Sofosbuvir/ Ledipasvir

Registered South African indications:

• Treatment of chronic hepatitis C (CHC) in adults and in adolescents aged 12 to <18 years

Registered South African contraindications

• Hypersensitivity to the active substances or to any of the excipients
• Pregnancy with or without ribavirin
• Lactation with or without ribavirin
• Concomitant use of sofosbuvir/ ledipasvir and amiodarone (in patients with or without symptomatic bradydysrhythmias or patients with or without treatment with beta-adrenergic blockers)
• Co-administration with rosuvastatin
• Concomitant use with potent P-gp inducers (e.g., rifampicin, rifabutin, St. John's wort [Hypericum perforatum], carbamazepine, phenobarbital, and phenytoin) as this will significantly decrease ledipasvir and sofosbuvir plasma concentrations and could result in loss of efficacy of sofosbuvir/ ledipasvir

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The medical practitioner should consult the professional information of ribavirin for further contraindications

Contraindications registered in other jurisdictions

• Hypersensitivity to the active substances or to any of the excipients
• 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 sofosbuvir/ ledipasvir

South African recommendations

Co-administration with sofosbuvir-containing medicines

• Sofosbuvir/ ledipasvir should not be administered concomitantly with other medicines containing sofosbuvir

Symptomatic bradycardia with amiodarone

• Post-marketing cases of symptomatic bradycardia, including fatal cardiac arrest and cases requiring pacemaker intervention, have been reported when amiodarone is co-administered with sofosbuvir/ ledipasvir
• Bradycardia generally occurs within hours to days, but cases have been observed up to 2 weeks after starting HCV treatment
• Patients taking beta-blockers, or those with underlying cardiac comorbidities and/or advanced liver disease, may be at increased risk
• Bradycardia generally resolves after discontinuation of HCV treatment. The mechanism for this effect is unknown
• Co-administration of amiodarone with sofosbuvir/ ledipasvir is contraindicated
• Should only be used in patients on sofosbuvir/ ledipasvir if no safer appropriate alternative is available, or if the alternative has failed or cannot be tolerated
• Counsel patients about the risk of symptomatic bradycardia. Cardiac monitoring for the first 48 hours of co-administration. Outpatient or self-monitoring of the heart rate daily for at least the first 2 weeks of treatment
• Similar cardiac monitoring if amiodarone therapy is initiated during sofosbuvir/ ledipasvir treatment. Patients discontinuing amiodarone just prior to starting sofosbuvir/ ledipasvir should also undergo similar cardiac monitoring
• Patients should seek medical evaluation immediately if they develop signs or symptoms of bradycardia such as near-fainting, dizziness, malaise, weakness, excessive tiredness, shortness of breath, chest pains, confusion, or memory problems

Hepatitis B virus reactivation

• Cases of hepatitis B virus (HBV) reactivation have been reported during treatment with HCV direct-acting antivirals, including sofosbuvir-containing regimens
• Reactivation may result in fulminant hepatitis, hepatic failure, and death
• HBV screening by measuring hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) should be performed in all patients before initiation of treatment with sofosbuvir/ ledipasvir
• HCV/HBV co-infected patients are at risk of HBV reactivation and should therefore be monitored and managed according to current clinical guidelines

Co-administration with other direct-acting antivirals against HCV

• In patients who fail treatment with sofosbuvir/ ledipasvir, selection of NS5A resistance mutations that substantially reduce the susceptibility to ledipasvir is seen in most cases. Limited data indicate that such NS5A mutations do not revert on long-term follow-up

Use with moderate P-gp inducers

• Medicines 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 sofosbuvir/ ledipasvir. Co-administration of such medicines is not recommended with sofosbuvir/ ledipasvir

Patients with decompensated cirrhosis and/or awaiting or post-liver transplant

• The efficacy of sofosbuvir/ ledipasvir 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

Use with HIV antiretroviral regimens

• Sofosbuvir/ ledipasvir 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 sofosbuvir/ ledipasvir and a pharmacokinetic enhancer has not been established
• The potential risks and benefits associated with co-administration of sofosbuvir/ ledipasvir 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 sofosbuvir/ ledipasvir concomitantly with these medications should be monitored for tenofovir-associated adverse reactions
• Refer to the Professional Information (PIs) for tenofovir disoproxil fumarate, emtricitabine/tenofovir disoproxil fumarate, or elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate for recommendations on renal monitoring

