Consumer medicine information

Epclusa Tablets

Sofosbuvir; Velpatasvir

BRAND INFORMATION

Brand name

Epclusa

Active ingredient

Sofosbuvir; Velpatasvir

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Epclusa Tablets.

SUMMARY CMI

Epclusa®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using Epclusa?

Epclusa contains the active ingredients sofosbuvir and velpatasvir in a single tablet. Epclusa is used to treat hepatitis C virus infection in adults and children 12 years of age and older and weighing 30 kg or more.

For more information, see Section 1. Why am I using Epclusa? in the full CMI.

2. What should I know before I use Epclusa?

Do not use if you have ever had an allergic reaction to sofosbuvir, velpatasvir or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use Epclusa? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Epclusa and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Epclusa?

The usual dose is one Epclusa tablet orally, once daily. Epclusa tablets can be taken with or without food.

More instructions can be found in Section 4. How do I use Epclusa? in the full CMI.

5. What should I know while using Epclusa?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using Epclusa
Things you should not do
  • Do not stop using this medicine suddenly.
  • Do not give Epclusa to anyone else, even if they have the same condition as you.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how Epclusa affects you.
Looking after your medicine
  • Keep your Epclusa tablets in the bottle with the cap tightly closed until you take them.
  • Store Epclusa in a cool, dry place where it stays below 30°C.

For more information, see Section 5. What should I know while using EPCLUSA? in the full CMI.

6. Are there any side effects?

Common side effects include headache, tiredness, feeling sick (nausea), inflammation of nose and throat (nasopharyngitis).

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

Epclusa®

Active ingredient(s): sofosbuvir and velpatasvir

Consumer Medicine Information (CMI)

This leaflet provides important information about using Epclusa. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Epclusa.

Where to find information in this leaflet:

1. Why am I using Epclusa?
2. What should I know before I use Epclusa?
3. What if I am taking other medicines?
4. How do I use Epclusa?
5. What should I know while using Epclusa?
6. Are there any side effects?
7. Product details

1. Why am I using Epclusa?

Epclusa contains the active ingredients sofosbuvir and velpatasvir in a single tablet. Epclusa is a direct acting antiviral. This medicine works by lowering the amount of hepatitis C virus in your body and may lead to a cure of your HCV infection over a number of weeks.

Cure means the HCV virus is cleared from your blood (remains at an undetectable level) when measured 3 months after finishing all treatment.

Epclusa does not protect against re-infection with the HCV virus if cure has been achieved.

Epclusa is used to treat hepatitis C virus infection in adults and children 12 years of age and older and weighing 30 kg or more.

Hepatitis C is a virus that infects the liver.

2. What should I know before I use Epclusa?

Warnings

Do not use Epclusa if:

  • you are allergic to ingredients sofosbuvir, velpatasvir or any of the ingredients listed at the end of this leaflet.
  • you are taking any other medicine that also contains sofosbuvir or velpatasvir

Check with your doctor if you:

  • Take any medicines for any other condition
  • Have liver problems, other than hepatitis C
  • Have a current or previous infection with the hepatitis B virus, since your doctor may want to monitor you more closely.
  • Have kidney problems or if you are on haemodialysis.
  • Have HIV infection
  • Have diabetes
  • Have any other medical condition.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant. Please speak to your doctor if you are unsure. Epclusa may be used with ribavirin. Ribavirin can damage your unborn baby. It is therefore absolutely essential that you (and your partner) take all precautions not to get pregnant if you are taking ribavirin. You and your partner must use an effective birth control method during ribavirin treatment and during the 6 months after completing ribavirin treatment. It is very important that you read the Pregnancy section in the ribavirin product information very carefully.

Talk to your doctor if you are breastfeeding or intend to breastfeed. It is not known whether velpatasvir or sofosbuvir, the two active ingredients of Epclusa, pass into human breast milk.

Use in Children

Epclusa is not recommended for children under 12 years of age or weighing less than 30 kg.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Tell your doctor if you take any of the following medicines:

  • amiodarone used to treat heart conditions
  • digoxin used to treat heart conditions
  • rosuvastatin used to treat high cholesterol
  • tenofovir disoproxil fumarate used to treat HIV infection
  • efavirenz used to treat HIV infection
  • rifampicin, rifapentine, rifabutin (antibiotics used to treat infections, including tuberculosis)
  • St. John's Wort (Hypericum perforatum – herbal medicine used to treat depression)
  • carbamazepine, phenytoin, phenobarbital (medicines used to treat epilepsy and prevent seizures)
  • Warfarin or other similar medicines called vitamin K antagonists used to thin the blood

Epclusa may interact with these medicines. As a result, the amounts of Epclusa or other medicines in your blood may be affected. This may stop your medicines from working properly, or make any side effects worse. In some cases, your doctor may need to give you a different medicine or adjust the dose of medicine you are taking.

Get advice from a doctor or pharmacist if you take medicines used to treat stomach ulcers, heartburn or acid reflux. These medicines include:

  • antacids (e.g. aluminium hydroxide or magnesium hydroxide)
  • Proton pump inhibitors (e.g. omeprazole)
  • H2-antagonists (e.g. famotidine)

These medicines can decrease the amount of velpatasvir in your blood. If you are taking one of these medicines your doctor will either give you a different medicine for stomach ulcers, heartburn, or acid reflux, or recommend how and when you take that medicine.

  • If you are taking an antacid, take it at least 4 hours before or at least 4 hours after Epclusa.
  • If you are taking a proton pump inhibitor, take Epclusa with food. Your doctor may give you a different medicine or adjust the dose of medicine you are taking.
  • If you are taking an H2-antagonist, your doctor may give you a different medicine or adjust the dose of the medicine you are taking.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Epclusa.

4. How do I use Epclusa?

How much to take

  • The usual dose is one Epclusa tablet orally, once daily.
  • Epclusa tablets can be taken with or without food.
  • Follow the instructions provided and use Epclusa until your doctor tells you to stop.

When to take Epclusa

  • Epclusa should be taken at about the same time each day. Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

If you forget to use Epclusa

Epclusa should be used regularly at the same time each day. If you miss your dose at the usual time, take your missed dose right away unless it is almost time for your next dose.

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Do not take a double dose to make up for the dose you missed. Continue with your regular dosing schedule.

Do not stop taking Epclusa unless your doctor tells you to. It is very important that you complete the full course of treatment to give the medicine the best chance to cure your hepatitis C virus infection.

If you use too much Epclusa

If you think that you have used too much Epclusa, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    by calling 13 11 26 (Australia), or 0800 764 766 (New Zealand)
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using Epclusa?

Things you should do

Remind any doctor, dentist or pharmacist you visit that you are using Epclusa.

Tell your doctor as soon as possible if there is any worsening of your condition

Things you should not do

  • Do not give Epclusa to anyone else, even if they have the same condition as you.
  • Do not stop using this medicine without checking with your doctor
  • Do not breastfeed.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Epclusa affects you.

Looking after your medicine

  • Keep your Epclusa tablets in the bottle with the cap tightly closed until you take them. If you take Epclusa tablets out of their pack they may not keep well.
  • Store Epclusa in a cool, dry place where it stays below 30°C.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight.

Do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
  • tiredness
  • headache
  • feeling sick (nausea)
  • inflammation of nose and throat (nasopharyngitis)
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Signs of allergic reaction such as:
  • Skin troubles such as lumpy skin rash or “hives”
  • Swelling of the face, lips, mouth, or throat which may cause difficulty in swallowing or breathing
  • Wheezing, chest pain, or tightness
  • Fainting
A wide-spread severe rash with peeling skin which may be accompanied by fever, flu like symptoms, blisters in the mouth, eyes, and/or genitals (Stevens-Johnson syndrome)		Do not take any more Epclusa.
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What Epclusa contains

Active ingredient
(main ingredient)		sofosbuvir
velpatasvir
Other ingredients
(inactive ingredients)		copovidone
microcrystalline cellulose
croscarmellose sodium
magnesium stearate
polyvinyl alcohol
macrogol 3350
titanium dioxide
talc-purified
iron oxide red
Potential allergensn/a

Do not take this medicine if you are allergic to any of these ingredients.

