Harvoni 90 mg/400 mg film-coated tablets

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.

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.

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.

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).

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

* 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.

Table 2: Ribavirin dose modification guideline for co-administration with Harvoni

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).

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

Co-administration with rosuvastatin or St. John's wort (Hypericum perforatum) (see section 4.5).

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 4 are limited (see section 5.1).

The efficacy of ledipasvir/sofosbuvir has not been studied against HCV genotype 2, 5 and 6; therefore, Harvoni should not be used in patients infected with these genotypes.

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 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 relative efficacy of 12 and 24 weeks of therapy has not been established. Therefore, 24 weeks of therapy is recommended (see sections 4.2 and 5.1). Treatment with Harvoni should be guided by an assessment of the potential benefits and risks for the individual patient.

Use with potent P-gp inducers

Medicinal products that are potent P-glycoprotein (P-gp) inducers (e.g. rifampicin, carbamazepine and phenytoin) may significantly decrease ledipasvir and sofosbuvir plasma concentration which may lead to reduced therapeutic effect of Harvoni. Such medicinal products should not be used 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

There are no data on the use of Harvoni in patients with HCV/HBV co-infection.

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.