Use with HMG-CoA reductase inhibitors

• Co-administration of sofosbuvir/ ledipasvir and HMG-CoA reductase inhibitors (statins) can significantly increase the concentration of the statin
• This increase can lead to a higher risk of myopathy and rhabdomyolysis

Use in diabetic patients

• Diabetics may experience improved glucose control, potentially resulting in symptomatic hypoglycaemia, after initiating HCV direct-acting antiviral treatment such as with  sofosbuvir/ ledipasvir
• Glucose levels of diabetic patients initiating direct-acting antiviral therapy should be closely monitored, particularly within the first 3 months
• Diabetic medications may need to be adjusted as necessary
• The medical practitioner in charge of the diabetic care of the patient should be informed when direct-acting antiviral therapy is initiated

Lactose content

• Sofosbuvir/ ledipasvir contains lactose
• Patients with rare hereditary conditions such as galactose intolerance (e.g., galactosaemia), Lapp lactose deficiency, glucose-galactose malabsorption, or fructose intolerance should not take sofosbuvir/ ledipasvir

Ability to drive and use machines

• Sofosbuvir/ ledipasvir may affect the ability to drive and use machines
• Patients should not drive or use machines until they know how sofosbuvir/ ledipasvir affects them. Headache, fatigue, and other side effects may impair the patient’s ability to drive or use machines

Recommendations in other jurisdictions

Caution in the following patient groups

• Pregnancy
• Breastfeeding

Severe renal impairment

• Limited safety data in patients with severe renal impairment (eGFR <30ml/min/1.73m²) and ESRD requiring haemodialysis
• Sofosbuvir/ ledipasvir can be used in these patients with no dose adjustment if no other relevant treatment options are available
• Refer to the product information for ribavirin for patients with CrCl <50ml/min when used in combination

Concomitant use with other sofosbuvir products

• Sofosbuvir/ ledipasvir should not be administered with other medicinal products containing sofosbuvir

Genotype-specific activity

• Clinical data supporting the use of sofosbuvir/ ledipasvir in adults infected with HCV genotype 3 are limited
• A 24-week conservative therapy is advised for all treatment-experienced genotype 3 patients and those treatment-naïve genotype 3 patients with cirrhosis
• In genotype 3-infection, sofosbuvir/ ledipasvir (always with ribavirin) should only be considered for high-risk patients with no alternative treatment options
• Limited clinical data support the use of sofosbuvir/ ledipasvir in adults infected with HCV genotype 2 and 6

Severe bradycardia and heart block

• Life-threatening severe bradycardia and heart block have been observed with sofosbuvir-containing regimens combined with amiodarone
• Amiodarone should only be used with sofosbuvir/ ledipasvir if other anti-arrhythmic treatments are not tolerated or are contraindicated
• If concomitant use is necessary, in-patient cardiac monitoring is recommended for the first 48 hours, followed by outpatient or self-monitoring of heart rate for at least the first 2 weeks
• Cardiac monitoring should also be carried out for patients who discontinued amiodarone within the past few months and are to be initiated on sofosbuvir/ ledipasvir
• Patients should be warned of symptoms of bradycardia and heart block and advised to seek urgent medical advice if they experience these symptoms

Use in diabetic patients

• Diabetic patients may experience improved glucose control, potentially leading to symptomatic hypoglycaemia, after initiating HCV direct-acting antiviral treatment
• Glucose levels should be closely monitored, particularly within the first 3 months, and diabetic medication should be adjusted as necessary
• The physician managing the patient’s diabetic care should be informed when direct-acting antiviral therapy is initiated

HCV/HBV co-infection

• Cases of HBV reactivation, some fatal, have been reported during or after treatment with direct-acting antiviral agents
• HBV screening should be performed before initiating treatment
• Monitor and manage HBV/HCV co-infected patients according to current clinical guidelines

