Consumer medicine information

Sovaldi

Sofosbuvir

BRAND INFORMATION

Brand name

Sovaldi Tablets

Active ingredient

Sofosbuvir

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Sovaldi.

What is in this leaflet

Read all of this leaflet carefully before you start taking this medicine.

This leaflet answers some common questions about SOVALDI tablets.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist about your medical condition or treatment.

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 SOVALDI 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 is SOVALDI used for

SOVALDI is given with other medicines to treat hepatitis C virus infection (also called HCV infection) in adults of 18 years and older.

Hepatitis C is a virus that infects the liver.

How SOVALDI works

SOVALDI contains the active ingredient sofosbuvir.

SOVALDI works together with other medicines by lowering the amount of hepatitis C virus in your body and may lead to a cure of your HCV infection over at least 12 weeks.

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

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

SOVALDI must always be taken together with other medicines as it will not work on its own.

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

Use in children

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

Before you take SOVALDI

When you must not take it

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

Do not take SOVALDI if you are allergic to:

  • sofosbuvir or
  • any of the other ingredients of SOVALDI. The ingredients of SOVALDI are listed 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 SOVALDI 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.

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.

Do not take SOVALDI 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 SOVALDI 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 HIV infection
  • Have severe kidney problems or if you are on haemodialysis as the effects of SOVALDI 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. SOVALDI is commonly used together with ribavirin or with peginterferon alfa and ribavirin. Ribavirin can damage your unborn baby. It is therefore absolutely essential that you (and your partner) take all precautions not to get pregnant during this therapy. You and your partner must use an effective birth control method during ribavirin treatment and during the 6 months after 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 if SOVALDI can pass into your breast milk and if it can harm your baby. Talk with your doctor about the best way to feed your baby.

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

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 SOVALDI may interfere with each other. Tell your doctor if you are taking any of the following medicines:

  • Rifampin
  • St John’s Wort
  • Amiodarone
  • any anti-epileptic medicines.

These medicines may be affected by SOVALDI or may affect how well it works. You may need different amounts of the medicine, or you may need to take different medicines. Your doctor or pharmacist will advise you. 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 SOVALDI. Do not start any new medicines while you are taking SOVALDI 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 SOVALDI.

How to take SOVALDI

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

How much to take

Take the exact amount of SOVALDI your doctor has prescribed for you. Never change the dose on your own. Do not stop this medicine unless your doctor tells you to stop.

How much to take

The dose is one SOVALDI tablet orally, once daily.

How to take it

SOVALDI tablets can be taken with or without food.

When to take it

Take SOVALDI 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 SOVALDI. If you forget to take SOVALDI, 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 SOVALDI 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 SOVALDI without first talking to your doctor, unless you suspect a serious allergic reaction (see When you must not take it above).

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 SOVALDI tablets. Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

While you are taking SOVALDI

Things you must do

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

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

Things you must not do

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

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

It is important not to suddenly stop taking your SOVALDI tablets, unless advised to do so by your doctor, since your condition may worsen.

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

Things to be careful of

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

Side effects

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

SOVALDI helps most people with Hepatitis C 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:

  • feeling tired and irritable
  • headache
  • diarrhoea, feeling sick (nausea), being sick (vomiting)
  • trouble sleeping (insomnia)
  • rash, itchy skin
  • loss of appetite
  • feeling dizzy
  • muscle aches and pains, pain in the joints
  • fever, chills, flu-like symptoms
  • shortness of breath, cough

Tell with your doctor as soon as possible if you have any problems while taking SOVALDI, 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 SOVALDI

Storage

Keep SOVALDI tablets where children cannot reach them.

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

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

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

Keep your SOVALDI tablets in the bottle with the cap tightly closed until you take them. If you take SOVALDI 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

SOVALDI tablets are capsuled-shaped and yellow in colour. Each tablet has “GSI” on one side and “7977” on the other side of the tablet.

SOVALDI tablets are supplied in bottles containing 28 tablets.

Ingredients

Active Ingredients: sofosbuvir

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

Film coating: polyvinyl alcohol, titanium dioxide, macrogol, talc purified, and iron oxide yellow.

Sponsor

Australia:

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

New Zealand:

Gilead Sciences (NZ)
c/- PricewaterhouseCoopers
Level 8 Pricewaterhousecoopers Tower
188 Quay Street
Auckland 1010

This leaflet was prepared in December 2016

AUST R 211019

SOVALDI, 7977 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.

BRAND INFORMATION

Brand name

Sovaldi Tablets

Active ingredient

Sofosbuvir

Schedule

S4

 

1 Name of Medicine

Sovaldi (400 mg sofosbuvir) tablets.
The active substance in Sovaldi tablets is sofosbuvir.

