Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Gilead Sciences Ireland UC, Carrigtohill, County Cork, T45 DP77, Ireland
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.
Harvoni treatment should be initiated and monitored by a physician experienced in the management of patients with CHC.
The recommended dose of Harvoni in adults is 90 mg/400 mg once daily with or without food (see section 5.2).
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).
A granule formulation of Harvoni is available for the treatment of chronic HCV-infection in paediatric patients aged 3 years and above having difficulty swallowing film-coated tablets. Please refer to the Summary of Product Characteristics for Harvoni 33.75 mg/150 mg or 45 mg/200 mg granules.
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 3 years of ageand 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 Tablets*:
| Body Weight (kg) | Dosing of Harvoni Tablets | Ledipasvir/Sofosbuvir Daily Dose |
|---|---|---|
| ≥35 | one 90 mg/400 mg tablet once daily or two 45 mg/200 mg tablets once daily | 90 mg/400 mg/day |
| 17 to <35 | one 45 mg/200 mg tablet once daily | 45 mg/200 mg/day |
* Harvoni 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 Harvoni 33.75 mg/150 mg or 45 mg/200 mg granules.
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.
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).
The safety and efficacy of Harvoni in paediatric patients aged <3 years have not been established. No data are available.
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.
No dose adjustment is warranted for elderly patients (see section 5.2).
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/1.73m2) 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).
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).
For oral use.
Patients should be instructed to swallow the tablet(s) whole with or without food. Due to the bitter taste, it is recommended that film-coated tablets are not chewed or crushed (see section 5.2).
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%.
6 years.
This medicinal product does not require any special storage conditions.
Harvoni tablets are supplied in high density polyethylene (HDPE) bottles with a polypropylene child-resistant closure containing 28 film-coated tablets with a silica gel desiccant and polyester coil.
The following pack sizes are available:
Not all pack sizes may be marketed.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
This medicinal product may pose a risk to the environment (see section 5.3).
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