Treatment of patients with prior exposure to HCV direct-acting antivirals

• Selection of NS5A resistance mutations is common in patients who fail treatment with ledipasvir/sofosbuvir
• Limited data indicate these mutations do not revert on long-term follow-up
• No data support the effectiveness of retreatment with an NS5A inhibitor or NS3/4A protease inhibitors in patients who previously failed therapy
• Consider longer treatment for patients with uncertain subsequent retreatment options

Adults with decompensated cirrhosis and/or awaiting liver transplant or post-liver transplant

• Efficacy of ledipasvir/sofosbuvir in genotype 5 and genotype 6 HCV-infected patients with decompensated cirrhosis has not been investigated
• Treatment should be guided by an assessment of potential benefits and risks for the individual patient

Use with moderate P-gp inducers

• Medicinal products that are moderate P-gp inducers (e.g. oxcarbazepine) may decrease ledipasvir and sofosbuvir plasma concentrations, reducing the therapeutic effect
• Co-administration is not recommended

Use with certain HIV antiretroviral regimens

• Sofosbuvir/ ledipasvir increases tenofovir exposure, especially with tenofovir disoproxil fumarate and a pharmacokinetic enhancer (ritonavir or cobicistat)
• Safety of tenofovir disoproxil fumarate with sofosbuvir/ ledipasvir and a pharmacokinetic enhancer has not been established
• Weigh potential risks and benefits, particularly in patients at increased risk of renal dysfunction
• Monitor for tenofovir-associated adverse reactions

Use with HMG-CoA reductase inhibitors

• Co-administration can significantly increase statin concentration, raising the risk of myopathy and rhabdomyolysis

Excipient cautions

• Sofosbuvir/ ledipasvir contains the azo colouring agent sunset yellow FCF (E110), which may cause allergic reactions
• Sofosbuvir/ ledipasvir contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product
• This medicine contains less than 1 mmol sodium (23mg) per tablet, essentially making it 'sodium-free'

Ability to drive and use machines

• Sofosbuvir/ ledipasvir (administered alone or in combination with ribavirin) has no or negligible influence on the ability to drive and use machines
• Patients should be advised that fatigue was more common in patients treated with ledipasvir/sofosbuvir compared to placebo

Forms avail. in SA and covered in this monograph: fct

South African registered indications and dosages

Sofosbuvir/ ledipasvir treatment should be initiated and monitored by a medical practitioner experienced in the management of patients with CHC

Treatment of chronic hepatitis C (CHC)

Sofosbuvir/Ledipasvir
400/90 (mg)

• Oral (fct): 1 tab, daily with or without food

The table below provides the recommended treatment durations for treatment-naïve and treatment-experienced patients infected with genotype 1, 3, 4, 5, or 6 CHC, with and without cirrhosis

Patient population (including HIV co-infected patients)	Treatment and duration
Adult with genotype 1, 4, 5 or 6 CHC
Patients without cirrhosis	Sofosbuvir/ ledipasvir for 12 weeks - Sofosbuvir/ ledipasvir for 8 weeks may be considered in previously untreated genotype 1-infected patients
Patients with compensated cirrhosis	Sofosbuvir/ ledipasvir + ribavirinA for 12 weeks or sofosbuvir/ ledipasvir (without ribavirin) for 24 weeks - Sofosbuvir/ ledipasvir (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	Sofosbuvir/ ledipasvir + ribavirinA for 12 weeks - Sofosbuvir/ ledipasvir (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	Sofosbuvir/ ledipasvir + ribavirinB for 12 weeks - Sofosbuvir/ ledipasvir (without ribavirin) for 24 weeks may be considered in patients who are ineligible for or intolerant to ribavirin
Adult with genotype 3 CHC
Patients with compensated cirrhosis and/or prior treatment failure	Sofosbuvir/ ledipasvir + ribavirinA for 24 weeks

^A Adults: weight based ribavirin (<75 kg = 1000mg and ≥ 75 kg = 1200mg), administered orally in two divided doses with food. Adolescents: for ribavirin dosing recommendations, see Additional Prescribing Points
^B For ribavirin dosing recommendations in patients with decompensated cirrhosis, see Additional Prescribing Points

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When ribavirin is added to sofosbuvir/ ledipasvir, refer also to the professional information for human medicines of ribavirin

