Posology : מינונים

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).
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
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).
-
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).
Patients with compensated cirrhosis     Harvoni + ribavirin 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).
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.
Patients with decompensated cirrhosis      Harvoni + ribavirin for 12 weeks (see section 5.1) irrespective of transplant status          - Harvoni (without ribavirin) for 24 weeks may be considered in patients who are ineligible for or intolerant to ribavirin.
Patients with genotype 3 CHC
Patients with compensated cirrhosis      Harvoni+ ribavirin for 24 weeks (see sections 4.4 and and/or prior treatment failure           5.1).
* Includes patients co-infected with human immunodeficiency virus (HIV).

When used in combination with ribavirin, refer also to the Physicians Leaflet 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 Laboratory values           Reduce ribavirin dose to        Discontinue ribavirin if: 600 mg/day if:
Haemoglobin in patients with   < 10 g/dL                       < 8.5 g/dL no cardiac disease
Haemoglobin in patients with   ≥ 2 g/dL decrease in            < 12 g/dL despite 4 weeks at history of stable cardiac      haemoglobin during any          reduced dose disease                        4-week treatment 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).

Missed dose
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.
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).

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. There is no information available regarding the crushing/splitting of the product. Due to the bitter taste, it is recommended that the film-coated tablet is not chewed or crushed (see section 5.2).