ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 1 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. 1. NAME OF THE MEDICINAL PRODUCT Harvoni 90 mg/400 mg film-coated tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each film-coated tablet contains 90 mg ledipasvir and 400 mg sofosbuvir. Excipients with known effect: Each film-coated tablet contains 156.8 mg of lactose (as monohydrate) and 261 micrograms of sunset yellow FCF aluminium lake. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Film-coated tablet. Orange, diamond-shaped, film-coated tablet of dimensions 19 mm x 10 mm, debossed with “GSI” on one side and “7985” on the other side. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Harvoni is indicated for the treatment of chronic hepatitis C (CHC) in adults (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 is one tablet once daily with or without food (see section 5.2). 2 Table 1: Recommended treatment duration for Harvoni and the recommended use of co-administered ribavirin for certain subgroups Patient population* Treatment and duration Patients with genotype 1, 4, 5 or 6 CHC 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 without cirrhosis - Harvoni + ribavirin for 12 weeks or Harvoni (without ribavirin) for 24 weeks should be considered for previously treated patients with uncertain subsequent retreatment options (see section 4.4). Harvoni + ribavirin for 12 weeks or Harvoni (without ribavirin) for 24 weeks. Patients with compensated cirrhosis - 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). Harvoni + ribavirin for 12 weeks (see section 5.1). Patients who are post-liver transplant - Harvoni (without ribavirin) for 12 weeks (in patients without cirrhosis or with compensated without cirrhosis) or 24 weeks (in patients with cirrhosis) cirrhosis may be considered for patients who are ineligible for or intolerant to ribavirin. Harvoni + ribavirin for 12 weeks (see section 5.1). Patients with decompensated cirrhosis, - Harvoni (without ribavirin) for 24 weeks may be irrespective of transplant status considered in patients who are ineligible for or intolerant to ribavirin. Patients with genotype 3 CHC Patients with compensated cirrhosis and/or Harvoni + ribavirin for 24 weeks (see sections 4.4 and 5.1). prior treatment failure * Includes patients co-infected with human immunodeficiency virus (HIV). When used in combination with ribavirin, refer also to the Summary of Product Characteristics of ribavirin. In patients without decompensated cirrhosis requiring the addition of ribavirin to their treatment regimen (see Table 1), the daily dose of ribavirin is weight based (< 75 kg = 1,000 mg and ≥ 75 kg = 1,200 mg) and administered orally in two divided doses with food. In patients with decompensated cirrhosis, ribavirin should be administered at a starting dose of 600 mg given in a divided daily dose. If the starting dose 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 is not well-tolerated, the dose should be reduced as clinically indicated based on haemoglobin levels. Dose modification of ribavirin in patients 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 2 provides guidelines for dose modifications and discontinuation based on the patient’s haemoglobin concentration and cardiac status. 3 Table 2: Ribavirin dose modification guideline for co-administration with Harvoni Laboratory values Reduce ribavirin dose to Discontinue ribavirin if: 600 mg/day if: Haemoglobin in patients with no < 10 g/dL < 8.5 g/dL cardiac disease Haemoglobin in patients with history ≥ 2 g/dL decrease in haemoglobin < 12 g/dL despite 4 weeks at of stable cardiac disease during any 4-week treatment reduced dose period 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). Patients should be instructed that if vomiting occurs within 5 hours of dosing an additional tablet 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 tablet 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. The safety of ledipasvir/sofosbuvir has not been assessed in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m2) or end stage renal disease (ESRD) requiring haemodialysis (see section 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). Paediatric population The safety and efficacy of Harvoni in children and adolescents aged less than 18 years have not yet been established. No data are available. Method of administration For oral use. Patients should be instructed to swallow the tablet whole with or without food. Due to the bitter taste, it is recommended that the film-coated tablet is not chewed or crushed (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 potent P-gp inducers Medicinal products that are potent P-glycoprotein (P-gp) inducers in the intestine (rifampicin, rifabutin, St. John’s wort [Hypericum perforatum], carbamazepine, phenobarbital and phenytoin). Co-administration will significantly decrease ledipasvir and sofosbuvir plasma concentrations and could result in loss of efficacy of Harvoni (see section 4.5). 4 4.4 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 patients 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). The clinical data to support the use of Harvoni in patients infected with HCV genotype 2 and 6 are limited (see section 5.1). Severe bradycardia and heart block Cases of severe bradycardia and heart block have been observed when Harvoni is used with concomitant amiodarone with or without other drugs that lower heart rate. The mechanism is not established. The concomitant use of amiodarone was limited through the clinical development of sofosbuvir plus direct-acting antivirals (DAAs). Cases are potentially life threatening, therefore 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 are closely monitored when initiating Harvoni. Patients who are identified as being high risk of bradyarrhythmia should be continuously monitored for 48 hours in an appropriate clinical setting. Due to the long half-life of amiodarone, appropriate monitoring 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 receiving Harvoni in combination with amiodarone with or without other drugs that lower heart rate should also be warned of the symptoms of bradycardia and heart block and should be advised to seek medical advice urgently should they experience them. 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 drug classes for clearance of HCV infection. Consequently, consideration should be given to longer treatment for patients with uncertain subsequent retreatment options. Renal impairment No dose adjustment of Harvoni is required for patients with mild or moderate renal impairment. The safety of Harvoni has not been assessed in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m2) or end stage renal disease (ESRD) requiring haemodialysis. When Harvoni is used in combination with ribavirin refer also to the Summary of 5 Product Characteristics for ribavirin for patients with creatinine clearance (CrCl) < 50 mL/min (see section 5.2). Patients 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). 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. Paediatric population Harvoni is not recommended for use in children and adolescents under 18 years of age because the safety and efficacy have not been established in this population. Excipients Harvoni contains the azo colouring agent sunset yellow FCF aluminium lake (E110), which may cause allergic reactions. It also contains lactose. Consequently, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product. 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. 6 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. In vitro data indicate that ledipasvir may be a weak inducer of metabolising enzymes such as CYP3A4, CYP2C and UGT1A1. Compounds that are substrates of these enzymes may have decreased plasma concentrations when co-administered with ledipasvir/sofosbuvir. In vitro ledipasvir inhibits intestinal CYP3A4 and UGT1A1. Medicinal products that have a narrow therapeutic range and which are metabolised by these isoenzymes should be used with caution and carefully monitored. 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 potent P-gp inducers (rifampicin, rifabutin, St. John’s wort, carbamazepine, phenobarbital and phenytoin) 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. Interactions between Harvoni and other medicinal products Table 3 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 3: Interactions between Harvoni and other medicinal products Medicinal product by Effects on medicinal Recommendation concerning co-administration therapeutic areas product levels. with Harvoni Mean ratio (90% confidence interval) for AUC, C , C a, b max min 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 Interaction not studied. It is recommended to separate antacid and Harvoni magnesium hydroxide; Expected: administration by 4 hours. calcium carbonate ↓ Ledipasvir ↔ Sofosbuvir ↔ GS-331007 (Increase in gastric pH) 7 Medicinal product by Effects on medicinal Recommendation concerning co-administration therapeutic areas product levels. with Harvoni Mean ratio (90% confidence interval) for AUC, C , C a, b max min H -receptor antagonists 2 Famotidine Ledipasvir H -receptor antagonists may be administered 2 (40 mg single dose)/ ↓ C 0.80 (0.69, 0.93) simultaneously with or staggered from Harvoni at a max ledipasvir (90 mg single ↔ AUC 0.89 (0.76, 1.06) dose that does not exceed doses comparable to dose)c/ sofosbuvir (400 mg famotidine 40 mg twice daily. single dose)c, d Sofosbuvir ↑ C 1.15 (0.88, 1.50) max Famotidine dosed ↔ AUC 1.11 (1.00, 1.24) simultaneously with Harvonid GS-331007 ↔ C 1.06 (0.97, 1.14) max ↔ AUC 1.06 (1.02, 1.11) Cimetidinee Nizatidinee (Increase in gastric pH) Ranitidinee Famotidine Ledipasvir (40 mg single dose)/ ↓ C 0.83 (0.69, 1.00) max ledipasvir (90 mg single ↔ AUC 0.98 (0.80, 1.20) dose)c/ sofosbuvir (400 mg single dose)c, d Sofosbuvir ↔ C 1.00 (0.76, 1.32) max Famotidine dosed 12 hours ↔ AUC 0.95 (0.82, 1.10) prior to Harvonid GS-331007 ↔ C 1.13 (1.07, 1.20) max ↔ AUC 1.06 (1.01, 1.12) (Increase in gastric pH) Proton pump inhibitors Omeprazole Ledipasvir Proton pump inhibitor doses comparable to (20 mg once daily)/ ↓ C 0.89 (0.61, 1.30) omeprazole 20 mg can be administered max ledipasvir (90 mg single ↓ AUC 0.96 (0.66, 1.39) simultaneously with Harvoni. Proton pump dose)c/ sofosbuvir (400 mg inhibitors should not be taken before Harvoni. single dose)c Sofosbuvir ↔ C 1.12 (0.88, 1.42) max Omeprazole dosed ↔ AUC 1.00 (0.80, 1.25) simultaneously with Harvoni GS-331007 ↔ C 1.14 (1.01, 1.29) max Lansoprazolee ↔ AUC 1.03 (0.96, 1.12) Rabeprazolee Pantoprazolee (Increase in gastric pH) Esomeprazolee ANTIARRHYTHMICS Amiodarone Interaction not studied. 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. Co-administration of Harvoni with digoxin may Expected: increase the concentration of digoxin. Caution is ↑ Digoxin warranted and therapeutic concentration monitoring ↔ Ledipasvir of digoxin is recommended when co-administered ↔ Sofosbuvir with Harvoni. ↔ GS-331007 (Inhibition of P-gp) 8 Medicinal product by Effects on medicinal Recommendation concerning co-administration therapeutic areas product levels. with Harvoni Mean ratio (90% confidence interval) for AUC, C , C a, b max min ANTICOAGULANTS Dabigatran etexilate Interaction not studied. Clinical monitoring, looking for signs of bleeding Expected: and anaemia, is recommended when dabigatran ↑ Dabigatran etexilate is co-administered with Harvoni. A ↔ Ledipasvir coagulation test helps to identify patients with an ↔ Sofosbuvir increased bleeding risk due to increased dabigatran ↔ GS-331007 exposure. (Inhibition of P-gp) Vitamin K antagonists Interaction not studied Close monitoring of INR is recommended with all vitamin K antagonists. This is due to liver function changes during treatment with Harvoni. ANTICONVULSANTS Carbamazepine Interaction not studied. Harvoni is contraindicated with carbamazepine, Phenobarbital Expected: phenobarbital and phenytoin, potent intestinal Phenytoin ↓ Ledipasvir P-gp inducers (see section 4.3). ↓ Sofosbuvir ↔ GS-331007 (Induction of P-gp) Oxcarbazepine Interaction not studied. Co-administration of Harvoni with oxcarbazepine is Expected: expected to decrease the concentration of ledipasvir ↓ Ledipasvir and sofosbuvir leading to reduced therapeutic effect ↓ Sofosbuvir of Harvoni. Such co-administration is not ↔ GS-331007 recommended (see section 4.4). (Induction of P-gp) ANTIMYCOBACTERIALS Rifampicin (600 mg once Interaction not studied. Harvoni is contraindicated with rifampicin, a potent daily)/ ledipasvir (90 mg Expected: intestinal P-gp inducer (see section 4.3). single dose)d Rifampicin ↔ C max ↔ AUC ↔ C min Observed: Ledipasvir ↓ C 0.65 (0.56, 0.76) max ↓ AUC 0.41 (0.36, 0.48) (Induction of P-gp) 9 Medicinal product by Effects on medicinal Recommendation concerning co-administration therapeutic areas product levels. with Harvoni Mean ratio (90% confidence interval) for AUC, C , C a, b max min Rifampicin (600 mg once Interaction not studied. daily)/ sofosbuvir (400 mg Expected: single dose)d Rifampicin ↔ C max ↔ AUC ↔ C min Observed: Sofosbuvir ↓ C 0.23 (0.19, 0.29) max ↓ AUC 0.28 (0.24, 0.32) GS-331007 ↔ C 1.23 (1.14, 1.34) max ↔ AUC 0.95 (0.88, 1.03) (Induction of P-gp) Rifabutin Interaction not studied. Harvoni is contraindicated with rifabutin, a potent Rifapentine Expected: intestinal P-gp inducer (see section 4.3). ↓ Ledipasvir ↓ Sofosbuvir Co-administration of Harvoni with rifapentine is ↔ GS-331007 expected to decrease the concentration of ledipasvir and sofosbuvir, leading to reduced therapeutic effect (Induction of P-gp) of Harvoni. Such co-administration is not recommended. HCV PRODUCTS Simeprevir (150 mg once Simeprevir Concentrations of ledipasvir, sofosbuvir and daily)/ ledipasvir (30 mg ↑ C 2.61 (2.39, 2.86) simeprevir are increased when simeprevir is max once daily) ↑ AUC 2.69 (2.44, 2.96) co-administered with Harvoni. Co-administration is not recommended. Ledipasvir ↑ C 1.81 (1.69, 2.94) max ↑ AUC 1.92 (1.77, 2.07) Simeprevirh Simeprevir ↔ C 0.96 (0.71, 1.30) max ↔ AUC 0.94 (0.67, 1.33) Sofosbuvir ↑ C 1.91 (1.26, 2.90) max ↑ AUC 3.16 (2.25, 4.44) GS-331007 ↓ C 0.69 (0.52, 0.93) max ↔ AUC 1.09 (0.87, 1.37) 10