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The film-coated tablet is for oral use. Patients should be instructed to swallow the tablet whole. The film-coated tablet should not be chewed or crushed, due to the bitter taste of the active substance

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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

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Missed doses
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

Forms avail. in SA and covered in this monograph: fct

South African registered indications and dosages

Treatment of chronic hepatitis C (CHC)

Sofosbuvir/Ledipasvir
400/90 (mg)

Younger than 12 years

• Not established for use

12 years and older

• See adult dosage

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The safety and efficacy of sofosbuvir/ ledipasvir in paediatric patients aged <12 years have not yet been established. No data on paediatric patients aged <12 years are available

Pregnancy

South African recommendations

• Contraindicated
• Sofosbuvir/ ledipasvir should not be used during pregnancy
• There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of ledipasvir, sofosbuvir or sofosbuvir/ ledipasvir 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

Women of childbearing potential/ contraception in males and females

• Sofosbuvir/ ledipasvir in combination with ribavirin must not be used in pregnancy
• When sofosbuvir/ ledipasvir 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 6 months after the treatment has concluded as recommended in the professional information for ribavirin
• Refer to the product information for ribavirin for additional information

Recommendations in other jurisdictions

• Caution; not recommended
• There are no or limited data (less than 300 pregnancy outcomes) from the use of ledipasvir, sofosbuvir, or sofosbuvir/ ledipasvir 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
• It has not been possible to fully estimate exposure margins achieved for sofosbuvir in rats relative to the exposure in humans at the recommended clinical dose
• As a precautionary measure, it is preferable to avoid the use of sofosbuvir/ ledipasvir during pregnancy

Women of childbearing potential/ contraception in males and females

• When sofosbuvir/ ledipasvir 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 product information for ribavirin
• Refer to the product information for ribavirin for additional information

Breastfeeding

South African recommendations

• Contraindicated
• It is unknown whether ledipasvir, sofosbuvir, or its metabolites are excreted in human milk
• Available pharmacokinetic data in animals have shown excretion of ledipasvir and metabolites of sofosbuvir in milk
• A risk to newborns/infants cannot be excluded
• Therefore, women receiving treatment with sofosbuvir/ ledipasvir should not breastfeed their babies

Recommendations in other jurisdictions

• Caution; not recommended
• It is unknown whether ledipasvir, sofosbuvir, or its metabolites are excreted in human milk
• Available pharmacokinetic data in animals have shown excretion of ledipasvir and metabolites of sofosbuvir in milk
• A risk to newborns/infants cannot be excluded
• Therefore, women receiving treatment with sofosbuvir/ ledipasvir should not breastfeed their babies

Fertility

Recommendations below are applicable to South Africa and other jurisdictions

• No human data on the effect of sofosbuvir/ ledipasvir on fertility are available
• Animal studies do not indicate harmful effects of ledipasvir or sofosbuvir on fertility
• If ribavirin is co-administered with sofosbuvir/ ledipasvir, the contraindications regarding use of ribavirin during pregnancy and breastfeeding apply (see also the product specific information for ribavirin)

South African recommendations

• No dose adjustment recommended
• No dose adjustment of sofosbuvir/ ledipasvir is required for patients with renal impairment, including end stage renal disease (ESRD) requiring dialysis

Recommendations in other jurisdictions

• Mild to moderate: No dose adjustment recommended
• Severe: Caution; no dose adjustment recommended
  Safety data are limited in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] <30ml/min/1.73 m²) and end stage renal disease (ESRD) requiring dialysis
  Sofosbuvir/ ledipasvir can be used in these patients with no dose adjustment when no other relevant treatment options are available

Recommendations below are applicable to South Africa and other jurisdictions

• No dose adjustment recommended
  No dose adjustment of sofosbuvir/ ledipasvir is required for patients with mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B or C)
  Safety and efficacy of sofosbuvir/ ledipasvir have been established in adult patients with decompensated cirrhosis

Recommendations below are applicable to South Africa and other jurisdictions

• No dose adjustment recommended

Nervous System Disorders

Very common

• Headache

Skin and Subcutaneous Tissue Disorders

Common

• Rash

Not known

• Angioedema

General Disorders

Very common

• Fatigue

Description of selected adverse reactions

Cardiac Disorders

• Cardiac arrhythmias
  - Cases of severe bradycardia and heart block have been observed when sofosbuvir/ ledipasvir is used with amiodarone and/or other drugs that lower heart rate

Skin Disorders

Frequency not known

• Stevens-Johnson syndrome

Blood Disorders

• Decreases in haemoglobin to <10g/dL and <8.5g/dL
  - Was experienced during treatment by 39% and 13% of patients treated with ledipasvir/sofosbuvir with ribavirin, respectively in adults with decompensated cirrhosis and/or who are awaiting liver transplant or post-liver transplant

• P-gp substrates
• Breast cancer resistance protein (BCRP) substrates
• Strong P-gp inducers
• Carbamazepine
• Moderate P-gp inducers
• Oxcarbazepine
• Vitamin K antagonists
• Immunosuppressive agents
• Calcineurin inhibitors
• Antacids
• Aluminium hydroxide
• Magnesium hydroxide
• Calcium carbonate
• H₂-receptor antagonists (when doses comparable to greater than famotidine 40mg twice daily are taken)
  - Famotidine
  - Cimetidine
  - Nizatidine
  - Ranitidine
• Proton pump inhibitors (doses comparable to omeprazole greater than 20mg) 
  - Omeprazole
  - Lansoprazole
  - Rabeprazole
  - Pantoprazole
  - Esomeprazole
• Antiarrhythmics
• Amiodarone
• Digoxin
• Anticoagulants
• Dabigatran etexilate
• Anticonvulsants
• Phenobarbital
• Phenytoin
• Antimycobacterials
• Rifampicin
• Rifabutin
• Rifapentine
• For the combination atazanavir/ ritonavir  + emtricitabine/ tenofovir disoproxil fumarate
• For the combination of tenofovir/emtricitabine + darunavir/ritonavir
• For the combination lopinavir/ritonavir + emtricitabine/ tenofovir disoproxil fumarate
• Tipranavir boosted with ritonavir
• Elvitegravir/ cobicistat/ emtricitabine/ tenofovir disoproxil fumarate
• HMG-CoA reductase inhibitors
• Rosuvastatin
• Pravastatin

Other interactions

• St. John's wort

Pretreatment assessment

• Evaluate for advanced hepatic fibrosis and hepatocellular carcinoma
• Confirm vaccination against hepatitis A and B
• Assess for potential drug-drug interactions and patient’s readiness for adherence

Laboratory tests recommended at any time before starting therapy

• Quantitative hepatitis C virus (HCV) RNA (HCV viral load), HCV genotype and subtype, HIV antigen/antibody
• Assessment for active hepatitis B virus coinfection
  - Hepatitis B virus (HBV) surface antigen (HBsAg)
  - HBV core antibody, and HBV surface antibody
  - If evidence of hepatitis B viral coinfection, HBV DNA level should be drawn
• HBsAg-positive patients not already receiving HBV suppressive therapy should be either: initiated on prophylactic HBV antiviral therapy (for those with low or undetectable HBV DNA levels), which should be continued until 12 weeks after completion of HCV therapy or monitor HBV DNA levels monthly during and immediately after HCV therapy

Laboratory tests recommended within 6 months prior to starting therapy

• Complete blood count (CBC)
• International normalised ratio (INR)
• Hepatic function panel
  - Serum albumin
  - Total and direct bilirubin
  - Alanine aminotransferase (ALT)
  - Aspartate aminotransferase (ALT)
  - Alkaline phosphatase (ALP)
• Estimated glomerular filtration rate(eGFR)

Laboratory tests immediately prior to starting therapy

• Serum pregnancy test for patients of childbearing potential
• Consider NS5A RAS testing for genotype 1a–infected, treatment-experienced patients with or without cirrhosis prior to treatment

On-treatment monitoring:

• Periodic monitoring of liver function tests (LFTs) and assessment for presence of symptoms of liver dysfunction (eg, weakness, nausea, vomiting, jaundice, or significantly elevated bilirubin, alkaline phosphatase, or INR)
• In patients with diabetes
  - Monitor blood glucose and for signs/symptoms of hypoglycemia
• In patients taking warfarin
  - Monitor INR during and post therapy
• If used in combination with amiodarone (or in patients who discontinued amiodarone just prior to initiating ledipasvir/sofosbuvir)
  - Inpatient cardiac monitoring for the first 48 hours of coadministration, then outpatient or self-monitoring of heart rate daily through at least the first 2 weeks of treatment

Post-treatment assessment of cure

• Quantitative HCV viral load testing 12 or more weeks after completion of therapy to document sustained virologic response and liver transaminases

Guidance for ribavirin dosing when administered with sofosbuvir/ ledipasvir to patients with decompensated cirrhosis

Patient	Ribavirin Dose
Child-Pugh-Turcotte (CPT) Class B cirrhosis pre-transplant	1000mg per day for patients <75kg and 1200mg for those weighing ≥75kg
CPT Class C cirrhosis pre-transplant CPT Class B or C cirrhosis posttransplant	Starting dose of 600mg, which can be titrated up to a maximum of 1000/1200mg (1000mg for patients weighing <75kg and 1200mg for patients weighing ≥75kg) 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 normalised dose of ribavirin (by weight and renal function) cannot be reached for reasons of tolerability, 24 weeks of sofosbuvir/ ledipasvir + ribavirin should be considered in order to minimise the risk for relapse.

In adolescent patients aged 12 to < 18 years the following ribavirin dosing is recommended where ribavirin is divided into two daily doses and given with food:

Guidance for ribavirin dosing when administered with sofosbuvir/ ledipasvir to adolescents aged 12 to < 18 years

Body weight kg	Ribavirin Dose*
<47	15mg/kg/day
47-49	600mg/day
50-65	800mg/day
66-74	1000mg/day
> or = 75	1200mg/day

* Ribavirin administered orally in two divided doses with food

• Dose modification of ribavirin in adults taking 1000-1200mg daily: If sofosbuvir/ ledipasvir 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
• The table below 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 sofosbuvir/ ledipasvir in adults

Laboratory values	Reduce ribavirin dose to 600mg/day if:	Discontinue ribavirin if:
Haemoglobin in patients with no cardiac disease	<10g/dL	<8.5g/dL
Haemoglobin in patients with history of stable cardiac disease	≥2g/dL decrease in haemoglobin during any 4-week treatment period	<12g/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 600mg daily and further increase the dose to 800mg daily
• However, it is not recommended that ribavirin be increased to the originally assigned dose (1000mg to 1200mg daily)
• Addition of ribavirin to sofosbuvir/ ledipasvir is recommended for liver transplant recipients
• It can also be considered for those treatment-experienced patients with compensated cirrhosis who are at high risk of clinical disease progression. sofosbuvir/ ledipasvir in combination with ribavirin for 12 weeks is recommended

Concomitant ribavirin dose

• When sofosbuvir/ ledipasvir is used in combination with ribavirin, the daily dose of ribavirin is 1000mg for patients weighing <75kg and 1200mg for those weighing ≥75 kg, except for patients with decompensated cirrhosis who should receive 600mg
• Ribavirin is administered orally in two divided doses with food. Refer to ribavirin prescribing information for ribavirin dose modifications

Ledipasvir is a HCV inhibitor targeting the HCV NS5A protein, which is essential for both RNA replication and the assembly of HCV virions. Biochemical confirmation of NS5A inhibition by ledipasvir is not currently possible as NS5A has no enzymatic function. In vitro resistance selection and cross-resistance studies indicate ledipasvir targets NS5A as its mode of action.

Sofosbuvir is a pan-genotypic inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is essential for viral replication. Sofosbuvir is a nucleotide prodrug that undergoes intracellular metabolism to form the pharmacologically active uridine analogue triphosphate (GS-461203), which can be incorporated into HCV RNA by the NS5B polymerase and acts as a chain terminator.

GS-461203 (the active metabolite of sofosbuvir) is neither an inhibitor of human DNA and RNA polymerases nor an inhibitor of mitochondrial RNA polymerase.

COMBINATION PREPARATIONS

Sofosbuvir/Ledipasvir

Film coated tablet 400 mg/90 mg

• Harvoni (Gilead Science) originator