2 Qualitative and Quantitative Composition

Sovaldi is available as 400 mg tablets, which contain 400 mg sofosbuvir and are yellow, capsule shaped, film coated with "GSI" on one side and "7977" on the other side. For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Each Sovaldi tablet is film-coated and yellow in colour. The tablets are capsule shaped debossed with "GSI" on one side and the number "7977" on the other side. The tablets are supplied in bottles with child resistant closures.

4 Clinical Particulars

4.1 Therapeutic Indications

Sovaldi is indicated for the treatment of adults with chronic hepatitis C (CHC) infection as a component of a combination antiviral treatment regimen.
(See Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 4.2 Dose and Method of Administration for detailed information on the studied combinations, dose regimens, and treatment durations for different subgroups of CHC patients).

4.2 Dose and Method of Administration

The recommended dosage of Sovaldi tablets is 400 mg once daily taken orally with or without food.
Sovaldi should be used in combination with other agents. The recommended treatment regimen and duration for Sovaldi combination therapy is provided in Table 1 and Figure 1.
Monotherapy of Sovaldi is not recommended.

Special patient populations.

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. Sovaldi is not indicated for treatment of children and adolescents less than 18 years of age.

Elderly.

No dose adjustment is warranted for elderly patients.

Patients with renal impairment.

No dose adjustment of Sovaldi is required for patients with mild or moderate renal impairment. The safety of Sovaldi has not been assessed in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m2) or end stage renal disease (ESRD) requiring haemodialysis (see Section 5.2 Pharmacokinetic Properties). There are no data to support Sovaldi in patients with severe renal failure. Refer also to ribavirin product information for patients with CrCL < 50 mL/min.

Patients with hepatic impairment.

No dose adjustment of Sovaldi 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 Sovaldi have not been established in patients with decompensated cirrhosis. See peginterferon alfa product information for contraindication in hepatic decompensation.

Patients awaiting liver transplantation.

Sovaldi in combination with ribavirin was administered for up to 24 weeks to 28 patients with hepatocellular carcinoma awaiting liver transplantation to prevent post-transplant HCV reinfection. The duration of administration of Sovaldi in patients awaiting liver transplantation should be guided by an assessment of the potential benefits and risks for the individual patient.

Dose modification.

Dose reduction of Sovaldi is not recommended.

Genotype 1, 4, 5 and 6.

If a patient has a serious adverse reaction potentially related to peginterferon alfa and/or ribavirin, the peginterferon alfa and/or ribavirin dose should be reduced or discontinued. Refer to the peginterferon alfa and ribavirin product information for additional information about how to reduce and/or discontinue the peginterferon alfa and/or ribavirin dose.

Genotype 2 and 3.

If a patient has a serious adverse reaction potentially related to ribavirin, the ribavirin dose should be modified or discontinued, if appropriate, until the adverse reaction abates or decreases in severity. Table 2 provides guidelines for dose modifications and discontinuation based on the patient's haemoglobin concentration and cardiac status.

Discontinuation of dosing.

If the other agents used in combination with Sovaldi are permanently discontinued, Sovaldi should also be discontinued.

4.3 Contraindications

When Sovaldi is used in combination with peginterferon alfa/ ribavirin or ribavirin, the contraindications applicable to those agents are applicable to combination therapies. Refer to the product information of peginterferon alfa and ribavirin for a list of their contraindications.

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 Sovaldi is not recommended. For patients taking amiodarone who have no other alternative, viable treatment options and who will be coadministered Sovaldi: 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 Sovaldi 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 Sovaldi 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 Sovaldi.
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 in the intestine (e.g. rifampin, St. John's wort) may significantly decrease sofosbuvir plasma concentration leading to reduced therapeutic effect of Sovaldi. Rifampin and St. John's wort should not be used with Sovaldi.

Treatment experienced patients with genotype 1, 4, 5 and 6 HCV infection.

Sovaldi has not been studied in a phase 3 study in treatment-experienced patients with genotype 1, 4, 5 and 6 HCV infection. Thus, the optimal treatment duration in this population has not been established (see Section 4.2 Dose and Method of Administration).

Treatment of patients with genotype 5 and 6 HCV infection.

The clinical data to support the use of Sovaldi in patients with genotype 5 and 6 HCV infection is very limited.

HCV/HBV (hepatitis B virus) coinfected patients.

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

HCV/HIV coinfected patients.

There is limited data on the safety and efficacy of Sovaldi in HCV/HIV co-infected patients with untreated HIV (see Section 5.1 Pharmacodynamic Properties, Clinical trials, HCV/HIV co-infected patients - PHOTON-1 (study 123)).

Use in the elderly.

Sovaldi was administered to 61 patients aged 65 and over. The response rates observed for patients over 65 years of age were similar to that of younger patients across treatment groups. No dose adjustment of Sovaldi is warranted in elderly patients. In general, caution should be exercised when administering Sovaldi 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 Sovaldi in children less than 18 years of age have not been established.

Effects on laboratory tests.

