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Harvoni is a brand name for Sofosbuvir. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: 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.
Verbatim from this product's EMA label. Tap a section to expand.
Harvoni treatment should be initiated and monitored by a physician experienced in the management of patients with CHC. 2). 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.
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.
1, ION-3 study). Patients with compensated cirrhosis Harvoni + ribavirinb,c for 12 weeks or Harvoni (without ribavirin) for 24 weeks. 4). 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.
1) - Harvoni (without ribavirin) for 24 weeks may be considered in patients who are ineligible for or intolerant to ribavirin. 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.
1). Patients that weigh < 17 kg are not recommended to take tablets. 75 mg/150 mg or 45 mg/200 mg granules. 4 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.
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).
21 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).
Harvoni should not be administered concomitantly with other medicinal products containing sofosbuvir. 2. 1. 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.
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.
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.
1. 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). 5).
Not medical advice. Always read the patient information leaflet and follow your prescriber or pharmacist.
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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. 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 […]
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. 1 for details of this study). 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). 5).
Skin disorders Frequency not known:
Stevens-Johnson syndrome 22 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 national reporting system listed in Appendix V.
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. 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 7 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. 73 m2) and ESRD requiring haemodialysis. 2). 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. g. oxcarbazepine) may decrease ledipasvir and sofosbuvir plasma concentrations leading to reduced therapeutic effect of Harvoni.
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 […]