Sofosbuvir and Ledipasvir interacts in the following cases:
Antacids e.g. aluminium or magnesium hydroxide; calcium carbonate.
It is recommended to separate antacid and Harvoni administration by 4 hours.
H2-receptor antagonists may be administered simultaneously with or staggered from ledipasvir/sofosbuvir at a dose that does not exceed doses comparable to famotidine 40 mg twice daily.
Proton pump inhibitor doses comparable to omeprazole 20 mg can be administered simultaneously with ledipasvir/sofosbuvir. Proton pump inhibitors should not be taken before ledipasvir/sofosbuvir.
Co-administration of ledipasvir/sofosbuvir and HMG-CoA reductase inhibitors (statins) can significantly increase the concentration of the statin, which increases the risk of myopathy and rhabdomyolysis.
Clinical monitoring, looking for signs of bleeding and anaemia, is recommended when dabigatran etexilate is co-administered with ledipasvir/sofosbuvir. A coagulation test helps to identify patients with an increased bleeding risk due to increased dabigatran exposure.
Co-administration of ledipasvir/sofosbuvir with digoxin may increase the concentration of digoxin. Caution is warranted and therapeutic concentration monitoring of digoxin is recommended when co-administered with ledipasvir/sofosbuvir.
Co-administration of ledipasvir/sofosbuvir with oxcarbazepine is expected to decrease the concentration of ledipasvir and sofosbuvir leading to reduced therapeutic effect of ledipasvir/sofosbuvir combination. Such co-administration is not recommended.
Co-administration of ledipasvir/sofosbuvir with pravastatin may significantly increase the concentration of pravastatin which is associated with increased risk of myopathy. Clinical and biochemical control is recommended in these patients and a dose adjustment may be needed.
Co-administration of ledipasvir/sofosbuvir with rifapentine is expected to decrease the concentration of ledipasvir and sofosbuvir, leading to reduced therapeutic effect of ledipasvir/sofosbuvir. Such co-administration is not recommended.
Ledipasvir/sofosbuvir 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 ledipasvir/sofosbuvir and a pharmacokinetic enhancer has not been established. The potential risks and benefits associated with co-administration of ledipasvir/sofosbuvir 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 ledipasvir/sofosbuvir 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.
There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of ledipasvir, sofosbuvir or ledipasvir/sofosbuvir in pregnant women.
Animal studies do not indicate direct harmful effects with respect to reproductive toxicity. No significant effects on foetal development have been observed with ledipasvir or sofosbuvir in rats and rabbits. However, it has not been possible to fully estimate exposure margins achieved for sofosbuvir in the rat relative to the exposure in humans at the recommended clinical dose.
As a precautionary measure, it is preferable to avoid the use of ledipasvir/sofosbuvir during pregnancy.
It is unknown whether ledipasvir or sofosbuvir and its metabolites are excreted in human milk.
Available pharmacokinetic data in animals has shown excretion of ledipasvir and metabolites of sofosbuvir in milk.
A risk to the newborns/infants cannot be excluded. Therefore, ledipasvir/sofosbuvir should not be used during breast-feeding.
When ledipasvir/sofosbuvir is used in combination with ribavirin, extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin. Women of childbearing potential or their male partners must use an effective form of contraception during treatment and for a period of time after the treatment has concluded as recommended in the Summary of Product Characteristics for ribavirin.
No human data on the effect of ledipasvir/sofosbuvir on fertility are available. Animal studies do not indicate harmful effects of ledipasvir or sofosbuvir on fertility.
If ribavirin is co-administered with ledipasvir/sofosbuvir, the contraindications regarding use of ribavirin during pregnancy and breast-feeding apply.
Ledipasvir/sofosbuvir (administered alone or in combination with ribavirin) has no or negligible influence on the ability to drive and use machines. However, patients should be advised that fatigue was more common in patients treated with ledipasvir/sofosbuvir compared to placebo.
The safety assessment of ledipasvir/sofosbuvir was mainly based on pooled Phase 3 clinical studies, without a control, in 1952 patients who received ledipasvir/sofosbuvir for 8, 12 or 24 weeks, including 872 patients who received ledipasvir/sofosbuvir 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.
The following adverse drug reactions have been identified with ledipasvir/sofosbuvir. 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).
| 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 |
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). 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. Although adverse events, including serious adverse events, occurred more frequently in this study compared to studies that excluded decompensated patients and/or patients who were postliver transplantation, the adverse events observed were those expected as clinical sequelae of advanced liver disease and/or transplantation or were consistent with the known safety profile of ribavirin.
Decreases in haemoglobin to <10 g/dL and <8.5 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.
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 ledipasvir/sofosbuvir 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 GS331007 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.
The safety and efficacy of ledipasvir/sofosbuvir 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.
Cases of severe bradycardia and heart block have been observed when ledipasvir/sofosbuvir is used with amiodarone and/or other drugs that lower heart rate.
Frequency not known: Stevens-Johnson syndrome
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