Sofosbuvir

The safety and appropriate dose of sofosbuvir have not been established 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.

Close monitoring of INR is recommended with all vitamin K antagonists. This is due to liver function changes during treatment with sofosbuvir.

Cases of severe bradycardia and heart block have been observed when sofosbuvir-containing regimens are used in combination with amiodarone with or without other medicinal products that lower heart rate. The mechanism is not established.

The concomitant use of amiodarone was limited through the clinical development of sofosbuvir. Cases are potentially life threatening, therefore amiodarone should only be used in patients on sofosbuvir when other alternative anti-arrhythmic treatments are not tolerated or are contraindicated. Patients also taking beta blockers, or those with underlying cardiac comorbidities and/or advanced liver disease may be at increased risk for symptomatic bradycardia with coadministration of amiodarone.

Should concomitant use of amiodarone be considered necessary it is recommended that patients are closely monitored when initiating sofosbuvir. Patients who are identified as being at high risk of bradyarrhythmia should be continuously monitored for 48 hours in an appropriate clinical setting.

Due to the long half-life of amiodarone, appropriate monitoring should also be carried out for patients who have discontinued amiodarone within the past few months and are to be initiated on sofosbuvir.

All patients receiving sofosbuvir in combination with amiodarone with or without other medicinal products that lower heart rate should also be warned of the symptoms of bradycardia and heart block and should be advised to seek medical advice urgently should they experience them.

No dose adjustment of sofosbuvir or ciclosporin is required at initiation of co-administration. Afterwards, close monitoring and potential dose adjustment of ciclosporin may be required.

Co-administration of sofosbuvir with modafinil is expected to decrease the concentration of sofosbuvir, leading to reduced therapeutic effect of sofosbuvir. Such co-administration is not recommended.

Co-administration of sofosbuvir with oxcarbazepine is expected to decrease the concentration of sofosbuvir, leading to reduced therapeutic effect of sofosbuvir. Such co-administration is not recommended.

Co-administration of sofosbuvir with rifapentine is expected to decrease the concentration of sofosbuvir, leading to reduced therapeutic effect of sofosbuvir. Such co-administration is not recommended.

No dose adjustment of sofosbuvir or tacrolimus is required at initiation of co-administration. Afterwards, close monitoring and potential dose adjustment of tacrolimus may be required.

HBV/HCV co-infected patients are at risk of HBV reactivation, and should therefore be monitored and managed according to current clinical guidelines.

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.

Sofosbuvir in combination with ribavirin is recommended for 24 weeks in liver transplant recipients. A starting ribavirin dose of 400 mg administered orally in two divided doses with food is recommended. If the starting dose of ribavirin 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 of ribavirin is not well-tolerated, the dose should be reduced as clinically indicated based on haemoglobin levels.

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of sofosbuvir in pregnant women.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. No effects on foetal development have been observed in rats and rabbits at the highest doses tested. 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 sofosbuvir during pregnancy. However, if ribavirin is co-administered with sofosbuvir, the contraindications regarding use of ribavirin during pregnancy apply.

It is unknown whether sofosbuvir and its metabolites are excreted in human milk. Available pharmacokinetic data in animals have shown excretion of metabolites in milk. A risk to newborns/infants cannot be excluded. Therefore, sofosbuvir should not be used during breast-feeding.

Women of childbearing potential/contraception in males and females

When sofosbuvir is used in combination with ribavirin or peginterferon alfa/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.

Fertility

No human data on the effect of sofosbuvir on fertility are available. Animal studies do not indicate harmful effects on fertility.

Sofosbuvir has moderate influence on the ability to drive and use machines. Patients should be informed that fatigue and disturbance in attention, dizziness and blurred vision have been reported during treatment with sofosbuvir in combination with peginterferon alfa and ribavirin.

Summary of the safety profile in adults

Assessment of adverse reactions is based on pooled data from five Phase 3 clinical studies (both controlled and uncontrolled).

Sofosbuvir has been studied in combination with ribavirin, with or without peginterferon alfa. In this context, no adverse drug reactions specific to sofosbuvir have been identified. The most common adverse drug reactions occurring in patients receiving sofosbuvir and ribavirin or sofosbuvir, ribavirin and peginterferon alfa were fatigue, headache, nausea and insomnia.

Tabulated summary of adverse reactions

The following adverse drug reactions have been identified with sofosbuvir in combination with ribavirin or in combination with peginterferon alfa and ribavirin (table). 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).

Adverse drug reactions identified with sofosbuvir in combination with ribavirin or peginterferon alfa and ribavirin:

^a SOF = sofosbuvir
^b RBV = ribavirin
^c PEG = peginterferon alfa
^d Decreased appetite was identified as an adverse drug reaction to sofosbuvir in combination with ribavirin oral solution in paediatric patients aged 3 to <12 years

Description of selected adverse reactions

Cardiac arrhythmias

Cases of severe bradycardia and heart block have been observed when sofosbuvir containing-regimes are used in combination with amiodarone and/or other medicinal products that lower heart rate.

Skin disorders

Frequency not known: Stevens-Johnson syndrome

Other special population(s)

HIV/HCV co-infection

The safety profile of sofosbuvir and ribavirin in HCV/HIV co-infected adult patients was similar to that observed in mono-infected HCV patients treated with sofosbuvir and ribavirin in Phase 3 clinical studies.

Patients awaiting liver transplantation

The safety profile of sofosbuvir and ribavirin in HCV infected adult patients prior to liver transplantation was similar to that observed in patients treated with sofosbuvir and ribavirin in Phase 3 clinical studies.

Patients with Renal Impairment

Sofosbuvir in a fixed dose combination with ledipasvir was administered for 12 weeks to 18 patients with genotype 1 CHC and severe renal impairment in an open-label study (Study 0154). The safety of sofosbuvir in a fixed dose combination with either ledipasvir or velpatasvir has been studied in 154 patients with ESRD requiring dialysis (Study 4062 and 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.

Adult liver transplant recipients

The safety profile of sofosbuvir and ribavirin in liver transplant adult recipients with chronic hepatitis C was similar to that observed in patients treated with sofosbuvir and ribavirin in Phase 3 clinical studies. In study 0126, decreases in haemoglobin during treatment were very common with 32.5% (13/40 patients) experiencing a decline in haemoglobin to <10 g/dL, 1 of whom also had a decline to <8.5 g/dL. Eight patients (20%) received epoetin and/or a blood product. In 5 patients (12.5%), study drugs were discontinued, modified or interrupted due to adverse events.

Paediatric population

The safety and efficacy of sofosbuvir in paediatric patients aged 3 years and above are based on data from 106 patients who were treated with sofosbuvir and ribavirin for 12 weeks (genotype 2 patients) and for 24 weeks (genotype 3 patients) in a Phase 2, open-label clinical trial. No adverse drug reactions specific to sofosbuvir have been identified. The adverse reactions observed were generally consistent with those observed in clinical studies of sofosbuvir plus ribavirin in adults (see table). Decreased appetite was observed as a very common adverse drug reaction to sofosbuvir when given in combination with ribavirin oral solution in paediatric patients aged 3 to <12 years.