Consumer medicine information

Zepatier

Elbasvir; Grazoprevir

BRAND INFORMATION

Brand name

Zepatier

Active ingredient

Elbasvir; Grazoprevir

Schedule

What is in this leaflet?

Read this information carefully before you start to take your medicine, even if you have just refilled your prescription. Some of the information may have changed.

This leaflet answers some common questions about ZEPATIER tablets. It does not contain all of the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking ZEPATIER against the benefits they expect it will have for you.

Your doctor might also want you to take ZEPATIER with ribavirin. It is very important that you also read the Consumer Medicine Information for ribavirin if you are taking it with ZEPATIER.

If you have any concerns about using this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again. Remember that your doctor has prescribed this medicine only for you. Never give it to anyone else.

What ZEPATIER is used for?

ZEPATIER is one tablet that contains two active substances called elbasvir and grazoprevir. ZEPATIER is used to treat chronic (long-lasting) hepatitis C infection in adults.

This medicine belongs to a group of medicines called direct-acting antivirals.

How ZEPATIER works

Hepatitis C is a virus that infects the liver. This medicine works by lowering the amount of Hepatitis C virus in your body. The active substances in ZEPATIER work together by blocking two different proteins that the hepatitis C virus needs to make more virus.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

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

Before you use ZEPATIER

When you must not take ZEPATIER

Do not take ZEPATIER if you:

are allergic to elbasvir, grazoprevir or any of the other ingredients of ZEPATIER. See the section on "Ingredients" at the end of this Consumer Medicine Information for a complete list of ingredients in ZEPATIER.
have certain liver problems
you are taking any of the following medicines:
- carbamazepine or phenytoin, for epilepsy and seizures
- cyclosporine to stop organ transplant rejection
- efavirenz, atazanavir, darunavir, lopinavir, saquinavir or tipranavir for HIV
- rifampicin for tuberculosis
- St. John's wort (Hypericum perforatum, a herbal medicine) for depression or other problems

Do not take ZEPATIER if the packaging is torn or shows signs of tampering.

Do not take ZEPATIER after the expiry date (EXP) printed on the pack has passed.

Before you start to take ZEPATIER

Tell your doctor if you:

have ever had hepatitis B
have ever taken any medicine for hepatitis C
have liver problems other than hepatitis C
have had, or are waiting for, a liver transplant
have any other medical conditions
are pregnant, trying to get pregnant, breastfeeding or planning to breastfeed.

Your doctor will decide if ZEPATIER is right for you.

Tell your doctor or pharmacist if you are pregnant or trying to get pregnant. It is not known if taking ZEPATIER while you are pregnant will harm your unborn baby. Your doctor can discuss the risks and benefits involved.

Do not take ZEPATIER in combination with ribavirin if you or your partner is pregnant or planning to become pregnant. It is very important that you or your partner avoid becoming pregnant during treatment and for 6 months after stopping treatment with ribavirin. Read the ribavirin Consumer Medicine Information for important pregnancy, contraception and breast feeding information. If you (or your partner) do become pregnant while taking ribavirin or within six months after you stop taking ribavirin, tell your doctor straight away.

Tell your doctor or pharmacist if you are breastfeeding or are planning to breastfeed. It is not known if ZEPATIER can be passed to your baby in your breast milk. Your doctor can discuss the risks and benefits involved.

You can obtain further information from your doctor or pharmacist, who has more detailed information.

Taking other medicines

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

You must also tell any doctor that is prescribing medicine to you about all the medicines you take, including ZEPATIER, other prescription and non-prescription medicines, vitamins and herbal supplements.

ZEPATIER may affect the way other medicines work, and other medicines may affect how ZEPATIER works.

Know the medicines you take. Keep a list of your medicines and show it to your doctor and pharmacist when you get a new medicine.

Tell your doctor or pharmacist if you are taking any of the following medicines:

bosentan for pulmonary arterial hypertension
cobicistat, elvitegravir, emtricitabine and tenofovir combination treatment for HIV
etravirine for HIV
oral ketoconazole for fungal infections
modafinil to help people who cannot stay awake
nafcillin for an infection
rosuvastatin, atorvastatin, fluvastatin, simvastatin, or lovastatin, for lowering blood cholesterol
sunitinib for treatment of certain cancers
tacrolimus to prevent organ transplant rejection
warfarin and other similar medicines called vitamin K antagonists
medicines to treat diabetes

Your doctor may have to change your medicines or change the dose of your medicines.

If any of the above apply to you (or you are not sure), talk to your doctor or pharmacist before taking ZEPATIER.

Use in Children

Do not give this medicine to a child under the age of 18 years. It is not known if ZEPATIER is safe or effective in children under 18 years old.

How to use ZEPATIER

Use ZEPATIER exactly as your doctor tells you to take it.

How much to take and when to take it

Take one tablet at the same time every day. Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

How to take it

ZEPATIER comes in a foil blister pack of individually packaged tablets. Keep the tablets in this pack until you are ready to take your medicine.

You can take ZEPATIER with or without food.

How long to take ZEPATIER

Continue taking your medicine for as long as your doctor tells you. Do not stop taking ZEPATIER without first talking to your doctor.

If you forget to take ZEPATIER

It is important not to miss a dose of this medicine. If you do miss a dose, work out how long it is since you should have taken ZEPATIER:

if it has been less than 16 hours since you should have taken your dose, take the missed dose as soon as possible. Then take you next dose at your usual time.
if it has been more than 16 hours since you should have taken your dose, do not take the missed dose. Wait and take the next dose at your usual time.
Do not take a double dose (two doses together) to make up for a forgotten dose.

If you have trouble remembering when to use your medicine, ask your pharmacist for some hints.

If you use too much (overdose)

Immediately telephone your doctor or Poisons Information Centre for advice (telephone number for Australia: 13 11 26).

Keep the telephone number handy.

While you are taking ZEPATIER

Things you must do

Use ZEPATIER exactly as your doctor has prescribed.
Tell all doctors, dentists and pharmacists who are treating you that you are using ZEPATIER.
Keep all your doctor's appointments so that your progress can be checked.
Your doctor will do blood tests to check how your liver is working before and while you are taking ZEPATIER.
Stop using ZEPATIER in combination with ribavirin if you become pregnant and immediately tell your doctor. If your partner becomes pregnant while you are using ZEPATIER in combination with ribavirin, ask your partner to tell her doctor immediately.

Things you must not do

Do not use it to treat any other complaints.
Do not give this medicine to anyone else, even if their symptoms seem similar to yours.
Do not let yourself run out of medicine over weekends or holiday periods.

Things to be careful of

If your doctor has prescribed this medicine together with another medicine called ribavirin, please read the Consumer Medicine Information for ribavirin for other things to be careful of when these medicines are used in combination.

Side effects

All medicines have side effects. Sometimes they are serious, most of the time they are not.

Ask your doctor or pharmacist any questions you may have.

Check with your doctor immediately:

Tell your doctor immediately if you start having any of the following symptoms, or if they get worse during treatment with ZEPATIER:

loss of appetite
nausea (feeling sick) and vomiting
feeling tired or weak
yellowing of your skin or eyes
colour changes in your stool

Tell your doctor immediately if you have an allergic reaction.

Symptoms of an allergic reaction may include:

hives, itching or skin rash
swelling of the face, lips or tongue. This may lead to difficulty in swallowing.
shortness of breath, wheezing, difficulty in breathing or a tight feeling in your chest.

Hepatitis B virus reactivation: Before starting treatment with ZEPATIER, your healthcare provider will do blood tests to check for hepatitis B virus infection.

If you have ever had hepatitis B virus infection, the hepatitis B virus could become active again during or after treatment of hepatitis C virus infection with ZEPATIER.

Hepatitis B virus becoming active again (called reactivation) may cause serious liver problems including liver failure and death.

Your healthcare provider will monitor you if you are at risk for hepatitis B virus reactivation during treatment and after you stop taking ZEPATIER.

Common side effects:

Tell your doctor if you notice any of the following and they worry you while taking ZEPATIER:

headache
feeling tired
nausea (feeling sick)

These are common side effects of ZEPATIER.

The following are common side effects of ZEPATIER in combination with ribavirin. Tell your doctor if you notice any of the following and they worry you:

headache
feeling tired or weak
nausea (feeling sick) or vomiting
itching
muscle aches
trouble sleeping
shortness of breath
indigestion
signs of a low red blood cell count (tiredness, headaches, being short of breath when exercising, dizziness and looking pale)

Other side effects not listed above may also occur in some patients. If you notice any other side effects, check with your doctor.

Check with your doctor as soon as possible if you have any problems while using ZEPATIER, even if you do not think the problems are connected with the medicines.

Do not be alarmed by the list of possible side effects. You may not experience any of them.

Please read the Consumer Medicine Information for ribavirin for other things to be careful of when ZEPATIER is used in combination with ribavirin.

After using ZEPATIER

Storage

Store below 30°C.

Keep ZEPATIER in its original blister pack until you are ready to take it. Do not take the tablets out of the original blister pack to store in another container such as a pill box. This is important because the tablets are sensitive to moisture. The pack is designed to protect them.

Do not store the tablets in the bathroom or near a sink. Heat and dampness can destroy some medicines.

Keep all medicines where children cannot reach. A locked cupboard at least 1.5 metres above the ground is a good place to store medicines.

Disposal

Return any unused medicine to your pharmacist.

Product description

What it looks like

ZEPATIER (elbasvir and grazoprevir) is a beige film-coated tablet with '770' imprinted on one side. Each tablet contains 50mg of elbasvir and 100mg of grazoprevir.

The tablets are packaged into a carton containing two cardboard wallets; each cardboard wallet contains 14 tablets within aluminium blisters. Each carton contains a total of 28 tablets.

Ingredients

Each ZEPATIER tablet contains:

elbasvir 50mg
grazoprevir 100mg
lactose monohydrate 72mg
sodium lauryl sulphate
copovidone
mannitol
croscarmellose sodium
sodium chloride
colloidal anhydrous silica
magnesium stearate
hypromellose
tocofersolan
microcrystalline cellulose

The tablet film coating contains:

lactose monohydrate
hypromellose
titanium dioxide
glycerol triacetate
iron oxide red
iron oxide yellow
ferrosoferric oxide
Carnauba wax

Supplier

Merck Sharp & Dohme (Australia) Pty Limited
Level 1 Building A
26 Talavera Road
Macquarie Park NSW 2113
Australia

Australian Registration Number

AUST R 259928

Date of Preparation

August 2020

RCN000011167-AU

Published by MIMS October 2020

BRAND INFORMATION

Brand name

Zepatier

Active ingredient

Elbasvir; Grazoprevir

Schedule

1 Name of Medicine

Zepatier (elbasvir/grazoprevir).

2 Qualitative and Quantitative Composition

Zepatier is a fixed-dose combination tablet containing elbasvir and grazoprevir for oral administration. Each film coated tablet contains 50 mg elbasvir and 100 mg grazoprevir.
Zepatier is available as a beige-coloured, oval-shaped tablet debossed with "770" on one side and plain on the other.
Elbasvir is practically insoluble in water (< 0.1 mg/mL) and very slightly soluble in ethanol (0.2 mg/mL), but is very soluble in ethyl acetate and acetone.
Grazoprevir is practically insoluble in water (< 0.1 mg/mL) but is freely soluble in ethanol and some organic solvents (e.g. acetone, tetrahydrofuran and N,N-dimethylformamide).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

See Section 2 Qualitative and Quantitative Composition.

4 Clinical Particulars

4.1 Therapeutic Indications

Zepatier is indicated for the treatment of chronic hepatitis C genotype 1 or 4 infection in adults (see Section 4.2 Dose and Method of Administration; Section 5.1 Pharmacodynamic Properties, Clinical trials).

4.2 Dose and Method of Administration

Zepatier is a two-drug, fixed-dose combination product containing 50 mg of elbasvir and 100 mg of grazoprevir in a single tablet. The recommended dosage of Zepatier is one tablet taken orally once daily with or without food.

Treatment regimen and duration of therapy.

Table 1 provides the recommended Zepatier treatment regimen and duration based on the patient population and genotype in HCV mono-infected and HCV/HIV-1 co-infected patients with or without cirrhosis.

Missed dose.

In case a dose of Zepatier is missed and it is within 16 hours of the time Zepatier is usually taken, the patient should be instructed to take Zepatier as soon as possible and then take the next dose of Zepatier at the usual time. If more than 16 hours have passed since Zepatier is usually taken, then the patient should be instructed that the missed dose should not be taken and to take the next dose per the usual dosing schedule. Patients should be instructed not to take a double dose.

Renal impairment.

In genotype 1 or 4 patients with severe renal impairment (eGFR) < 30 mL/min/1.73 m²) or with ESRD, including patients on dialysis, administer Zepatier without ribavirin according to the treatment duration in Table 1 (see Section 4.4 Special Warnings and Precautions for Use, Renal impairment). In genotype 1a or 4 patients with severe renal impairment or with ESRD who experienced on treatment-failure during prior peginterferon alfa + ribavirin or interferon only treatment, 12 weeks treatment duration of Zepatier may be considered.

Hepatic impairment.

No dosage adjustment of Zepatier is recommended in patients with mild hepatic impairment (Child-Pugh A). Zepatier is contraindicated in patients with moderate hepatic impairment (Child-Pugh B) due to a lack of clinical safety and efficacy experience in this patient population and the expected increase in grazoprevir plasma concentration. Zepatier is contraindicated in patients with severe hepatic impairment (Child-Pugh C) due to the expected significant increase in grazoprevir plasma concentration (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment).
The safety and efficacy of Zepatier have not been established in patients awaiting liver transplant or in liver transplant recipients. The plasma concentration of grazoprevir is increased if Zepatier is co-administered with ciclosporin. Co-administration with ciclosporin is contraindicated (see Section 4.3 Contraindications).

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

The safety and efficacy of Zepatier have not been studied in HCV/HBV co-infected patients. For dosing recommendations of HBV medicinal products, see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions and Table 3, Drug interactions.

Paediatric patients.

Safety and efficacy of Zepatier have not been established in paediatric patients less than 18 years of age.

Geriatric patients.

No dosage adjustment of Zepatier is recommended in geriatric patients (see Section 4.4 Special Warnings and Precautions for Use, Use in the elderly).

4.3 Contraindications

Zepatier is contraindicated in patients with known hypersensitivity to elbasvir, grazoprevir, or any of its components.
Zepatier is contraindicated in patients with moderate hepatic impairment (Child-Pugh B) due to a lack of clinical safety and efficacy experience in this patient population and the expected increase in grazoprevir plasma concentration. Zepatier is contraindicated in patients with severe hepatic impairment (Child-Pugh C) due to the expected significantly increased grazoprevir plasma concentration and the increased risk of alanine aminotransferase (ALT) elevations (see Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment).
Zepatier is contraindicated with inhibitors of organic anion transporting polypeptides 1B1/3 (OATP1B1/3) that are known or expected to significantly increase grazoprevir plasma concentrations, strong inducers of cytochrome P450 3A (CYP3A), and efavirenz (see Section 4.4 Special Warnings and Precautions for Use, Risk of adverse reactions or reduced therapeutic effect due to drug interactions; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Table 2 lists medicines that are contraindicated with Zepatier.
If Zepatier is administered with ribavirin, the contraindications to ribavirin also apply to this combination regimen. Refer to the ribavirin prescribing information for a list of contraindications for ribavirin.

4.4 Special Warnings and Precautions for Use

Hepatitis B virus (HBV) reactivation in patients co-infected with HCV and HBV.

Hepatitis B virus (HBV) reactivation has been reported in HCV/HBV co-infected patients who were undergoing or had completed treatment with HCV direct acting antivirals, and who were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure and death. Cases have been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in patients with serologic evidence of resolved HBV infection (i.e. HBsAg negative and hepatitis B core antibody (anti-HBc) positive). HBV reactivation has also been reported in patients receiving certain immunosuppressant or chemotherapeutic agents; the risk of HBV reactivation associated with treatment with HCV direct acting antivirals may be increased in these patients.
HBV reactivation is characterised as an abrupt increase in HBV replication manifesting as a rapid serum HBV DNA level. In patients with resolved HBV infection reappearance of HBsAg can occur. Reactivation of HBV replication may be accompanied by hepatitis, i.e. increase in aminotransferase levels; and, in severe cases, increases in bilirubin levels, liver failure and death can occur.
Test all patients for evidence of current or prior HBV infection by measuring HBsAg and anti-HBc before initiating treatment with Zepatier. In patients with serologic evidence of HBV infection - monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during HCV treatment with Zepatier and during post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated.

Increased risk of ALT elevations.

During clinical trials with Zepatier with or without ribavirin, < 1% of subjects experienced elevations of ALT from normal levels to greater than 5 times the upper limit of normal (ULN), generally at or after treatment week 8. ALT elevations were typically asymptomatic and most resolved with ongoing or completion of therapy. Higher rates of late ALT elevations occurred in females (2% [11/652]), Asians (2% [4/165]), and subjects aged ≥ 65 years (2% [3/187]) (see Section 4.8 Adverse Effects (Undesirable Effects)).
Hepatic laboratory testing should be performed prior to therapy, at treatment week 8, and as clinically indicated. For patients receiving 16 weeks of therapy, additional hepatic laboratory testing should be performed at treatment week 12.
Patients should be instructed to consult their healthcare professional without delay if they have onset of fatigue, weakness, lack of appetite, nausea and vomiting, jaundice or discoloured faeces.
Consider discontinuing Zepatier if ALT levels remain persistently greater than 10 times the ULN.
Discontinue Zepatier if ALT elevation is accompanied by signs or symptoms of liver inflammation or increasing conjugated bilirubin, alkaline phosphatase, or International Normalised Ratio (INR).

Risks associated with ribavirin combination.

If Zepatier is administered with ribavirin, the warnings and precautions for ribavirin, including the pregnancy avoidance warning, also apply to this combination regimen. Refer to the ribavirin prescribing information for a list of warnings and precautions for ribavirin.

Risk of adverse reactions or reduced therapeutic effect due to drug interactions.

OATP1B inhibitors.

Co-administration of Zepatier and OATP1B inhibitors that are known to or expected to significantly increase grazoprevir plasma concentrations is contraindicated (see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Strong CYP3A inducers or efavirenz.

The concomitant use of Zepatier and strong CYP3A inducers or efavirenz may significantly decrease elbasvir and grazoprevir plasma concentrations and may lead to a reduced therapeutic effect of Zepatier. Therefore, the use of Zepatier with strong CYP3A inducers or efavirenz is contraindicated (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Moderate CYP3A inducers.

The concomitant use of Zepatier and moderate CYP3A inducers may decrease elbasvir and grazoprevir plasma concentrations and may lead to a reduced therapeutic effect of Zepatier. Therefore, the use of Zepatier with moderate CYP3A inducers is not recommended (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Effects of other drugs on Zepatier and Table 3).

Strong CYP3A inhibitors.

The concomitant use of Zepatier and strong CYP3A inhibitors increases elbasvir and grazoprevir concentrations. Co-administration of Zepatier with certain strong CYP3A inhibitors is not recommended (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Effects of other drugs on Zepatier and Table 3). See Table 3 Drug interactions. Alteration in dose may be recommended or coadministration contraindicated based on results from drug interaction studies or predicted interactions for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Consider the potential for drug interactions prior to and during Zepatier therapy; review concomitant medications during Zepatier therapy; and monitor for the adverse reactions associated with the concomitant drugs (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
If Zepatier is co-administered with ribavirin, the information for ribavirin with regard to contraception, pregnancy testing, pregnancy, breast-feeding, and fertility also applies to this combination regimen (refer to the prescribing information of the co-administered medicinal product for additional information).

Use in hepatic impairment.

Use in renal impairment.

No dosage adjustment of Zepatier is recommended in patients with mild, moderate, or severe renal impairment. No dosage adjustment of Zepatier is recommended in patients who are on dialysis (including haemodialysis or peritoneal dialysis).
In patients with severe renal impairment (eGFR < 30 mL/min/1.73 m²) or with ESRD, including patients on dialysis, administer Zepatier without ribavirin (see Section 4.2 Dose and Method of Administration).

Use in the elderly.

No overall differences in safety or efficacy were observed between subjects aged 65 years and over and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.
Higher elbasvir and grazoprevir plasma concentrations were observed in subjects aged 65 years and over. No dosage adjustment of Zepatier is recommended in geriatric patients.

Paediatric use.

Safety and efficacy of Zepatier have not been established in paediatric patients less than 18 years of age.

Gender.

Higher elbasvir and grazoprevir plasma concentrations were observed in females compared to males. No dose adjustment of Zepatier is recommended based on gender.

Race.

Higher elbasvir and grazoprevir plasma concentrations were observed in Asians compared to Whites. No dose adjustment of Zepatier is recommended based on race/ ethnicity.

Other HCV genotypes.

The efficacy of Zepatier has not been established in patients infected with HCV genotypes 2, 3, 5 and 6 (see Section 4.1 Therapeutic Indications; Section 4.2 Dose and Method of Administration).

Effects on laboratory tests.

Please refer to "Increased risk of ALT elevations" subheading, see Section 4.4 Special Warnings and Precautions for Use for further information.

4.5 Interactions with Other Medicines and Other Forms of Interactions

See Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use, Risk of adverse reactions or reduced therapeutic effect due to drug interactions.
As Zepatier contains elbasvir and grazoprevir, interactions that have been identified with these agents individually may occur with Zepatier (see Section 5.2 Pharmacokinetic Properties, Drug interaction studies).

Effects of other drugs on Zepatier.

Grazoprevir is a substrate of OATP1B drug transporters. Co-administration of Zepatier with OATP1B inhibitors that are known or expected to significantly increase grazoprevir plasma concentrations is contraindicated (see Section 4.3 Contraindications).
Elbasvir and grazoprevir are substrates of CYP3A and P-gp. Co-administration of strong inducers of CYP3A or efavirenz with Zepatier may significantly decrease elbasvir and grazoprevir plasma concentrations, leading to reduced therapeutic effect of Zepatier. Co-administration of Zepatier with strong CYP3A inducers or efavirenz is contraindicated (see Section 4.3 Contraindications).
Co-administration of moderate inducers of CYP3A with Zepatier may decrease elbasvir and grazoprevir plasma concentrations, leading to reduced therapeutic effect of Zepatier. Co-administration of Zepatier with moderate CYP3A inducers is not recommended (see Section 4.4 Special Warnings and Precautions for Use, Risk of adverse reactions or reduced therapeutic effect due to drug interactions and Table 3).
Co-administration of Zepatier with strong CYP3A4 inhibitors increases elbasvir and grazoprevir plasma concentrations. Co-administration of Zepatier with certain strong CYP3A inhibitors is not recommended (see Section 4.4 Special Warnings and Precautions for Use, Risk of adverse reactions or reduced therapeutic effect due to drug interactions and Table 3). Co-administration of Zepatier with P-gp inhibitors is expected to have a minimal effect on the plasma concentrations of Zepatier.

Effects of Zepatier on other drugs.

Elbasvir and grazoprevir are inhibitors of the drug transporter breast cancer resistance protein (BCRP) at the intestinal level in humans and may increase plasma concentrations of co-administered BCRP substrates. Elbasvir is not a CYP3A inhibitor in vitro and grazoprevir is a weak, but not clinically relevant, CYP3A inhibitor in humans. Therefore, no dose adjustment is required for CYP3A substrates when co-administered with Zepatier.
Elbasvir has minimal intestinal P-gp inhibition in humans and grazoprevir is not a P-gp inhibitor in vitro. Therefore, P-gp substrates may be administered without dose adjustment when co-administered with Zepatier. Elbasvir and grazoprevir are not OATP1B inhibitors in humans. Clinically significant drug interactions with Zepatier as an inhibitor of other CYP enzymes, UGT1A1, esterases (CES1, CES2, and CatA), organic anion transporters (OAT)1 and OAT3, and organic cation transporters (OCT)2 are not expected, and multiple-dose administration of elbasvir or grazoprevir is unlikely to induce the metabolism of drugs metabolised by CYP isoforms based on in vitro data.
Clearance of HCV infection with direct acting antivirals (DAAs) may lead to changes in hepatic function, which may impact the safe and effective use of concomitant medications. For example, altered blood glucose control resulting in serious symptomatic hypoglycaemia has been reported in diabetic patients in post-marketing case reports and published epidemiological studies. Management of hypoglycaemia in these cases required either discontinuation or dose modification of concomitant medications used for diabetes treatment. Glucose levels of diabetic patients initiating DAA therapy should be closely monitored, particularly within the first 3 months, and their diabetic medication modified when necessary. The physician in charge of the diabetic care of the patient should be informed when DAA therapy is initiated.
Frequent monitoring of relevant laboratory parameters (e.g. International Normalized Ratio [INR] in patients taking vitamin K antagonists, blood glucose levels in diabetic patients) or drug concentrations of concomitant medications such as CYP3A substrates with a narrow therapeutic index (e.g. certain immunosuppressants) is recommended to ensure safe and effective use. Dose adjustments of concomitant medications may be necessary.

Established and other potential drug interactions.

If dose adjustments of concomitant medications are made due to treatment with Zepatier, doses should be readjusted after administration of Zepatier is completed.
Table 3 provides a listing of established or potentially clinically significant drug interactions. The drug interactions described are based on studies conducted with either Zepatier, the components of Zepatier (elbasvir [EBR] and grazoprevir [GZR]) as individual agents, or are predicted drug interactions that may occur with Zepatier (see Section 4.4 Special Warnings and Precautions for Use, Risk of adverse reactions or reduced therapeutic effect due to drug interactions).

Drugs without clinically significant interactions with Zepatier.

The interaction between the components of Zepatier (elbasvir or grazoprevir) or Zepatier and the following drugs were evaluated in clinical studies, and no dose adjustments are needed when Zepatier is used with the following drugs individually: acid reducing agents (proton pump inhibitors, H2 blockers, antacids), buprenorphine/ naloxone, digoxin, dolutegravir, methadone, mycophenolate mofetil, oral contraceptive pills, phosphate binders, pitavastatin, pravastatin, prednisone, raltegravir, ribavirin, rilpivirine, tenofovir disoproxil fumarate, and sofosbuvir.
No clinically relevant drug drug interaction is expected when Zepatier is co-administered with abacavir, emtricitabine, entecavir, and lamivudine.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No human data on the effect of elbasvir or grazoprevir on fertility are available. No effects on mating, female or male fertility, or early embryonic development were observed in rats up to the highest oral doses tested (1000 mg/kg/day elbasvir, 200 mg/kg grazoprevir twice daily). AUC exposure to elbasvir and grazoprevir was approximately 7- and 107-fold, respectively, the exposure in humans at the recommended clinical dose.

Use with ribavirin.

In fertility studies in animals, ribavirin caused reversible testicular toxicity in males. Refer to the product information for ribavirin for additional information.
(Category B1)
There are no adequate and well controlled studies with Zepatier in pregnant women. No effects on embryofoetal development were observed in rats or rabbits at elbasvir or grazoprevir exposures higher than exposures in humans at the recommended clinical dose. Because animal reproduction studies are not always predictive of human response, Zepatier should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Elbasvir.

No effects on embryofoetal development or maternal toxicity have been observed in rats or rabbits when dams were administered elbasvir up to the highest dose tested (1000 mg/kg/day PO to rats and rabbits) during early embryonic development (rats), organogenesis (rats and rabbits), or perinatal period (rats). In the rat and rabbit, AUC exposure to elbasvir was approximately 9- and 17-fold, respectively, the exposure in humans at the recommended clinical dose. In both species, elbasvir has been shown to cross the placenta.

Grazoprevir.

No effects on embryofoetal development or maternal toxicity have been observed in rats or rabbits when dams were administered grazoprevir up to the highest dose tested (200 mg/kg PO bid in rats, 100 mg /kg/day IV in rabbits) during early embryonic development (rats), organogenesis (rats and rabbits), or perinatal period (rats). In the rat and rabbit, AUC exposure to grazoprevir was approximately 110- and 37-fold, respectively, the exposure in humans at the recommended clinical dose. In both species, grazoprevir has been shown to cross the placenta.

Use with ribavirin (Pregnancy category X).

Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin. When Zepatier 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 Zepatier, the contraindications regarding use of ribavirin apply (refer to ribavirin product information).
There are no human data to assess whether Zepatier is excreted in human breast milk. Elbasvir and grazoprevir are excreted in the milk of lactating rats. Concentrations of elbasvir were higher and concentrations of grazoprevir were lower in breast milk than maternal plasma in rats. No effects on postnatal development were observed in nursing rats when lactating dams were exposed to elbasvir or grazoprevir.
The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Zepatier and any potential adverse effects on the breastfed child from Zepatier or from the underlying maternal condition.

Elbasvir.

No effects on postnatal development in nursing rats and no maternal toxicity have been observed when lactating dams were administered elbasvir up to the highest oral dose tested (1000 mg/kg/day). AUC exposure to elbasvir was approximately 9-fold the exposure in humans at the recommended clinical dose. Elbasvir has been shown to be excreted into the milk of lactating rats. Elbasvir was excreted into the milk of lactating rats with concentrations 4-fold that of the maternal plasma concentrations.

Grazoprevir.

No effects on postnatal development in nursing rats and no maternal toxicity have been observed when lactating dams were administered grazoprevir up to the highest oral dose tested (200 mg/kg bid). AUC exposure to grazoprevir was approximately 110-fold the exposure in humans at the recommended clinical dose. Grazoprevir has been shown to be excreted into the milk of lactating rats. Grazoprevir was excreted into the milk of lactating rats with concentrations approximately 60-80% of the maternal plasma concentrations.

Use with ribavirin.

Refer to the product information for ribavirin.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

If Zepatier is administered with ribavirin, refer to the prescribing information for ribavirin for a list of ribavirin associated adverse reactions.

Clinical trials experience.

Adults.

The safety of Zepatier was assessed based on 2 placebo controlled trials and 8 uncontrolled Phase 2 and 3 clinical trials in approximately 2000 subjects with chronic hepatitis C infection with compensated liver disease (with or without cirrhosis).

Adverse reactions in subjects receiving Zepatier alone.

C-EDGE TN was a Phase 3 placebo controlled trial in treatment naïve (TN) subjects. Adverse reactions (adverse events assessed as causally related by the investigator, all grades) occurring in C-EDGE TN at ≥ 5% frequency in subjects treated with Zepatier for 12 weeks are presented in Table 4. No subjects treated with Zepatier or placebo had serious adverse reactions. The proportion of subjects treated with Zepatier or placebo who permanently discontinued treatment due to adverse reactions was < 1% and 1%, respectively.
Adverse reactions occurring in a pooled analysis of Phase 2 and 3 clinical trials at ≥ 5% frequency in subjects treated with Zepatier for 12 weeks are presented in Table 4. The majority of the adverse reactions were mild in severity. No subjects treated with Zepatier had serious adverse reactions. The proportion of subjects who permanently discontinued treatment due to adverse reactions was < 1%. The type and severity of adverse reactions in subjects with cirrhosis were comparable to those seen in subjects without cirrhosis.

The type and severity of adverse reactions were comparable among subjects treated with 8, 12 or 16 weeks of Zepatier.

Adverse reactions in subjects receiving Zepatier with ribavirin.

C-EDGE TE was a Phase 3 open label trial in treatment experienced (TE) subjects. Adverse reactions occurring in C-EDGE TE at ≥ 5% frequency in subjects treated with Zepatier with ribavirin for 16 weeks are presented in Table 5.
The majority of the adverse reactions were mild in severity. The proportion of subjects treated with Zepatier with ribavirin with serious adverse reactions was < 1%. The portion of subjects who permanently discontinued treatment due to adverse reactions was 2%. The type and severity of adverse reactions in subjects with cirrhosis were comparable to those seen in subjects without cirrhosis.

Laboratory abnormalities in subjects receiving Zepatier with or without ribavirin.

Serum late ALT elevations.

During clinical trials with Zepatier with or without ribavirin, regardless of treatment duration, < 1% (13/1690) of subjects experienced elevations of ALT from normal levels to greater than 5 times the ULN, generally at or after treatment week 8 (mean onset time 10 weeks, range 6-12 weeks). These late ALT elevations were typically asymptomatic. Most late ALT elevations resolved with ongoing therapy with Zepatier or after completion of therapy (see Section 4.4 Special Warnings and Precautions for Use, Increased risk of ALT elevations). The frequency of late ALT elevations was higher in subjects with higher grazoprevir plasma concentration (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). The incidence of late ALT elevations was not affected by treatment duration. Cirrhosis was not a risk factor for late ALT elevations.

Serum bilirubin elevations.

During clinical trials with Zepatier with or without ribavirin, regardless of treatment duration, elevations in bilirubin at greater than 2.5 times ULN were observed in 6% of subjects receiving Zepatier with ribavirin compared to < 1% in those receiving Zepatier alone. These bilirubin increases were predominately indirect and generally observed in association with ribavirin co-administration. Bilirubin elevations were typically not associated with serum ALT elevations.

Decreased haemoglobin.

During clinical trials with Zepatier with or without ribavirin, the mean change from baseline in haemoglobin levels in subjects treated with Zepatier for 12 weeks was - 0.3 g/dL and with Zepatier with ribavirin for 16 weeks was approximately - 2.2 g/dL. Haemoglobin declined during the first 8 weeks of treatment, remained low during the remainder of treatment, and normalised to baseline levels during follow-up. Less than 1% of subjects treated with Zepatier with ribavirin had haemoglobin levels decrease to less than 8.5 g/dL during treatment. No subjects treated with Zepatier alone had a haemoglobin level less than 8.5 g/dL.

Zepatier in subjects with HCV/HIV-1 co-infection.

Zepatier and Zepatier with ribavirin were assessed in 298 subjects with HCV/HIV-1 co-infection. The type and severity of adverse reactions in subjects with HCV/HIV-1 co-infection were comparable to subjects without HCV/HIV-1 co-infection. Median increase in CD4+ T-cell counts of 32 cells/mm³ was observed at the end of 12 weeks of treatment with Zepatier alone. Median decrease in CD4+ T-cell counts of 135 cells/mm³ was observed at the end of 16 weeks of treatment with Zepatier with ribavirin. No subject experienced an AIDS-related opportunistic infection.

Zepatier in subjects with advanced chronic kidney disease.

The safety of elbasvir and grazoprevir in comparison to placebo in subjects with advanced chronic kidney disease (severe renal impairment or ESRD, including patients on dialysis) and genotype 1 chronic hepatitis C infection with compensated liver disease (with or without cirrhosis) was assessed in 235 subjects (C-SURFER). The adverse reactions occurring at ≥ 5% frequency in subjects treated with Zepatier for 12 weeks are presented in Table 6. The majority of the adverse reactions were mild in severity. The proportion of subjects treated with Zepatier or placebo with serious adverse reactions was 0% and < 1%, respectively, and 0% and 3% of subjects permanently discontinued treatment due to adverse reactions in each treatment arm.

Adverse reactions in subjects receiving Zepatier with sofosbuvir.

The safety of Zepatier with sofosbuvir in treatment naive subjects with chronic hepatitis C infection was assessed in 143 subjects (C-SWIFT). No adverse reactions were reported at a greater than 5% frequency. The most commonly reported adverse reactions ≥ 2% of subjects were nausea (2%) and headache (3%). No subjects treated with Zepatier with sofosbuvir had serious adverse reactions and no subjects permanently discontinued treatment due to adverse reactions.

Reporting suspected adverse 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 http://www.tga.gov.au/reporting-problems.

4.9 Overdose

Human experience of overdose with Zepatier is limited. No specific antidote is available for overdose with Zepatier. In case of overdose, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment instituted.
Haemodialysis does not remove elbasvir or grazoprevir since elbasvir and grazoprevir are highly bound to plasma protein.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

Pharmacotherapeutic group.

Antivirals for systemic use; direct acting antivirals, antivirals for treatment of HCV infections, other antivirals. ATC code: J05AP54.

5.1 Pharmacodynamic Properties

Mechanism of action.

Zepatier is a fixed-dose combination of elbasvir and grazoprevir which are direct-acting antiviral agents against the hepatitis C virus (see Section 5.1 Pharmacodynamic Properties, Microbiology, Mechanism of action).
Elbasvir is an HCV NS5A inhibitor and grazoprevir is a hepatitis C virus (HCV) NS3/4A protease inhibitor.

Cardiac electrophysiology.

Thorough QT studies have been conducted for elbasvir and grazoprevir.
The effect of elbasvir 700 mg on the QTc interval was evaluated in a randomised, single-dose, placebo- and active-controlled (moxifloxacin 400 mg) 3-period crossover thorough QT trial in 42 healthy subjects. At a plasma concentration 3 to 4 times the therapeutic plasma concentration, elbasvir does not prolong QTc to any clinically relevant extent.
The effect of grazoprevir 1600 mg on QTc interval was evaluated in a randomised, single-dose, placebo- and active-controlled (moxifloxacin 400 mg) 3-period crossover thorough QT trial in 41 healthy subjects. At a plasma concentration 40 times the therapeutic plasma concentration, grazoprevir does not prolong QTc to any clinically relevant extent.

Microbiology.

Zepatier combines two direct-acting antiviral agents with distinct mechanisms of action and non-overlapping resistance profiles to target HCV at multiple steps in the viral lifecycle.
Elbasvir is an inhibitor of HCV NS5A, which is essential for viral RNA replication and virion assembly. The mechanism of action of elbasvir has been characterised based on cell culture antiviral activity and drug resistance mapping studies.
Grazoprevir is an inhibitor of the HCV NS3/4A protease which is necessary for the proteolytic cleavage of the HCV encoded polyprotein (into mature forms of the NS3, NS4A, NS4B, NS5A, and NS5B proteins) and is essential for viral replication. In a biochemical assay, grazoprevir inhibited the proteolytic activity of the recombinant NS3/4A protease enzymes from HCV genotypes 1a, 1b, 2, 3, 4, 5, and 6, with IC₅₀ values ranging from 4 to 690 picoM.

Antiviral activity.

In HCV replicon assays, the EC₅₀ values of elbasvir against full-length replicons from genotypes 1a, 1b, 2a, 3a, 4, 5, and chimeric replicons from genotype 6, were 0.004 nanoM, 0.003 nanoM, 0.003 nanoM, 0.14 nanoM, 0.0003 nanoM, 0.001 nanoM, and 0.009 nanoM, respectively. The median EC₅₀ values of elbasvir against chimeric replicons encoding NS5A sequences from clinical isolates were 0.005 nanoM for genotype 1a (range 0.003-0.009 nanoM; N = 5), 0.009 nanoM for genotype 1b (range 0.005-0.010 nanoM; N = 4), 1.85 nanoM for genotype 2 (range 0.003-20 nanoM; N = 6), 0.02 nanoM for genotype 3a (range 0.01-0.33 nanoM; N = 9), 0.0007 nanoM for genotype 4 (range 0.0002-34 nanoM; N = 14), 0.0007 nanoM for genotype 5 (range 0.0004-43 nanoM; N = 11), and 0.016 nanoM for genotype 6 (range 0.002-2.7 nanoM; N = 11).
In HCV replicon assays, the EC₅₀ values of grazoprevir against full-length replicons from genotypes 1a, 1b, 2, 3, 4, and 5, and chimeric replicons from genotype 6, were 0.4 nanoM, 0.5 nanoM, 2.3 nanoM, 35 nanoM, 0.3 nanoM, 1.5 nanoM, and 0.9 nanoM, respectively.
The median EC₅₀ values of grazoprevir against chimeric replicons encoding NS3/4A sequences from clinical isolates were 0.8 nanoM for genotype 1a (range 0.4-5.1 nanoM; N = 10), 0.3 nanoM for genotype 1b (range 0.2-5.9 nanoM; N = 9), 2.9 nanoM for genotype 2 (range 2.3-3.7 nanoM; N = 3), 5.85 nanoM for genotype 3 (range 2.1-7.6 nanoM; N = 6), 0.2 nanoM for genotype 4 (range 0.11-0.33 nanoM; N = 5), 1.5 nanoM for genotype 5 (range 0.4-6.6 nanoM; N = 5), and 0.2 nanoM for genotype 6 (range 0.1-0.9 nanoM; N = 9).
Evaluation of elbasvir in combination with grazoprevir, ribavirin, or sofosbuvir showed no antagonistic effect in reducing HCV RNA levels in replicon cells. Evaluation of grazoprevir in combination with ribavirin or sofosbuvir showed no antagonistic effect in reducing HCV RNA levels in replicon cells.

Resistance.

In Cell Culture. HCV replicons with reduced susceptibility to elbasvir and grazoprevir have been selected in cell culture for genotypes 1a, 1b, 3, 4, and 6.
For elbasvir, in HCV genotype 1a replicons, single NS5A substitutions Q30D/E/H/R, L31M/V and Y93C/H/N reduced elbasvir antiviral activity by 6- to 2000-fold. In genotype 1b replicons, single NS5A substitutions L31F and Y93H reduced elbasvir antiviral activity by 17-fold. In genotype 3 replicons, single NS5A substitution Y93H reduced elbasvir antiviral activity by 485-fold. In genotype 4 replicons, single NS5A substitutions L30S, M31V, and Y93H reduced elbasvir antiviral activity by 3 to 23-fold. In general, in HCV genotype 1a, 1b or 4 replicons, combinations of elbasvir resistance-associated substitutions further reduced elbasvir antiviral activity.
For grazoprevir, in HCV genotype 1a replicons, single NS3 substitutions D168A/E/G/S/V reduced grazoprevir antiviral activity by 2 to 81-fold. In genotype 1b replicons, single NS3 substitutions F43S, A156S/T/V, and D168A/G/V reduced grazoprevir antiviral activity by 2 to 375-fold. In genotype 3 replicons, single NS3 substitutions N77S, V163I, Q168R and Q178R reduced grazoprevir antiviral activity by 3- to 7-fold. In genotype 4 replicons, single NS3 substitutions D168A/V reduced grazoprevir antiviral activity by 110- to 320-fold. In general, in HCV genotype 1a, 1b or 4 replicons, combinations of grazoprevir resistance-associated substitutions further reduced grazoprevir antiviral activity.
In clinical studies. In a pooled analysis of genotype 1 or 4 subjects treated with regimens containing Zepatier or elbasvir + grazoprevir with or without ribavirin in Phase 2 and 3 clinical trials, resistance analyses were conducted for 50 subjects who experienced virologic failure and had sequence data available (6 with on-treatment virologic failure, 44 with post-treatment relapse).
Treatment-emergent substitutions observed in the viral populations of these subjects based on genotypes are shown in Table 7. Treatment-emergent substitutions were detected in both HCV drug targets in 23/37 (62%) genotype 1a, 1/8 (13%) genotype 1b and 2/5 (40%) genotype 4 subjects.

In an analysis of genotype 3 subjects treated with Zepatier and sofosbuvir for 12 weeks in a Phase 2 clinical study, one subject experienced relapse. This subject had a treatment-emergent NS5A Y93H substitution.

In vitro cross resistance.

Elbasvir is active in vitro against genotype 1a NS5A substitutions, M28V and Q30L, genotype 1b substitutions, L28M/V, R30Q, L31V, Y93C, and genotype 4 substitution, M31V which confer resistance to other NS5A inhibitors. In general, other NS5A substitutions conferring resistance to NS5A inhibitors may also confer resistance to elbasvir. NS5A substitutions conferring resistance to elbasvir may reduce the antiviral activity of other NS5A inhibitors. Elbasvir is fully active against substitutions conferring resistance to NS3/4A protease inhibitors.
Grazoprevir is active in vitro against the following genotype 1a NS3 substitutions which confer resistance to other NS3/4A protease inhibitors: V36A/L/M, Q41R, F43L, T54A/S, V55A/I, Y56F, Q80K/R, V107I, S122A/G/R/T, I132V, R155K, A156S, D168N/S, I170T/V. Grazoprevir is active in vitro against the following genotype 1b NS3 substitutions conferring resistance to other NS3/4A protease inhibitors: V36A/I/L/M, Q41L/R, F43S, T54A/C/G/S, V55A/I, Y56F, Q80L/R, V107I, S122A/G/R, R155E/K/N/Q/S, A156G/S, D168E/N/S, V170A/I/T. Some NS3 substitutions at A156 and at D168 confer reduced antiviral activity to grazoprevir as well as to other NS3/4A protease inhibitors. Grazoprevir is fully active against resistance-associated variants selected by NS5A inhibitors.
The substitutions associated with resistance to NS5B inhibitors are susceptible to elbasvir or grazoprevir.

Persistence of resistance-associated substitutions.

The persistence of elbasvir and grazoprevir treatment-emergent amino acid substitutions in NS5A and NS3 respectively, was assessed in genotype 1-infected subjects in Phase 2 and 3 trials whose virus had treatment-emergent resistance-associated substitution in the drug target and with available data through at least 24 weeks post-treatment.
Treatment-emergent NS5A resistance-associated substitutions were generally more persistent than NS3 resistance-associated substitutions. Among genotype 1-infected subjects who had one or more treatment emergent NS5A resistance-associated substitutions, these substitutions became undetectable at follow-up week 12 in only 5% (2/44) of subjects and 0% (0/12) of subjects with follow-up week 24 data.
Among genotype 1-infected subjects with treatment-emergent NS3 resistance-associated substitutions, these substitutions became undetectable at follow-up week 24 in 67% (10/15) of subjects based on population sequencing.
Due to the limited number of genotype 3- and 4-infected subjects with treatment-emergent NS5A and NS3 resistance-associated substitutions, trends in persistence of treatment-emergent substitutions in these genotypes could not be established.

Effect of baseline HCV polymorphisms on treatment response.

Analyses in Phase 2 and 3 clinical studies of Zepatier, or elbasvir + grazoprevir, with or without ribavirin were conducted to explore the association between baseline NS5A and/or NS3 polymorphisms and treatment response among subjects who achieved SVR or experienced virologic failure (see Section 5.1 Pharmacodynamic Properties, Clinical trials) and for whom baseline sequences were available. Baseline NS5A polymorphism at position 28, 30, 31, 58, and 93 were evaluated. Compared to a reference HCV genotype 1a replicon, the following NS5A substitutions reduced elbasvir antiviral activity by greater than 5-fold: M28T/A, Q30E/H/R/G/K/D, L31M/V/F, H58D, and Y93C/H/N. Baseline NS3 polymorphisms at position 36, 54, 55, 56, 80, 107, 122, 132, 155, 156, 158, 168, 170, and 175 were evaluated.

Genotype 1a.

In pooled analyses of genotype 1a-infected subjects, baseline NS5A polymorphisms that confer greater than 5-fold reduction of elbasvir antiviral activity in vitro were identified in 6% (29/491) of treatment-naive subjects and 8% (26/334) of treatment-experienced subjects. Among treatment-naive subjects, SVR was achieved in 98% (432/439) of subjects without baseline NS5A polymorphisms and 55% (16/29) of subjects with baseline NS5A polymorphisms that confer greater than 5-fold reduction of elbasvir antiviral activity in vitro. Among treatment-experienced subjects, SVR was achieved in 99% (291/295) of subjects without baseline NS5A polymorphisms and 50% (13/26) of subjects with baseline NS5A polymorphisms that confer greater than 5-fold reduction of elbasvir antiviral activity in vitro.
In pooled analyses, presence of NS3 polymorphisms, including Q80K, prior to the start of therapy did not impact treatment response among genotype 1a-infected subjects.

Genotype 1b.

In pooled analyses, presence of NS5A polymorphisms prior to the start of therapy did not impact treatment response among treatment-naive genotype 1b-infected subjects. NS5A polymorphisms that confer greater than 5-fold reduction of elbasvir antiviral activity in vitro were detected in 14% (36/259) of treatment-experienced subjects. SVR was achieved in 100% (223/223) of subjects without baseline NS5A polymorphisms and 86% (31/36) of subjects with baseline NS5A polymorphisms that confer greater than 5-fold reduction of elbasvir antiviral activity in vitro.
In pooled analyses, presence of NS3 polymorphisms prior to the start of therapy did not impact treatment response among genotype 1b-infected subjects.

Genotype 4.

In pooled analyses, presence of NS5A polymorphisms prior to the start of therapy did not impact treatment response among genotype 4-infected subjects.
In pooled analyses, presence of NS3 polymorphisms prior to the start of therapy did not impact treatment response among treatment-naive, genotype 4-infected subjects. Baseline NS3 polymorphisms were identified by population sequencing in 19% (7/36) of treatment-experienced genotype 4-infected subjects. In these subjects, SVR was achieved in 100% (7/7) of subjects with baseline NS3 polymorphisms compared with 86% (25/29) in those without baseline NS3 polymorphism.

Genotype 3.

In a Phase 2 study (C-SWIFT) of Zepatier with sofosbuvir, presence of NS5A polymorphisms prior to the start of therapy did not impact treatment response among genotype 3-infected subjects. Baseline NS5A polymorphisms were identified by population sequencing in 12% (3/25) of treatment-naive genotype 3 infected subjects. In these subjects, SVR was achieved in 100% (3/3) of subjects with baseline NS5A polymorphisms compared with 95% (21/22) in those without baseline NS5A polymorphism.
In this analysis, presence of NS3 polymorphisms prior to the start of therapy did not impact treatment response among treatment-naive, genotype 3-infected subjects.
No subject had NS5B polymorphisms detected at baseline.

Clinical trials.

The safety and efficacy of Zepatier or elbasvir + grazoprevir were evaluated in 8 clinical trials in approximately 1800 subjects with genotype (GT) 1, 3, 4, or 6 chronic hepatitis C (CHC) infection with compensated liver disease (with and without cirrhosis). An overview of the trials is provided in Table 8.

C-EDGE TN was a randomised, double-blind, placebo-controlled trial in treatment-naive subjects with genotype 1, 4, or 6 infection with or without cirrhosis. Subjects were randomised in a 3:1 ratio to: Zepatier for 12 weeks (immediate treatment group) or placebo for 12 weeks followed by open-label treatment with Zepatier for 12 weeks (deferred treatment group).
C-EDGE COINFECTION was an open-label trial in treatment-naive HCV/HIV-1 co-infected subjects with genotype 1, 4, or 6 infection with or without cirrhosis. Subjects received Zepatier for 12 weeks.
C-SURFER was a randomised, double-blind, placebo-controlled trial in subjects with genotype 1 infection, with or without cirrhosis, with chronic kidney disease (CKD) Stage 4 (eGFR 15-29 mL/min/1.73 m²) or Stage 5 (eGFR < 15 mL/min/1.73 m²), including subjects on haemodialysis, who were treatment-naive or who had failed prior therapy with IFN or peg-IFN ± RBV therapy. Subjects were randomised in a 1:1 ratio to one of the following treatment groups: EBR + GZR for 12 weeks (immediate treatment group) or placebo for 12 weeks followed by open-label treatment with EBR + GZR for 12 weeks (deferred treatment group). In addition, 11 subjects received open-label EBR + GZR for 12 weeks (intensive PK arm).
C-WORTHY was a multi-arm, multi-stage, randomised, open-label trial which included subjects with genotype 1 or 3 infection who were treatment-naive or who had failed prior therapy with peg-IFN ± RBV therapy. In the stage evaluating shorter duration of therapy in subjects with genotype 1b infection without cirrhosis, subjects were randomised in a 1:1 ratio to EBR + GZR with or without RBV for 8 weeks. In the stage evaluating subjects with genotype 3 infection without cirrhosis who were treatment-naive, subjects were randomised to EBR + GZR with RBV for 12 or 18 weeks. In the other stages, subjects with GT 1 infection with or without cirrhosis who were treatment-naive (with or without HCV/HIV-1 co-infection) or who were peg-IFN + RBV null responders, were randomised to EBR + GZR with or without RBV for 8, 12 or 18 weeks.
C-SCAPE was a randomised, open-label trial which included treatment-naive subjects with genotype 4 or 6 infection without cirrhosis. Subjects were randomised in a 1:1 ratio to EBR + GZR for 12 weeks or EBR + GZR + RBV for 12 weeks.
C-EDGE TE was a randomised, open-label trial in subjects with genotype 1, 4, or 6 infection, with or without cirrhosis, with or without HCV/HIV-1 co-infection, who had failed prior therapy with peg-IFN + RBV therapy. Subjects were randomised in a 1:1:1:1 ratio to one of the following treatment groups: Zepatier for 12 weeks, Zepatier + RBV for 12 weeks, Zepatier for 16 weeks, or Zepatier + RBV for 16 weeks.
C-SALVAGE was an open-label trial in subjects with genotype 1 infection, with or without cirrhosis, who had failed prior treatment with boceprevir, simeprevir, or telaprevir in combination with peg-IFN + RBV. Subjects received EBR + GZR + RBV for 12 weeks.
C-SWIFT was an open-label trial of Zepatier + sofosbuvir in treatment-naive subjects with genotype 1 or 3 infection. Non-cirrhotic genotype 3 infected subjects, were randomised (1:1) to 8 or 12 weeks of treatment, and cirrhotic genotype 3 infected subjects received 12 weeks of treatment. Non-cirrhotic genotype 1 infected subjects, were randomised (1:1) to 4 or 6 weeks of treatment, and cirrhotic genotype 1 infected subjects were randomised (1:1) to 6 or 8 weeks of treatment.
Sustained virologic response was the primary endpoint in all trials and was defined as HCV RNA less than lower limit of quantification (LLOQ) at 12 weeks after the cessation of treatment (SVR). Serum HCV RNA values were measured during these clinical trials using the COBAS AmpliPrep/COBAS Taqman HCV test (version 2.0) with an LLOQ of 15 HCV RNA IU/mL, with the exception of C-WORTHY and C-SCAPE where the assay had an LLOQ of 25 HCV RNA IU/mL.

Clinical trials in treatment-naive subjects with genotype 1 or 4 chronic hepatitis C infection.

Treatment-naive subjects with genotype 1, 4, or 6 chronic hepatitis C infection treated with Zepatier for 12 weeks in C-EDGE TN, C-EDGE COINFECTION, C-SURFER, C-WORTHY, and C-SCAPE had a median age of 53 years (range: 20 to 82); 67% of the subjects were male; 67% were White; 21% were Black or African American; 8% were Hispanic or Latino; mean body mass index was 26 kg/m²; 66% had baseline HCV RNA levels greater than 800,000 IU/mL; 18% had cirrhosis; 68% had non-C/C IL28B alleles (CT or TT); 33% had HCV/HIV-1 co-infection; and 91% had genotype 1, 7% had genotype 4, and 2% had genotype 6 chronic hepatitis C infection.
Table 9 presents treatment outcomes for Zepatier in treatment-naive subjects from C-EDGE TN, C-EDGE COINFECTION, C-SURFER, C-WORTHY, and C-SCAPE trials and from the pooled data from these trials. In trials C-EDGE TN and C-SURFER, the treatment outcomes for subjects treated with Zepatier in the immediate treatment groups and intensive PK arm are presented. In the C-WORTHY and C-SCAPE trials, the addition of RBV to the regimens was not shown to improve the treatment outcomes. Therefore, only the 12 weeks treatment arms without RBV are presented in Table 9.

No HIV-1 infected subjects switched their antiretroviral therapy regimen due to loss of plasma HIV-1 RNA suppression. In treatment-naive subjects, treatment outcomes were consistent in subjects with or without compensated cirrhosis and in subjects with or without HCV/HIV-1 co-infection. Treatment outcomes were consistent in subjects with or without advanced CKD, including subjects on haemodialysis.

Clinical trial with 8 week treatment in treatment-naive subjects without cirrhosis with genotype 1b chronic hepatitis C infection.

An 8-week treatment regimen with Zepatier has been evaluated in a limited number of non-cirrhotic patients with GT1b infection. In the C-WORTHY trial, 31 treatment-naive subjects with genotype 1b CHC without cirrhosis were treated with EBR + GZR with or without RBV for 8 weeks. In subjects treated with EBR + GZR without RBV, the subjects had a median age of 56 years (range: 28 to 71); 42% of the subjects were male; 81% were White; 19% were Black or African American; 3% were Hispanic or Latino; mean body mass index was 28 kg/m²; 87% had baseline HCV RNA levels greater than 800,000 IU/mL; and 90% had non-C/C IL28B alleles (CT or TT). By liver biopsy or non-invasive tests, all were non-cirrhotic and 94% (29/31) had METAVIR scores of F0-F2 and the other 2 subjects had a METAVIR score of F3.
Overall SVR was achieved in 94% (29/31) in treatment-naive subjects with genotype 1b without cirrhosis who received EBR + GZR for 8 weeks. Two of the thirty one subjects did not achieve SVR due to relapse. SVR was achieved in 97% (28/29) of subjects with METAVIR scores of F0-F2 and 50% (1/2) subjects with METAVIR score of F3. The addition of RBV was not shown to improve the treatment outcomes observed with EBR + GZR.

Clinical trials in treatment-experienced subjects with genotype 1 or 4 chronic hepatitis C infection.

C-EDGE TE trial. Treatment-experienced subjects who failed prior Peg-IFN with RBV therapy.

In the C-EDGE TE trial, treatment-experienced subjects who failed prior Peg-IFN with RBV therapy with genotype 1, 4, or 6 chronic hepatitis C infection had a median age of 56 years (range: 19 to 77); 65% of the subjects were male; 68% were White; 17% were Black or African American; 9% were Hispanic or Latino; mean body mass index was 27 kg/m²; 75% had baseline HCV RNA levels greater than 800,000 IU/mL; 35% had cirrhosis; 79% had non-C/C IL28B alleles (CT or TT); 5% had HCV/HIV-1 co-infection; 90% had genotype 1, 9% had genotype 4, and 1% had genotype 6 chronic hepatitis C infection.
Treatment outcomes in subjects treated with Zepatier with or without RBV for 12 or 16 weeks are presented in Table 10.

Overall SVR was achieved in 92% and 97% of subjects receiving Zepatier for 12 weeks and Zepatier + RBV for 16 weeks, respectively. SVR was 100% in prior relapsers who received Zepatier for 12 weeks, regardless of genotype or presence of cirrhosis. SVR was 100% in genotype 1b subjects who received Zepatier for 12 weeks, regardless of the presence of cirrhosis or response to prior HCV therapy.
Among genotype 1a or 4, null or partial responders, the highest response was achieved with the administration of Zepatier + RBV for 16 weeks. In subjects receiving Zepatier + RBV for 16 weeks, treatment outcomes were consistent in subjects with or without cirrhosis, and no subject failed due to virologic failure. Among genotype 1a or 4, null or partial responders, SVR was achieved in 93% of subjects receiving Zepatier + RBV for 16 weeks; 90% in subjects receiving Zepatier alone for 16 weeks; 90% in subjects receiving Zepatier + RBV for 12 weeks; and 84% in subjects receiving Zepatier alone for 12 weeks.
No HIV-1 virological failures were observed in subjects who failed prior peg-IFN + RBV with HCV/HIV-1 co-infection. In treatment-experienced subjects, treatment outcomes were consistent in subjects with or without compensated cirrhosis and in subjects with or without HCV/HIV-1 co-infection.

C-SALVAGE trial. Treatment-experienced subjects who failed prior Peg-IFN + RBV + HCV protease inhibitor therapy (Boceprevir, Simeprevir, or Telaprevir).

In the C-SALVAGE trial, subjects who failed prior peg-IFN + RBV with an HCV protease inhibitor with genotype 1 infection with or without cirrhosis treated with EBR + GZR + RBV for 12 weeks had a median age of 55 years (range: 23 to 75); 58% of the subjects were male; 97% were White; 3% were Black or African American; 15% were Hispanic or Latino; mean body mass index was 28 kg/m²; 63% had baseline HCV RNA levels greater than 800,000 IU/mL; 43% had cirrhosis; 97% had non-C/C IL28B alleles (CT or TT); and 46% had baseline NS3 resistance-associated substitutions.
Overall SVR was achieved in 96% (76/79) of subjects receiving EBR + GZR + RBV for 12 weeks. Four percent (3/79) of subjects did not achieve SVR due to relapse. Treatment outcomes were consistent in genotype 1a and genotype 1b subjects, in subjects with different response to previous HCV therapy, and in subjects with or without cirrhosis. Treatment outcomes were consistent in subjects with or without NS3 resistance associated substitutions at baseline (see Section 5.1 Pharmacodynamic Properties, Microbiology, Resistance).
Based on the lack of impact of baseline NS3 resistance-associated substitutions on treatment outcomes, and efficacy analyses among treatment-experienced subjects in the C-SALVAGE and C-EDGE TE trials, the recommended treatment regimen for treatment-experienced patients who have failed peg-IFN + RBV with boceprevir, simeprevir or telaprevir is as follows: for genotype 1 relapsers, administer Zepatier for 12 weeks; for genotype 1b prior on-treatment virologic failures, administer Zepatier for 12 weeks; and for genotype 1a prior on-treatment virologic failures, administer Zepatier + RBV for 16 weeks (see Section 4.2 Dose and Method of Administration).

Clinical trial in subjects with advanced chronic kidney disease with genotype 1 chronic hepatitis C infection.

In the C-SURFER trial, subjects with genotype 1 infection, with or without cirrhosis, with advanced chronic kidney disease (CKD) stage 4 (eGFR 15-29 mL/min/1.73 m²) or Stage 5 (eGFR < 15 mL/min/1.73 m²), including subjects on haemodialysis, who were treatment-naive or who had failed prior therapy with IFN or peg-IFN ± RBV therapy had a median age of 58 years (range: 31 to 76); 75% of the subjects were male; 50% were White; 45% were Black or African American; 11% were Hispanic or Latino; 57% had baseline HCV RNA levels greater than 800,000 IU/mL; 75% were on dialysis; 6% had cirrhosis; and 72% had non-C/C IL28B alleles (CT or TT).
Treatment outcomes in subjects treated with Zepatier for 12 weeks in the immediate treatment group and intensive PK arm are presented in Table 11.

Clinical trial in treatment-naive subjects with genotype 3 chronic hepatitis C infection.

Zepatier + sofosbuvir has been evaluated in a limited number of patients with genotype 3 infection. In the C-SWIFT study, 41 treatment naive subjects with genotype 3 CHC with or without cirrhosis were treated with Zepatier + sofosbuvir for 8 or 12 weeks. The median age was 52 years (range: 26 to 69); 71% of the subjects were male; 100% were White; 49% were Hispanic or Latino; mean body mass index was 29 kg/m²; 51% had baseline HCV RNA levels greater than or equal to 800,000 IU/mL; 29% had cirrhosis; and 63% had non-C/C IL28B alleles (CT or TT). Treatment outcomes are presented in Table 12.

Overall SVR was achieved in 92% (24/26) in treatment-naive subjects with genotype 3 with or without cirrhosis who received Zepatier with sofosbuvir for 12 weeks and in 93% (14/15) treatment-naive subjects without cirrhosis who received Zepatier with sofosbuvir for 8 weeks.

5.2 Pharmacokinetic Properties

The pharmacokinetic properties of elbasvir and grazoprevir have been evaluated in non-HCV-infected adult subjects and in HCV-infected adult subjects. Elbasvir pharmacokinetics were similar in healthy subjects and HCV-infected subjects and were approximately dose proportional over the range of 5-100 mg once daily. Grazoprevir oral exposures are approximately 2-fold greater in HCV-infected subjects as compared to healthy subjects. Grazoprevir pharmacokinetics increased in a greater than dose-proportional manner over the range of 10-800 mg once daily in HCV-infected subjects. Ribavirin or sofosbuvir co-administration with Zepatier had no clinically relevant impact on plasma AUC and C_max of elbasvir and grazoprevir compared to administration of Zepatier alone. Based on the population pharmacokinetic modelling in non-cirrhotic, HCV-infected subjects, the geometric mean steady-state elbasvir AUC_0-24 and C_max at 50 mg were 2180 nanoM.hr and 137 nanoM respectively and the geometric mean steady-state grazoprevir AUC_0-24 and C_max at 100 mg were 1860 nanoM.hr and 220 nanoM, respectively. Following once daily administration of Zepatier to HCV-infected subjects, elbasvir and grazoprevir reached steady state within approximately 6 days.

Absorption.

Following administration of Zepatier to HCV-infected subjects, elbasvir peak plasma concentrations occur at a median T_max of 3 hours (range of 3 to 6 hours); grazoprevir peak plasma concentrations occur at a median T_max of 2 hours (range of 30 minutes to 3 hours). The absolute bioavailability of elbasvir is estimated to be 32%, and grazoprevir is estimated to be 10 to 40%.

Effect of food.

Relative to fasting conditions, the administration of a single dose of Zepatier with a high-fat (900 kcal, 500 kcal from fat) meal to healthy subjects resulted in decreases in elbasvir AUC_0-inf and C_max of approximately 11% and 15%, respectively, and increases in grazoprevir AUC_0-inf and C_max of approximately 1.5-fold and 2.8-fold, respectively. These differences in elbasvir and grazoprevir exposure are not clinically relevant; therefore, Zepatier may be taken without regard to food.

Distribution.

Elbasvir and grazoprevir are extensively bound (> 99.9% and 98.8%, respectively) to human plasma proteins. Both elbasvir and grazoprevir bind to human serum albumin and α1-acid glycoprotein. Plasma protein binding is not meaningfully altered in patients with renal or hepatic impairment.
In preclinical distribution studies, elbasvir distributes into most tissues including the liver; whereas grazoprevir distributes predominantly to the liver likely facilitated by active transport through the OATP1B liver uptake transporter.

Metabolism.

Elbasvir and grazoprevir are partially eliminated by oxidative metabolism, primarily by CYP3A. No circulating metabolites of either elbasvir or grazoprevir were detected in human plasma.

Excretion.

The geometric mean apparent terminal half-life (% geometric mean coefficient of variation) is approximately 24 (24%) hours at 50 mg elbasvir and approximately 31 (34%) hours at 100 mg grazoprevir in HCV-infected subjects. The primary route of elimination of elbasvir and grazoprevir is through faeces with almost all (> 90%) of radiolabeled dose recovered in faeces compared to < 1% in urine.

Special populations.

Renal impairment.

The pharmacokinetics of elbasvir and grazoprevir were evaluated in non-HCV infected subjects with severe renal impairment (eGFR < 30 mL/min/1.73 m²) with or without haemodialysis and also in HCV-infected subjects with severe renal impairment with or without haemodialysis.
Relative to non-HCV-infected subjects with normal renal function (eGFR > 80 mL/min/1.73 m²), elbasvir and grazoprevir AUC values were increased by 86% and 65%, respectively, in non-HCV-infected subjects with severe renal impairment who were not on dialysis. Relative to subjects with normal renal function, elbasvir and grazoprevir AUC values were unchanged in non-HCV-infected subjects with dialysis dependent, severe renal impairment. Elbasvir and grazoprevir are highly bound to plasma protein. Elbasvir and grazoprevir are not removed by haemodialysis. Concentrations of elbasvir were not quantifiable in the dialysate samples. Less than 0.5% of grazoprevir was recovered in dialysate over a 4-hour dialysis session. Elbasvir and grazoprevir are not expected to be removed by peritoneal dialysis.
In population pharmacokinetic analysis, elbasvir AUC was 25% higher in dialysis-dependent subjects and 46% higher in non-dialysis dependent subjects with severe renal impairment compared to elbasvir AUC in subjects without severe renal impairment. In population pharmacokinetic analysis in HCV-infected subjects, grazoprevir AUC was 10% higher in dialysis-dependent subjects and 40% higher in non-dialysis dependent subjects with severe renal impairment compared to grazoprevir AUC in subjects without severe renal impairment.
Overall, changes in exposure of elbasvir and grazoprevir in HCV-infected subjects with renal impairment with or without dialysis are not clinically relevant. Therefore, no dosage adjustment of Zepatier is recommended in HCV-infected subjects with renal impairment regardless of dialysis status (see Section 4.4 Special Warnings and Precautions for Use, Renal impairment; Section 4.2 Dose and Method of Administration, Renal impairment).

Hepatic impairment

The pharmacokinetics of elbasvir and grazoprevir were evaluated in non-HCV-infected subjects with mild hepatic impairment (Child-Pugh Category A [CP-A], score of 5-6), moderate hepatic impairment (Child-Pugh Category B [CP-B], score of 7-9) and severe hepatic impairment (Child-Pugh Category C [CP-C], score of 10-15). In addition, the pharmacokinetics of elbasvir and grazoprevir were also evaluated in HCV-infected subjects with mild hepatic impairment (CP-A) or moderate hepatic impairment (CP-B).
Elbasvir AUC_0-inf was decreased by 40% in non-HCV-infected subjects with mild hepatic impairment (CP-A) compared to matching healthy subjects. In non-HCV infected subjects with mild hepatic impairment, grazoprevir steady-state AUC_0-24 was increased 70% compared to matching healthy subjects. Population PK analyses of HCV-infected subjects in Phase 2 and 3 studies demonstrated that elbasvir steady-state AUC was similar in HCV-infected subjects with mild hepatic impairment (CP-A) compared to subjects without hepatic impairment. Grazoprevir steady-state AUC_0-24 increased by approximately 65% in HCV-infected subjects with compensated cirrhosis compared to HCV-infected, non-cirrhotic subjects. Based on these data, no dosage adjustment of Zepatier is recommended in HCV-infected subjects with mild hepatic impairment (CP-A), including those with compensated cirrhosis.
Elbasvir AUC decreased by 28% in non-HCV-infected subjects with moderate hepatic impairment (CP-B) compared to matched healthy subjects. Elbasvir steady-state AUC was similar in HCV-infected subjects with moderate hepatic impairment (CP-B) compared to subjects without hepatic impairment. Compared to healthy matched subjects, grazoprevir steady-state AUC_0-24 was increased 5-fold in non-HCV-infected subjects with moderate hepatic impairment (CP-B). Zepatier is contraindicated in HCV-infected subjects with moderate hepatic impairment (CP-B) due to lack of clinical safety and efficacy experience in this population and the expected increase in grazoprevir exposure.
Elbasvir AUC_0-inf is decreased by 12% in non-HCV-infected subjects with severe hepatic impairment (CP-C) compared to matching healthy subjects. Grazoprevir steady-state AUC_0-24 was increased 12-fold in non-HCV-infected subjects with severe hepatic impairment (CP-C) compared to healthy matched subjects. Zepatier is contraindicated in HCV-infected subjects with severe hepatic impairment (CP-C) based on the significant increase in grazoprevir exposure observed in non-HCV-infected subjects with severe hepatic impairment (CP-C) (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use, Hepatic impairment).

Gender.

In population pharmacokinetic analyses, elbasvir and grazoprevir AUCs are estimated to be 50% and 30% higher, respectively, in females compared to males. These changes are not clinically relevant; therefore, no dose adjustment of Zepatier is recommended based on sex.

Race.

In population pharmacokinetic analyses, elbasvir and grazoprevir AUCs are estimated to be 15% and 50% higher, respectively, for Asians compared to Whites. Population pharmacokinetics estimates of exposure of elbasvir and grazoprevir were comparable between Whites and Black/ African Americans. These changes are not clinically relevant; therefore, no dose adjustment of Zepatier is recommended based on race/ ethnicity.

Paediatric.

The pharmacokinetics of Zepatier in paediatric patients less than 18 years of age have not been established.

Geriatric.

In population pharmacokinetic analyses, elbasvir and grazoprevir AUCs are estimated to be 16% and 45% higher, respectively, in ≥ 65 year old subjects compared to subjects less than 65 years of age. No dose adjustment of Zepatier is recommended based on age (see Section 4.4 Special Warnings and Precautions for Use, Use in elderly; Section 4.2 Dose and Method of Administration, Geriatric patients).

Weight/BMI.

In population pharmacokinetic analyses, there was no effect of weight on elbasvir pharmacokinetics. Grazoprevir AUC is estimated to be 15% higher in a 53 kg subject compared to a 77 kg subject. This change is not clinically relevant for grazoprevir. Therefore, no dose adjustment of Zepatier is recommended based on weight/BMI.

Drug interaction studies.

Drug interaction studies were performed in healthy adults with elbasvir, grazoprevir, or coadministered elbasvir and grazoprevir and drugs likely to be co-administered or drugs commonly used as probes for pharmacokinetic interactions. Table 13 summarises the effects of co-administered drugs on the exposures of the individual components of Zepatier (elbasvir and grazoprevir). Table 14 summarises the effects of the individual components of Zepatier on the exposures of the co-administered drugs. For information regarding clinical recommendations, (see Section 4.4 Special Warnings and Precautions for Use, Risk of adverse reactions or reduced therapeutic effect due to drug interactions; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Elbasvir and grazoprevir are substrates of CYP3A/P-gp, but the role of intestinal P-gp in the absorption of elbasvir and grazoprevir is minimal. Co-administration of moderate and strong CYP3A/P-gp inducers with Zepatier may decrease elbasvir and grazoprevir plasma concentrations, leading to reduced therapeutic effect of Zepatier. Co-administration of strong CYP3A inhibitors with Zepatier may increase elbasvir and grazoprevir plasma concentrations (see Table 13).
Grazoprevir is a substrate of OATP1B. Co-administration of Zepatier with drugs that inhibit OATP1B transporters may result in a clinically relevant increase in grazoprevir plasma concentrations.
Elbasvir is not a CYP3A inhibitor in vitro and grazoprevir is a weak CYP3A inhibitor in humans. Co-administration with grazoprevir resulted in a 34% increase in plasma exposure of midazolam and a 43% increase in plasma exposure of tacrolimus (see Table 14 and 3).
Clinically significant drug interactions with Zepatier as an inhibitor of other CYP enzymes, UGT1A1, esterases (CES1, CES2, and CatA), organic anion transporters (OAT)1 and OAT3, and organic cation transporters (OCT)2 are not expected, and multiple-dose administration of elbasvir or grazoprevir is unlikely to induce the metabolism of drugs metabolised by CYP isoforms based on in vitro data. A clinical interaction study with montelukast confirmed that grazoprevir is not a CYP2C8 inhibitor (CYP isoform with lowest in vitro IC₅₀).
Elbasvir has minimal intestinal P-gp inhibition in humans, and does not result in clinically relevant increases in concentrations of digoxin (a P-gp substrate), with an 11% increase in plasma AUC (see Table 14). Grazoprevir is not a P-gp inhibitor in vitro. Therefore, P-gp substrates may be administered without dose adjustment when co-administered with Zepatier.
Elbasvir and grazoprevir are inhibitors of the drug transporter breast cancer resistance protein (BCRP) at the intestinal level in humans and may increase plasma concentrations of co-administered BCRP substrates. Neither elbasvir nor grazoprevir are inhibitors of OATP1B in humans (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

5.3 Preclinical Safety Data

Genotoxicity.

Elbasvir and grazoprevir were not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenesis, chromosomal aberration in Chinese hamster ovary cells, and in in vivo rat micronucleus assays.
If Zepatier is administered in a regimen containing ribavirin, the information for ribavirin on mutagenesis also applies to this combination regimen (see prescribing information for ribavirin).

Carcinogenicity.

Carcinogenicity studies with elbasvir or grazoprevir have not been conducted.
If Zepatier is administered in a regimen containing ribavirin, the information for ribavirin on carcinogenesis also applies to this combination regimen (see prescribing information for ribavirin).

6 Pharmaceutical Particulars

6.1 List of Excipients

Tablet core.

The tablets include the following inactive ingredients: sodium lauryl sulfate, tocofersolan, copovidone, hypromellose, microcrystalline cellulose, mannitol, lactose monohydrate, croscarmellose sodium, sodium chloride, colloidal anhydrous silica, magnesium stearate.

Film coating.

The tablets are film-coated with a coating material containing the following inactive ingredients: lactose monohydrate, hypromellose, titanium dioxide, glycerol triacetate, iron oxide yellow, iron oxide red, ferrosoferric oxide, carnauba wax.

6.2 Incompatibilities

Not applicable.
Please see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions for further information.

6.3 Shelf Life

2 years.

6.4 Special Precautions for Storage

Store Zepatier below 30°C. Store Zepatier in the original blister package until use to protect from moisture.

6.5 Nature and Contents of Container

The tablets are packaged into a carton containing two cardboard wallets, each cardboard wallet containing 14-count tablets within Aluminium/Aluminium blisters. Each carton contains a total of 28 tablets.

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 sturtcure.

Elbasvir.

Elbasvir has the following structural formula:

Elbasvir has the following chemical name: Dimethyl N,N'-([(6S)-6-phenylindolo [1,2-c][1,3]benzoxazine-3,10-diyl]bis{1H-imidazole-5,2-diyl-(2S)-pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-1,2-diyl]})dicarbamate.
It has a molecular formula of C₄₉H₅₅N₉O₇ and a molecular weight of 882.02.

Grazoprevir.

Grazoprevir has the following structural formula:

Grazoprevir has the following chemical name: (1aR,5S,8S,10R,22aR)-N-[(1R,2S)-1-[(cyclopropylsulfonamido)carbonyl]-2-ethenylcyclopropyl]-14-methoxy-5-(2-methylpropan-2-yl)-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10 methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino [11,12-b]quinoxaline-8-carboxamide.
It has a molecular formula of C₃₈H₅₀N₆O₉S and a molecular weight of 766.90.

CAS number.

Elbasvir.

CAS registry number: 1370468-36-2.

Grazoprevir.

CAS registry number: 1350514-68-9.

7 Medicine Schedule (Poisons Standard)

Schedule 4 Prescription Only Medicine.

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Zepatier

Elbasvir; Grazoprevir

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BRAND INFORMATION

Zepatier 50 mg/100 mg Tablets