What Epclusa looks like

Epclusa tablets are diamond-shaped and pink in colour. Each tablet has “GSI” on one side and “7916” on the other side of the tablet.

Epclusa tablets are supplied in bottles containing 28 tablets.

AUST R 266823

Who distributes Epclusa

Australia

Gilead Sciences Pty Ltd
Level 6, 417 St Kilda Road Melbourne, Victoria 3004

New Zealand

c/- Grant Thornton New Zealand Limited,
L4, 152 Fanshawe Street
Auckland 1010

This leaflet was prepared in February 2022.

Epclusa, 7916, and GSI are trademarks of Gilead Sciences, Inc. or one of its related companies. Other brands listed are trademarks of their respective owners and are not trademarks of Gilead Sciences, Inc.

Published by MIMS April 2022

BRAND INFORMATION

Brand name

Epclusa

Active ingredient

Sofosbuvir; Velpatasvir

Schedule

S4

 

1 Name of Medicine

Epclusa (sofosbuvir/velpatasvir 400 mg/100 mg) tablets.
The active substances in Epclusa tablets are sofosbuvir and velpatasvir.

2 Qualitative and Quantitative Composition

Epclusa is available as a fixed-dose combination tablet. Each tablet contains 100 mg velpatasvir and 400 mg sofosbuvir. Epclusa tablets are pink, diamond-shaped, film coated tablets, debossed with "GSI" on one side and "7916" on the other side. For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Each Epclusa tablet is film-coated and pink in colour. The tablets are diamond shaped debossed with 'GSI' on one side and the number '7916' on the other side. The tablets are supplied in bottles with child-resistant closures.

4 Clinical Particulars

4.1 Therapeutic Indications

Epclusa is indicated for the treatment of chronic hepatitis C virus (HCV) infection (genotype 1, 2, 3, 4, 5 or 6) in adults and paediatric patients ≥ 12 years of age and weighing ≥ 30 kg.
See Section 4.2 Dose and Method of Administration for the recommended regimens for different patient subgroups.

4.2 Dose and Method of Administration

The recommended dose of Epclusa in adults is one tablet, taken orally, once daily with or without food.
Table 1 provides the recommended treatment regimen based on adult patient population.

Special populations.

Paediatrics.

In paediatric patients ≥ 12 years of age and weighing ≥ 30 kg, the recommended dosage of Epclusa is one tablet taken orally once daily with or without food for 12 weeks.
Epclusa is not indicated for use in paediatric patients < 12 years of age or weighing < 30 kg.

Elderly.

No dose adjustment is warranted for elderly patients.

Renal impairment.

No dose adjustment of Epclusa is required for patients with renal impairment, including end stage renal disease (ESRD) requiring dialysis (see Section 5.2 Pharmacokinetic Properties, Special populations). Safety data are limited in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m2) and ESRD who are not receiving haemodialysis.

Hepatic impairment.

No dose adjustment of Epclusa is required for patients with mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, or C) (see Section 5.2 Pharmacokinetic Properties, Special populations). Safety and efficacy of Epclusa have been established in adult patients with decompensated cirrhosis (see Section 4.8 Adverse Effects (Undesirable Effects); Section 5.1 Pharmacodynamic Properties, Clinical trials).

4.3 Contraindications

Epclusa tablets are contraindicated in patients with known hypersensitivity to the active substance or to any other component of the tablets.
Epclusa is a fixed dose combination of sofosbuvir and velpatasvir. Epclusa should not be administered concurrently with other medicinal products containing any of the same active components.

4.4 Special Warnings and Precautions for Use

Serious symptomatic bradycardia when sofosbuvir is coadministered with amiodarone.

Postmarketing cases of symptomatic bradycardia and cases requiring pacemaker intervention have been reported when amiodarone is coadministered with a sofosbuvir-containing regimen. A fatal cardiac arrest was reported in a patient taking amiodarone who was coadministered a sofosbuvir containing regimen (ledipasvir/ sofosbuvir).
Bradycardia has generally occurred within hours to days, but cases have been observed up to 2 weeks after initiating HCV treatment. 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. Bradycardia generally resolved after discontinuation of HCV treatment. The mechanism for this effect is unknown.
Coadministration of amiodarone with Epclusa is not recommended. For patients taking amiodarone who have no other alternative, viable treatment options and who will be coadministered Epclusa:
counsel patients about the risk of symptomatic bradycardia;
cardiac monitoring in an in-patient setting for the first 48 hours of coadministration is recommended, after which outpatient or self monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment.
Patients who are taking Epclusa who need to start amiodarone therapy due to no other alternative, viable treatment options should undergo similar cardiac monitoring as outlined above.
Due to amiodarone's long half-life, patients discontinuing amiodarone just prior to starting Epclusa should also undergo similar cardiac monitoring as outlined above.
Patients who develop signs or symptoms of bradycardia should seek medical evaluation immediately. Symptoms may include near fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pains, confusion, or memory problems.

Hepatitis B virus reactivation.

Cases of hepatitis B virus (HBV) reactivation, including fatal cases, have been reported during and after treatment of HCV with direct acting antiviral agents in HCV/HBV co-infected patients. Screening for current or past HBV infection, including testing for HBV surface antigen (HBsAg) and HBV core antibody (anti-HBc), should be performed in all patients before initiation of treatment with Epclusa.
Patients with serologic evidence of current or past HBV infection should be monitored and treated according to current clinical practice guidelines to manage potential HBV reactivation. Consider initiation of HBV antiviral therapy, if indicated.

Potential for dysglycaemia in diabetic patients.

Diabetics may experience dysglycaemia, 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 three 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 (also see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Use with moderate inducers of P-gp and/or moderate to strong inducers of CYP.

Drugs that are moderate inducers of P-gp and/or moderate to strong inducers of CYP2B6, CYP2C8, or CYP3A4 (e.g. rifampin, St John's wort, carbamazepine) may significantly decrease plasma concentrations of sofosbuvir and/or velpatasvir leading to reduced therapeutic effect of Epclusa. The use of these agents with Epclusa is not recommended (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Use in the elderly.

Clinical studies of Epclusa included 156 patients aged 65 and over (12% of total number of patients in the phase 3 clinical trials). No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Paediatric use.

The safety and efficacy of Epclusa in paediatric patients ≥ 12 years of age receiving Epclusa once daily have been established [see Section 4.8 Adverse Effects (Undesirable Effects); Section 5.1 Pharmacodynamic Properties, Clinical trials]. Exposures to Epclusa in paediatric patients ≥ 12 to < 18 years of age and weighing ≥ 30 kg were similar to those observed in adults.

Effects on laboratory tests.

As liver function may change during treatment with Epclusa, please see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Other forms of interaction for additional guidance on monitoring of certain laboratory parameters and/or concomitant medications.

4.5 Interactions with Other Medicines and Other Forms of Interactions

As Epclusa contains sofosbuvir and velpatasvir, any interactions that have been identified with these agents individually may occur with Epclusa.

Potential for Epclusa to affect other drugs.

Velpatasvir is an inhibitor of drug transporter P-gp, BCRP, OATP1B1 and OATP1B3. Coadministration of Epclusa with drugs that are substrates of these transporters may increase the exposure of such drugs. The drug-drug interaction potential of velpatasvir is limited to the presystemic processes (intestinal efflux and hepatic uptake); clinically relevant interactions in systemic circulation are not expected.

Potential for other drugs to affect Epclusa.

Sofosbuvir and velpatasvir are substrates of drug transporters P-gp and BCRP while GS-331007 is not. In vitro, slow metabolic turnover of velpatasvir by CYP2B6, CYP2C8, and CYP3A4 was observed.
Drugs that are moderate inducers of P-gp and/or moderate to strong inducers of CYP2B6, CYP2C8, or CYP3A4 (e.g. rifampin, St. John's wort, carbamazepine) may decrease plasma concentrations of sofosbuvir and/or velpatasvir leading to reduced therapeutic effect of Epclusa. The use of these agents with Epclusa is not recommended (see Section 4.4 Special Warnings and Precautions for Use, Use with moderate inducers of P-gp and/or moderate to strong inducers of CYP). Coadministration with drugs that inhibit P-gp and/or BCRP may increase sofosbuvir and/or velpatasvir plasma concentrations without increasing GS-331007 plasma concentration. Drugs that inhibit CYP2B6, CYP2C8, or CYP3A4 may increase plasma concentration of velpatasvir. Epclusa may be coadministered with P-gp, BCRP, and CYP inhibitors.

Established and other potentially significant drug interactions.

Table 2 provides a listing of established or potentially clinically significant drug interactions. The drug interactions described are based on studies conducted with either Epclusa, the components of Epclusa (sofosbuvir and velpatasvir) as individual agents, or are predicted drug interactions that may occur with Epclusa. This table is not all inclusive (see Section 5.2 Pharmacokinetic Properties, Assessment of drug interactions).

Drugs without clinically significant interactions with Epclusa.

Based on drug interaction studies conducted with the components of Epclusa (sofosbuvir or velpatasvir) or Epclusa, no clinically significant drug interactions have either been observed or are expected when Epclusa is combined with the following drugs (see Section 5.2 Pharmacokinetic Properties, Assessment of drug interactions): atazanavir/ ritonavir, atorvastatin, cyclosporine, darunavir/ ritonavir, dolutegravir, elvitegravir/ cobicistat/ emtricitabine/ tenofovir alafenamide, emtricitabine, ketoconazole, lopinavir/ ritonavir, methadone, oral contraceptives, oxcarbazepine, pravastatin, raltegravir, rilpivirine, or tacrolimus (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Other forms of interaction).

Other forms of interaction.

Change in hepatic function as a result of treatment of HCV with DAAs may require monitoring of relevant laboratory parameters in susceptible patients (e.g. International Normalized Ratio [INR] in patients taking vitamin K antagonists, blood glucose levels in diabetic patients [also see Section 4.4 Special Warnings and Precautions for Use, Potential for dysglycaemia in diabetic patients]). Concomitant medications significantly affected by changes in hepatic function (e.g. calcineurin inhibitors) may require monitoring or dose modification to ensure continued efficacy.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Sofosbuvir.

Sofosbuvir had no effects on embryofetal viability or on fertility when evaluated in rats. At the highest dose tested, AUC exposure to the predominant circulating metabolite GS-331007 was approximately 4-fold the exposure in humans at the recommended clinical dose.

Velpatasvir.

Velpatasvir had no effects on embryofetal viability or on fertility when evaluated in rats. At the highest dose tested, velpatasvir exposure was approximately 6-fold the exposure in humans at the recommended clinical dose.
(Category B1)
There are no adequate and well controlled studies with Epclusa in pregnant women.
In animal reproduction studies, no evidence of adverse developmental outcomes was observed with the administration of sofosbuvir or velpatasvir.

Sofosbuvir.

No effect on fetal development has been observed in rats and rabbits at the highest doses tested. In the rat and rabbit, exposure to the predominant circulating metabolite GS-331007 was approximately 2- to 5-fold and 6- to 14-fold the exposure in humans at the recommended clinical dose, respectively. Sofosbuvir had no adverse effects on behaviour, reproduction, or development of the offspring in the rat pre- and postnatal development study at AUC exposures approximately 6-fold higher than the human exposure at the recommended clinical dose.

Velpatasvir.

No effects on fetal development have been observed in mice, rats and rabbits at the highest doses tested. In the mouse, rat and rabbit, AUC exposure to velpatasvir was approximately 31-, 6-, and 0.7-fold, respectively, the exposure in humans at the recommended clinical dose. Velpatasvir had no adverse effects on behaviour, reproduction, or development of the offspring in the rat pre- and post-natal development study at AUC exposures approximately 5-fold higher, respectively than the human exposure at the recommended clinical dose.
Because animal reproduction studies are not always predictive of human response, Epclusa should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Ribavirin (pregnancy category X).

Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin. When Epclusa is used in combination with ribavirin extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Women of childbearing potential and their male partners must use effective contraception during treatment and for approximately six months after the treatment has concluded as recommended in the product information for ribavirin. If ribavirin is coadministered with Epclusa, the contraindications regarding use of ribavirin apply (see ribavirin product information).
 It is not known whether sofosbuvir or velpatasvir or their metabolites are present in human breast milk.
The predominant circulating metabolite of sofosbuvir (GS-331007) was the primary component observed in the milk of lactating rats, without effect on nursing pups. Velpatasvir was present in the milk of lactating rats, without clear effects on nursing pups. The development and health benefits of breastfeeding should be considered along with the mother's clinical need for Epclusa and any potential adverse effects on the breastfed infant from Epclusa or from the underlying maternal condition.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects of Epclusa on the ability to drive and use machines have been performed.

4.8 Adverse Effects (Undesirable Effects)

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at https://www.tga.gov.au/reporting-problems.

Adults.

Clinical trials. The safety assessment of Epclusa is based on pooled phase 3 clinical trial data (ASTRAL-1, ASTRAL-2, and ASTRAL-3) from patients with genotype 1, 2, 3, 4, 5, or 6 HCV infection (with or without compensated cirrhosis) including:
1035 patients who received Epclusa for 12 weeks;
116 patients who received placebo (PBO) for 12 weeks;
132 patients who received sofosbuvir (SOF) + ribavirin (RBV) for 12 weeks;
275 patients who received SOF + RBV for 24 weeks.
The proportion of patients who permanently discontinued treatment due to adverse events was 0.2% for patients receiving Epclusa for 12 weeks.
No adverse drug reactions specific to Epclusa have been identified. In clinical trials, headache, fatigue, nausea, and nasopharyngitis were the most common (incidence ≥ 10%) treatment emergent adverse events reported in patients treated with 12 weeks of Epclusa.
Table 3 lists adverse events observed in at least 5% of patients receiving 12 weeks treatment with Epclusa in clinical trials compared to placebo. The majority of adverse events presented in Table 3 occurred at severity of grade 1.

Patients with decompensated cirrhosis.

No adverse drug reactions specific to Epclusa were identified from one open label trial (ASTRAL-4) in which patients with Child-Pugh class B cirrhosis received Epclusa for 12 weeks (N = 90), Epclusa + RBV for 12 weeks (N = 87) or Epclusa for 24 weeks (N = 90). The adverse events observed were consistent with expected clinical sequelae of decompensated liver disease, or the known toxicity profile of ribavirin for patients receiving Epclusa in combination with RBV.
Among the 87 patients who were treated with Epclusa + RBV for 12 weeks, decreases in haemoglobin to less than 10 mg/dL and 8.5 mg/dL during treatment were experienced by 23% and 7% patients, respectively. Ribavirin was discontinued in 15% of patients treated with Epclusa + RBV for 12 weeks due to adverse events.

HCV/HIV-1 co-infection.

No adverse drug reactions specific to Epclusa were identified from a Phase 3 open-label clinical trial (ASTRAL-5) in which patients with HCV/HIV-1 co-infection received treatment with Epclusa for 12 weeks (N=106).

Patients with renal impairment.

No adverse reactions specific to Epclusa were identified from an open-label clinical trial (GS-US-342-4062) in which a total of 59 patients with HCV and ESRD requiring dialysis received Epclusa for 12 weeks. The adverse events observed were consistent with expected clinical sequelae of ESRD.

Paediatrics.

The safety of Epclusa in paediatric patients ≥ 12 years of age was assessed in an open-label trial (Study GS-US-342-1143, Cohort 1) of 102 patients who were treated with Epclusa for 12 weeks. The adverse reactions observed were consistent with those observed in clinical trials of Epclusa in adults (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Post marketing surveillance.

The following possible adverse reactions were identified during postapproval use of sofosbuvir or Epclusa. Because these reactions were reported voluntarily from a population of unknown size, estimates of frequency cannot be made.

Cardiac disorders.

Symptomatic bradycardia (when amiodarone is coadministered with Epclusa) (see Section 4.4 Special Warnings and Precautions for Use, Serious symptomatic bradycardia when sofosbuvir is coadministered with amiodarone).

Skin and subcutaneous tissue disorders.

Angioedema, rash, Stevens-Johnson syndrome.

4.9 Overdose

The highest documented doses of sofosbuvir and velpatasvir were a single dose of 1200 mg and a single dose of 500 mg, respectively. In these healthy volunteer studies, there were no untoward effects observed at these dose levels, and adverse events were similar in frequency and severity to those reported in the placebo groups. The effects of higher doses/ exposures are not known.
No specific antidote is available for overdose with Epclusa. If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with Epclusa consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient. Haemodialysis can efficiently remove the predominant circulating metabolite of sofosbuvir, GS-331007, with an extraction ratio of 53%. Haemodialysis is unlikely to result in significant removal of velpatasvir since velpatasvir is highly bound to plasma protein.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia) and 0800 764 766 (New Zealand).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antivirals for systemic use; direct acting antivirals, other antivirals. ATC code: J05AX69.

Mechanism of action.

Sofosbuvir is a pangenotypic 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 by HCV NS5B and acts as a chain terminator. In a biochemical assay, GS-461203 inhibited the polymerase activity of the recombinant NS5B from HCV genotype 1b, 2a, 3a and 4a with an IC50 value ranging from 0.36 to 3.3 microM. GS-461203 is neither an inhibitor of human DNA and RNA polymerases nor an inhibitor of mitochondrial RNA polymerase.
Velpatasvir is a HCV inhibitor targeting the HCV NS5A protein, which is essential for both RNA replication and the assembly of HCV virions. In vitro resistance selection and cross resistance studies indicate velpatasvir targets NS5A as its mode of action.

Antiviral activity in vitro.

The EC50 values of sofosbuvir and velpatasvir against full length or chimeric replicons encoding NS5B and NS5A sequences from the laboratory strains are presented in Table 4.
The EC50 values of sofosbuvir and velpatasvir against chimeric replicons representing clinical isolates are presented in Table 5.
The presence of 40% human serum had no effect on the anti-HCV activity of sofosbuvir, but reduced the anti-HCV activity of velpatasvir by 13-fold against genotype 1a HCV replicons.
Evaluation of sofosbuvir in combination with velpatasvir showed no antagonistic effect in reducing HCV RNA levels in replicon cells.

Drug resistance.

In cell culture. HCV replicons with reduced susceptibility to sofosbuvir have been selected in cell culture for multiple genotypes including 1b, 2a, 2b, 3a, 4a, 5a, and 6a. Reduced susceptibility to sofosbuvir was associated with the primary NS5B substitution S282T in all replicon genotypes examined. Site directed mutagenesis of the S282T substitution in replicons of genotype 1 to 6 conferred 2- to 18-fold reduced susceptibility to sofosbuvir and reduced the replication viral capacity by 89% to 99% compared to the corresponding wild type. In biochemical assays, the ability of the active triphosphate of sofosbuvir (GS-461203) to inhibit recombinant NS5B polymerase from genotypes 1b, 2a, 3a, and 4a expressing the S282T substitution was reduced compared to its ability to inhibit wild type recombinant NS5B polymerase, as indicated by a 8.5- to 24-fold increase in IC50.
In vitro selection of HCV replicons with reduced susceptibility to velpatasvir was performed in cell culture for multiple genotypes including 1a, 1b, 2a, 3a, 4a, 5a, and 6a. Variants were selected at NS5A resistance associated positions 24, 28, 30, 31, 32, 58, 92, and 93. The resistance associated variants (RAVs) selected in 2 or more genotypes were F28S, L31I/V, and Y93H. Site directed mutagenesis of known NS5A RAVs showed that substitutions conferring a > 100-fold reduction in velpatasvir susceptibility are M28G, A92K, and Y93H/N/R/W in genotype 1a, A92K in genotype 1b, C92T and Y93H/N in genotype 2b, Y93H in genotype 3, and L31V and P32A/L/Q/R in genotype 6. No individual substitutions tested in genotypes 2a, 4a, or 5a conferred a > 100-fold reduction in velpatasvir susceptibility. Combinations of these variants often showed greater reductions in susceptibility to velpatasvir than single RAVs alone.
In clinical trials.

Studies in patients without cirrhosis and patients with compensated cirrhosis.

In a pooled analysis of patients without cirrhosis or with compensated cirrhosis who received Epclusa for 12 weeks in phase 3 trials (ASTRAL-1, ASTRAL-2, and ASTRAL-3), 12 patients (2 with genotype 1 and 10 with genotype 3) qualified for resistance analysis due to virologic failure. One additional patient with genotype 3 HCV infection at baseline was reinfected with genotype 1a HCV at virologic failure and was excluded from the virological analysis. No patients with genotype 2, 4, 5, or 6 HCV infection experienced virologic failure.
Of the 2 genotype 1 virologic failure patients, 1 patient had virus with emergent NS5A RAV Y93N and the other patient had virus with emergent NS5A RAVs L31I/V and Y93H at virologic failure. Both patients had virus at baseline harboring NS5A RAVs. No NS5B nucleoside inhibitor (NI) RAVs were observed at failure in the two patients.
Of the 10 genotype 3 virologic failure patients, Y93H was observed in all 10 patients at failure (6 had Y93H emerge post-treatment and 4 patients had Y93H at baseline and post-treatment). No NS5B NI RAVs were observed at failure in the 10 patients.

Studies in patients with decompensated cirrhosis.

In the ASTRAL-4 trial, in patients with decompensated cirrhosis who received Epclusa + ribavirin (RBV) for 12 weeks, 3 patients (1 with genotype 1 and 2 with genotype 3) qualified for resistance analysis due to virologic failure. No patients with genotype 2 or 4 HCV infection in the Epclusa + RBV 12 weeks group experienced virologic failure.
The 1 virologic failure patient with genotype 1 HCV had no NS5A or NS5B RAVs at failure.
Of the 2 genotype 3 virologic failure patients, one had NS5A RAV Y93H emerge at failure. Another patient had virus with Y93H at baseline and virologic failure and also developed low levels (< 5%) of NS5B NI RAVs N142T and E237G at failure. Pharmacokinetic data from this patient was consistent with nonadherence.
In the ASTRAL-4 trial, 2 patients treated with Epclusa for 12 or 24 weeks without ribavirin had emergent NS5B S282T at low levels (< 5%) along with L159F.
Effect of baseline HCV resistance associated variants on treatment outcome.

Adults. Studies in patients without cirrhosis and patients with compensated cirrhosis.

Analyses were conducted to explore the association between pre-existing baseline NS5A RAVs and treatment outcome for patients without cirrhosis or with compensated cirrhosis (ASTRAL-1, ASTRAL-2, and ASTRAL-3). Of the 1035 patients treated with Epclusa in the ASTRAL-1, ASTRAL-2, and ASTRAL-3 trials, 1023 patients were included in the analysis of NS5A RAVs; 7 patients were excluded as they neither achieved sustained virologic response (SVR12) nor had virologic failure and 5 additional patients were excluded as NS5A gene sequencing failed. In the pooled analysis of the phase 3 trials, 380/1023 (37%) patients' virus had baseline NS5A RAVs. Genotype 2, 4, and 6 HCV infected patients had a higher prevalence of NS5A RAVs (70%, 63%, and 52%, respectively) compared to genotype 1 (23%), genotype 3 (16%), and genotype 5 (18%) HCV infected patients.
SVR12 in patients with or without baseline NS5A RAVs in ASTRAL-1, ASTRAL-2, and ASTRAL-3 trials is shown in Table 6.
Among the 75 genotype 1 patients who had baseline NS5A RAVs, SVR12 was 97% (67/69) and 100% (6/6) in patients with baseline NS5A RAVs that confer ≤ 100-fold and > 100-fold reduced susceptibility to velpatasvir, respectively. Among the 43 genotype 3 patients who had baseline NS5A RAVs, SVR12 was 94% (15/16) and 85% (23/27) in patients with NS5A RAVS that confer ≤ 100-fold and > 100-fold reduced susceptibility to velpatasvir, respectively. The 4 genotype 3 patients who had baseline NS5A RAVs conferring > 100-fold reduced susceptibility to velpatasvir and failed to achieve SVR12, all had NS5A substitution Y93H at baseline. Twenty one of 25 (84%) genotype 3 patients with baseline NS5A substitution Y93H achieved SVR12.
The NS5B NI RAV S282T was not detected in the baseline NS5B sequence of any patient in phase 3 trials. SVR12 was achieved in all 77 patients who had baseline NS5B NI RAVs including N142T, L159F, E/N237G, C/M289L/I, L320F/I/V, V321A/I, and S282G + V321I.

Studies in patients with decompensated cirrhosis.

Analyses were conducted to explore the association between pre-existing baseline NS5A RAVs and treatment outcome for patients with decompensated cirrhosis (ASTRAL-4). Of the 87 patients treated with Epclusa + RBV in the ASTRAL-4 trial, 85 patients were included in the analysis of NS5A RAVs; 2 patients were excluded as they neither achieved SVR12 nor had virologic failure. Among the patients who received treatment with Epclusa + RBV for 12 weeks, 29% (25/85) of patients had baseline virus with NS5A RAVs [29% (19/66), 75% (3/4), 15% (2/13), and 50% (1/2) for patients with genotype 1, 2, 3, and 4 HCV, respectively].
SVR12 in patients with or without baseline NS5A RAVs in the Epclusa + RBV 12 week group of ASTRAL-4 trial is shown in Table 7.
The single genotype 3 patient who had baseline NS5A RAVs and failed to achieve SVR12 had NS5A substitution Y93H at baseline; pharmacokinetic data from this patient was consistent with nonadherence.
Three patients in the Epclusa + RBV 12 week group had baseline NS5B NI RAVs (N142T and L159F) and all three patients achieved SVR12.

Paediatrics.

In Study GS-US-342-1143, the presence of NS5A and NS5B RAVs did not impact treatment outcome; all paediatric patients 12 years to < 18 years of age with baseline NS5A or NS5B NI RAVs (16.3% [16/98] and 5.2% [5/97], respectively) achieved SVR following 12 weeks treatment with Epclusa.

Cross resistance.

In vitro data suggest that the majority of NS5A RAVs that confer resistance to ledipasvir and daclatasvir remained susceptible to velpatasvir. Velpatasvir was fully active against the sofosbuvir resistance associated substitution S282T in NS5B, while all velpatasvir resistance associated substitutions in NS5A were fully susceptible to sofosbuvir. Both sofosbuvir and velpatasvir were fully active against substitutions associated with resistance to other classes of direct acting antivirals with different mechanisms of actions, such as NS5B non-nucleoside inhibitors and NS3 protease inhibitors. The efficacy of Epclusa has not been established in patients who have previously failed treatment with other regimens that include an NS5A inhibitor.

Clinical trials.

Adults. Description of clinical studies. The efficacy of Epclusa was evaluated in three phase 3 trials in patients with genotype 1 to 6 HCV infection with or without compensated cirrhosis and one phase 3 trial in patients with genotype 1 to 6 HCV infection with decompensated cirrhosis, one Phase 3 study in HCV/HIV-1 co-infected patients with genotype 1 to 6 HCV infection and one Phase 2 trial in patients with HCV infection and ESRD requiring dialysis, as summarised in Table 8.
The ribavirin dose was weight based (1000 mg daily administered in two divided doses for patients < 75 kg and 1200 mg for those ≥ 75 kg) and administered in two divided doses when used in combination with sofosbuvir in the ASTRAL-2 and ASTRAL-3 trials or in combination with Epclusa in the ASTRAL-4 trial. RBV dose adjustments were performed according to the RBV product information. Serum HCV RNA values were measured during the clinical trials using the COBAS AmpliPrep/ COBAS Taqman HCV test (version 2.0) with a lower limit of quantification (LLOQ) of 15 IU per mL. Sustained virologic response (SVR12), defined as HCV RNA less than LLOQ at 12 weeks after the cessation of treatment, was the primary endpoint to determine the HCV cure rate.
Clinical studies in patients without cirrhosis and patients with compensated cirrhosis.

Genotype 1, 2, 4, 5, and 6 HCV infected adults (ASTRAL-1).

ASTRAL-1 was a randomised, double blind, placebo controlled trial that evaluated 12 weeks of treatment with Epclusa compared with 12 weeks of placebo in patients with genotype 1, 2, 4, 5, or 6 HCV infection. Patients with genotype 1, 2, 4, or 6 HCV infection were randomised in a 5:1 ratio to treatment with Epclusa for 12 weeks or placebo for 12 weeks. Patients with genotype 5 HCV infection were enrolled to the Epclusa group. Randomisation was stratified by HCV genotype (1, 2, 4, 6, and indeterminate) and the presence or absence of cirrhosis.
Demographics and baseline characteristics were balanced between the Epclusa and placebo group. Of the 740 treated patients, the median age was 56 years (range: 18 to 82); 60% of the patients were male; 79% were white, 9% were black; 21% had a baseline body mass index at least 30 kg/m2; the proportions of patients with genotype 1, 2, 4, 5, or 6 HCV infection were 53%, 17%, 19%, 5%, and 7%, respectively; 69% had non-CC IL28B alleles (CT or TT); 74% had baseline HCV RNA levels at least 800,000 IU/mL; 19% had compensated cirrhosis; and 32% were treatment experienced.
Table 9 presents the SVR12 and other virologic outcomes in Epclusa treated patients in the ASTRAL-1 trial by HCV genotype. No patients in the placebo group achieved SVR12.

Genotype 2 HCV infected adults (ASTRAL-2).

ASTRAL-2 was a randomised, open label trial that evaluated 12 weeks of treatment with Epclusa compared with 12 weeks of treatment with SOF + RBV in patients with genotype 2 HCV infection. Patients were randomised in a 1:1 ratio to treatment with Epclusa for 12 weeks or SOF + RBV for 12 weeks. Randomisation was stratified by the presence or absence of cirrhosis and prior treatment experience (treatment naive vs treatment experienced).
Demographics and baseline characteristics were balanced across the two treatment groups. Of the 266 treated patients, the median age was 58 years (range: 23 to 81); 59% of the patients were male; 88% were white, 7% were black; 33% had a baseline body mass index at least 30 kg/m2; 62% had non-CC IL28B alleles (CT or TT); 80% had baseline HCV RNA levels at least 800,000 IU/mL; 14% had compensated cirrhosis; and 15% were treatment experienced.
Table 10 presents the SVR12 and other virologic outcomes from the ASTRAL-2 trial.
Treatment with Epclusa for 12 weeks demonstrated statistical superiority (p = 0.018) compared to treatment with SOF + RBV for 12 weeks (treatment difference +5.2%; 95% confidence interval: +0.2% to +10.3%).

Genotype 3 HCV infected adults (ASTRAL-3).

ASTRAL-3 was a randomised, open label trial that evaluated 12 weeks of treatment with Epclusa compared with 24 weeks of treatment with SOF + RBV in patients with genotype 3 HCV infection. Patients were randomised in a 1:1 ratio to treatment with Epclusa for 12 weeks or SOF + RBV for 24 weeks. Randomisation was stratified by the presence or absence of cirrhosis and prior treatment experience (treatment naive vs treatment experienced).
Demographics and baseline characteristics were balanced across the treatment groups. Of the 552 treated patients, the median age was 52 years (range: 19 to 76); 62% of the patients were male; 89% were white, 9% were Asian; 20% had a baseline body mass index at least 30 kg/m2; 61% had non-CC IL28B alleles (CT or TT); 70% had baseline HCV RNA levels at least 800,000 IU/mL; 30% had compensated cirrhosis; and 26% were treatment experienced.
Table 11 presents the SVR12 and other virologic outcomes for the ASTRAL-3 trial.
Treatment with Epclusa for 12 weeks demonstrated statistical superiority (p < 0.001) compared to treatment with SOF + RBV for 24 weeks (treatment difference +14.8%; 95% confidence interval: +9.6% to +20.0%).
SVR12 for selected subgroups are presented in Table 12.
Clinical studies in patients with decompensated cirrhosis.

ASTRAL-4.

ASTRAL-4 was a randomised, open label trial in patients with genotype 1, 2, 3, 4, 5, or 6 HCV infection and Child-Pugh B cirrhosis. Patients were randomised in a 1:1:1 ratio to treatment with Epclusa for 12 weeks, Epclusa + RBV for 12 weeks, or Epclusa for 24 weeks. Randomisation was stratified by HCV genotype (1, 2, 3, 4, 5, 6 and indeterminate).
Demographics and baseline characteristics were balanced across the treatment groups. Of the 267 treated patients, the median age was 59 years (range: 40 to 73); 70% of the patients were male; 90% were white, 6% were black; 42% had a baseline body mass index at least 30 kg/m2. The proportions of patients with genotype 1, 2, 3, 4, or 6 HCV were 78%, 4%, 15%, 3%, and < 1% (1 patient), respectively. No patients with genotype 5 HCV infection were enrolled. 76% had non-CC IL28B alleles (CT or TT); 56% had baseline HCV RNA levels at least 800,000 IU/mL; 55% were treatment experienced; 90% and 95% of patients had CPT B cirrhosis and Model for End Stage Liver Disease (MELD) score ≤ 15 at baseline, respectively.
Table 13 presents the SVR12 for the ASTRAL-4 trial by HCV genotype.
Table 14 presents the virologic outcome for patients with genotype 1 or 3 HCV infection in the ASTRAL-4 trial.
No patients with genotype 2, 4, or 6 HCV infection experienced virologic failure.
Changes in MELD and CPT score from baseline to post-treatment week 12 were analysed for patients who achieved SVR12 to assess the effect of SVR12 on hepatic function. Of the 82 patients treated with Epclusa + RBV for 12 weeks who achieved SVR12, 81 had MELD and CPT assessments at baseline and post-treatment week 12.
Change in MELD score: among those who achieved SVR12 with 12 weeks treatment with Epclusa + RBV, 51% (41/81) and 15% (12/81) had an improvement or no change in MELD score from baseline to post-treatment week 12, respectively. Of the 10 patients whose MELD score was ≥ 15 at baseline, 40% (4/10) had a MELD score < 15 at post-treatment Week 12; Improvement in MELD score was due to improvements (decreases) in bilirubin.
Change in CPT: among those who achieved SVR12 with 12 weeks treatment with Epclusa + RBV, 41% (33/81) and 49% (40/81) had an improvement or no change of CPT scores from baseline to post-treatment week 12, respectively; improvement in CPT score was due to improvements in albumin (increases) and bilirubin (decreases).
Similar proportions of patients treated with Epclusa for 12 or 24 weeks had improvements in MELD and CPT scores compared with patients treated with Epclusa + RBV for 12 weeks.
Clinical studies in patients with HCV/HIV-1 co-infection.

ASTRAL-5.

ASTRAL-5 was a single arm, open-label study conducted in the US evaluating 12 weeks of treatment with Epclusa once daily in patients with genotype 1, 2, 3, 4, 5 or 6 HCV infection who were co-infected with HIV-1. Patients were on a stable HIV-1 antiretroviral therapy that included emtricitabine/ tenofovir disoproxil fumarate or abacavir/ lamivudine administered with ritonavir boosted atazanavir, ritonavir boosted darunavir, ritonavir boosted lopinavir, rilpivirine, raltegravir or elvitegravir/ cobicistat.
The study population included patients who were in general good health with exception of HCV and HIV. Exclusion criteria included HBV co-infection, HIV RNA > 50 copies/mL, CD4+ count < 100 cells/microlitre, opportunistic infection within 6 months of screening, active serious infection, decompensated liver disease, malignancy other than those cured by surgical resection and clinically significant illness other than HCV and HIV. The overall mean CD4+ count was 598 cells/microlitre (range: 183-1513 cells/microlitre), 57% of patients had CD4+ counts > 500 cells/microlitre, and 26% of patients had CD4+ counts ≥ 351 cells/microlitre and ≤ 500 cells/microlitre.
Of the 106 treated patients, the median age was 57 years (range: 25 to 72); 86% of the patients were male; 51% were White; 45% were Black; 22% had a baseline body mass index at least 30 kg/m2; the proportions of patients with genotype 1a, 1b, 2, 3, or 4 HCV infection were 62%, 11%, 10%, 11%, and 5% respectively; 77% had non-CC IL28B alleles (CT or TT); 74% had baseline HCV RNA levels of at least 800,000 IU/mL; 18% had compensated cirrhosis; and 29% were treatment experienced. No patients with genotype 5 or 6 HCV infection were enrolled.
Table 15 presents the SVR12 for the ASTRAL-5 study by HCV genotype.
No patient had HIV-1 rebound during the study, and CD4+ counts were stable during treatment.
Clinical trial in patients with renal impairment. Study GS-US-342-4062 was an open-label clinical trial that evaluated 12 weeks of treatment with Epclusa in 59 HCV-infected patients with ESRD requiring dialysis. The proportions of patients with genotype 1, 2, 3, 4, 6 or indeterminate HCV infection were 42%, 12%, 27%, 7%, 3%, and 9%, respectively. At baseline, 29% of patients had cirrhosis, 22% were treatment-experienced, 32% had received a kidney transplant, 92% were on haemodialysis, and 8% were on peritoneal dialysis; mean duration on dialysis was 7.3 years (range: 0 to 40 years). The overall SVR rate was 95% (56/59); of the 3 patients that did not achieve SVR12, 1 had completed Epclusa treatment and relapsed and 2 did not meet virologic failure criteria.
Clinical trial in paediatrics. The efficacy of 12 weeks of treatment with Epclusa in HCV-infected paediatric patients 12 years of age and older was evaluated in a Phase 2, open-label clinical trial in 102 patients (Cohort 1) with HCV infection.
Epclusa was evaluated in 102 patients 12 years to < 18 years of age with genotype 1, 2, 3, 4 or 6 HCV infection. A total of 80 patients (78%) were treatment-naïve and 22 patients (22%) were treatment-experienced. The mean weight was 61 kg (range 22 to 147 kg), median age was 15 years (range: 12 to 17); 51% of the patients were female; 73% were White, 9% were Black, and 11% were Asian; 14% were Hispanic/Latino; mean body mass index was 22.7 kg/m2 (range: 12.9 to 48.9 kg/m2); 58% had baseline HCV RNA levels ≥ 800,000 IU/mL; the proportions of patients with genotype 1, 2, 3, 4 or 6 HCV infection were 74%, 6%, 12%, 2%, and 6%, respectively; no patients had known cirrhosis. The majority of patients (89%) had been infected through vertical transmission.
The SVR rate was 95% overall (97/102), 93% (71/76) in patients with genotype 1 HCV infection, and 100% in patients with genotype 2 (6/6), genotype 3 (12/12), genotype 4 (2/2), and genotype 6 (6/6) HCV infection. One patient who discontinued treatment early relapsed at Post Treatment Week 4; the other four patients who did not achieve SVR12 did not meet virologic failure criteria (e.g. lost to follow-up).

5.2 Pharmacokinetic Properties

Absorption.

The pharmacokinetic properties of sofosbuvir, GS-331007 (the predominant circulating metabolite of sofosbuvir), and velpatasvir have been evaluated in healthy adult subjects and in patients with chronic hepatitis C. Following oral administration of Epclusa, sofosbuvir was absorbed quickly and the peak median plasma concentration was observed 0.5-1.0 hour postdose. Median peak plasma concentration of GS-331007 was observed 3.0 hours postdose. Velpatasvir median peak concentrations were observed 3.0 hours postdose.
Based on the population pharmacokinetic analysis in HCV infected patients, mean steady-state AUC0-24 for sofosbuvir (N = 982), GS-331007 (N = 1428), and velpatasvir (N = 1425) were 1260, 13,970, and 2970 nanogram.hr/mL, respectively. Steady-state Cmax for sofosbuvir, GS-331007, and velpatasvir were 566, 868, and 259 nanogram/mL, respectively. Sofosbuvir and GS-331007 AUC0-24 and Cmax were similar in healthy adult subjects and patients with HCV infection. Relative to healthy subjects (N = 331), velpatasvir AUC0-24 and Cmax were 37% lower and 41% lower, respectively in HCV infected patients.
Sofosbuvir and GS-331007 AUCs are near dose proportional over the dose range of 200 mg to 1200 mg. Velpatasvir AUC increases in a greater than proportional manner from 5 to 50 mg and in a less than proportional manner from 50 to 450 mg, indicating velpatasvir absorption is solubility limited. Sofosbuvir and velpatasvir are substrates for both P-gp and breast cancer resistance protein (BCRP) mediated transport.

Distribution.

Sofosbuvir is approximately 61-65% bound to human plasma proteins and the binding is independent of drug concentration over the range of 1 microgram/mL to 20 microgram/mL. Protein binding of GS-331007 was minimal in human plasma. After a single 400 mg dose of [14C]-sofosbuvir in healthy subjects, the blood to plasma ratio of 14C-radioactivity was approximately 0.7.
Velpatasvir is > 99.5% bound to human plasma proteins and binding is independent of drug concentration over the range of 0.09 microgram/mL to 1.8 microgram/mL. After a single 100 mg dose of [14C]-velpatasvir in healthy subjects, the blood to plasma ratio of 14C-radioactivity ranged between 0.52 and 0.67.

Metabolism.

Sofosbuvir is extensively metabolised in the liver to form the pharmacologically active nucleoside analog triphosphate GS-461203. The metabolic activation pathway involves sequential hydrolysis of the carboxyl ester moiety catalysed by human cathepsin A (CatA) or carboxylesterase 1 (CES1) and phosphoramidate cleavage by histidine triad nucleotide binding protein 1 (HINT1) followed by phosphorylation by the pyrimidine nucleotide biosynthesis pathway. Dephosphorylation results in the formation of nucleoside metabolite GS-331007 that cannot be efficiently rephosphorylated and lacks anti-HCV activity in vitro. After a single 400 mg oral dose of [14C]-sofosbuvir, GS-331007 accounted for approximately > 90% of total systemic exposure.
Velpatasvir is a substrate of CYP2B6, CYP2C8, and CYP3A4 with slow turnover. Following a single dose of 100 mg [14C]-velpatasvir, the majority (> 98%) of radioactivity in plasma was parent drug. Monohydroxylated and desmethylated velpatasvir were the metabolites identified in human plasma. Unchanged velpatasvir is the major species present in faeces.

Excretion.

Following a single 400 mg oral dose of [14C]-sofosbuvir, mean total recovery of the [14C]-radioactivity 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. These data indicate that renal clearance is the major elimination pathway for GS-331007. The median terminal half-lives of sofosbuvir and GS-331007 following administration of Epclusa were 0.5 and 25 hours, respectively.
Following a single 100 mg oral dose of [14C]-velpatasvir, mean total recovery of the [14C]-radioactivity was 95%, consisting of approximately 94% and 0.4% recovered from the faeces and urine, respectively. Unchanged velpatasvir was the major species in faeces accounting for a mean of 77% of the administered dose, followed by monohydroxylated velpatasvir (5.9%) and desmethylated velpatasvir (3.0%). These data indicate that biliary excretion of parent drug was the major route of elimination for velpatasvir. The median terminal half-life of velpatasvir following administration of Epclusa was approximately 15 hours.

Effect of food.

Relative to fasting conditions, the administration of a single dose of Epclusa with a moderate fat (~600 kcal, 30% fat) or high fat (~800 kcal, 50% fat) meal increased sofosbuvir AUC0-inf by 60% and 78%, respectively, but did not substantially affect the sofosbuvir Cmax. The moderate or high fat meal did not alter GS-331007 AUC0-inf, but resulted in a 25% and 37% decrease in Cmax, respectively. The moderate or high fat meal resulted in a 34% and 21% increase in velpatasvir AUC0-inf, respectively, and a 31% and 5% increase in velpatasvir Cmax, respectively. The response rates in phase 3 trials were similar in HCV infected patients who received Epclusa with food or without food. Epclusa can be administered without regard to food.

Special populations.

Race and gender.

No clinically relevant pharmacokinetic differences due to race have been identified for sofosbuvir, GS-331007, or velpatasvir.
No clinically relevant pharmacokinetic differences due to gender have been identified for sofosbuvir, GS-331007, or velpatasvir.

Elderly patients.

Population pharmacokinetic analysis in HCV infected patients showed that within the age range (18 to 82 years) analysed, age did not have a clinically relevant effect on the exposure to sofosbuvir, GS-331007, or velpatasvir. Clinical studies of Epclusa included 156 patients aged 65 and over (12% of total number of patients in the phase 3 clinical trials). The response rates observed for patients ≥ 65 years of age were similar to that of patients < 65 years of age, across treatment groups.

Paediatric patients.

Exposure of sofosbuvir, GS-331007 and velpatasvir in 102 paediatric patients ≥ 12 years of age who received Epclusa in Study GS-US-342-1143 were similar to those observed in adult patients following administration of Epclusa. Population pharmacokinetics-based simulations indicated exposures of sofosbuvir, GS-331007, and velpatasvir in paediatric patients weighing ≥ 30 kg receiving oral once daily doses of sofosbuvir/velpatasvir 400/100 mg were similar to those observed in adults.

Patients with impaired renal function.

A summary of the effect of varying degrees of renal impairment (RI) on the exposures of the components of Epclusa compared to subjects with normal renal function, as described in the text below, are provided in Table 16.
The pharmacokinetics of sofosbuvir was studied in HCV negative adult patients with mild (eGFR ≥ 50 and < 80 mL/min/1.73 m2), moderate (eGFR ≥ 30 and < 50 mL/min/1.73 m2), severe renal impairment (eGFR < 30 mL/min/1.73 m2) and patients with ESRD requiring haemodialysis following a single 400 mg dose of sofosbuvir, relative to patients with normal renal function (eGFR > 80 mL/min/1.73 m2). GS-331007 is efficiently removed by haemodialysis with an extraction coefficient of approximately 53%. Following a single 400 mg dose of sofosbuvir, a 4 hour haemodialysis removed 18% of administered dose.
In HCV-infected patients with severe renal impairment treated with sofosbuvir 200 mg with ribavirin (n=10) or sofosbuvir 400 mg with ribavirin (n=10) for 24 weeks or ledipasvir/sofosbuvir 90/400 mg (n=18) for 12 weeks, the pharmacokinetics of sofosbuvir and GS-331007 were consistent with that observed in HCV negative adult patients with severe renal impairment.
The pharmacokinetics of velpatasvir was studied with a single dose of 100 mg velpatasvir in HCV negative patients with severe renal impairment (eGFR < 30 mL/min by Cockcroft-Gault).
The pharmacokinetics of sofosbuvir, GS-331007, and velpatasvir were studied in HCV-infected patients with ESRD requiring dialysis treated with Epclusa (n=59) for 12 weeks, and compared to patients without renal impairment in the sofosbuvir/velpatasvir Phase 2/3 trials.

Patients with hepatic impairment.

The pharmacokinetics of sofosbuvir were studied following 7 day dosing of 400 mg sofosbuvir in HCV infected patients with moderate and severe hepatic impairment (Child-Pugh class B and C). Relative to patients with normal hepatic function, the sofosbuvir AUC0-24 was 126% and 143% higher in moderate and severe hepatic impairment, while the GS-331007 AUC0-24 was 18% and 9% higher, respectively. Population pharmacokinetics analysis in HCV infected patients indicated that cirrhosis (including decompensated cirrhosis) had no clinically relevant effect on the exposure of sofosbuvir and GS-331007. No dose adjustment of sofosbuvir is recommended for patients with mild, moderate, and severe hepatic impairment.
The pharmacokinetics of velpatasvir were studied with a single dose of 100 mg velpatasvir in HCV negative patients with moderate and severe hepatic impairment (Child-Pugh class B and C). Velpatasvir plasma exposure (AUCinf) was similar in patients with moderate hepatic impairment, severe hepatic impairment, and control patients with normal hepatic function. Population pharmacokinetics analysis in HCV infected patients indicated that cirrhosis (including decompensated cirrhosis) had no clinically relevant effect on the exposure of velpatasvir. No dose adjustment of velpatasvir is required for patients with mild, moderate, or severe hepatic impairment.

Assessment of drug interactions.

After oral administration of Epclusa, sofosbuvir is rapidly absorbed and subject to extensive first-pass hepatic extraction. Hydrolytic prodrug cleavage and sequential phosphorylation steps results in formation of the pharmacologically active uridine nucleoside analog triphosphate. Dephosphorylation of nucleotide metabolites results in conversion to the predominant circulating metabolite GS-331007 that accounts for approximately 85% of total systemic exposure. In clinical pharmacology studies, both sofosbuvir and GS-331007 were monitored for purposes of pharmacokinetic analyses.
Sofosbuvir and velpatasvir are substrates of drug transporters P-gp and BCRP, while GS-331007 is not. Velpatasvir is poorly transported by OATP1B1 and OATP1B3. In vitro, slow metabolic turnover of velpatasvir by CYP2B6, CYP2C8, and CYP3A4 was observed.
Sofosbuvir and GS-331007 are not inhibitors of drug transporters P-gp, BCRP, OATP1B1, OATP1B3, and OCT1, and GS-331007 is not an inhibitor of OAT1, OAT3, OCT2, and MATE1. Sofosbuvir and GS-331007 are not inhibitors or inducers of CYP or UGT1A1 enzymes.
Velpatasvir is an inhibitor of drug transporter P-gp, BCRP, OATP1B1, and OATP1B3, and its involvement in drug interactions with these transporters is primarily limited to the process of absorption. At clinically relevant concentration, velpatasvir is not an inhibitor of hepatic transporters OATP1A2 or OCT1, renal transporters OCT2, OAT1, OAT3 or MATE1, or CYP or UGT1A1 enzymes.
The effects of coadministered drugs on the exposure of sofosbuvir, GS-331007, and velpatasvir are shown in Table 17. The effects of sofosbuvir, velpatasvir or Epclusa on the exposure of coadministered drugs are shown in Table 18.

5.3 Preclinical Safety Data

Genotoxicity.

Sofosbuvir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes, and in vivo mouse micronucleus assays.
Velpatasvir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes, and in vivo rat micronucleus assays.

Carcinogenicity.

Carcinogenicity studies in mice and rats do not indicate any carcinogenicity potential of sofosbuvir administered at doses up to 200 mg/kg/day in male mice and 600 mg/kg/day in female mice, and 750 mg/kg/day in rats. Exposure to GS-331007 in these studies in mice was up to 3 x (male) and 15 x (female), and in rats up to 7 x (male) and 9 x (female) higher than the clinical exposure at 400 mg sofosbuvir.
Velpatasvir was not carcinogenic in a 26-week transgenic mouse study and a 2-year rat carcinogenicity study at up to 1000 mg/kg/day and 200 mg/kg/day, respectively, which resulted in systemic exposures approximately 74 times and 6 times, respectively, the human exposure based on AUC.

6 Pharmaceutical Particulars

6.1 List of Excipients

Epclusa tablets contain the following ingredients as excipients:

Tablet core.

Copovidone, croscarmellose sodium, magnesium stearate, and microcrystalline cellulose.

Film coating.

Polyvinyl alcohol, macrogol 3350, titanium dioxide, talc-purified, and iron oxide red.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Epclusa should be stored below 30°C.

6.5 Nature and Contents of Container

Epclusa is supplied in high density polyethylene (HDPE) bottles containing 28 tablets and is closed with a child resistant closure.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

Sofosbuvir is a nucleotide inhibitor of HCV NS5B RNA-dependent RNA polymerase and velpatasvir is an HCV NS5A inhibitor.
The chemical name of sofosbuvir is (S)-Isopropyl 2-((S)-(((2R, 3R, 4R, 5R)-5- (2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)- 4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)-(phenoxy)phosphorylamino) propanoate. It has a molecular formula of C22H29FN3O9P and a molecular weight of 529.45. It has the following structural formula:
Sofosbuvir is a white to off white powder with a solubility of ≥ 2 mg/mL across the pH range of 2-7.7 at 37°C. The partition coefficient (log P) for sofosbuvir is 1.62 and the pKa is 9.3.
The chemical name of velpatasvir is Methyl {(1R)-2-[(2S,4S)-2-(5-{2-[(2S,5S)-1-{(2S)-2- [(methoxycarbonyl)amino]-3-methylbutanoyl}-5-methylpyrrolidin-2-yl]-1, 11-dihydro[2]benzopyrano[4',3':6,7]naphtho [1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)- 4-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate. It has a molecular formula of C49H54N8O8 and a molecular weight of 883.0. It has the following structural formula:
Velpatasvir is practically insoluble (less than 0.1 mg/mL) above pH 5, slightly soluble (3.6 mg/mL) at pH 2, and soluble (greater than 36 mg/mL) at pH 1.2.

CAS number.

Sofosbuvir CAS registry number: 1190307-88-0.
Velpatasvir CAS registry number: 1377049-84-7.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes