Consumer medicine information

Harvoni

Ledipasvir; Sofosbuvir

BRAND INFORMATION

Brand name

Harvoni Tablets

Active ingredient

Ledipasvir; Sofosbuvir

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Harvoni.

What is in this leaflet

This leaflet answers some common questions about HARVONI tablets. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

This leaflet was last updated on the date at the end of this leaflet. More recent information may be available. The latest Consumer Medicine Information is available from your pharmacist or doctor and may contain important information about the medicine and its use of which you should be aware.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking HARVONI against the benefits it is expected to have for you.

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

Keep this leaflet with the medicine.

You may need to read it again.

This medicine has been prescribed for you personally and you should not pass it on to others. It may harm them, even if their symptoms are the same as yours.

What HARVONI is used for

HARVONI is used to treat hepatitis C virus infection in adults of 18 years and older.

Hepatitis C is a virus that infects the liver.

How HARVONI works

HARVONI is one tablet that contains two active substances, ledipasvir and sofosbuvir. 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.

HARVONI is sometimes taken with another medicine, ribavirin.

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

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

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

Use in children

HARVONI is for adults. HARVONI has not been studied in children under the age of 18.

Before you take HARVONI

When you must not take it

Together with your doctor, you need to decide whether HARVONI is right for you.

Do not take HARVONI if you are allergic to:

  • ledipasvir,
  • sofosbuvir or
  • any of the other ingredients of HARVONI. The ingredients of HARVONI are in the product description section of this leaflet.

Some people are allergic to medicines. If you have any of the following symptoms soon after taking your medicine, DO NOT TAKE ANY MORE HARVONI and tell your doctor IMMEDIATELY or go to the accident and emergency department at your nearest hospital:

  • 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

These are very serious effects. If you have them, you may have a serious allergic reaction. You may need urgent medical attention or hospitalisation. Hypersensitivity reactions are very rare.

Ask your doctor or pharmacist if you don’t understand anything in this list.

Do not take HARVONI if you are taking any medicine other than HARVONI that contains sofosbuvir.

If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. You should not breast feed during treatment with HARVONI.

Do not take HARVONI after the expiry or “use by” date (EXP) printed on the bottle.

If you take it after the expiry date has passed, it may not work as well.

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

Before you start to take it

Tell your doctor if you are allergic to foods, dyes, preservatives or any other medicines.

Tell your doctor if you have, or have had, any of the following medical conditions:

  • 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 severe kidney problems or if you are on haemodialysis as the effects of HARVONI on patients with severe kidney problems have not been fully tested
  • Have any other medical condition

Tell your doctor if you:

  • Are pregnant or planning to become pregnant. Please speak to your doctor if you are unsure. HARVONI 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
  • Are breastfeeding or plan to breast-feed. It is not known whether ledipasvir or sofosbuvir, the two active substances of HARVONI, pass into human breast milk

If you have not told your doctor or pharmacist about any of the above, tell them before you start taking HARVONI.

Taking other medicines

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

Some medicines and HARVONI may interfere with each other.

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
  • tipranavir used to treat HIV infection
  • tenofovir disoproxil fumarate 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 (medicines used to treat epilepsy and prevent seizures).

HARVONI may interact with these medicines. As a result, the amounts of HARVONI 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.

Take any medicines used to treat stomach ulcers, heartburn or acid reflux, such as:

  • 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 ledipasvir 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 HARVONI.
  • If you are taking a proton pump inhibitor, take it at the same time as HARVONI or up to 2 hours after taking HARVONI. Do not take before HARVONI.
  • 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.

It is very important to let your doctor or pharmacist know what medications, herbal supplements, or vitamins you are taking.

Know the medicines you take. Keep a list of medicines and show it to your doctor and pharmacist when you get a new medicine. Your doctor and your pharmacist can tell you if you can take these medicines with HARVONI. Do not start any new medicines while you are taking HARVONI without first talking with your doctor or pharmacist.

Your doctor and pharmacist may have more information on medicines to be careful with or to avoid while taking HARVONI.

How to take HARVONI

Follow all directions given to you by your doctor or pharmacist carefully.

How much to take

The usual dose is one HARVONI tablet orally, once daily. Never change the dose on your own. Do not stop this medicine unless your doctor tells you to stop.

How to take it

HARVONI tablets can be taken with or without food.

When to take it

Take HARVONI 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 take it

Do not miss a dose of HARVONI. If you forget to take HARVONI, take your missed dose right away unless it is almost time for your next dose.

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

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

Do not change your dose or stop taking HARVONI without first talking to your doctor.

If you are not sure what to do, ask your doctor or pharmacist.

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

If you take too much (overdose)

Immediately telephone your doctor or Poisons Information Centre: 131126 (Australia) and 0800 764 766 (New Zealand) or go to the Accident and Emergency department at your nearest hospital if you think you or anyone else may have taken too many HARVONI tablets. Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

While you are taking HARVONI

Things you must do

Tell all doctors and pharmacists who are treating you that you are taking HARVONI.

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

Things you must not do

Do not give HARVONI to anyone else, even if they have the same condition as you.

Do not stop taking HARVONI or change the dose without checking with your doctor.

It is important not to suddenly stop taking your HARVONI tablets, unless advised to do so by your doctor.

Do not breastfeed. See “Before you take it”.

Things to be careful of

Be careful driving or operating machinery until you know how HARVONI affects you.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking HARVONI.

HARVONI helps most people with Hepatitis C virus infection, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects. Do not be alarmed by these lists of possible side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

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

  • tiredness
  • headache
  • nausea
  • trouble sleeping (insomnia)
  • cough, shortness of breath
  • rash, itchy skin
  • feeling irritable

Tell your doctor as soon as possible if you have any problems while taking HARVONI, even if you do not think the problems are connected with the medicine or are not listed in this leaflet.

Tell your doctor immediately if you or your family notice any of the following side effects:

  • signs of allergy such as rash or hives on the skin; swelling of the face, lips, tongue or other parts of the body; wheezing or difficulty breathing

Tell your doctor if you notice anything else that is making you feel unwell.

Other side effects not listed above may also occur in some people.

After taking HARVONI

Storage

Keep your HARVONI where young children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Keep HARVONI tablets in a cool, dry place where it stays below 30°C.

Do not store HARVONI or any other medicine in a bathroom or near a sink. Do not leave HARVONI in the car or on a window sill – heat and dampness can destroy some medicines.

Keep your HARVONI tablets in the bottle with the cap tightly closed until you take them. If you take HARVONI tablets out of their pack they may not keep well.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

HARVONI tablets are diamond-shaped and orange in colour. Each tablet has “GSI” on one side and “7985” on the other side of the tablet.

HARVONI tablets are supplied in bottles containing 28 tablets.

Ingredients

Active Ingredients: ledipasvir and sofosbuvir

Inactive Ingredients: silicon dioxide, copovidone, croscarmellose sodium, lactose, magnesium stearate and microcrystalline cellulose.

Film-coating: polyvinyl alcohol, macrogol 3350, titanium dioxide, purified talc, and sunset yellow FCF aluminium lake.

Sponsor

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

New Zealand
c/- PricewaterhouseCoopers
Level 8 Pricewaterhousecoopers Tower
188 Quay Street
Auckland 1010

This leaflet was prepared in December 2016.

HARVONI, 7985 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.

AUST R 222848

BRAND INFORMATION

Brand name

Harvoni Tablets

Active ingredient

Ledipasvir; Sofosbuvir

Schedule

S4

 

1 Name of Medicine

Harvoni (ledipasvir/sofosbuvir 90 mg/400 mg) tablets.
The active substances in Harvoni tablets are ledipasvir and sofosbuvir.

2 Qualitative and Quantitative Composition

Harvoni is available as a fixed-dose combination tablet. Each tablet contains 90 mg ledipasvir and 400 mg sofosbuvir and are orange diamond shaped, film coated with "GSI" on one side and "7985" on the other side. For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Each Harvoni tablet is film-coated and orange in colour. The tablets are diamond shaped debossed with "GSI" on one side and the number "7985" on the other side. The tablets are supplied in bottles with child resistant closures.

4 Clinical Particulars

4.1 Therapeutic Indications

Harvoni (ledipasvir/sofosbuvir fixed-dose combination) is indicated for the treatment of chronic hepatitis C (CHC) infection in adults.
(See Section 4.4 Special Warnings and Precautions for Use; Section 5.1 Pharmacodynamic Properties, Clinical trials for information on the available data for HCV patients of each genotype, see Section 4.2 Dose and Method of Administration for recommended regimens and treatment durations for different patient subgroups).

4.2 Dose and Method of Administration

The recommended dose of Harvoni tablets is one tablet, taken orally, once daily with or without food.
The recommended treatment regimen and duration for Harvoni is provided in Table 1.
For patients with HCV/HIV-1 co-infection, follow the dosage recommendations in Table 1.
There are insufficient data to determine the optimal treatment duration for genotype 4 patients with decompensated liver disease.

Concomitant ribavirin dose.

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

Children and adolescents up to 18 years of age.

No data are available on which to make a dose recommendation for children < 18 years of age.

Elderly.

No dose adjustment is warranted for elderly patients.

Renal impairment.

No dose adjustment of Harvoni is required for patients with mild or moderate renal impairment. No dose recommendations can be given for patients with severe renal impairment eGFR < 30 mL/min/1.73 m2 or with end stage renal disease requiring haemodialysis due to higher exposure of the predominant sofosbuvir metabolite (see Section 5.2 Pharmacokinetic Properties).

Hepatic impairment.

No dose adjustment of Harvoni is required for patients with mild, moderate or severe hepatic impairment (Child-Pugh class A, B or C) (see Section 5.2 Pharmacokinetic Properties). Safety and efficacy of Harvoni have not been established in patients with decompensated cirrhosis.

4.3 Contraindications

Harvoni tablets are contraindicated in patients with known hypersensitivity to the active substance or to any other component of the tablets.
Harvoni is a fixed-dose combination of ledipasvir and sofosbuvir. Harvoni 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 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 Harvoni is not recommended. For patients taking amiodarone who have no other alternative, viable treatment options and who will be coadministered Harvoni:
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 Harvoni 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 Harvoni 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 (DAAs) 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 Harvoni.
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.

Use with potent P-gp inducers.

Drugs that are potent P-gp inducers (e.g. rifampicin, St. John's wort) may significantly decrease ledipasvir and sofosbuvir plasma concentration leading to reduced therapeutic effect of Harvoni. Rifampicin and St. John's wort should not be used with Harvoni.

HCV/HBV (hepatitis B virus) coinfected patients.

The safety and efficacy of Harvoni has not been established in patients coinfected with HBV.

Genotype specific activity (genotype 2 and 3).

The clinical data to support the use of Harvoni in patients infected with HCV genotype 2 are limited.
The clinical data to support the use of Harvoni in patients infected with HCV genotype 3 are limited. The relative efficacy of a 12 week regimen consisting of ledipasvir/ sofosbuvir + ribavirin, compared to a 24 week regimen of sofosbuvir + ribavirin has not been investigated.

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

In patients who fail treatment with Harvoni, selection of NS5A resistance mutations that substantially reduce the susceptibility to ledipasvir is seen in the majority of cases. Limited data indicate that such NS5A mutations do not revert on long-term follow-up. There are presently no data to support the effectiveness of retreatment of patients who have failed Harvoni with a subsequent regimen that contains an NS5A inhibitor. Similarly, there are presently no data to support the effectiveness of NS3/4A protease inhibitors in patients who previously failed prior therapy that included an NS3/4A protease inhibitor. Such patients may therefore be dependent on other drug classes for clearance of HCV infection.

Use with certain HIV antiretroviral regimens.

Harvoni has been shown to increase tenofovir exposure. The potential risks and benefits associated with coadministration of tenofovir DF with Harvoni should be considered, particularly in patients at increased risk for renal dysfunction (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Use in the elderly.

Clinical trials of Harvoni included 351 patients aged 65 and over. The response rates observed for subjects over 65 years of age were similar to that of younger patients across treatment groups. No dose adjustment of Harvoni is warranted in elderly patients. In general, caution should be exercised when administering Harvoni in elderly patients, reflecting the greater frequency of anaemia, decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

Paediatric use.

Safety and effectiveness of Harvoni in children less than 18 years of age have not been established.

Effects on laboratory tests.

As liver function may change during treatment with Harvoni, 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 Harvoni contains ledipasvir and sofosbuvir, any interactions that have been identified with these agents individually may occur with Harvoni.
After oral administration of Harvoni, 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.

Potential for Harvoni to affect other drugs.

Ledipasvir is an inhibitor of drug transporter P-gp and breast cancer resistance protein (BCRP) and may increase intestinal absorption of coadministered substrates for these transporters. Ledipasvir is an inhibitor of transporters OATP1B1, OATP1B3 and BSEP only at concentrations exceeding those achieved in clinic. Ledipasvir is not an inhibitor of transporters MRP2, MRP4, OCT2, OAT1, OAT3, MATE1, and OCT1. The drug-drug interaction potential of ledipasvir is primarily limited to the process of intestinal absorption. Clinically relevant transporter inhibition by ledipasvir in the systemic circulation is not expected due to its high protein binding. Sofosbuvir and GS-331007 are not inhibitors of drug transporters P-gp, BCRP, MRP2, BSEP, OATP1B1, OATP1B3 and OCT1 and GS-331007 is not an inhibitor of OAT1, OCT2, and MATE1.
Ledipasvir, sofosbuvir and GS-331007 are not inhibitors or inducers of CYP or UGT1A1 enzymes.

Potential for other drugs to affect Harvoni.

Ledipasvir and sofosbuvir are substrates of drug transporters P-gp and BCRP while GS-331007 is not. Drugs that are potent P-gp inducers (e.g. rifampicin or St. John's wort) may decrease ledipasvir and sofosbuvir plasma concentrations leading to reduced therapeutic effect of Harvoni and thus should not be used with Harvoni (see Section 4.4 Special Warnings and Precautions for Use, Use with potent P-gp inducers). Coadministration with drugs that inhibit P-gp and/or BCRP may increase ledipasvir and sofosbuvir plasma concentrations without increasing GS-331007 plasma concentration; Harvoni may be coadministered with P-gp and/or BCRP inhibitors. Neither ledipasvir nor sofosbuvir is a substrate for hepatic uptake transporters OCT1, OATP1B1 or OATP1B3. GS-331007 is not a substrate for renal transporters including organic anion transporter OAT1 or OAT3, or organic cation transporter OCT2.
Ledipasvir is subject to slow oxidative metabolism via an unknown mechanism. In vitro, no detectable metabolism of ledipasvir by CYP enzymes has been observed. Biliary excretion of unchanged ledipasvir is a major route of elimination. Sofosbuvir is not a substrate for CYP and UGT1A1 enzymes. Clinically significant drug interactions with Harvoni mediated by CYP or UGT1A1 enzymes are not expected.

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 Harvoni, the components of Harvoni (ledipasvir and sofosbuvir) as individual agents, or are predicted drug interactions that may occur with Harvoni. This table is not all inclusive.

Drugs without clinically significant interactions with Harvoni.

Based on drug interaction studies conducted with the components of Harvoni (ledipasvir or sofosbuvir) or Harvoni, no clinically significant drug interactions have been either observed or are expected when Harvoni is combined with the following individual drugs: abacavir, atazanavir/ ritonavir, cyclosporin, darunavir/ ritonavir, dolutegravir, efavirenz, elvitegravir/ cobicistat/ emtricitabine/ tenofovir alafenamide, emtricitabine, lamivudine, methadone, oral contraceptives, pravastatin, raltegravir, rilpivirine, tacrolimus (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Other forms of interaction) or verapamil.

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). 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.

Ledipasvir.

Ledipasvir had no adverse effects on mating and fertility in rats. In female rats, the mean number of corpora lutea and implantation sites were slightly reduced at maternal exposures 6-fold the exposure in humans at the recommended clinical dose. At the no observed effect level, AUC exposure to ledipasvir was approximately 7- and 3-fold, in males and females, respectively, the human exposure at the recommended clinical dose.

Sofosbuvir.

Sofosbuvir had no effects on embryo-foetal viability or on fertility when evaluated in rats. At the highest dose tested, AUC exposure to the predominant circulating metabolite GS-331007 was approximately 5-fold the exposure in humans at the recommended clinical dose.
(Category B1)
There are no adequate and well-controlled studies with Harvoni in pregnant women. Because animal reproduction studies are not always predictive of human response, Harvoni should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Use with ribavirin (Pregnancy Category X).

Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin. When Harvoni 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 Harvoni, the contraindications regarding use of ribavirin apply (refer to ribavirin product information).

Ledipasvir.

No effects on fetal development have been observed in rats and rabbits at the highest doses tested. In the rat and rabbit, AUC exposure to ledipasvir was 5- and 2-fold, respectively, the exposure in humans at the recommended clinical dose.
In a rat pre- and postnatal study, at a maternally toxic dose, the developing rat offspring exhibited mean decreased body weight and body weight gain when exposed in utero (via maternal dosing) and during lactation (via maternal milk) at a maternal exposure approximately 4 times the exposure in humans at the recommended clinical dose. There were no effects on survival, physical and behavioural development and reproductive performance in the offspring at maternal exposures similar to the exposure in humans at the recommended clinical dose.

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 10-fold and 28-fold the exposure in humans at the recommended clinical dose, respectively.
When administered to lactating rats, ledipasvir was detected in the plasma of suckling rats likely due to excretion of ledipasvir via milk. Ledipasvir had no effects on the nursing pups. The predominant circulating metabolite of sofosbuvir (GS-331007) was the primary component observed in the milk of lactating rats, without effect on nursing pups. It is not known whether ledipasvir, sofosbuvir or metabolites of sofosbuvir are present in human breast milk. Because of the potential for adverse reactions from the drug in nursing infants, a decision must be made whether to discontinue nursing or discontinue treatment with Harvoni, taking into account the importance of the therapy to the mother.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects of Harvoni 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.

Clinical trials.

The safety assessment of Harvoni in patients with genotype 1 CHC is based on pooled data from three phase 3 clinical trials (ION-3, ION-1 and ION-2) including 215, 539 and 326 patients who received Harvoni for 8, 12 and 24 weeks, respectively; and 216, 328 and 328 patients who received Harvoni + ribavirin combination therapy for 8, 12 and 24 weeks, respectively.
The proportion of patients who permanently discontinued treatment due to adverse events was 0%, < 1% and 1% for patients receiving Harvoni for 8, 12 and 24 weeks, respectively; and < 1%, 0%, and 2% for patients receiving Harvoni + ribavirin combination therapy for 8, 12 and 24 weeks, respectively.
No adverse drug reactions specific to Harvoni have been identified. In clinical trials ION-1, ION-2, and ION-3, fatigue, headache and nausea were the most common (incidence ≥ 10%) treatment emergent adverse events reported in patients treated with 8 or 12 weeks of Harvoni which are the recommended regimens for patients (see Section 4.2 Dose and Method of Administration). The type of treatment emergent adverse events observed during 24 weeks of treatment with Harvoni was consistent with those observed during 8 or 12 weeks of treatment but the frequency of adverse events is generally higher in the 24 week treatment group than the 8 or 12 week treatment groups. When Harvoni was studied with ribavirin, the most frequent adverse events to Harvoni + ribavirin combination therapy were consistent with the known safety profile of ribavirin, without increasing the frequency or severity of the expected adverse events.
Table 3 lists adverse reactions (adverse events assessed as causally related by the investigator, all grades) observed in ≥ 5% of patients receiving 8, 12, or 24 weeks treatment with Harvoni in clinical trials. The majority of adverse reactions presented in Table 3 occurred at severity of grade 1.
The safety of Harvoni with or without ribavirin in treatment experienced genotype 1 patients with compensated cirrhosis was compared to placebo in study SIRIUS. Patients were randomised to receive 24 weeks of Harvoni without ribavirin or 12 weeks of placebo followed by 12 weeks of Harvoni + ribavirin. Table 4 presents the adverse reactions, as defined above, that were reported more frequently (≥ 5%) in patients during the first 12 weeks of treatment in the Harvoni 24 week treatment group or in patients treated with 12 weeks of Harvoni + ribavirin, compared with those reported for 12 weeks of placebo. The majority of the adverse reactions presented in Table 4 were grade 1 or 2 in severity.
No adverse drug reactions specific to Harvoni were identified from the clinical trials conducted in patients with genotype 2, 3, 4, 5 or 6 CHC.

HCV/HIV-1 coinfection.

No adverse drug reactions specific to Harvoni were identified from an open label trial (ION-4) in which patients with HCV/HIV-1 coinfection received treatment with Harvoni for 12 weeks (N = 335).

Liver transplant recipients and/or patients with decompensated cirrhosis.

No adverse drug reactions specific to Harvoni were identified from two open-label trials (SOLAR-1 and SOLAR-2) in which liver transplant recipients and/or patients with decompensated cirrhosis received Harvoni with ribavirin for 12 or 24 weeks (N = 670). The adverse events observed were consistent with expected clinical sequelae of liver transplantation and/or decompensated liver disease, or the known toxicity profile of ribavirin.
Decreases in haemoglobin to less than 10 mg/dL and 8.5 mg/dL during treatment were experienced by 39% and 13% of patients treated with Harvoni + ribavirin, respectively. Ribavirin was discontinued in 15% of the subjects. Due to improved organ function, 7% of liver transplant recipients had a dose modification of their immunosuppressive agents.

Post marketing surveillance.

In addition to adverse reactions from clinical studies, the following possible adverse reactions were also identified during postapproval use of Harvoni. 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 Harvoni) (see Section 4.4 Special Warnings and Precautions for Use, Serious symptomatic bradycardia when coadministered with amiodarone).

Hepatobiliary disorders.

Hepatitis B reactivation (see Section 4.4 Special Warnings and Precautions for Use).

Skin and subcutaneous tissue disorders.

Angioedema, rash.

4.9 Overdose

The highest documented doses of ledipasvir and sofosbuvir were 120 mg twice daily for 10 days and a single dose of 1200 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 Harvoni. If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with Harvoni consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient. Haemodialysis is unlikely to result in significant removal of ledipasvir since ledipasvir is highly bound to plasma protein. Haemodialysis can efficiently remove the predominant circulating metabolite of sofosbuvir, GS-331007, with an extraction ratio of 53%.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia) and 0800 764 766 (New Zealand).

5 Pharmacological Properties

Pharmacotherapeutic group: antivirals for systemic use; direct acting antivirals, other antivirals, ATC code: J05AX65.

5.1 Pharmacodynamic Properties

Mechanism of action.

Ledipasvir is a HCV inhibitor targeting the HCV NS5A protein, which is essential for both RNA replication and the assembly of HCV virions. Biochemical confirmation of NS5A inhibition of ledipasvir is not currently possible as NS5A has no enzymatic function. In vitro resistance selection and cross resistance studies indicate ledipasvir targets NS5A as its mode of action.
Sofosbuvir is a 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 0.7 to 2.6 microM. GS-461203 is neither an inhibitor of human DNA and RNA polymerases nor an inhibitor of mitochondrial RNA polymerase.

Antiviral activity in vitro.

The EC50 values of ledipasvir and sofosbuvir against full length or chimeric replicons encoding NS5A and NS5B sequences from clinical isolates are detailed in Table 5. The presence of 40% human serum reduced anti-HCV activity of ledipasvir by 12-fold against genotype 1a HCV replicon.

Drug resistance.

In cell culture.

HCV replicons with reduced susceptibility to ledipasvir have been selected in cell culture for genotype 1a and 1b. Reduced susceptibility to ledipasvir was associated with the primary NS5A substitution Y93H in both genotype 1a and 1b. Additionally a Q30E substitution emerged in genotype 1a replicons. Site directed mutagenesis of the Y93H in both genotype 1a and 1b as well as the Q30E substitution in genotype 1a conferred high levels of reduced susceptibility to ledipasvir (fold change in EC50 greater than 500-fold).
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 8 genotypes including 1a, 1b, 2a, 2b, 3a, 4a, 5a and 6a conferred 2 to 18-fold reduced susceptibility to sofosbuvir and reduced the replication capacity by 89% to 99% compared to the corresponding wild type. In biochemical assays, recombinant NS5B polymerase from genotypes 1b, 2a, 3a and 4a expressing the S282T substitution showed reduced susceptibility to GS-461203 compared to respective wild types.

In clinical studies.

Genotype 1.

In a pooled analysis of patients who received Harvoni in phase 3 trials (ION-3, ION-1 and ION-2), 37 patients (29 with genotype 1a and 8 with genotype 1b) qualified for resistance analysis due to virologic failure or early study drug discontinuation and having HCV RNA > 1000 IU/mL. Postbaseline NS5A and NS5B deep sequencing data (assay cutoff of 1%) were available for 37/37 and 36/37 patients, respectively.
NS5A resistance associated variants (RAVs) were observed in postbaseline isolates from 29/37 patients not achieving SVR. Of the 29 genotype 1a patients who qualified for resistance testing, 22/29 (76%) patients harbored one or more NS5A RAVs at positions K24, Q30, L31, S38 and Y93 at failure, while the remaining 7/29 patients had no NS5A RAVs detected at failure. The most common variants were Q30R, Y93H, L31M, Y93N and Q30H. Of the 8 genotype 1b patients who qualified for resistance testing, 7/8 (88%) harbored one or more NS5A RAVs at positions L31 and Y93 at failure, while 1/8 patients had no NS5A RAVs at failure. The most common variant was Y93H. Among the 8 patients who had no NS5A RAVs at failure, 7 patients received 8 weeks of treatment (N = 3 with Harvoni; N = 4 with Harvoni + ribavirin) and 1 patient received Harvoni for 12 weeks. In phenotypic analyses, postbaseline isolates from patients who harbored NS5A RAVs at failure showed 20 to > 243-fold reduced susceptibility to ledipasvir.
Among post-transplant patients with compensated liver disease or patients with decompensated liver disease (pre- and post-transplant) (SOLAR-1 and SOLAR-2 trials), relapse was associated with the detection of one or more of the following NS5A RAVs: K24R, M28T, Q30R/H/K, L31V, H58D and Y93H/C in 12/14 genotype 1a patients, and L31M, Y93H/N in 6/6 genotype 1b patients.
The NS5B nucleoside inhibitor resistance associated variants (NS5B NI RAVs) L159F and V321A were each detected in one patient with genotype 1a infection in the phase 3 trials (ION-1, ION-2, and ION-3). The single L159F and V321A variants demonstrated 1.2-fold and 1.2-fold change in EC50 to sofosbuvir in genotype 1a replicon, respectively. The NS5B substitution E237G was detected in 3 patients (1 genotype 1b and 2 genotype 1a) in the phase 3 trials (ION-3, ION-1 and ION-2) and 3 patients (all genotype 1a) in the phase 2 trials of patients with advanced liver disease (SOLAR-1 and SOLAR-2) at the time of relapse. The E237G substitution showed a 1.3-fold reduction in susceptibility to sofosbuvir in the genotype 1a replicon assay. The clinical significance of these substitutions is currently unknown.
The NS5B NI RAV S282T in NS5B was not detected in any failure isolate from the ION-1, ION-2, ION-3, SOLAR-1 or SOLAR-2 trials. However, the NS5B S282T substitution in combination with NS5A RAVs L31M, Y93H and Q30L were detected in one patient at failure following 8 week treatment with Harvoni from the phase 2 trial LONESTAR. This patient was subsequently retreated with Harvoni + ribavirin for 24 weeks and achieved SVR following retreatment.

Genotype 2, 3, 4, 5, and 6.

Resistance analysis was performed for virologic failures in clinical trials with genotype 2, 3, 4, 5 and 6 CHC. Patients in these trials were treated with Harvoni or Harvoni + RBV for 12 weeks (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Genotype 2.

None of the genotype 2 patients experienced virologic failure in the LEPTON study.

Genotype 3.

Of the 17 patients who experienced virologic failures in the ELECTRON-2 study, one patient developed the NS5A RAV Y93C (1.1%), one patient developed the NS5B NI RAV S282T and one patient developed the NS5B NI RAV L159F.

Genotype 4.

Of the 3 patients who experienced virologic failure in study 1119, one patient developed the NS5B NI RAV S282T along with the NS5A RAV Y93C. In SOLAR-2 trial, one patient with genotype 4d developed NS5B substitution E237G at the time of relapse. The clinical significance of this substitution is currently unknown.

Genotype 5.

NS5A sequencing was successful in 1 of 2 virologic failure patients in study 1119. This patient developed NS5B NI RAVs S282T (1.6%) and M289I (16%).

Genotype 6.

Virologic failure occurred in one patient in the ELECTRON-2 study who discontinued treatment early at approximately week 8 and subsequently relapsed in study ELECTRON-2. This patient developed NS5B NI RAV S282T.

Effect of baseline HCV polymorphisms on treatment outcome.

Genotype 1.

Analyses were conducted to explore the association between pre-existing baseline NS5A resistance associated variants (RAVs) and treatment outcome. In the pooled analysis of the phase 3 trials (ION-1, ION-2 and ION-3), 256/1618 (16%) patients had baseline NS5A RAVs identified by population or deep sequencing irrespective of subtype.
In treatment naive patients in ION-3 with NS5A RAVs, SVR12 rates of 89% (34/38) after 8 weeks and 96% (66/69) after 12 weeks of therapy were observed with Harvoni. No association between any individual NS5A RAV and treatment outcome was observed.
In treatment experienced patients in ION-2 who had baseline NS5A RAVs, an SVR12 rate of 76% (13/17) after 12 weeks of therapy was observed with Harvoni. When NS5A RAVs were grouped by their EC50 fold change from wild type, among those treatment experienced patients with any NS5A RAV conferring < 100-fold resistance in vitro, 4/4 (100%) patients achieved SVR following 12 weeks of treatment with Harvoni. Among those treatment experienced patients with any NS5A RAV conferring ≥ 100-fold resistance, 9/13 (69%) patients achieved SVR following 12 weeks of treatment with Harvoni compared to 93/96 (97%) in those without any baseline RAVs or RAVs conferring a fold change of ≤ 100. In another study in treatment experienced patients with compensated cirrhosis (SIRIUS, N = 77), 8/8 (100%) patients with baseline NS5A RAVs conferring > 100-fold reduced susceptibility to ledipasvir achieved SVR following 12 weeks of treatment with Harvoni + RBV.
Among post-transplant patients with compensated liver disease (SOLAR-1 and SOLAR-2 studies), no relapse occurred in patients with baseline NS5A RAVs (N = 23) following 12 weeks of treatment with Harvoni + RBV. Among patients with decompensated liver disease (pre- and post-transplant), 4/16 (25%) patients with NS5A RAVs conferring > 100-fold resistance relapsed after 12 weeks treatment with Harvoni + RBV compared to 7/120 (6%) in those without any baseline NS5A RAVs or RAVs conferring a fold-change of ≤ 100.
The group of NS5A RAVs that conferred > 100-fold shift were defined as any of the following substitutions in genotype 1a (M28A/G, Q30E/G/H/K/R, L31I/M/V, P32L, H58D, Y93C/H/N/S) or in genotype 1b (P58D, A92K, Y93H).
The NS5B NI RAV S282T was not detected in the baseline NS5B sequence of any patient in phase 3 trials (ION-1, ION-2, ION-3) by population or deep sequencing. SVR was achieved in all 24 patients (N = 21 with L159F and N = 3 with N142T) who had baseline NS5B NI RAVs.

Genotype 2, 3, 4, 5 and 6.

Baseline NS5A RAVs did not have a clinically meaningful effect on treatment outcome in clinical studies of patients with genotype 2, 4, 5 or 6 CHC. For patients with genotype 3 CHC, the role of baseline NS5A RAVs varied depending on the patient population.
For patients with genotype 2, 4, 5 and 6 CHC, SVR was achieved in 14/14 (100%), 25/28 (89%), 7/8 (88%) and 17/18 (94%) patients who had baseline NS5A RAVs following 12 weeks treatment with Harvoni, respectively. The specific baseline NS5A RAVs observed in patients with virologic failure were L28M/V and L30R for genotype 4, L31M for genotype 5 and F28V for genotype 6.
Among treatment naive patients with genotype 3 CHC who were treated with Harvoni + RBV for 12 weeks, SVR was achieved in 4/4 (100%) patients with baseline NS5A RAVs. Among treatment experienced patients with genotype 3 CHC, SVR was achieved in 4/6 (67%) and 37/44 (84%) patients with or without baseline NS5A RAVs, respectively. The specific baseline NS5A RAVs observed in patients with virologic failure were S24G, A30K, L31M and Y93H.
The NS5B NI RAV S282T was not detected in the baseline NS5B sequence of any patient with genotype 2, 3, 4, 5 or 6 CHC in clinical trials by population or deep sequencing. For patients with genotype 2, 3 and 5 CHC, SVR was achieved in all 14 patients who had baseline NS5B NI RAVs (N = 4 with M289I in genotype 2; N = 1 with N142T in genotype 3; N = 7 with N142T and N = 2 with M289I in genotype 5).
Relapse occurred in 2/3 genotype 4 patients who had the baseline NS5B NI RAV V321I along with two baseline NS5A RAVs.
In patients with genotype 6 CHC, SVR was achieved in one patient each with the baseline NS5B NI RAVs M289L + S282G or M289L + V321A and 13/14 patients with M289L/I.

Cross resistance.

Ledipasvir was fully active against the sofosbuvir associated resistance substitution S282T in NS5B while all ledipasvir resistance associated substitutions in NS5A were fully susceptible to sofosbuvir. Both sofosbuvir and ledipasvir were fully active against substitutions associated with resistance to other classes of direct acting antivirals with different mechanisms of action, such as NS5B non-nucleoside inhibitors and NS3 protease inhibitors. NS5A substitutions conferring resistance to ledipasvir may reduce the antiviral activity of other NS5A inhibitors. The efficacy of Harvoni has not been established in patients who have previously failed treatment with other regimens that include an NS5A inhibitor.

Clinical trials.

Overview of clinical studies.

Genotype 1 CHC.

The efficacy of Harvoni was evaluated in 2105 patients with genotype 1 CHC in four trials including one trial conducted in noncirrhotic treatment naive patients (ION-3), one trial in cirrhotic and noncirrhotic treatment naive patients (ION-1), and one trial in cirrhotic and noncirrhotic patients who failed prior therapy with an interferon based regimen, including regimens containing an HCV protease inhibitor (ION-2) and one trial in patients with cirrhosis who failed prior therapy with a Peg-IFN + ribavirin regimen followed by a Peg-IFN + ribavirin + HCV protease inhibitor regimen (SIRIUS). Patients in these trials had compensated liver disease. All four trials evaluated efficacy of Harvoni with or without ribavirin.

Genotype 2, 3, 4, 5 or 6.

The efficacy of Harvoni in patients with genotype 2, 3, 4, 5 and 6 CHC was evaluated in the following clinical trials.

Genotype 2 (LEPTON).

Treatment naive and treatment experienced patients, with or without cirrhosis (N = 26).

Genotype 3 (ELECTRON-2).

Treatment naive and treatment experienced patients with or without cirrhosis (N = 101).

Genotype 4.

Study 1119: Treatment naive and treatment experienced patients, with or without cirrhosis (N = 44).
ION-4: HCV/HIV-1 coinfected patients, with or without cirrhosis (N = 8).

Genotype 5 (study 1119).

Treatment naive and treatment experienced patients, with or without cirrhosis (N = 25).

Genotype 6 (ELECTRON-2).

Treatment naive and treatment experienced patients, with or without cirrhosis (N = 25).
For patients with genotype 2, 4, 5, or 6 CHC, Harvoni was administered for 12 weeks without ribavirin. For patients with genotype 3 CHC, Harvoni with or without ribavirin was administered for 12 weeks in treatment naive patients and Harvoni with ribavirin was administered for 12 weeks in treatment experienced patients.

HCV/HIV-1 coinfection.

The efficacy of Harvoni in HCV/HIV-1 coinfected patients was evaluated in an open label phase 3 trial (ION-4) that enrolled 335 patients with genotype 1 or 4 CHC, with or without cirrhosis, coinfected with HIV-1. All patients in the trial were treated with Harvoni for 12 weeks.

Patients who failed prior treatment with Sovaldi and ribavirin, with or without interferon.

The efficacy of Harvoni in genotype 1 CHC patients who failed prior treatment with regimens containing Sovaldi was evaluated in two clinical trials. In study 1118, patients who had previously failed Sovaldi + RBV ± Peg-IFN, with or without cirrhosis, were treated with Harvoni + RBV for 12 weeks (N = 45). In study ION-4, 13 patients who had failed Sovaldi + RBV were treated with Harvoni without ribavirin for 12 weeks.

Liver transplant recipients and/or patients with decompensated cirrhosis.

The efficacy of Harvoni in liver transplant recipients and/or patients with decompensated cirrhosis was evaluated in two open label phase 2 trials (SOLAR-1 and SOLAR-2) that enrolled 670 patients with genotype 1 and 4 CHC postliver transplant and/or with decompensated cirrhosis. Patients in the two trials were treated with Harvoni + RBV for 12 or 24 weeks.
Serum HCV RNA values were measured during the clinical trials using the COBAS TaqMan HCV test (version 2.0), for use with the High Pure System in ION-3, ION-1, ION-2, SIRIUS and ION-4 studies or the COBAS AmpliPrep/COBAS Taqman HCV test (version 2.0) in ELECTRON-2, LEPTON, SOLAR-1, SOLAR-2, study 1118 and 1119. The COBAS Taqman HCV test (version 2.0) for use with the High Pure System has a lower limit of quantification (LLOQ) of 25 IU per mL and the COBAS AmpliPrep/COBAS Taqman HCV test (version 2.0) has a LLOQ of 15 IU per mL. Sustained virologic response (SVR) was the primary endpoint to determine the HCV cure rate which was defined as HCV RNA less than LLOQ at 12 weeks after the cessation of treatment.

Clinical trials in patients with genotype 1 CHC.

Treatment naive patients - ION-3 (study 0108).

ION-3 was a randomised, open label trial that evaluated 8 weeks of treatment with Harvoni with or without ribavirin and 12 weeks of treatment with Harvoni in treatment naive noncirrhotic patients with genotype 1 CHC. Patients were randomised in a 1:1:1 ratio to one of the three treatment groups and stratified by HCV genotype (1a vs 1b).
Demographics and baseline characteristics were balanced across the treatment groups. Of the 647 treated patients, the median age was 55 years (range: 20 to 75); 58% of the patients were male; 78% were white, 19% were black; 6% were Hispanic or Latino; mean body mass index was 28 kg/m2 (range: 18 to 56 kg/m2); 81% had baseline HCV RNA levels greater than or equal to 800,000 IU/mL; 80% had genotype 1a HCV infection; 73% had non-CC IL28B alleles (CT or TT).
Table 6 presents the response rates for the treatment groups in the ION-3 trial.
The 8 week treatment of Harvoni without ribavirin was noninferior to the 8 week treatment of Harvoni with ribavirin (treatment difference 0.9%; 95% confidence interval: -3.9% to 5.7%) and the 12 week treatment of Harvoni (treatment difference -2.3%; 97.5% confidence interval: -7.2% to 2.5%). Among patients with a baseline HCV RNA < 6 million IU/mL, the SVR was 97% (119/123) with 8 week treatment of Harvoni and 96% (126/131) with 12 week treatment of Harvoni.
Response rates for selected subgroups are presented in Table 7.
Relapse rates by baseline viral load are presented in Table 8.

Treatment naive adults with or without compensated cirrhosis - ION-1 (study 0102).

ION-1 is an ongoing randomised, open label trial to evaluate 12 and 24 weeks of treatment with Harvoni with or without ribavirin in 865 treatment naive patients with genotype 1 CHC including those with cirrhosis. Patients were randomised in a 1:1:1:1 ratio to receive Harvoni for 12 weeks, Harvoni + ribavirin for 12 weeks, Harvoni for 24 weeks or Harvoni + ribavirin for 24 weeks. Randomisation was stratified by the presence or absence of cirrhosis and HCV genotype (1a vs 1b). The interim primary endpoint analysis for SVR only included all patients enrolled in the 12 week treatment groups (N = 431). SVR rates for all patients enrolled in the 24 week treatment groups (N = 434) were not available at the time of interim analysis.
Demographics and baseline characteristics were balanced across the treatment groups. Of the 865 treated patients, the median age was 54 years (range: 18 to 80); 59% of the patients were male; 85% were white, 12% were black; 12% were Hispanic or Latino; mean body mass index was 27 kg/m2 (range: 18 to 48 kg/m2); 79% had baseline HCV RNA levels greater than or equal to 800,000 IU/mL; 67% had genotype 1a HCV infection; 70% had non-CC IL28B alleles (CT or TT) and 16% had cirrhosis.
Table 9 presents the response rates for the treatment groups of Harvoni with or without ribavirin for 12 weeks in the ION-1 trial.
Response groups for selected subgroups are presented in Table 10.

Previously treated adults with or without compensated cirrhosis - ION-2 (study 0109).

ION-2 was a randomised, open label trial that evaluated 12 and 24 weeks of treatment with Harvoni with or without ribavirin in genotype 1 HCV infected patients with or without cirrhosis who failed prior therapy with an interferon based regimen, including regimens containing an HCV protease inhibitor. Patients were randomised in a 1:1:1:1 ratio to receive Harvoni for 12 weeks, Harvoni + ribavirin for 12 weeks, Harvoni for 24 weeks or Harvoni + ribavirin for 24 weeks. Randomisation was stratified by the presence or absence of cirrhosis, HCV genotype (1a vs 1b) and response to prior HCV therapy (relapse/ breakthrough vs nonresponse).
Demographics and baseline characteristics were balanced across the treatment groups. Of the 440 treated patients, the median age was 57 years (range: 24 to 75); 65% of the patients were male; 81% were white, 18% were black; 9% were Hispanic or Latino; mean body mass index was 28 kg/m2 (range: 19 to 50 kg/m2); 89% had baseline HCV RNA levels greater than or equal to 800,000 IU/mL; 79% had genotype 1a HCV infection; 88% had non-C/C IL28B alleles (CT or TT) and 20% had cirrhosis. Forty seven percent (47%) of the patients failed a prior therapy of pegylated interferon and ribavirin. Among these patients, 49% were relapse/ breakthrough and 51% were nonresponder. Fifty three percent (53%) of the patients failed a prior therapy of pegylated interferon and ribavirin with an HCV protease inhibitor. Among these patients, 62% were relapse/ breakthrough and 38% were nonresponder.
Table 11 presents the response rates for the treatment groups in the ION-2 trial.
Response rates for selected subgroups are presented in Table 12.
Relapse rates for selected subgroups are presented in Table 13.

Previously treated adults with compensated cirrhosis - SIRIUS (study 0121).

SIRIUS was a randomised, double blind and placebo controlled trial that evaluated the efficacy of Harvoni + ribavirin for 12 weeks or Harvoni without ribavirin for 24 weeks in genotype 1 HCV infected patients with compensated cirrhosis who failed prior therapy with a Peg-IFN + RBV regimen followed by a subsequent Peg-IFN + RBV + an HCV protease inhibitor regimen. Patients were randomised in a 1:1 ratio to receive placebo for 12 weeks followed by Harvoni + ribavirin for 12 weeks or Harvoni for 24 weeks. Randomisation was stratified by HCV genotype (1a vs 1b) and response to prior HCV therapy (never achieved HCV RNA less than LLOQ vs achieved HCV RNA less than LLOQ).
Demographics and baseline characteristics were balanced across the treatment groups. Of the 155 randomised patients, the median age was 56 years (range: 23 to 77); 74% of the patients were male; 97% were white; mean body mass index was 27 kg/m2 (range: 19 to 47 kg/m2); 63% had genotype 1a HCV infection; 94% had non-C/C IL28B alleles (CT or TT). All patients (with the exception of 1) met the protocol defined definition of cirrhosis as defined by biopsy, transient elastography (> 12.5 kPa) or FibroTest score > 0.75 and an AST: platelet ratio index (APRI) > 2. One patient discontinued therapy while on placebo, and was not included in the efficacy analysis.
The SVR rate was 96% (74/77) and 97% (75/77) in patients treated with Harvoni + ribavirin for 12 weeks and Harvoni for 24 weeks without ribavirin, respectively. All 5 patients who did not achieve SVR12 relapsed.

Clinical trials in patients with genotype 2, 3, 4, 5, or 6 CHC.

Harvoni has been evaluated for the treatment of nongenotype 1 infection in a number of phase 2 and 3 studies, as summarised below.
The clinical studies enrolled patients with or without cirrhosis, who were treatment naive or with prior treatment failure after therapy with PEG-IFN + ribavirin +/- an HCV protease inhibitor.
For genotype 2, 4, 5 and 6 infection, therapy consisted of Harvoni without ribavirin, given for 12 weeks (Table 14). For genotype 3 infection, Harvoni was given with or without ribavirin, also for 12 weeks (Table 15).