As liver function may change during treatment with Sovaldi, 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

Sofosbuvir is a nucleotide prodrug. After oral administration of Sovaldi, sofosbuvir is rapidly converted to the predominant circulating metabolite GS-331007 that accounts for greater than 90% of drug related material systemic exposure, while the parent sofosbuvir accounts for approximately 4% of drug related material.
Sofosbuvir is a substrate of drug transporter P-gp and breast cancer resistance protein (BCRP) while GS-331007 is not. Drugs that are potent P-gp inducers in the intestine (e.g. rifampin or St John's wort) may decrease sofosbuvir plasma concentration leading to reduced therapeutic effect of Sovaldi and thus should not be used with Sovaldi. Coadministration of Sovaldi with drugs that inhibit P-gp and/or BCRP may increase sofosbuvir plasma concentration without increasing GS-331007 plasma concentration; accordingly, Sovaldi may be coadministered with P-gp and/or BCRP inhibitors. Sofosbuvir and GS-331007 are not inhibitors of P-gp and BCRP and thus are not expected to increase exposures of drugs that are substrates of these transporters.
Co-administration of ribavirin and didanosine in HIV-HCV co-infected patients is not permitted, please refer to ribavirin product information for guidance.
The intracellular metabolic activation pathway of sofosbuvir is mediated by generally low affinity and high capacity hydrolase and nucleotide phosphorylation pathways that are unlikely to be affected by concomitant drugs.
Drug interaction information for Sovaldi with potential concomitant drugs is summarized in Table 3. The drug interactions described are based on potential drug interactions that may occur with Sovaldi. The table is not all inclusive.

Drugs without clinically significant interactions with Sovaldi.

In addition to the drugs included in Table 3, the interaction between Sovaldi and the following drugs were evaluated in clinical trials and no dose adjustment is needed for either drug (see Tables 18 and 19): cyclosporin, darunavir/ ritonavir, emtricitabine, efavirenz, methadone, raltegravir, rilpivirine, tacrolimus (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Other forms of interaction), tenofovir disoproxil fumarate or oral contraceptives (norgestimate/ ethinyl estradiol).

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.

Sovaldi.

Sofosbuvir had no effects on fertility in male or female rats, at the highest test dose of 500 mg/kg/day, estimated exposure (AUC) to the main metabolite GS-331007 was about 12-fold higher than in humans at the recommended clinical dose.
In a pre- and post-natal developmental study, fertility was normal in the offspring of rats exposed daily from before birth (in utero) through lactation day 20 at daily GS-331007 exposures (AUC) approximately 12-fold higher than human exposures at the recommended clinical dose.

Use with ribavirin or peginterferon.

In fertility studies in animals, ribavirin caused reversible testicular toxicity in males, while perinterferon alfa may impair fertility in females. Refer to the product information for ribavirin and peginterferon for additional information.

Sovaldi (pregnancy category B1).

Sovaldi must not be used as monotherapy (see Section 4.1 Therapeutic Indications). There are no adequate and well controlled clinical studies with Sovaldi in pregnant women. 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.

Use with ribavirin or peginterferon (pregnancy category X).

Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin. When Sovaldi is used in combination with ribavirin or peginterferon alfa/ 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 co-administered with Sovaldi, the contraindications regarding use of ribavirin apply (refer to ribavirin product information).
The predominant circulating metabolite GS-331007, but not sofosbuvir, is excreted in rat milk. It is not known whether sofosbuvir and its metabolites are excreted in human breast milk. Mothers should be instructed not to breast-feed if they are taking Sovaldi. See also the product information for ribavirin and peginterferon alfa.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects of Sovaldi on the ability to drive and use machines have been performed. However, patients should be informed that fatigue and disturbance in attention have been reported during treatment with Sovaldi in combination with ribavirin and fatigue, dizziness, blurred vision and disturbance in attention have been reported during treatment with Sovaldi in combination with peginterferon alfa and ribavirin.

4.8 Adverse Effects (Undesirable Effects)

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 https://www.tga.gov.au/reporting-problems.

Clinical trials.

Assessment of adverse reactions is based on pooled phase 3 data (both controlled and uncontrolled) including 650 patients who received Sovaldi + ribavirin combination therapy for 12 weeks, 98 patients who received Sovaldi + ribavirin combination therapy for 16 weeks, 250 patients received Sovaldi + ribavirin combination therapy for 24 weeks, 327 patients who received Sovaldi + peginterferon alfa + ribavirin combination therapy for 12 weeks, 243 patients who received peginterferon alfa + ribavirin for 24 weeks and 71 patients who received placebo for 12 weeks.
The proportion of patients who permanently discontinued treatment due to adverse events was 4% for patients receiving placebo, 1% for patients receiving Sovaldi + ribavirin for 12 weeks, < 1% for patients receiving Sovaldi + ribavirin for 24 weeks, 11% for patients receiving peginterferon alfa + ribavirin for 24 weeks and 2% for patients receiving Sovaldi + peginterferon alfa + ribavirin for 12 weeks.
Treatment-emergent adverse events observed in ≥ 15% of patients in clinical trials are provided in Table 4. A side-by-side tabulation is to simplify presentation; direct comparison across trials should not be made due to differing trial designs.
The most common adverse events (≥ 20%) for Sovaldi + ribavirin combination therapy were fatigue and headache. The most common adverse events (≥ 20%) for Sovaldi + peginterferon alfa + ribavirin combination therapy were fatigue, headache, nausea, insomnia and anaemia.
With the exception of anaemia and neutropenia, the majority of events presented in Table 4 occurred at severity of grade 1 in Sovaldi-containing regimens.

Less common adverse reactions reported in clinical trials (< 1%).

The following ADRs occurred in < 1% of patients receiving Sovaldi in a combination regimen in any one trial. These events have been included because of their seriousness or assessment of potential causal relationship.

Haematologic effects.

Pancytopenia (particularly in patients receiving concomitant pegylated interferon).

Psychiatric disorders.

Severe depression (particularly in patients with pre-existing history of psychiatric illness), including suicidal ideation and suicide.

Other special population(s).

HIV/HCV co-infection.

The safety profile of Sovaldi and ribavirin in HCV/HIV co-infected patients was similar to that observed in mono-infected HCV patients treated with Sovaldi and ribavirin in phase 3 clinical studies.

Patients awaiting liver transplantation.

The safety profile of Sovaldi and ribavirin in HCV infected patients prior to liver transplantation was similar to that observed in patients treated with Sovaldi and ribavirin in phase 3 clinical studies.

Liver transplant recipients.

The safety profile of Sovaldi and ribavirin in liver transplant recipients with chronic hepatitis C was similar to that observed in patients treated with sofosbuvir and ribavirin in phase 3 clinical studies (see Section 5.1 Pharmacodynamic Properties, Clinical trials). In study 0126, decreases in haemoglobin during treatment were very common with 32.5% (13/40 patients) experiencing a decline in haemoglobin to < 10 g/dL, 1 of whom also had a decline to < 8.5 g/dL. Eight patients (20%) received epoetin and/or a blood product. In 5 patients (12.5%), study drugs were discontinued, modified or interrupted due to adverse events. See Section 5.1 Pharmacodynamic Properties, Clinical trials, Liver transplant recipients - study 0126.

Long term safety.

There is currently no long term safety data on the use of Sovaldi (beyond 24 weeks).

Post marketing surveillance.

In addition to adverse reactions from clinical studies, the following adverse reactions were also identified during postapproval use of Sovaldi. 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 Sovaldi) (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, Hepatitis B virus reactivation).

4.9 Overdose

The highest documented dose of sofosbuvir was a single supratherapeutic dose of sofosbuvir 1200 mg administered to 59 healthy patients. In that trial, there were no untoward effects observed at this dose level, and adverse events were similar in frequency and severity to those reported in the placebo and sofosbuvir 400 mg treatment groups. The effects of higher doses are not known.
No specific antidote is available for overdose with Sovaldi. If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with Sovaldi consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient. Haemodialysis can efficiently remove the predominant circulating metabolite GS-331007 with an extraction ratio of 53%.
For information on the management of overdose, contact the Poison Information Centre on 131 126 (Australia) and 0800 764 766 (New Zealand).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group.

Antivirals for systemic use; direct acting antivirals, other antivirals, ATC code: J05AX15.

Mechanism of action.

Sofosbuvir is a pan-genotypic inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is essential for viral replication. Sofosbuvir is a nucleotide prodrug that undergoes intracellular metabolism to form the pharmacologically active uridine 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 micromolar. GS-461203 is not an inhibitor of human DNA and RNA polymerases nor an inhibitor of mitochondrial RNA polymerase in vitro.

Antiviral activity in vitro.

In HCV replicon assays, the EC50 values of sofosbuvir against full length replicons from genotype 1a, 1b, 2a, 3a and 4a, and chimeric 1b replicons encoding NS5B from genotype 2b, 5a or 6a ranged from 0.014 to 0.11 micromolar. The median ± SD EC50 of sofosbuvir against chimeric replicons encoding NS5B sequences from clinical isolates was 0.068 ± 0.024 micromolar for genotype 1a (N = 67), 0.11 ± 0.029 micromolar for genotype 1b (N = 29), 0.035 ± 0.018 micromolar for genotype 2 (N = 15) and 0.085 ± 0.034 micromolar for genotype 3a (N = 106). In infectious virus assays, the EC50 values of sofosbuvir against genotype 1a and 2a were 0.03 and 0.02 micromolar, respectively. The presence of 40% human serum had no effect on the anti-HCV activity of sofosbuvir. Evaluation of sofosbuvir in combination with interferon alpha or ribavirin showed no antagonistic effect in reducing HCV RNA levels in replicon cells.

Drug resistance.

In cell culture.

HCV replicons with reduced susceptibility to sofosbuvir have been selected in cell culture for multiple genotypes including 1b, 2a, 2b, 3a, 4a, 5a and 6a. Reduced susceptibility to sofosbuvir was associated with the primary NS5B substitution S282T in all replicon genotypes examined. Site-directed mutagenesis of the S282T substitution in replicons of 8 genotypes including 1b, 1a, 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.

In a pooled analysis of 991 patients who received Sovaldi in phase 3 trials, 226 patients qualified for resistance analysis due to virologic failure or early study drug discontinuation and having HCV RNA > 1000 IU/mL. Post-baseline NS5B sequences were available for 225 of the 226 patients, with deep sequencing data (assay cutoff of 1%) from 221 of these patients. The NS5B-associated resistance substitution S282T was not detected in any of these patients by deep sequencing or population sequencing. No other NS5B substitutions were identified to be associated with resistance to sofosbuvir by deep sequencing and phenotypic analyses.

Effect of baseline HCV polymorphisms on treatment outcome.

Baseline NS5B sequences were obtained for 1292 patients from phase 3 trials by population sequencing and the S282T substitution was not detected in any patient with available baseline sequence. In an analysis evaluating the effect of baseline polymorphisms on treatment outcome, no statistically significant association was observed between the presence of any HCV NS5B variant at baseline and treatment outcome.

Cross-resistance.

HCV replicons expressing the NS5B-associated resistance substitution S282T were fully susceptible to other classes of anti-HCV agents and were 3-10 fold more sensitive to ribavirin as compared to wild-type replicons. Sofosbuvir retained activity against the NS5B substitutions L159F and L320F associated with resistance to other nucleoside inhibitors. Sofosbuvir was fully active against substitutions associated with resistance to other direct-acting antivirals with different mechanisms of actions, such as NS5B non-nucleoside inhibitor, NS3 protease inhibitors and NS5A inhibitors.

Clinical trials.

Overview of clinical trials.

The efficacy of Sovaldi was evaluated in five phase 3 trials in a total of 1568 patients with genotypes 1 to 6 chronic hepatitis C (CHC). One study was conducted in treatment-naïve patients with genotype 1, 4, 5 or 6 CHC in combination with peginterferon alfa 2a and ribavirin, and the other four trials were conducted in patients with genotype 2 or 3 CHC in combination with ribavirin including one in treatment naïve patients, one in interferon intolerant, ineligible or unwilling patients, one in patients previously treated with an interferon-based regimen and one in all patients irrespective of prior treatment history or ability to take interferon. Patients in these trials had compensated liver disease including cirrhosis. Sovaldi was administered at a dose of 400 mg once daily. Peginterferon (Peg-IFN) alfa 2a dose was 180 microgram per week and the ribavirin (RBV) dose was weight-based 1000-1200 mg daily administered in two divided doses. Ribavirin used in the phase 3 program was Ribasphere and was deemed to be equivalent to Copegus. Treatment duration was fixed in each trial and was not guided by patients' HCV RNA levels (no response guided algorithm).
Plasma 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. The assay had a lower limit of quantification (LLOQ) of 25 IU per mL. Sustained virologic response (SVR) was the primary endpoint to determine the HCV cure rate for all trials which was defined as HCV RNA less than LLOQ at 12 weeks after the end of treatment (SVR 12).

Clinical trials in patients with genotype 1, 4, 5 or 6 chronic hepatitis C.

Treatment-naïve adult patients - NEUTRINO (study 110).

NEUTRINO was an open-label, single-arm trial that evaluated 12 weeks of treatment with Sovaldi in combination with peginterferon alfa 2a and ribavirin in treatment-naïve patients with genotype 1, 4, 5 or 6 HCV infection.
Treated patients (N = 327) had a median age of 54 years (range: 19 to 70); 64% of the patients were male; 79% were White, 17% were Black; 14% were Hispanic or Latino, 2% were Asian; mean body mass index was 29 kg/m2 (range: 18 to 56 kg/m2); 78% had baseline HCV RNA greater than 6 log10 IU per mL; 17% had cirrhosis; 89% had HCV genotype 1 and 11% had HCV genotype 4, 5 or 6. 4% were on opiate replacement therapy. Table 5 presents the response rates for the treatment group of Sovaldi + peginterferon alfa + ribavirin.
Response rates for selected subgroups are presented in Table 6.
SVR rates were similarly high in patients with baseline IL28B C/C allele [93/95 (98%)] and non-C/C (C/T or T/T) allele [202/232 (87%)].

Clinical trials in patients with genotype 2 or 3 chronic hepatitis C.

Treatment naïve adults - FISSION (study 1231).

FISSION was a randomised, open label, active controlled trial that evaluated 12 weeks of treatment with Sovaldi and ribavirin compared to 24 weeks of treatment with peginterferon alfa 2a and ribavirin in treatment-naïve patients with genotype 2 and 3 HCV. The ribavirin doses used in the Sovaldi + ribavirin and peginterferon alfa 2a + ribavirin arms were weight-based 1000-1200 mg per day and 800 mg per day regardless of weight, respectively. Patients were randomised in a 1:1 ratio and stratified by cirrhosis (presence vs absence), HCV genotype (2 vs 3) and baseline HCV RNA level (< 6 log10 IU/mL vs ≥ 6 log10 IU/mL). Patients with genotype 2 or 3 HCV were enrolled in an approximately 1:3 ratio.
Treated patients (N = 499) had a median age of 50 years (range: 19 to 77); 66% of the patients were male; 87% were White, 3% were Black; 14% were Hispanic or Latino, 29% were Asian; mean body mass index was 28 kg/m2 (range: 17 to 52 kg/m2); 57% had baseline HCV RNA levels greater than 6 log10 IU per mL; 20% had cirrhosis; 72% had HCV genotype 3. 9% were on opiate replacement therapy. Table 7 presents the response rates for the treatment groups of Sovaldi + ribavirin and peginterferon alfa + ribavirin.
The difference in the overall SVR rates between Sovaldi + ribavirin and peginterferon alfa + ribavirin treatment groups was 0.3% (95% confidence interval: -7.5% to 8.0%) and the study met the predefined noninferiority criterion.
Among the small number of Black/ African Americans enrolled in the trial, 75% (9/12) patients achieved SVR in the Sovaldi + ribavirin treatment group compared to 40% (2/5) in the peginterferon alfa + ribavirin treatment group.
Response rates for patients with cirrhosis at baseline are presented in Table 8 by genotype.

Interferon intolerant, ineligible or unwilling adults - POSITRON (study 107).

POSITRON was a randomized, double-blinded, placebo-controlled trial that evaluated 12 weeks of treatment with Sovaldi and ribavirin (N = 207) compared to placebo (N = 71) in patients who are interferon intolerant, ineligible or unwilling. Patients were randomised in 3:1 ratio and stratified by cirrhosis (presence vs absence).
Treated patients (N = 278) had a median age of 54 years (range: 21 to 75); 54% of the patients were male; 91% were White, 5% were Black; 11% were Hispanic or Latino, 8% were Asian; mean body mass index was 28 kg/m2 (range: 18 to 53 kg/m2); 70% had baseline HCV RNA levels greater than 6 log10 IU per mL; 16% had cirrhosis; 49% had HCV genotype 3. 8% were on opiate replacement therapy. The proportions of patients who were interferon intolerant, ineligible, or unwilling were 9%, 44%, and 47%, respectively. Most patients had no prior HCV treatment (81.3%). Table 9 presents the response rates for the treatment groups of Sovaldi + ribavirin and placebo.
The SVR12 rate in the Sovaldi + ribavirin treatment group was statistically significant when compared to placebo (p < 0.001).
Table 10 presents the subgroup analysis by genotype for cirrhosis and interferon classification.

Previously treated adults - FUSION (study 108).

FUSION was a randomised, double-blinded trial that evaluated 12 or 16 weeks of treatment with Sovaldi and ribavirin in patients who did not achieve SVR with prior interferon-based treatment (relapsers and nonresponders). Patients were randomised in a 1:1 ratio and stratified by cirrhosis (presence vs absence) and HCV genotype (2 vs 3).
Treated patients (N = 201) had a median age of 56 years (range: 24 to 70); 70% of the patients were male; 87% were White; 3% were Black; 9% were Hispanic or Latino, 12% were Asian; mean body mass index was 29 kg/m2 (range: 19 to 44 kg/m2); 73% had baseline HCV RNA levels greater than 6 log10 IU per mL; 34% had cirrhosis; 63% had HCV genotype 3; 75% were prior relapsers. 3% were on opiate replacement therapy. Table 11 presents the response rates for the treatment groups of Sovaldi + ribavirin for 12 weeks and 16 weeks.
Table 12 presents the subgroup analysis by genotype for cirrhosis and response to prior HCV treatment.

Treatment naïve and previously treated adults - VALENCE (study 133).

VALENCE was a phase 3 study that evaluated Sovaldi in combination with weight based ribavirin for the treatment of genotype 2 or 3 HCV infection in treatment-naïve patients or patients who did not achieve SVR with prior interferon-based treatment, including patients with compensated cirrhosis. The study was designed as a direct comparison of Sovaldi and ribavirin versus placebo for 12 weeks. However, based on emerging data, the study was unblinded and all HCV genotype 2 patients continued to receive Sovaldi and ribavirin for 12 weeks, whilst treatment for HCV genotype 3 patients was extended to 24 weeks. Eleven HCV genotype 3 patients had already completed treatment with Sovaldi and ribavirin for 12 weeks at the time of the amendment.
Treated patients (n = 419) had a median age of 51 years (range: 19 to 74); 60% of the patients were male; median body mass index was 25 kg/m2 (range: 17 to 44 kg/m2); the mean baseline HCV RNA level was 6.4 log10 IU/mL; 21% had cirrhosis; 78% had HCV genotype 3; 65% were prior relapsers. Table 13 presents the response rates for the treatment groups of Sovaldi + ribavirin for 12 weeks and 24 weeks.
Placebo recipients are not included in the tables since none achieved SVR12.
Table 14 presents the subgroup analysis by genotype for cirrhosis and exposure to prior HCV treatment.

SVR12 to SVR24 concordance.

The concordance between SVR12 and SVR24 (SVR 24 weeks after the end of the treatment) following treatment with Sovaldi in combination with ribavirin or ribavirin and pegylated interferon demonstrates a positive predictive value of 99% and a negative predictive value of 99%.

Clinical efficacy and safety in special populations.

HCV/HIV co-infected patients - PHOTON-1 (study 123).

Sofosbuvir was studied in an open-label clinical study evaluating the safety and efficacy of 12 or 24 weeks of treatment with Sovaldi and ribavirin in patients with genotype 1, 2 or 3 chronic hepatitis C co-infected with HIV-1. Genotype 2 and 3 patients were either treatment-naïve or experienced, whereas genotype 1 patients were naïve to prior treatment. Patients received 400 mg Sovaldi and weight-based ribavirin (1,000 mg for patients weighing < 75 kg or 1,200 mg for patients weighing ≥ 75 kg) daily for 12 or 24 weeks based on genotype and prior treatment history. Patients were either not on antiretroviral therapy with a CD4+ cell count > 500 cells/mm3 or had virologically suppressed HIV-1 with a CD4+ cell count > 200 cells/mm3. Efficacy data 12 weeks post-treatment are available for 210 patients (Table 15).
There is limited data on the safety and efficacy of Sovaldi in HCV/HIV co-infected patients with untreated HIV.
Table 16 presents the subgroup analysis by genotype for cirrhosis.

Patients awaiting liver transplantation.

Sovaldi was studied in HCV-infected patients prior to undergoing liver transplantation in an open-label clinical trial evaluating the safety and efficacy of Sovaldi and ribavirin administered pre-transplant to prevent post-transplant HCV reinfection. The primary endpoint of the trial was post-transplant virologic response (pTVR) (HCV RNA < lower limit of quantification [LLOQ] at 12 weeks post-transplant). HCV-infected patients, regardless of genotype, with hepatocellular carcinoma (HCC) meeting the MILAN criteria received 400 mg Sovaldi and 1000-1200 mg ribavirin daily for a maximum of 24 weeks or until the time of liver transplantation, whichever occurred first. An interim analysis was conducted on 61 patients who received Sovaldi and ribavirin; 45 had genotype 1; 44 patients had a baseline CPT score less than 7. Of these 61 patients, 44 patients underwent liver transplantation following up to 48 weeks of treatment with Sovaldi and ribavirin; 41 had HCV RNA < LLOQ at the time of transplantation, one of whom received an HCV-infected liver. The viral response rates of the 41 patients transplanted with HCV RNA < LLOQ are described in Table 17.

Liver transplant recipients - study 0126.

Sovaldi was studied in an open-label clinical study evaluating the safety and efficacy of 24 weeks of treatment with Sovaldi and ribavirin in liver transplant recipients (N = 40) with chronic hepatitis C. Eligible patients were ≥ 18 years old who had undergone liver or liver/kidney transplantation 6 to 150 months prior to screening and who had HCV RNA ≥ 104 IU/mL at screening and documented evidence of chronic HCV infection pre-transplantation. Key exclusion criteria included: Child-Pugh-Turcotte Score > 7, MELD score > 17, ABO incompatible organ, histological evidence of unresolved rejection, co-infection with hepatitis B or HIV, and history of immunologic disorders. Exclusion criteria also specified use or planned use of T-cell depleting/masking antibodies, systemic antineoplastic agents, cyclosporine > 300 mg/day, sirolimus, everolimus or prednisone ≥ 5 mg/day or equivalent.
Forty patients were enrolled and treated, 33 with HCV genotype 1 infection, 6 with HCV genotype 3 infection, and 1 with HCV genotype 4 infection. Thirty-five participants had previously failed interferon-based treatment, and 16 had cirrhosis. SVR was achieved by 28 patients (70% [90% CI 56.0-81.7%]): 22/33 with HCV genotype 1 infection, 6/6 with HCV genotype 3 infection, and 0/1 with HCV genotype 4 infection. All patients who achieved SVR12 achieved SVR24 and SVR48.

5.2 Pharmacokinetic Properties

Absorption.

The pharmacokinetic properties of 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 Sovaldi, sofosbuvir was absorbed quickly and the peak plasma concentration was observed ~0.5-2 hour post-dose, regardless of dose level. Peak plasma concentration of GS-331007 was observed between 2 to 4 hours post-dose. Based on population pharmacokinetic analysis in patients with genotypes 1 to 6 HCV infection (N = 986), steady-state AUC0-24 for sofosbuvir was 860 nanogram.hr/mL and steady-state AUC0-24 and Cmax for GS-331007 were 7200 nanogram.hr/mL and 582 nanogram/mL, respectively. Relative to healthy patients (N = 284), the sofosbuvir AUC0-24 was 36% higher and the GS-331007 AUC0-24 and Cmax were 39% and 49% lower, respectively in HCV-infected patients. Sofosbuvir and GS-331007 AUCs are near dose proportional over the dose range of 200 mg to 1200 mg.

Distribution.

Sofosbuvir is approximately 61-65% bound to human plasma proteins and the binding is independent of drug concentration over the range of 1 microgram/mL to 20 microgram/mL. Protein binding of GS-331007 was minimal in human plasma. After a single 400 mg dose of [14C]-sofosbuvir in healthy patients, the blood to plasma ratio of 14C radioactivity was approximately 0.7.

Metabolism.

Sofosbuvir is extensively metabolized 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 catalyzed 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, sofosbuvir and GS-331007 accounted for approximately 4% and > 90% of drug related material (sum of molecular weight-adjusted AUC of sofosbuvir and its metabolites) systemic exposure, respectively.

Excretion.

Following a single 400 mg oral dose of 14C-sofosbuvir, mean total recovery of the dose was greater than 92%, consisting of approximately 80%, 14%, and 2.5% recovered in urine, faeces, and expired air, respectively. The majority of the sofosbuvir dose recovered in urine was GS-331007 (78%) while 3.5% was recovered as sofosbuvir. This data indicate that renal clearance is the major elimination pathway for GS-331007. The median terminal half-life 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 Sovaldi with a standardised high fat meal slowed the rate of absorption of sofosbuvir but did not substantially affect the extent of absorption. The exposure of GS-331007 was not altered in the presence of a high-fat meal. Therefore, Sovaldi can be administered without regard to food.

Age.

The pharmacokinetics of sofosbuvir and GS-331007 in paediatric patients has not been established. Sofosbuvir is not indicated for use in the patients less than 18 years of age.
Population pharmacokinetic analysis in HCV-infected patients showed that within the age range (19 to 75 years) analysed, age did not have a clinically relevant effect on the exposure to sofosbuvir and GS-331007. Sovaldi was administered to 61 patients aged 65 and over. The response rates observed for patients over 65 years of age were similar to that of younger patients across treatment groups (see Section 4.4 Special Warnings and Precautions for Use, Use in the elderly).

Gender.

No clinically relevant pharmacokinetic differences due to gender have been identified for sofosbuvir and GS-331007.

Race/ethnicity.

Although not all ethnicities have been studied, no clinically relevant pharmacokinetic differences due to ethnicity have been identified for sofosbuvir and GS-331007.
No clinically relevant pharmacokinetic differences due to race have been identified for sofosbuvir and GS-331007.

Patients with impaired renal function.

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 adjustment is required for patients with mild or moderate renal impairment. The safety of Sovaldi has not been assessed in patients with severe renal impairment or ESRD.

Patients with hepatic impairment.

The pharmacokinetics of sofosbuvir was 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 had no clinically relevant effect on the exposure of sofosbuvir and GS-331007. No dose adjustment of sofosbuvir is recommended for patients with mild, moderate and severe hepatic impairment.

Assessment of drug interactions.

In clinical pharmacology studies, both sofosbuvir and GS-331007 were monitored for purposes of pharmacokinetic analyses. The effects of coadministered drugs on the exposure of sofosbuvir and GS-331007 are shown in Table 18. The effects of sofosbuvir on the exposure of coadministered drugs are shown in Table 19.

5.3 Preclinical Safety Data

Genotoxicity.

Sofosbuvir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo mouse micronucleus assays. See also the product information for ribavirin and peginterferon alfa.

Carcinogenicity.

Carcinogenicity studies in mice and rats do not indicate any carcinogenicity potential of sofosbuvir administered at doses up to 200 mg/kg/day in male mice and 600 mg/kg/day in female mice and 750 mg/kg/day in rats. Exposure to GS-331007 in these studies in mice was up to 7 x (male) and 30 x (female) and in rats up to 13 x (male) and 17 x (female) higher than the clinical exposure at 400 mg sofosbuvir. See also the product information for ribavirin and peginterferon alfa.

6 Pharmaceutical Particulars

6.1 List of Excipients

Sovaldi tablets contain the following ingredients as excipients:

Tablet core.

Mannitol, microcrystalline cellulose, croscarmellose sodium, silicon dioxide and magnesium stearate.

Film coating.

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

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

Sovaldi should be stored below 30°C.

6.5 Nature and Contents of Container

Sovaldi 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

Sofosbuvir is a nucleotide inhibitor of HCV NS5B RNA-dependent RNA polymerase.

Chemical structure.

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.

CAS registry number: 1190307-88-0.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes