Sovoled

Sofosbuvir 400 mg and Ledipasvir 90 mg
Film Coated Tablets

COMPOSITION AND EXCIPIENTS

Active substances:

Each film coated tablet contains 400 mg of Sofosbuvir and 90 mg of Ledipasvir.

Excipients:

Colloidal silicon dioxide, Copovidone, Croscarmellose sodium, Lactose monohydrate, Magnesium Stearate, Microcrystalline cellulose, Polyethylene glycol, Polyvinyl alcohol, Talc, Titanium dioxide, Sunset yellow.

MECHANISM OF ACTION

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.

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 analog triphosphate (GS-461203), which can be incorporated into HCV RNA by the NS5B polymerase and acts as a chain terminator.

PHARMCOKINETICS

Absorption:

Following oral administration of ledipasvir/sofosbuvir to HCV-infected patients, ledipasvir median peak plasma concentration was observed at 4.0 hours post-dose. Sofosbuvir was absorbed quickly and the median peak plasma concentration was observed ~1 hour post-dose, regardless of dose level. Peak plasma concentration of GS-331007 was observed at 4 hours post-dose.

Effects of food:

Relative to fasting conditions, the administration of a single dose of Ledipasvir/sofosbuvir with a moderate fat or high fat meal increased the sofosbuvir AUC0-inf by approximately 2-fold, but did not significantly affect the sofosbuvir Cmax. The exposures to GS-331007 and ledipasvir were not altered in the presence of either meal type.

Distribution:

Ledipasvir is > 99.8% bound to human plasma proteins. Sofosbuvir is approximately 61- 65% bound to human plasma proteins and the binding is independent of drug concentration over the range of 1 µg/mL to 20 µg/mL. Protein binding of GS-331007 was minimal in human plasma.

Biotransformation:

Following a single dose of 90 mg [14C]-ledipasvir, systemic exposure was almost exclusively due to the parent drug (> 98%). Unchanged ledipasvir is also the major species present in faeces.

Sofosbuvir is extensively metabolised in the liver to form the pharmacologically active nucleoside analog triphosphate GS-461203. The active metabolite is not observed.

Elimination:

Following a single 90 mg oral dose of [14C]-ledipasvir, mean total recovery of the [14C]-radioactivity in faeces and urine was 87%, with most of the radioactive dose recovered from faeces (86%). Unchanged ledipasvir excreted in faeces accounted for a mean of 70% of the administered dose and the oxidative metabolite M19 accounted for 2.2% of the dose. These data suggest that biliary excretion of unchanged ledipasvir is a major route of elimination with renal excretion being a minor pathway (approximately 1%).

Following a single 400 mg oral dose of sofosbuvir, mean total recovery of the dose was greater than 92%, consisting of approximately 80%, 14%, and 2.5% recovered in urine, faeces, and expired air, respectively. The majority of the sofosbuvir dose recovered in urine was GS-331007 (78%) while 3.5% was recovered as sofosbuvir. This data indicate that renal clearance is the major elimination pathway for GS-331007 with a large part actively secreted. The median terminal half-livesof sofosbuvir and GS-331007 following administration of ledipasvir/sofosbuvir were 0.5 and 27 hours, respectively.

INDICATIONS

Ledipasvir / Sofosbuvir is indicated for the treatment of chronic hepatitis C (CHC) in adults. For hepatitis C virus (HCV) genotype-specific activity.

CONTRAINDICATIONS

Hypersensitivity to the active substances or to any of the excipients.

Co-administration with rosuvastatin.

SIDE EFFECTS

Adverse drug reactions identified with Sovoled:

headache, rash, fatigue.

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

Decreases in haemoglobin, patients treated with ledipasvir/sofosbuvir with ribavirin, respectively. Ribavirin was discontinued in 19% of the patients. 10% of liver transplant recipients had a modification of their immunosuppressive agents.

Cardiac arrhythmias :

Cases of severe bradycardia and heart block have been observed when Ledipasvir / Sofosbuvir is used with concomitant amiodarone and/or other drugs that lower heart rate.

WARNINGS AND PRECAUYIONS FOR USE

Ledipasvir / Sofosbuvir should not be administered concomitantly with other medicinal products containing sofosbuvir.

Genotype-specific activity:

The clinical data to support the use of Ledipasvir / Sofosbuvir in patients infected with HCV genotype 3 are limited.

A conservative 24 weeks of therapy is advised in all treatment-experienced genotype 3 patients and those treatment-naïve genotype 3 patients with cirrhosis.

The clinical data to support the use of Ledipasvir / Sofosbuvir in patients infected with HCV genotype 2 and 6 are limited.

Severe bradycardia and heart block:

Cases of severe bradycardia and heart block have been observed when Ledipasvir / Sofosbuvir is used with concomitant amiodarone with or without other drugs that lower heart rate. The mechanism is not established. All patients receiving Ledipasvir / Sofosbuvir in combination with amiodarone with or without other drugs 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.

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. 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 failed prior therapy that included an NS3/4A protease inhibitor. Such patients may therefore be dependent on other drug classes for clearance of HCV infection.

Patients 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.

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 Sovoled. Co-administration of such medicinal products is not recommended with Sovoled.

Use with certain HIV antiretroviral regimens:

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 one of previous drugs should be monitored for tenofovir-associated adverse reactions.

Use with HMG-CoA reductase inhibitors:

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.

HCV/HBV (hepatitis B virus) co-infection:

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

Excipients:

Ledipasvir / Sofosbuvir contains the azo colouring agent sunset yellow FCF aluminium lake (E110), which may cause allergic reactions. It also contains lactose. Consequently, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

pregnancy and lactation:

Women of childbearing potential / contraception in males and females:

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 for ribavirin.

Pregnancy:

There are no or limited amount of data from the use of ledipasvir, sofosbuvir or Ledipasvir / Sofosbuvir in pregnant women.

As a precautionary measure, it is preferable to avoid the use of Ledipasvir / Sofosbuvir during pregnancy.

Breast-feeding:

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.

INTERACTIONS WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF INTERACTION

Patients treated with vitamin K antagonists:

As liver function may change during treatment with Sovoled, a close monitoring of International Normalised Ratio (INR) values is recommended.

ACID REDUCING AGENTS:

Ledipasvir solubility decreases as pH increases. Medicinal products that increase gastric pH are expected to decrease concentration of ledipasvir.

Antacids (e.g. Aluminium or magnesium hydroxide; calcium carbonate): It is recommended to separate antacid and Ledipasvir / Sofosbuvir administration by 4 hours.

H2-receptor antagonists (Famotidine, Cimetidine, Nizatidine, Ranitidine): 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 inhibitors (Omeprazole, Lansoprazole, Rabeprazole, Pantoprazole, Esomeprazole): Proton pump inhibitor doses comparable to omeprazole 20 mg can be administered simultaneously with Sovoled. Proton pump inhibitors should not be taken before Sovoled.

ANTIARRHYTHMICS:

.Amiodarone: Use only if no other alternative is available. Close monitoring is recommended if this medicinal product is administered with Sovole

Digoxin: 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 Sovoled.

ANTICOAGULANTS:

Dabigatran etexilate: Clinical monitoring, looking for signs of bleeding and anaemia, is recommended when dabigatran etexilate is co-administered with Sovoled. A coagulation test helps to identify patients with an increased bleeding risk due to increased dabigatran exposure.

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

ANTICONVULSANTS:

Carbamazepine, Phenobarbital, Phenytoin: Ledipasvir / Sofosbuvir is contraindicated with carbamazepine, phenobarbital and phenytoin.

Oxcarbazepine: Co-administration of Ledipasvir / Sofosbuvir with oxcarbazepine is expected to decrease the concentration of ledipasvir and sofosbuvir leading to reduced therapeutic effect of Sovoled. Such co-administration is not recommended.

ANTIMYCOBACTERIALS:

Rifabutin, Rifampicin, Rifapentine: Ledipasvir / Sofosbuvir is contraindicated with rifampicin, a potent intestinal P-gp inducer. Co-administration of Ledipasvir / Sofosbuvir with rifapentine is expected to decrease the concentration of ledipasvir and sofosbuvir, leading to reduced therapeutic effect of Sovoled. Such co-administration is not recommended.

HCV PRODUCTS:

Simeprevir: Concentrations of ledipasvir, sofosbuvir and simeprevir are increased when simeprevir is co-administered with Sovoled. Co-administration is not recommended.

HIV ANTIVIRAL AGENTS:

REVERSE TRANSCRIPTASE INHIBITORS:

No dose adjustment of Ledipasvir / Sofosbuvir or efavirenz/ emtricitabine/ tenofovir disoproxil fumarate is required.

HIV PROTEASE INHIBITORS:

No dose adjustment of Ledipasvir / Sofosbuvir or atazanavir (ritonavir boosted) is required.

INTEGRASE INHIBITORS:

Raltegravir: No dose adjustment of Ledipasvir / Sofosbuvir or raltegravir is required.

HERBAL SUPPLEMENTS:

St. John’s wort: Ledipasvir / Sofosbuvir is contraindicated with St. John’s wort, a potent intestinal P-gp inducer.

HMG-CoA REDUCTASE INHIBITORS:

Rosuvastatin, Pravastatin: Co-administration of Ledipasvir / Sofosbuvir with rosuvastatin may significantly increase the concentration of rosuvastatin (several fold-increase in AUC) which is associated with increased risk of myopathy, including rhabdomyolysis. Co-administration of Ledipasvir / Sofosbuvir with rosuvastatin is contraindicated.

Other statins: Interactions cannot be excluded with other HMG-CoA reductase inhibitors. When co-administered with Sovoled, a reduced dose of statins should be considered and careful monitoring for statin adverse reactions should be undertaken.

NARCOTIC ANALGESICS:

Methadone: No dose adjustment of Ledipasvir / Sofosbuvir or methadone is required.

IMMUNOSUPPRESSANTS:

Ciclosporin, Tacrolimus: No dose adjustment of Ledipasvir / Sofosbuvir or tacrolimus is required.

ORAL CONTRACEPTIVES:

Norgestimate/ ethinyl estradiol: No dose adjustment of oral contraceptives is required.

POSOLOGY AND METHOD OF ADMINISTRATION

Ledipasvir / Sofosbuvir treatment should be initiated and monitored by a physician experienced in the management of patients with CHC.

Posology:

The recommended dose of Ledipasvir / Sofosbuvir is one tablet once daily with or without food.

Recommended treatment duration for Ledipasvir / Sofosbuvir and the recommended use of co-administered ribavirin for certain subgroups:

Patient population*	Treatment and duration
Patients with genotype 1, 4, 5 or 6 CHC
Patients without cirrhosis	Ledipasvir / Sofosbuvir for 12 weeks. – Ledipasvir / Sofosbuvir for 8 weeks may be considered in previously untreated genotype 1-infected patients. – Ledipasvir / Sofosbuvir + ribavirin for 12 weeks or Ledipasvir / Sofosbuvir (without ribavirin) for 24 weeks should be considered for previously treated patients with uncertain subsequent retreatment options.
Patients with compensated cirrhosis	Ledipasvir / Sofosbuvir + ribavirin for 12 weeks or Ledipasvir / Sofosbuvir (without ribavirin) for 24 weeks. – Ledipasvir / Sofosbuvir (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	Ledipasvir / Sofosbuvir + ribavirin for 12 weeks – Ledipasvir / Sofosbuvir (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	Ledipasvir / Sofosbuvir + ribavirin for 12 weeks – Ledipasvir / Sofosbuvir (without ribavirin) for 24 weeks may be considered in patients who are ineligible for or intolerant to ribavirin.
Patients with genotype 3 CHC
Patients with compensated cirrhosis and/or prior treatment failure	Ledipasvir / Sofosbuvir + ribavirin for 24 weeks

*Includes patients co-infected with human immunodeficiency virus (HIV).

In patients without decompensated cirrhosis requiring the addition of ribavirin to their treatment regimen, 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 Ledipasvir / Sofosbuvir 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.

Ribavirin dose modification guideline for co-administration with Sovoled:

Laboratory Values	Reduce ribavirin dose to 600 mg/day if:	Discontinue ribavirin if:
Haemoglobin in patients with no cardiac disease	<10 g/dL	<8.5 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.

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 Ledipasvir / Sofosbuvir 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 Ledipasvir / Sofosbuvir is required for patients with mild, moderate or severe hepatic impairment. Safety and efficacy of ledipasvir / sofosbuvir have been established in patients with decompensated cirrhosis.

Paediatric population:

The safety and efficacy of Ledipasvir / Sofosbuvir 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. Due to the bitter taste, it is recommended that the film-coated tablet is not chewed or crushed.

OVERDOSE

No specific antidote is available for overdose with Sovoled. If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with Ledipasvir / Sofosbuvir 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%.

STORAGE CONDITIONS

Store at temperature below 30 °C.

PACKAGING

Sovoled is supplied in a carton pack includes plastic container contains 28 film coated tablets and enclosed leaflet.