavirin was discontinued in 15% of the patients.

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

Patients with renal impairment

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

The safety of Harvoni has been evaluated in a 12-week non-controlled study including 95 patients with ESRD requiring dialysis (Study 4063). In this setting, exposure of sofosbuvir metabolite GS- 331007 is 20-fold increased, exceeding levels where adverse reactions have been observed 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.

Paediatric population

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

Description of selected adverse reactions

Cardiac arrhythmias

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

Skin disorders

Frequency not known: Stevens-Johnson syndrome

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

No specific antidote is available for overdose with Harvoni. If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with Harvoni consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient. Haemodialysis is unlikely to result in significant removal of ledipasvir as ledipasvir is highly bound to plasma protein. Haemodialysis can efficiently remove the predominant circulating metabolite of sofosbuvir, GS-331007, with an extraction ratio of 53%.