Presentation and Status in Health Basket
Film Coated Tablets
Treatment should be initiated and monitored by a physician experienced in the management of patients with CHC.
The recommended dose of this formulation is one tablet once daily with or without food.
Patients with genotype 1, 4, 5 or 6 CHC (* Includes patients co-infected with human immunodeficiency virus (HIV))
Patients without cirrhosis: Harvoni for 12 weeks. Harvoni for 8 weeks may be considered in previously untreated genotype 1-infected patients.
Harvoni + ribavirin for 12 weeks or Harvoni (without ribavirin) for 24 weeks should be considered for previously treated patients with uncertain subsequent retreatment options.
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.
Patients who are post-liver transplant without cirrhosis or with compensated cirrhosis: Harvoni + ribavirin for 12 weeks.
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 + ribavirin for 12 weeks.
Harvoni (without ribavirin) for 24 weeks may be considered in patients who are ineligible for or intolerant to ribavirin.
Patients with genotype 3 CHC (* Includes patients co-infected with human immunodeficiency virus (HIV))
Patients with compensated cirrhosis and/or prior treatment failure: Harvoni + ribavirin for 24 weeks.
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 above), 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 at the attached doctor’s leaflet provides guidelines for dose modifications and discontinuation based on the patient’s haemoglobin concentration and cardiac status.
Ribavirin dose modification guideline for co-administration with Harvoni
Reduce ribavirin dose to 600 mg/day if Haemoglobin in patients with no cardiac disease < 10 g/dL. Discontinue ribavirin if < 8.5 g/dL.
Reduce ribavirin dose to 600 mg/day if Haemoglobin in patients with history
of stable cardiac disease ≥ 2 g/dL decrease in haemoglobin during any 4-week treatment period. Discontinue ribavirin if < 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).
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.
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.
Renal impairment: No dose adjustment of the drug 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.
Hepatic impairment: No dose adjustment of the drug is required for patients with mild, moderate or severe hepatic impairment (Child-Pugh-Turcotte [CPT] class A, B or C). Safety and efficacy of ledipasvir/sofosbuvir have been established in patients with decompensated cirrhosis.
Paediatric population: The safety and efficacy of the drug 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.
Treatment of chronic hepatitis C (CHC) genotype 1, 3 and 4 infection in adults.
Hypersensitivity to active ingredients.
Co‑administration with rosuvastatin.
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). Co-administration will significantly decrease ledipasvir and sofosbuvir plasma concentrations and could result in loss of efficacy of Harvoni.
Harvoni should not be administered concomitantly with other medicinal products containing sofosbuvir.
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.
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. 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.
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. Consideration should be given to longer treatment for patients with uncertain subsequent retreatment options.
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.
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).
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.
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.
See prescribing information for full details.
Very common: Headache and fatigue.
See prescribing information for full details.
As this drug contains ledipasvir and sofosbuvir, any interactions that have been identified with these active substances individually may occur with this drug. Potential for this formulation 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 this formulation: Ledipasvir and sofosbuvir are substrates of drug transporter P-gp and BCRP while GS-331007 is not.
Medicinal products that are strong P-gp inducers (carbamazepine, phenobarbital, phenytoin, rifampicin, rifabutin and St. John’s wort) may significantly decrease ledipasvir and sofosbuvir plasma concentrations leading to reduced therapeutic effect of ledipasvir/sofosbuvir and should not be used with this formulation. 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 this agent. Co-administration with such medicinal products is not recommended. 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; This product 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.
Impact of DAA therapy on drugs metabolized by the liver: The pharmacokinetics of drugs that are metabolized by the liver (e.g. immunosuppressive agents such as calcineurin inhibitors) may be impacted by changes in liver function during DAA therapy, related to clearance of HCV virus.
Interactions between this formulation and other medicinal products: Table 3 at the attached doctor’s leaflet 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.
Pregnancy and Lactation
Pregnancy: There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of ledipasvir, sofosbuvir or this drug in pregnant women. As a precautionary measure, it is preferable to avoid the use of Harvoni during pregnancy.
Lactation: It is unknown whether ledipasvir or sofosbuvir and its metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. Therefore, Harvoni should not be used during breast-feeding.
See prescribing information for full details.
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 this drug. If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with this drug 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%.
Lactose: Contains lactose.
Storage: Store below 30°C.
Shelf life after first opening: 45 days.