Clinical trials in patients with HCV/HIV-1 coinfection.

ION-4 was an open label clinical trial that evaluated the safety and efficacy of 12 weeks of treatment with Harvoni without ribavirin in HCV treatment naive and treatment experienced patients with genotype 1 or 4 CHC who were coinfected with HIV-1. Treatment experienced patients had failed prior treatment with Peg-IFN + RBV, Peg-IFN + RBV + an HCV protease inhibitor or Sovaldi + RBV ± Peg-IFN. Patients were on a stable HIV-1 antiretroviral therapy that included emtricitabine + tenofovir DF, administered with efavirenz, rilpivirine or raltegravir.
Of the 335 treated patients, the median age was 52 years (range: 26 to 72); 82% of the patients were male; 61% were white; 34% were black; mean body mass index was 27 kg/m2 (range: 18 to 66 kg/m2); 75% had genotype 1a HCV infection; 2% had genotype 4 infection; 76% had non-C/C IL28B alleles (CT or TT); and 20% had compensated cirrhosis. Fifty-five percent (55%) of the patients were treatment experienced.
Table 16 presents the response rates in the ION-4 trial after 12 weeks of Harvoni treatment.
SVR rates were 94% (63/67) in patients with cirrhosis and 98% (46/47) in patients who were previously treated and had cirrhosis.
No patient had HIV-1 rebound during the study and no clinically meaningful changes in CD4+ cell count from baseline were observed.

Clinical trials in Sovaldi + RBV ± Peg-IFN treatment failures.

The efficacy of Harvoni in patients who had previously failed treatment with Sovaldi + RBV ± Peg-IFN is supported by two clinical trials. In study 1118, 44 patients with genotype 1 infection who had previously failed a Sovaldi + Peg-IFN + RBV or a Sovaldi + RBV regimen were treated with Harvoni + RBV for 12 weeks; the SVR was 100% (44/44). In study ION-4, 13 HCV/HIV-1 coinfected patients with genotype 1 HCV infection who had failed a Sovaldi + RBV regimen were enrolled; the SVR was 100% (13/13) after 12 weeks of treatment with Harvoni without ribavirin.
There are no data in nongenotype 1 patients who have previously failed a sofosbuvir containing regimen.

Clinical trials in liver transplant recipients and/or patients with decompensated cirrhosis.

SOLAR-1 and SOLAR-2 were two open label clinical trials that evaluated 12 and 24 weeks of treatment with Harvoni in combination with ribavirin in genotype 1 and 4 HCV infected patients who have undergone liver transplantation and/or who have decompensated liver disease. The two trials were identical in study design. Patients were enrolled in one of the seven groups based on liver transplantation status and severity of hepatic impairment (see Table 15). Patients with a CPT score > 12 were excluded. Within each group, patients were randomised in a 1:1 ratio to receive Harvoni + RBV for 12 weeks or Harvoni + RBV for 24 weeks.
Demographics and baseline characteristics were balanced across the treatment groups. Of the 670 treated patients, the median age was 59 years (range: 21 to 81); 77% of the patients were male; 91% were white; mean body mass index was 28 kg/m2 (range: 18 to 49 kg/m2); 94% and 6% had genotype 1 and 4 HCV infection, respectively; 78% of the patients failed a prior HCV therapy. Among the patients who had decompensated cirrhosis (pre- or post-transplant), 64% and 36% were CPT class B and C at screening, respectively, and 24% had a baseline Model for End Stage Liver Disease (MELD) score greater than 15.
Table 17 presents the pooled response rates of SOLAR-1 and SOLAR-2 in patients with genotype 1 CHC.
Among the 26 patients with genotype 1 CHC who did not achieve SVR12 after 12 weeks of treatment, 14 patients relapsed and the other 12 subjects were considered treatment failure due to death (N = 11) or withdrawal of consent (N = 1). Among the 19 patients with genotype 1 CHC who did not achieve SVR12 after 24 weeks of treatment, 6 patients relapsed and the other 13 patients were considered treatment failure due to death (N = 11), withdrawal of consent (N = 1) or early discontinuation after 8 days on treatment (N = 1).
Among 40 patients with genotype 4 CHC enrolled in SOLAR-1 and SOLAR-2 studies, SVR12 were 92% (11/12) and 100% (10/10) in post-transplant patients without decompensated cirrhosis treated for 12 or 24 weeks, respectively. No subjects relapsed. SVR12 were 60% (6/10) and 75% (6/8) in patients with decompensated cirrhosis (pre- and post-liver transplantation) treated for 12 or 24 weeks, respectively. Of the 7 patients who failed to achieve SVR12, 3 relapsed, all of whom had decompensated cirrhosis and were treated with Harvoni + ribavirin for 12 weeks.
Changes in MELD and CPT score from baseline to post-treatment week 12 were analysed for all patients with decompensated cirrhosis (pre- or post-transplant) who achieved SVR12 and for whom data were available (N = 123) to assess the effect of SVR12 on hepatic function.

Change in MELD score.

Among those who achieved SVR12 with 12 weeks treatment with Harvoni + RBV, 57% (70/123) and 19% (23/123) had an improvement or no change in MELD score from baseline to post-treatment week 12, respectively; of the 32 patients whose MELD score was ≥ 15 at baseline, 59% (19/32) had a MELD score < 15 at post-treatment week 12. Improvement in MELD score was driven largely by improvement in bilirubin.

Change in CPT.

Among those who achieved SVR12 with 12 weeks treatment with Harvoni + RBV, 60% (74/123) and 34% (42/123) had an improvement or no change of CPT scores from baseline to post-treatment week 12, respectively; of the 32 subjects who had CPT C cirrhosis at baseline, 53% (17/32) had CPT B cirrhosis at post-treatment week 12; of the 88 patients who had CPT B cirrhosis at baseline, 25% (22/88) had CPT A cirrhosis at post-treatment week 12. Improvement in CPT score was driven largely by improvement in albumin and bilirubin.

5.2 Pharmacokinetic Properties

Absorption.

The pharmacokinetic properties of ledipasvir, sofosbuvir and the predominant circulating metabolite GS-331007 have been evaluated in healthy adult patients and in patients with chronic hepatitis C. Following oral administration of Harvoni, ledipasvir median peak concentrations were observed 4.0 to 4.5 hours postdose. Sofosbuvir was absorbed quickly and the peak median plasma concentration was observed ~ 0.8 to 1 hour postdose. Median peak plasma concentration of GS-331007 was observed between 3.5 to 4 hours postdose.
Based on the population pharmacokinetic analysis in HCV infected patients, geometric mean steady-state AUC0-24 for ledipasvir (N = 2113), sofosbuvir (N = 1542), and GS-331007 (N = 2113) were 7290, 1320 and 12,000 nanogram.hr/mL, respectively. Steady-state Cmax for ledipasvir, sofosbuvir and GS-331007 were 323, 618 and 707 nanogram/mL, respectively. Sofosbuvir and GS-331007 AUC0-24 and Cmax were similar in healthy adult patients and patients with HCV infection. Relative to healthy subjects (N = 191), ledipasvir AUC0-24 and Cmax were 24% lower and 32% lower, respectively in HCV infected patients.
Ledipasvir AUC is dose proportional over the dose range of 3 to 100 mg. Sofosbuvir and GS-331007 AUCs are near dose proportional over the dose range of 200 mg to 1200 mg.

Distribution.

Ledipasvir is > 99.8% bound to human plasma proteins. After a single 90 mg dose of [14C]-ledipasvir in healthy subjects, the blood to plasma ratio of 14C-radioactivity ranged between 0.51 and 0.66.
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.

Metabolism.

In vitro, no detectable metabolism of ledipasvir was observed by human CYP1A2, CYP2C8, CYP2C9, CYP 2C19, CYP2D6 and CYP3A4. Evidence of slow oxidative metabolism via an unknown mechanism has been observed. Following a single dose of 90 mg [14C]-LDV, systemic exposure was almost exclusively to the parent drug (> 98%). Unchanged ledipasvir is the major species present in faeces.
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.

Excretion.

Following a single 90 mg oral dose of [14C]-ledipasvir, mean total recovery of the [14C]-radioactivity in faeces and urine was approximately 87%, with most of the radioactive dose recovered from faeces (approximately 86%). Unchanged ledipasvir excreted in faeces accounted for a mean of 70% of the administered dose and the oxidative metabolite M19 accounted for 2.2% of the dose. These data suggest that biliary excretion of unchanged ledipasvir is a major route of elimination with renal excretion being a minor pathway (approximately 1%). The median terminal half-life of ledipasvir was 47 hours.
Following a single 400 mg oral dose of [14C]-sofosbuvir, mean total recovery of the dose greater than 92%, consisting of approximately 80%, 14%, and 2.5% recovered in urine, faeces and expired air, respectively. The majority of the sofosbuvir dose recovered in urine was GS-331007 (78%) while 3.5% was recovered as sofosbuvir. This data indicate that renal clearance is the major elimination pathway for GS-331007. The median terminal half-lives of sofosbuvir and GS-331007 were 0.4 and 27 hours, respectively.

Effect of food.

Relative to fasting conditions, the administration of a single dose of Harvoni with a moderate fat (~ 600 kcal, 25% to 30% fat) or high fat (~ 1000 kcal, 50% fat) meal did not substantially affect the sofosbuvir Cmax and AUC0-inf. The exposures of GS-331007 and ledipasvir were not altered in the presence of either meal type. The response rates in phase 3 trials were similar in HCV infected patients who received Harvoni with food or without food. Harvoni can be administered without regard to food.

Age, gender and ethnicity.

No clinically relevant pharmacokinetic differences due to race have been identified for ledipasvir, sofosbuvir or GS-331007. No clinically relevant pharmacokinetic differences due to gender have been identified for sofosbuvir or GS-331007.
AUC and Cmax of ledipasvir were 77% and 58% higher respectively in females than males; however, the relationship between gender and ledipasvir exposures was not considered clinically relevant as high response rates (SVR > 90%) were achieved in males across the phase 3 studies.

Elderly patients.

Population pharmacokinetic analysis in HCV infected patients showed that within the age range (18 to 80 years) analysed, age did not have a clinically relevant effect on the exposure to ledipasvir, sofosbuvir or GS-331007. Clinical studies of Harvoni included 351 patients aged 65 and over. The response rates observed for patients ≥ 65 years of age were similar to that of subjects < 65 years of age, across treatment groups.

Paediatric patients.

The pharmacokinetics of ledipasvir, sofosbuvir and GS-331007 in paediatric patients have not been established.

Patients with impaired renal function.

The pharmacokinetics of ledipasvir were studied with a single dose of 90 mg ledipasvir in HCV negative patients with severe renal impairment (eGFR < 30 mL/min by Cockcroft-Gault). No clinically relevant differences in ledipasvir pharmacokinetics were observed between healthy patients and patients with severe renal impairment. No dose adjustment of ledipasvir is required for patients with mild, moderate or severe renal impairment. The pharmacokinetics of sofosbuvir were studied in HCV negative 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 end stage renal disease (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), the sofosbuvir AUC0-inf was 61%, 107% and 171% higher in mild, moderate and severe renal impairment, while the GS-331007 AUC0-inf was 55%, 88% and 451% higher, respectively. In patients with ESRD, relative to patients with normal renal function, sofosbuvir and GS-331007 AUC0-inf was 28% and 1280% higher when sofosbuvir was dosed 1 hour before haemodialysis compared with 60% and 2070% higher when sofosbuvir was dosed 1 hour after haemodialysis. Haemodialysis is required for the elimination of GS-331007 in patients with ESRD, with a 4 hour haemodialysis removing approximately 18% of administered dose. No dose recommendations can be given for patients with severe renal impairment eGFR < 30 mL/min/1.73 m2 or with end stage renal disease requiring haemodialysis due to higher exposure of the predominant sofosbuvir metabolite.

Patients with hepatic impairment.

The pharmacokinetics of ledipasvir were studied with a single dose of 90 mg ledipasvir in HCV negative patients with severe hepatic impairment (Child-Pugh class C). Ledipasvir plasma exposure (AUC0-inf) was similar in patients with 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 ledipasvir. No dose adjustment of ledipasvir is recommended for patients with mild, moderate or severe 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 or severe hepatic impairment.

Assessment of drug interactions.

The effects of coadministered drugs on the exposure of ledipasvir, sofosbuvir and GS-331007 are shown in Table 18. The effects of ledipasvir or sofosbuvir on the exposure of coadministered drugs are shown in Table 19.

5.3 Preclinical Safety Data

Genotoxicity.

Ledipasvir 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.
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.

Carcinogenicity.

Carcinogenicity studies (6-month rasH2 transgenic mouse and 2-year rat) in male and female mice and rats do not indicate any carcinogenicity potential of ledipasvir administered at doses up to 300 mg/kg/day in mice, 100 mg/kg/day in male rats and 30 mg/kg/day in female rats. Exposure to ledipasvir in these studies were up to 26-fold in mice and 8-fold in male rates and 3-fold in female rats higher than the clinical exposure at 90 mg ledipasvir.
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 was up 4-fold in male mice, 17-fold in female mice and 9-fold higher in rats than the clinical exposure at 400 mg sofosbuvir.

6 Pharmaceutical Particulars

6.1 List of Excipients

Harvoni tablets contain the following ingredients as excipients.

Tablet core.

Silicon dioxide, copovidone, croscarmellose sodium, lactose, magnesium stearate and microcrystalline cellulose.

Film-coating.

Polyvinyl alcohol, macrogol 3350, titanium dioxide, purified talc, and sunset yellow FCF aluminium lake.

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

Harvoni should be stored below 30°C.

6.5 Nature and Contents of Container

Harvoni 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.

Ledipasvir is an HCV NS5A inhibitor and sofosbuvir is a nucleotide inhibitor of HCV NS5B RNA-dependent RNA polymerase.
The chemical name of ledipasvir is Methyl [(2S)-1-{(6S)-6-[5-(9,9-difluoro-7-{2-[(1R,3S,4S)-2- {(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl} -2-azabicyclo [2.2.1]hept-3-yl]-1H- benzimidazol-6-yl}-9H- fluoren-2-yl)-1H-imidazol-2-yl]-5- azaspiro[2.4]hept-5-yl}- 3-methyl-1-oxobutan-2-yl] carbamate.
It has a molecular formula of C49H54F2N8O6 and a molecular weight of 889.00. It has the following structural formula:
Ledipasvir is practically insoluble (< 0.1 mg/mL) across the pH range of 3.0-7.5 and is slightly soluble below pH 2.3 (1.1 mg/mL). The partition coefficient (log P) for ledipasvir is 3.8 and the pKa1 is 4.0 and pKa2 is 5.0.
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.

CAS number.

Sofosbuvir CAS registry number: 1190307-88-0.
Ledipasvir CAS registry number: 1256388-51-8.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes