Consumer medicine information

Stribild Tablets

Tenofovir disoproxil fumarate; Emtricitabine; Cobicistat; Elvitegravir

BRAND INFORMATION

Brand name

Stribild

Active ingredient

Tenofovir disoproxil fumarate; Emtricitabine; Cobicistat; Elvitegravir

Schedule

S4

 

Consumer medicine information (CMI) leaflet

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

What is in this leaflet

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

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

It does not take the place of talking to your doctor or pharmacist about your medical condition or treatment. If you have further questions, please ask your doctor or your pharmacist.

Keep this leaflet with your STRIBILD 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 STRIBILD

STRIBILD is used to treat HIV infection. STRIBILD is for people who have never taken HIV medicines before, or who do not have a resistant HIV virus to STRIBILD.

STRIBILD consists of four medicines:

  • tenofovir disoproxil fumarate, also called tenofovir DF (VIREAD®)
  • emtricitabine or FTC (EMTRIVA®)
  • elvitegravir
  • cobicistat (TYBOST®)

These are combined in one tablet to help control Human Immunodeficiency Virus (HIV) infection.

VIREAD and EMTRIVA belong to a group of antiviral medicines known as nucleoside and nucleotide reverse transcriptase inhibitors (NRTI).

Elvitegravir belongs to a class of antiviral medicines known as integrase inhibitors.

Cobicistat is a “booster”, to help increase the levels of elvitegravir.

How STRIBILD works

HIV infection destroys CD4 T cells, which are important to the immune system. The immune system helps fight infection. After a large number of T cells are destroyed, acquired immune deficiency syndrome (AIDS) may develop.

STRIBILD helps block HIV-1 reverse transcriptase, a viral chemical in your body (enzyme) that is needed for HIV-1 to multiply. STRIBILD lowers the amount of HIV in the blood (viral load). STRIBILD may also help to increase the number of T cells (CD4+ cells), allowing your immune system to improve. Lowering the amount of HIV in the blood lowers the chance of death or infections that happen when your immune system is weak (opportunistic infections).

Use in Children and Elderly

STRIBILD is for adults. STRIBILD has not been studied in children under the age of 18 or adults over the age of 65.

Does STRIBILD cure HIV OR AIDS

STRIBILD does not cure HIV infection or AIDS.

The long-term effects of STRIBILD are not known at this time. People taking STRIBILD may still get opportunistic infections or other conditions that happen with HIV infection. Opportunistic infections are infections that develop because the immune system is weakened.

Some of these conditions are:

  • pneumonia,
  • herpes virus infections, and
  • Mycobacterium avium complex (MAC) infection.

This medicine is only available from a pharmacist after it has been prescribed by a doctor who specialises in the treatment of HIV infection.

If you wish to continue receiving treatment with STRIBILD it is important you remain under the care of a hospital or doctor who specialises in the treatment of HIV infection.

Does STRIBILD reduce the risk of passing HIV to others

STRIBILD does not lower your chance of passing HIV to other people through sexual contact, sharing needles, or being exposed to your blood.

For your health and the health of others, it is important to always practice safer sex by using a latex or polyurethane condom or other barrier to lower the chance of sexual contact with semen, vaginal secretions, or blood.

Never re-use or share needles.

Before you take STRIBILD

Who must not take it

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

Do not take STRIBILD if you are allergic to:

  • tenofovir
  • tenofovir DF
  • emtricitabine
  • elvitegravir
  • cobicistat or
  • any of the other ingredients of STRIBILD

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • rash, itching or hives on the skin
  • swelling of the face, lips, tongue or other parts of the body

The ingredients of STRIBILD are listed in the product description section of this leaflet.

Do not take STRIBILD if you are already taking any other medicines that contain the same active ingredients.

Do not take STRIBILD if you are taking tenofovir alafenamide.

Do not take STRIBILD if you are taking other medicines that contain:

  • lamivudine (e.g. Combivir, Zeffix, Kivexa, Trizivir)
  • ritonavir (e.g. Kaletra)
  • efavirenz (e.g. Stocrin)

Do not take STRIBILD if you are already taking any of the following medicines:

  • carbamazepine (e.g. Tegretol)
  • phenobarbital
  • phenytoin (e.g. Dilantin)
  • lovastatin (e.g. Mevacor)
  • midazolam (e.g. Hypnovel)
  • rifabutin (e.g. Mycobutin)
  • rifampicin (e.g. Rifadin/Rimycin)
  • sildenafil (e.g. Viagra/Revatio)
  • simvastatin (e.g. Invast/Zimcol)
  • tadalafil (e.g. Cialis/Adcirca)
  • triazolam (e.g. Halcion)
  • St John’s Wort or products containing St John’s Wort.
  • alfuzosin hydrochloride (e.g. Xatral)
  • ergot-containing medicines like dihydroergotamine, ergotamine (e.g. Cafergot, Dihydergot, Migerot).

Do not take STRIBILD to treat your HIV infection if you are also taking adefovir dipivoxil to treat your hepatitis B virus (HBV) infection.

This is not a complete list of medicines that you should tell your doctor about.

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

Before you start to take it

Tell your doctor if you take an antacid medicine that contains aluminum, magnesium hydroxide, or calcium carbonate. Take antacids at least 2 hours before or after you take STRIBILD.

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

Tell your doctor if you are pregnant, or likely to become pregnant during your course of medication. We do not know if STRIBILD can harm your unborn child. You and your doctor will need to decide if STRIBILD is right for you.

Tell your doctor if you are breastfeeding, or likely to breastfeed during your course of medication. You should not breastfeed if you are HIV-positive because of the chance of passing the HIV virus to your baby. Two active substances in this medicine (tenofovir disoproxil fumarate and emtricitabine) have been found in breast milk at low concentrations.

Talk with your doctor about the best way to feed your baby.

Tell your doctor if you have kidney problems or are undergoing kidney dialysis treatment.

Tell your doctor if you have bone problems.

Tell your doctor if you have liver problems, including hepatitis B or C virus infection.

Tell your doctor if you are taking medication to treat your hepatitis C virus (HCV) infection (e.g. ledipasvir/sofosbuvir [HARVONI], sofosbuvir/velpatasvir [EPCLUSA], or sofosbuvir/velpatasvir/ voxilaprevir [VOSEVI]).

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 may affect the levels of STRIBILD or STRIBILD may affect the levels of other medicines in the body when they are taken at the same time as STRIBILD.

Your doctor may change your other medicines or change their doses. Other medicines, including herbal products may affect STRIBILD.

For this reason, 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 STRIBILD.

Do not start any new medicines while you are taking STRIBILD without first talking with your doctor or pharmacist.

How to take STRIBILD

Take the exact amount of STRIBILD your doctor has prescribed for you.

Never change the dose on your own.

Do not stop this medicine unless your healthcare provider tells you to stop.

How much to take

The usual dose is one STRIBILD tablet orally, once daily.

How to take it

Always take STRIBILD with a meal. A meal is important to get the right drug levels in your body.

A protein drink does not constitute a meal.

If you forget to take STRIBILD

Do not miss a dose of STRIBILD.

If you forget to take STRIBILD, 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.

When your STRIBILD supply starts to run low, get more from your doctor or pharmacy. This is very important because the amount of virus in your blood may increase if the medicine is stopped for even a short time. The virus may develop resistance to STRIBILD and become harder to treat.

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

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 STRIBILD tablets. Do this even if there are no signs of discomfort or poisoning. This may need urgent medical attention.

While you are taking STRIBILD

Things you must not do

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

Avoid doing things that can spread HIV infection since STRIBILD does not stop you from passing the HIV infection to others:

  • Do not share needles or other injection equipment.
  • Do not share personal items that can have blood or body fluids on them, like toothbrushes or razor blades.
  • Do not have any kind of sex without protection.
    Always practice safer sex by using a latex or polyurethane condom or other barrier to reduce the chance of sexual contact with semen, vaginal secretions, or blood.

Things to be careful of

Be careful driving or operating machinery until you know how STRIBILD affects you. If you are dizzy, have trouble concentrating, or are drowsy, avoid activities that may be dangerous, such as driving or operating machinery.

SIDE EFFECTS

Like all medicines, STRIBILD can have side effects, although not everybody gets them. Some may be serious and need medical attention.

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

STRIBILD may cause the following serious side effects:

Lactic Acidosis

If you have any of the following symptoms after taking your medication, tell your doctor IMMEDIATELY or go to the accident and emergency department at your nearest hospital:

  • You feel very weak or tired
  • You have unusual (not normal) muscle pain
  • You have trouble breathing
  • You have stomach pain with nausea and vomiting
  • You feel cold, especially in your arms and legs
  • You feel dizzy or light headed
  • You have a fast or irregular heartbeat

These side effects may be due to a condition called lactic acidosis (build-up of an acid in the blood).

Lactic acidosis can be a medical emergency and may need to be treated in the hospital.

Serious Liver Problems (hepatotoxicity)

If you have any of the following symptoms while taking your medication, tell your doctor IMMEDIATELY or go to the accident and emergency department at your nearest hospital:

  • Your skin or the white part of your eyes turns yellow (jaundice)
  • Your urine turns dark
  • Your bowel movements (stools) turn light in colour
  • You don’t feel like eating food for several days or longer
  • You feel sick to your stomach (nausea)
  • You have lower stomach area (abdominal) pain

These side effects may be due to a condition called hepatotoxicity with liver enlargement (hepatomegaly) and fat deposits in the liver (steatosis) which sometimes occurs in patients taking anti-HIV medicines.

You may be more likely to get lactic acidosis or liver problems if you are female, very overweight (obese), or have been taking similar nucleoside analog-containing medicines, like STRIBILD, for a long time.

Hepatic Flares

If you have HIV infection and HBV infection you should not stop your STRIBILD treatment without first discussing this with your doctor. Some patients have had blood tests or symptoms indicating a worsening of their hepatitis (“hepatic flare”) after stopping individual components (tenofovir DF and emtricitabine) of STRIBILD.

You may require medical exams and blood tests for several months after stopping treatment. STRIBILD is not approved for the treatment of HBV, so you must discuss your HBV therapy with your doctor.

Kidney Problems

If you have had kidney problems in the past or take other medicines that can cause kidney problems, your doctor should do regular blood tests to check your kidneys.

Symptoms that may be related to kidney problems include a high volume of urine, thirst, muscle pain, and muscle weakness.

Changes in Bone Mineral Density (thinning bones)

Laboratory tests show changes in the bones of patients treated with tenofovir DF, a component of STRIBILD.

Some people living with HIV treated with VIREAD developed thinning of the bones (osteopaenia).

If you have had bone problems in the past, your doctor may need to do tests to check your bone mineral density or may prescribe medicines to help your bone mineral density.

Additionally, bone pain and softening of the bone (which may contribute to fractures) may occur as a consequence of kidney problems.

Signs and Symptoms of Inflammation

In some patients with advanced HIV infection (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started. It is believed that these symptoms are due to an improvement in the body’s immune response, which lets the body fight infections that may have been present with no obvious symptoms.

If you notice any symptoms of infection, please tell your doctor immediately.

Pancreatitis

If you have any of the following symptoms after starting your medication, tell your doctor IMMEDIATELY or go to the accident and emergency department at your nearest hospital:

  • severe stomach pain or cramps
  • nausea
  • vomiting

These side effects may be due to a condition called pancreatitis which sometimes occurs in patients taking anti-HIV medicines.

Common Side Effects:

The most common side effects of STRIBILD are:

  • diarrhoea
  • upper respiratory tract infection
  • depression

Other side effects include:

  • vomiting
  • nausea
  • headache
  • intestinal gas
  • dizziness
  • back pain
  • tiredness
  • sleeping problems (including difficulty falling asleep or sleepiness)
  • bronchitis
  • abnormal dreams
  • stomach pain or discomfort
  • rash
  • serious kidney problems

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

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

Ask your doctor or pharmacist for a more complete list of side effects of STRIBILD and all the medicines you will take. This is not a complete list of side effects possible with STRIBILD.

After taking STRIBILD

Storage

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

Do not store STRIBILD or any other medicine in a bathroom or near a sink.

Do not leave STRIBILD in the car or on a window sill. Heat and dampness can destroy some medicines.

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

PRODUCT DESCRIPTION

What the tablets look like

STRIBILD is the brand name of your medicine.

STRIBILD tablets are capsule-shaped and green in colour.

Each tablet is debossed with “GSI” on one side and the number “1” surrounded by a square box ( ) on the other side.

STRIBILD tablets are supplied in bottles containing 30 tablets.

Ingredients

Each STRIBILD tablet contains the following active ingredients:

  • elvitegravir
  • cobicistat
  • tenofovir disoproxil fumarate
  • emtricitabine

Each STRIBILD tablet also contains the following ingredients:

  • lactose
  • cellulose-microcrystalline (E460)
  • silicon dioxide
  • croscarmellose sodium
  • hyprolose
  • magnesium stearate (E572)
  • sodium lauryl sulphate

Film-coating:

  • indigo carmine (FD&C blue #2)
  • aluminum lake
  • macrogol 3350
  • polyvinyl alcohol
  • talc
  • titanium dioxide (E171)
  • yellow iron oxide

SPONSOR

STRIBILD tablets are supplied in Australia by:

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

In New Zealand by:

Gilead Sciences (NZ)
c/- Grant Thornton New Zealand Limited
Level 4, 152 Fanshawe Street,
Auckland 1010

Date of preparation: 15 July 2020

AUST R 194081

ATRIPLA, EPCLUSA, HARVONI, STRIBILD, GENVOYA, DESCOVY, ODEFSEY, EMTRIVA, TRUVADA, EVIPLERA, VIREAD, VOSEVI and GSI are trademarks of Gilead Sciences, Inc. or one of its related companies. All other trademarks referenced herein are the property of their respective owners.

Published by MIMS September 2020

BRAND INFORMATION

Brand name

Stribild

Active ingredient

Tenofovir disoproxil fumarate; Emtricitabine; Cobicistat; Elvitegravir

Schedule

S4

 

1 Name of Medicine

Stribild (tenofovir disoproxil fumarate/emtricitabine/elvitegravir/cobicistat).

2 Qualitative and Quantitative Composition

The active substances in Stribild tablets are tenofovir disoproxil fumarate (tenofovir DF), emtricitabine, elvitegravir and cobicistat. Each tablet contains 300 mg tenofovir DF (which is equivalent to 245 mg of tenofovir disoproxil), 200 mg emtricitabine, 150 mg of elvitegravir and 150 mg of cobicistat.
Tenofovir DF is a white to off-white crystalline powder with a solubility of 13.4 mg/mL in water at 25°C. The partition coefficient (log p) for tenofovir disoproxil is 1.25 and the pKa is 3.75.
Emtricitabine is a white to off-white crystalline powder with a solubility of approximately 112 mg/mL in water at 25°C. The partition coefficient (log p) for emtricitabine is -0.43 and the pKa is 2.65.
Elvitegravir is a white to pale yellow powder with a solubility of less than 0.5 microgram/mL in water at 20°C. The partition coefficient (log p) for elvitegravir is 4.5 and the pKa is 6.6.
Cobicistat is a white to pale yellow solid with a solubility of 0.1 mg/mL in water with pH 6.8 phosphate buffer at 20°C. The partition coefficient (log p) for cobicistat is 4.3 and the pKa is 6.4.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Stribild is available as tablets. The tablets are film-coated, capsule shaped and green in colour. Each tablet is debossed with 'GSI' on one side and the number "1" surrounded by a square box on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Stribild is indicated as a single tablet regimen for the treatment of HIV infection in treatment naïve adults. Stribild is also indicated in certain virologically suppressed (HIV-1 RNA < 50 copies/mL) adult patients on a stable antiretroviral regimen at start of therapy in order to replace their current antiretroviral treatment regimen (see Section 5.1 Pharmacodynamic Properties). Patients must not have a history of treatment failure or known mutations associated with resistance to the antiretroviral components of Stribild (tenofovir DF, emtricitabine or elvitegravir).
Stribild is a fixed dose combination of one integrase inhibitor, one pharmacokinetic enhancer and two nucleos(t)ide HIV-1 reverse transcriptase inhibitors.

4.2 Dose and Method of Administration

Dosage.

Adults.

The recommended dose of Stribild is one tablet once daily taken orally with a meal.

Children and adolescents.

Stribild is not recommended for use in children or adolescents below 18 years of age due to insufficient data on safety and efficacy.

Dosage adjustment.

Renal impairment.

Stribild should not be initiated in patients with estimated creatinine clearance below 70 mL/min. Stribild should be discontinued if estimated creatinine clearance declines below 50 mL/min during treatment with Stribild as dose interval adjustment required for emtricitabine and tenofovir DF cannot be achieved with the fixed-dose combination tablet (see Section 4.4 Special Warnings and Precautions for Use).

Not recommended during pregnancy.

Stribild is not recommended for use during pregnancy because of substantially lower exposures of cobicistat and elvitegravir during the second and third trimesters (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).
Stribild should not be initiated in pregnant individuals. An alternative regimen is recommended for individuals who become pregnant during therapy with Stribild (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).

4.3 Contraindications

Stribild is contraindicated in patients with known hypersensitivity to any of the active substances or any other component of the tablets.
Stribild must not be administered to children or adolescents under the age of 18 years.
Coadministration is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events, and with drugs that are potent inducers of CYP3A due to the potential for loss of virologic response and possible resistance to Stribild. Therefore, coadministration is contraindicated with, but not limited to, the following drugs (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions):
Alpha 1-adrenoreceptor antagonists: alfuzosin.
Anticonvulsants: carbamazepine, phenobarbital, phenytoin.
Antimycobacterials: rifampicin.
Ergot derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovine.
Gastrointestinal (GI) motility agents: cisapride.
Herbal products: St. John's wort (Hypericum perforatum).
HMG-CoA reductase inhibitors: lovastatin, simvastatin.
Other lipid-modifying agents: lomitapide.
Neuroleptics: pimozide.
Phosphodiesterase-5 (PDE-5) inhibitors: sildenafil for the treatment of pulmonary arterial hypertension.
Sedative/hypnotics: orally administered midazolam, triazolam.
Stribild is a fixed dose combination of tenofovir DF, emtricitabine, elvitegravir and cobicistat. Stribild should not be administered concurrently with other medicinal products containing any of the same active components: tenofovir DF, emtricitabine, elvitegravir or cobicistat. Stribild should not be administered with adefovir dipivoxil or tenofovir alafenamide.

4.4 Special Warnings and Precautions for Use

General.

Patients receiving Stribild or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection, and therefore should remain under close clinical observation by physicians experienced in the treatment of patients with HIV associated diseases.
Patients should be advised that antiretroviral therapies, including Stribild, have not been proven to prevent the risk of transmission of HIV to others through sexual contact or blood contamination. Appropriate precautions must continue to be used. Patients should also be informed that Stribild is not a cure for HIV infection.

Lactic acidosis/severe hepatomegaly with steatosis.

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases have been reported with the use of antiretroviral nucleoside analogues including the tenofovir DF component of Stribild, alone or in combination with other antiretrovirals, in the treatment of HIV infection. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogues to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with Stribild should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

Renal impairment.

The emtricitabine and tenofovir DF components of Stribild are primarily excreted by the kidney. Renal failure, renal impairment, elevated creatinine, hypophosphataemia and Fanconi syndrome have been reported with the use of tenofovir DF.
Estimated creatinine clearance, urine glucose, and urine protein should be documented in all patients prior to initiating therapy with Stribild. Stribild should not be initiated in patients with estimated creatinine clearance below 70 mL/min.
Routine monitoring of estimated creatinine clearance should be performed during Stribild therapy in patients, additionally, serum phosphorus should be measured in patients at risk for renal impairment. Stribild should be discontinued if estimated creatinine clearance declines below 50 mL/min as dose interval adjustment required for tenofovir DF and emtricitabine cannot be achieved with the fixed dose combination tablet.
Although cobicistat may cause modest increases in serum creatinine and modest declines in estimated creatinine clearance without affecting renal glomerular function, patients who experience a confirmed increase in serum creatinine of greater than 0.4 mg per dL from baseline should be monitored for renal safety, including measuring serum phosphorus, urine glucose and urine protein (see Section 4.8 Adverse Effects (Undesirable Effects)).
Stribild should be avoided with concurrent or recent use of a nephrotoxic agent.

Hepatic impairment.

Stribild has not been studied in patients with severe hepatic impairment (Child-Pugh class C). Therefore, Stribild is not recommended for use in patients with severe hepatic impairment.

Bone effects.

Bone toxicity including a reduction in bone mineral density (BMD) have been observed in tenofovir DF studies in three animal species. Clinically relevant bone abnormalities have not been seen in long-term clinical studies (> 3 years) with Viread, or in 144 week studies with Stribild. However, bone abnormalities (infrequently contributing to fractures) may be associated with proximal renal tubulopathy (see Section 4.8 Adverse Effects (Undesirable Effects)). If bone abnormalities are suspected during therapy then appropriate consultation should be obtained.

HIV and hepatitis B virus (HBV) co-infection.

The safety and efficacy of Stribild have not been established in patients coinfected with HIV and HBV. Discontinuation of Stribild therapy in patients co-infected with HIV and HBV may be associated with severe acute exacerbations of hepatitis due to the emtricitabine and tenofovir DF components of Stribild. Patients co-infected with HIV and HBV should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping Stribild treatment. If appropriate, initiation of antihepatitis B therapy may be warranted. In patients with advanced liver disease or cirrhosis, discontinuation of antihepatitis B therapy is not recommended since post-treatment exacerbation of hepatitis may lead to hepatic decompensation. Stribild should not be administered concomitantly with other medicinal products used for the treatment of hepatitis B virus infection (tenofovir disoproxil [as fumarate or alafenamide], lamivudine or adefovir dipivoxil).

Use with hepatitis C virus antiviral agents.

Coadministration of tenofovir DF with Harvoni (ledipasvir/sofosbuvir), Epclusa (sofosbuvir/velpatasvir), or Vosevi (sofosbuvir/velpatasvir/voxilaprevir) has been shown to increase plasma concentrations of tenofovir, especially when used together with an HIV regimen containing tenofovir DF and a pharmacokinetic enhancer (ritonavir or cobicistat). The safety of tenofovir DF in the setting of Harvoni, Epclusa or Vosevi and a pharmacokinetic enhancer has not been established. The potential risks and benefits associated with coadministration of Harvoni with Stribild should be considered, particularly in patients at increased risk of renal dysfunction. Patients receiving Stribild concomitantly with Harvoni, Epclusa or Vosevi should be monitored for adverse reactions related to tenofovir DF.

Use with other antiretroviral products.

Stribild is indicated for use as a complete regimen for the treatment of HIV-1 infection and should not be coadministered with other antiretroviral products. Stribild should not be used in conjunction with protease inhibitors or non-nucleoside reverse transcriptase inhibitors due to potential drug-drug interactions including altered and/or suboptimal pharmacokinetics of cobicistat, elvitegravir, and/or the coadministered antiretroviral products.
Stribild should not be coadministered with products containing any of the same active components, emtricitabine, tenofovir DF, elvitegravir or cobicistat; or with products containing lamivudine. Stribild should not be administered concurrently with ritonavir or ritonavir containing products or regimens due to similar effects of cobicistat and ritonavir on CYP3A. Stribild should not be administered with adefovir dipivoxil or tenofovir alafenamide.

Immune reconstitution syndrome.

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including tenofovir DF and emtricitabine. In HIV infected patients with severe immune deficiency at the time of initiation of antiretroviral therapy, an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of antiretroviral therapy. Relevant examples include cytomegalovirus retinitis, generalised and/or focal mycobacterial infections and Pneumocystis jirovecii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.
Autoimmune disorders (such as autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the reported time to onset is more variable, and these events can occur many months after initiation of treatment.

Use in the elderly.

Clinical studies of Stribild did not contain sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. Caution should be exercised when prescribing Stribild to the elderly, keeping in mind the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

Paediatric use.

Stribild is not recommended for use in children or adolescents below 18 years of age due to insufficient data on safety and efficacy.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

General.

As Stribild contains tenofovir DF, emtricitabine, elvitegravir and cobicistat, any interactions that have been identified with these agents individually may occur with Stribild.

CYP3A associated drug-drug interactions.

Cobicistat, a component of Stribild, is a strong inhibitor of cytochrome P450 (CYP3A) and a CYP3A substrate. Thus, coadministration of Stribild with drugs that are primarily metabolized by CYP3A may result in increased plasma concentrations of such drugs (see Section 4.3 Contraindications). Coadministration of Stribild with drugs that inhibit CYP3A may decrease the clearance of cobicistat, resulting in increased plasma concentration of cobicistat. Coadministration of Stribild with drugs that have active metabolite(s) formed by CYP3A may result in reduced plasma concentrations of these active metabolite(s), potentially leading to loss of therapeutic effect of the coadministered drug. Cobicistat is also an inhibitor of CYP2D6. The transporters that cobicistat inhibits included P-glycoprotein (P-gp), BCRP, OATP1B1 and OATP1B3. Thus, coadministration of Stribild with drugs that are primarily metabolized by CYP3A or CYP2D6, or are substrates of P-gp, BCRP, OATP1B1 or OATP1B3 may result in increased plasma concentrations of such drugs.
Elvitegravir, a component of Stribild, is metabolized by CYP3A. Drugs that induce CYP3A activity are expected to increase the clearance of elvitegravir and cobicistat, resulting in decreased plasma concentration of elvitegravir and cobicistat, which may lead to loss of therapeutic effect of Stribild and development of resistance (see Section 4.3 Contraindications).

Drugs affecting renal functions.

Tenofovir and emtricitabine and are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion. No drug-drug interactions due to competition for renal excretion have been observed; however, coadministration of Stribild with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and emtricitabine, and/or the coadministered drug. Some examples include, but are not limited to acyclovir, adefovir dipivoxil, cidofovir, ganciclovir, valacyclovir, and valganciclovir. Drugs that decrease renal function may increase concentrations of tenofovir and/or emtricitabine.

Coadministration of other medicinal products.

Exposure to didanosine is significantly increased following coadministration with tenofovir DF that may increase the risk of didanosine related adverse reactions. Rarely, pancreatitis and lactic acidosis, sometimes fatal, have been reported (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Established and other potentially significant interactions.

Stribild is indicated for use as a complete regimen for the treatment of HIV-1 infection and should not be administered with other antiretroviral products. Therefore, information regarding drug-drug interactions with other antiretroviral products (including protease inhibitors and non-nucleoside reverse transcriptase inhibitors) is not provided. Drug interaction information for Stribild with potential concomitant drugs is summarized in Table 1. The drug interactions described are based on studies conducted with Stribild or the components of Stribild (tenofovir DF, emtricitabine, elvitegravir and cobicistat) as individual agents and/or in combination, or are potential drug interactions that may occur with Stribild.
The table is not all inclusive (see Section 4.3 Contraindications).

Drugs without clinically significant interactions with Stribild.

Based on drug interaction studies conducted with Stribild or the components of Stribild, no clinically significant drug interactions have been either observed or are expected between the components of Stribild and the following drugs: entecavir, famciclovir, famotidine, omeprazole, sertraline, telaprevir and ribavirin.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No reproductive toxicity studies have been conducted with tenofovir DF, emtricitabine, and elvitegravir and cobicistat in combination.

Tenofovir disoproxil fumarate.

Male and female rat fertility and mating performance or early embryonic development were unaffected by an oral tenofovir DF dose (600 mg/kg/day) that achieved systemic drug exposures that were in excess of the expected value in humans receiving the therapeutic dose (5-fold based on plasma AUC). There was, however, an alteration of the oestrous cycle in female rats.

Emtricitabine.

Emtricitabine did not affect fertility in male rats or in female and male mice at respective approximate exposures (AUC) of 130 and 50 to 80 times the exposure in humans. The fertility of offspring was unaffected by treatment of mice from early gestation to the end of lactation (50 times the human exposure).

Elvitegravir.

Elvitegravir did not affect fertility in male and female rats at a dose achieving greater than 10-fold higher exposures (AUC), than in humans with the therapeutic 150 mg daily dose.
Fertility was normal in the offspring of rats exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 18-fold higher than human exposures at the recommended 150 mg daily dose.

Cobicistat.

Cobicistat did not affect fertility in male or female rats at daily exposures (AUC) greater than 4-fold higher than human exposures with the 150 mg daily dose.
Fertility was normal in the offspring of rats exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 1.2-fold higher than human exposures at the recommended 150 mg daily dose.
(Category B3)
There are no adequate and well controlled clinical studies of Stribild or its components in pregnant women. Animal reproductive studies have only been conducted with the individual pharmaceutical components and not the fixed dose combination. Animal reproductive studies are not always predictive of human response.
Lower exposures of elvitegravir and cobicistat have been reported during pregnancy compared to postpartum. Treatment during pregnancy may be associated with an increased risk of treatment failure and an increased risk of HIV transmission to the child. Therefore, Stribild is not recommended during pregnancy.
An alternative regimen is recommended for individuals who become pregnant during therapy with Stribild. Viral load should be closely monitored during pregnancy.

Tenofovir disoproxil fumarate.

Reproductive toxicity studies performed in rats and rabbits did not reveal any evidence of harm to the foetus due to tenofovir at respective exposures (AUC) of 4-13 and 66-fold the human exposure. Subcutaneous treatment of pregnant rhesus monkeys with a dose of 30 mg/kg/day of the tenofovir base during the last half of pregnancy resulted in reduced foetal serum phosphorus concentrations.

Emtricitabine.

No evidence of embryofoetal toxicity or teratogenicity was observed in mice or rabbits at respective emtricitabine exposures (AUC) of 50 and 130-fold the clinical exposure. Impaired weight gain observed in pregnant rabbits at doses resulting in emtricitabine exposures (AUC) at least 33 times the clinical exposure was not associated with any adverse foetal effects.

Elvitegravir.

Studies in animals have shown no evidence of teratogenicity or an effect on reproductive function. In offspring from rat and rabbit dams treated with elvitegravir during pregnancy, there were no toxicologically significant effects on developmental endpoints. The exposures at the embryofoetal no observed adverse effects levels (NOAELs) in rats and rabbits were respectively 23 and 0.2 times higher than the exposure in humans at the recommended dose of 150 mg/day.

Cobicistat.

Studies in animals have shown no evidence of teratogenicity or an effect on reproductive function. In offspring from rat and rabbit dams treated with cobicistat during pregnancy, there were no toxicologically significant effects on developmental endpoints. The exposures at the embryofoetal no observed adverse effects levels (NOAELs) in rats and rabbits were respectively 1.8 and 4.3 times higher than the exposure in humans at the recommended daily dose of 150 mg.

Women of childbearing potential.

Since there are no well controlled clinical studies with Stribild in pregnant women, adequate contraception is recommended for women of childbearing potential when taking Stribild.
It is not known whether elvitegravir and cobicistat are excreted in human milk.
Studies in rats have demonstrated that elvitegravir and cobicistat are secreted into milk.

Tenofovir disoproxil fumarate.

In humans, samples of breast milk obtained from five HIV-1 infected mothers show that tenofovir was secreted in human milk at low concentrations (estimated neonatal concentrations 128 to 266 times lower than the tenofovir IC50 (50% maximal inhibitory concentration)). Tenofovir associated risks, including the risk of developing viral resistance to tenofovir, in infants breastfed by mothers being treated with tenofovir DF are unknown.

Emtricitabine.

Samples of breast milk obtained from five HIV-1 infected mothers show that emtricitabine was secreted in human milk at estimated neonatal concentrations 3 to 12 times higher than the emtricitabine IC50 but 3 to 12 times lower than the Cmin (minimal expected trough concentrations in adults) achieved from oral administration of emtricitabine. Breastfeeding infants whose mothers are being treated with emtricitabine may be at risk for developing viral resistance to emtricitabine. Other emtricitabine associated risks in infants breastfed by mothers being treated with emtricitabine are unknown.
Because of the potential for both HIV transmission and for serious adverse events in nursing infants, mothers should be instructed not to breastfeed if they are receiving Stribild.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects of Stribild on the ability to drive and use machines have been performed. However, patients should be informed that dizziness has been reported during treatment with Stribild.

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 http://www.tga.gov.au/reporting-problems.
As Stribild contains tenofovir DF, emtricitabine, elvitegravir and cobicistat, adverse events associated with these individual antiretroviral agents may be expected to occur with the fixed combination tablet.
For additional safety information about Viread (tenofovir DF), Emtriva (emtricitabine) in combination with other antiretroviral agents, consult the product information for these products.

Clinical trials.

Treatment naïve patients. The safety assessment of Stribild is based on pooled data from 1408 patients in the phase 3 trials study GS-US-236-0102 and study GS-US-236-0103 in antiretroviral treatment naïve HIV-1 infected adult patients. A total of 701 patients received Stribild once daily for 144 weeks.
The proportion of patients who discontinued treatment with Stribild, Atripla or atazanavir/r + Truvada due to adverse events, regardless of severity, was 6.0%, 7.4% and 8.5%, respectively. The most common adverse reactions (incidence greater than or equal to 8%) occurring in patients receiving Stribild in studies GS-US-236-0102 and GS-US-236-0103 include diarrhoea, upper respiratory tract infection, and depression. See also Table 2 for the frequency of adverse reaction (grade 2-4) occurring in at least 5% of subjects receiving Stribild in studies GS-US-236-0102 and GS-US-236-0103.
Treatment emergent adverse drug reactions of at least moderate intensity (≥ grade 2) that occurred in less than 5% of patients treated with Stribild in studies GS-US-236-0102 and GS-US-236-0103 include back pain, fatigue, nausea, vomiting, abdominal pain, dyspepsia, flatulence, dizziness, insomnia, abnormal dreams, renal failure, Fanconi syndrome acquired, blood creatinine increased, and rash.
In the clinical trials of Stribild over 144 weeks, 13 (1.9%) patients in the Stribild group (N = 701) and 8 (2.3%) patients in the atazanavir + ritonavir + Truvada group (N = 355) discontinued study drug due to a renal adverse reaction. Of these discontinuations, 7 in the Stribild group and 1 in the atazanavir + ritonavir + Truvada group occurred during the first 48 weeks. The renal adverse reactions seen with Stribild were consistent with previous experience with tenofovir DF. Four (0.6%) patients who received Stribild developed laboratory findings consistent with proximal renal tubular dysfunction leading to discontinuation of Stribild during the first 48 weeks. No additional proximal renal tubular dysfunction cases were reported from week 48 to week 144. Two of the four patients had renal impairment (i.e. estimated creatinine clearance less than 70 mL per min) at baseline. The laboratory findings in these 4 patients with evidence of proximal tubulopathy improved without clinical consequence upon discontinuation of Stribild but did not completely resolve in all patients. Three (0.8%) patients who received atazanavir + ritonavir + Truvada developed laboratory findings consistent with proximal renal tubular dysfunction leading to discontinuation of atazanavir + ritonavir + Truvada after week 96.
Additional adverse drug reactions observed with Stribild included suicidal ideation and suicide attempt (0.3%, 2 of 701), these two patients had a pre-existing history of depression or psychiatric illness.
The cobicistat component of Stribild has been shown to decrease estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting renal glomerular function. In studies 102 and 103, decreases in estimated creatinine clearance occurred early in treatment with Stribild, after which they stabilized. The mean ± SD change in estimated glomerular filtration rate (eGFR) by Cockcroft-Gault method after 144 weeks of treatment was -14.0 ± 16.6 mL/min for Stribild, -1.9 ± 17.9 mL/min for Atripla, and -9.8 ± 19.4 mL/min for ATV + RTV + Truvada.
Clinical trials in patients with mild to moderate renal impairment. In study GS-US-236-0118, 33 HIV-1 infected treatment naïve patients with mild to moderate renal impairment (eGFR by Cockcroft-Gault method between 50 and 89 mL/minute) were studied in an open label clinical trial evaluating the safety of 48 weeks of treatment with Stribild. By week 48 three (9.1%) patients all of whom had baseline eGFR between 50-60 mL/minute discontinued due to a renal adverse event; none developed laboratory findings consistent with proximal renal tubular dysfunction. After 48 weeks of treatment, the mean change in serum creatinine was 0.17 ± 0.14 mg/dL and the mean change in eGFR by Cockcroft-Gault method was -6.9 ± 9.0 mL/minute for Stribild. The renal safety of Stribild in study GS-US-236-0118 in patients with mild to moderate renal impairment was consistent with the overall renal findings in studies GS-US-236-102 and GS-US-236-103.
Virologically suppressed patients. No new adverse reactions to Stribild through week 48 were identified in virologically stably suppressed patients switching to Stribild from a regimen containing a ritonavir boosted protease inhibitor (PI), a non-nucleoside reverse transcriptase inhibitor (NNRTI) or raltegravir. Overall, most adverse reactions were grade 1; the frequency of adverse reactions (grades 2-4) was 4% in the patients switching to Stribild (N = 293) and 1% in the patients remaining on a ritonavir boosted PI (N = 140) in study GS-US-236-0115, and 5% in the patients switching to Stribild (N = 291) and 1% in the patients remaining on an NNRTI (N = 143) in study GS-US-236-0121, and 2% in the patients switching to Stribild (N = 48) in study GS-US-236-0123.

Tenofovir disoproxil fumarate and emtricitabine.

In addition to the adverse drug reactions observed with Stribild, the following adverse drug reactions occurred in at least 5% of treatment experienced or treatment naïve patients receiving emtricitabine or tenofovir DF with other antiretroviral agents in other clinical trials: fever, pain, nasopharyngitis, pneumonia, sinusitis, myalgia, paresthesia, peripheral neuropathy (including peripheral neuritis and neuropathy), anxiety, increased cough, and rhinitis.
Skin discoloration has been reported with higher frequency among emtricitabine treated subjects; it was manifested by hyperpigmentation on the palms and/or soles and was generally mild and asymptomatic. The mechanism and clinical significance are unknown.
Laboratory abnormalities. The frequency of treatment emergent laboratory abnormalities (grade 3-4) occurring in at least 2% of patients receiving Stribild in studies 102 and 103 are presented in Table 3.

Tenofovir disoproxil fumarate or emtricitabine.

In addition to the laboratory abnormalities observed with Stribild, the following laboratory abnormalities have been previously reported in patients treated with emtricitabine or tenofovir DF with other antiretroviral agents in other clinical trials: grade 3 or 4 laboratory abnormalities of ALT (M: > 215 U/L; F: > 170 U/L), alkaline phosphatase (> 550 U/L), bilirubin (> 2.5 x ULN), serum glucose (< 40 or > 250 mg/dL), glycosuria (≥ 3+), neutrophils (< 750/mm3), fasting cholesterol (> 240 mg/dL), and fasting triglycerides (> 750 mg/dL).

Post marketing surveillance.

In addition to adverse events reported from clinical trials, the following events have been reported in post marketing surveillance. Because these events have been reported voluntarily from a population of unknown size, estimates of frequency cannot be made.
Tenofovir disoproxil fumarate.

Immune system disorders.

Allergic reaction (including angioedema), immune reconstitution syndrome.

Metabolism and nutrition disorders.

Lactic acidosis, hypokalaemia, hypophosphataemia.

Respiratory, thoracic and mediastinal disorders.

Dyspnoea.

Gastrointestinal disorders.

Increased amylase, abdominal pain, pancreatitis.

Hepatobiliary disorders.

Hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT, gamma-GT).

Skin and subcutaneous tissue disorders.

Rash.

Musculoskeletal and connective tissue disorders.

Rhabdomyolysis, muscular weakness, myopathy, osteomalacia (manifested as bone pain and infrequently contributing to fractures).

Renal and urinary disorders.

Increased creatinine, renal insufficiency, renal failure, acute renal failure, Fanconi syndrome, proximal renal tubulopathy, nephrogenic diabetes insipidus, proteinuria, acute tubular necrosis, polyuria, interstitial nephritis (including acute cases).

General disorders and administration site conditions.

Asthenia.
The following adverse reactions, listed under the body system headings above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia (manifested as bone pain and infrequently contributing to fractures), hypokalaemia, muscular weakness, myopathy, hypophosphataemia. These events are not considered to be causally associated with tenofovir DF therapy in the absence of proximal renal tubulopathy.

Exacerbations of hepatitis after discontinuation of treatment.

In HIV infected patients coinfected with HBV, clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of treatment (see Section 4.4 Special Warnings and Precautions for Use).

4.9 Overdose

If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with Stribild consists of general supportive measures including monitoring of vital signs and ECG (QT interval) as well as observation of the clinical status of the patient.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia) and 0800 764 766 (New Zealand).

Tenofovir disoproxil fumarate.

Clinical experience of doses higher than the therapeutic dose of Viread 300 mg is available from two studies. In one study, intravenous tenofovir, equivalent to 16.7 mg/kg/day of tenofovir DF, was administered daily for 7 days. In the second study, 600 mg of tenofovir DF was administered to patients orally for 28 days. No unexpected or severe adverse reactions were reported in either study. The effects of higher doses are not known.
Tenofovir is efficiently removed by haemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of Viread, a four hour haemodialysis session removed approximately 10% of the administered tenofovir dose.

Emtricitabine.

Limited clinical experience is available at doses higher than the therapeutic dose of Emtriva. In one clinical pharmacology study single doses of emtricitabine 1200 mg were administered to 11 patients. No severe adverse reactions were reported. The effects of higher doses are not known.
Haemodialysis treatment removes approximately 30% of the emtricitabine dose over a 3 hour dialysis period starting within 1.5 hours of emtricitabine dosing (blood flow rate of 400 mL/min and a dialysate flow rate of 600 mL/min). It is not known whether emtricitabine can be removed by peritoneal dialysis.

Elvitegravir.

Limited clinical experience is available at doses higher than the therapeutic dose of elvitegravir. In one study, boosted elvitegravir equivalent to 2 times the therapeutic dose of 150 mg once daily for 10 days was administered to 42 healthy subjects. No severe adverse reactions were reported. The effects of higher doses are not known. As elvitegravir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by haemodialysis or peritoneal dialysis.

Cobicistat.

Limited clinical experience is available at doses higher than the therapeutic dose of cobicistat. In two studies, single dose of cobicistat 400 mg was administered to a total of 60 healthy subjects. No severe adverse reactions were reported. The effects of higher doses are not known. As cobicistat is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antivirals for treatment of HIV infections, combinations, ATC code: J05AR09.

Mechanism of action.

Stribild is a fixed dose combination of antiviral drugs tenofovir DF, emtricitabine and elvitegravir, boosted by the pharmacokinetic enhancer cobicistat.

Tenofovir disoproxil fumarate.

Is an acyclic nucleoside phosphonate diester analogue of adenosine monophosphate. Tenofovir DF requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate. Tenofovir diphosphate inhibits the activity of HIV-1 RT by competing with the natural substrate deoxyadenosine 5'-triphosphate and, after incorporation into deoxyribonucleic acid (DNA), by DNA chain termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases α, β, and mitochondrial DNA polymerase γ.

Emtricitabine.

A synthetic nucleoside analogue of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate. Emtricitabine 5'-triphosphate inhibits the activity of the HIV-1 RT by competing with the natural substrate deoxycytidine 5'-triphosphate by being incorporated into nascent viral DNA which results in chain termination. Emtricitabine 5'-triphosphate is a weak inhibitor of mammalian DNA polymerases α, β, ε and mitochondrial DNA polymerase γ.

Elvitegravir.

Elvitegravir is an HIV-1 integrase strand transfer inhibitor (INSTI). Integrase is an HIV-1 encoded enzyme that is required for viral replication. Inhibition of integrase prevents the integration of HIV-1 DNA into host genomic DNA, blocking the formation of the HIV-1 provirus and propagation of the viral infection. Elvitegravir does not inhibit human topoisomerases I or II.

Cobicistat.

Cobicistat is a selective mechanism based inhibitor of cytochromes P450 of the CYP3A subfamily (primarily CYP3A4 and CYP3A5). Inhibition of CYP3A mediated metabolism by cobicistat enhances the systemic exposure of CYP3A substrates, such as elvitegravir, where bioavailability is limited and half-life is shortened by CYP3A dependent metabolism.

Antiviral activity in vitro.

Tenofovir disoproxil fumarate, emtricitabine and elvitegravir/ cobicistat.

The triple combination of tenofovir, emtricitabine, and elvitegravir demonstrated synergistic antiviral activity in cell culture. Antiviral synergy was maintained for tenofovir, emtricitabine, and elvitegravir when tested in the presence of cobicistat.

Tenofovir disoproxil fumarate.

The in vitro antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, primary monocyte/macrophage cells and peripheral blood lymphocytes. The IC50 (50% inhibitory concentration) values for tenofovir were in the range of 0.04 to 8.5 microM. In drug combination studies of tenofovir with nucleoside reverse transcriptase inhibitors (NRTIs) (abacavir, didanosine, lamivudine (3TC), stavudine (d4T), zalcitabine, zidovudine (AZT)), non-nucleoside reverse transcriptase inhibitors (NNRTIs) (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir, saquinavir), additive to synergistic effects were observed. Tenofovir displayed antiviral activity in vitro against HIV-1 clades A, B, C, D, E, F, G and O (IC50 values ranged from 0.5 to 2.2 microM). In addition, tenofovir has also been shown to be active in vitro against HIV-2, with similar potency as observed against HIV-1.

Emtricitabine.

The in vitro antiviral activity of emtricitabine against laboratory and clinical isolates of HIV was assessed in lymphoblastoid cell lines, the MAGI-CCR5 cell line, and peripheral blood mononuclear cells (PBMCs). The IC50 value for emtricitabine was in the range of 0.0013 to 0.64 microM (0.0003 to 0.158 microgram/mL). In drug combination studies of emtricitabine with NRTIs (abacavir, 3TC, d4T, zalcitabine, AZT), NNRTIs (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, nelfinavir, ritonavir, saquinavir), additive to synergistic effects were observed. Emtricitabine displayed antiviral activity in vitro against HIV-1 clades A, C, D, E, F, and G (IC50 values ranged from 0.007 to 0.075 microM) and showed strain specific activity against HIV-2 (IC50 values ranged from 0.007 to 1.5 microM).

Elvitegravir.

The antiviral activity of elvitegravir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cells, monocyte/ macrophage cells, and peripheral blood lymphocytes and the 50% effective concentration (EC50) values were in the range of 0.02 to 1.7 nanoM. Elvitegravir displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G, and O (EC50 values ranged from 0.1 to 1.3 nanoM) and activity against HIV-2 (EC50 of 0.53 nanoM). The antiviral activity of elvitegravir with antiretroviral drugs in two-drug combination studies was additive to synergistic when combined with nucleoside reverse transcriptase inhibitors (NRTIs abacavir, didanosine, emtricitabine, 3TC, d4T, tenofovir, or AZT); NNRTIs (efavirenz, etravirine, or nevirapine); protease inhibitors (amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, or tipranavir); INSTI raltegravir; the fusion inhibitor enfuvirtide, or the CCR5 coreceptor antagonist, maraviroc. No antagonism was observed for these combinations.
Elvitegravir did not show inhibition of replication of HBV or HCV in vitro.

Cobicistat.

Cobicistat has no detectable antiviral activity against HIV-1, HBV or HCV and does not antagonise the antiviral effects of elvitegravir, emtricitabine, or tenofovir.

Drug resistance.

In cell culture.

Tenofovir disoproxil fumarate.

HIV-1 isolates with reduced susceptibility to tenofovir have been selected in vitro. These viruses expressed a K65R mutation in reverse transcriptase and showed a 2 to 4-fold reduction in susceptibility to tenofovir. In addition, a K70E mutation in HIV-RT has been selected clinically by tenofovir DF and results in low level reduced susceptibility to abacavir, emtricitabine, tenofovir and lamivudine.

Emtricitabine.

Emtricitabine resistant isolates of HIV have been selected in vitro. Genotypic analysis of these isolates showed that the reduced susceptibility to emtricitabine was associated with a mutation in the HIV reverse transcriptase gene at codon 184 which resulted in an amino acid substitution of methionine by valine or isoleucine (M184V/I).

Elvitegravir.

HIV-1 isolates with reduced susceptibility to elvitegravir have been selected in cell culture. Reduced susceptibility to elvitegravir was most commonly associated with the primary integrase substitutions T66I, E92Q, and Q148R. Additional integrase substitutions observed in cell culture selection included H51Y, F121Y, S147G, S153Y, E157Q, and R263K.
Elvitegravir showed cross resistance in vitro to the raltegravir selected mutations T66A/K, Q148H/K, and N155H.

Cobicistat.

No in vitro resistance can be demonstrated with cobicistat due to its lack of antiviral activity.
In clinical studies: in treatment naïve patients.

Tenofovir disoproxil fumarate, emtricitabine and elvitegravir/ cobicistat.

In a pooled analysis of antiretroviral naïve patients receiving Stribild in clinical trials GS-US-236-0102 and GS-US-236-0103, genotyping was performed on plasma HIV-1 isolates from all patients with confirmed virologic failure or had HIV-1 RNA > 400 copies/mL at virologic failure at week 48, week 96 and week 144 or at the time of early study drug discontinuation. As of week 144, the development of one or more primary elvitegravir, emtricitabine, or tenofovir resistance associated mutations was observed in 18 of the 42 patients with evaluable genotypic data from paired baseline and Stribild treatment failure isolates (2.6%, 18/701 patients). Of the 18 patients with resistance development, 13 occurred through week 48, 3 between week 48-week 96, and 2 between week 96-week 144 of treatment. The mutations that emerged were M184V/I (N = 17) and K65R (N = 5) in reverse transcriptase; and T66I (N = 2), E92Q (N = 9), Q148R (N = 3), T97A (N = 1) and N155H (N = 5) in integrase. Other mutations in integrase that occurred in addition to a primary INSTI resistance substitution each in single cases were H51Y, L68V, G140C, S153A, E157Q and G163R. Most patients who developed resistance mutations to elvitegravir developed resistance mutations to both emtricitabine and elvitegravir. In phenotypic analyses of patients in the resistance analysis population, 13/42 (31%) patients had HIV-1 isolates with reduced susceptibility to elvitegravir, 17/42 (40%) had reduced susceptibility to emtricitabine, and 2/42 (5%) had reduced susceptibility to tenofovir.
In study GS-US-236-0103, 27 patients treated with Stribild had the NNRTI associated K103N substitution in RT at baseline and had virologic success (82% at week 144) similar to the overall population (78%), and no emergent resistance to elvitegravir, emtricitabine or tenofovir DF.
In virologically suppressed patients. Through week 48, no patients who switched to Stribild in study GS-US-236-0115 (0 of 290 subjects), study GS-US-236-0121 (0 of 290 patients), or study GS-US-236-0123 (0 of 48 subjects) developed genotypic or phenotypic resistance to Stribild.
Twenty patients from these studies who switched to Stribild had the NNRTI associated K103N mutation in their historical genotype prior to starting antiretroviral therapy. Eighteen of these 20 patients maintained virologic suppression through 48 weeks. Due to protocol violation, two patients with historical K103N mutations discontinued early with HIV-1 RNA < 50 copies/mL.

Cross resistance.

Tenofovir disoproxil fumarate, emtricitabine, elvitegravir/ cobicistat.

No significant cross resistance has been demonstrated for elvitegravir resistant HIV-1 isolates and emtricitabine or tenofovir, or for emtricitabine or tenofovir resistant isolates and elvitegravir. Substantial cross resistance was observed between elvitegravir resistant HIV-1 isolates and raltegravir, and between emtricitabine resistant isolates and lamivudine. These patient isolates remained susceptible to PIs, NNRTIs, and most other NRTIs.

Tenofovir disoproxil fumarate.

The K65R and K70E mutations selected by tenofovir also show reduced susceptibility to abacavir, didanosine, emtricitabine and 3TC. Therefore, cross resistance among these drugs may occur in patients whose virus harbours the K65R mutation. Patients with HIV-1 expressing three or more thymidine analogue associated mutations (TAMs) that included either the M41L or L210W reverse transcriptase mutation showed reduced susceptibility to tenofovir DF. Multinucleoside resistant HIV-1 with a T69S double insertion mutation in the reverse transcriptase showed reduced susceptibility to tenofovir.

Emtricitabine.

Emtricitabine resistant isolates (M184V/I) were cross resistant to 3TC and zalcitabine but retained sensitivity to abacavir, didanosine, d4T, tenofovir, AZT and NNRTIs (delavirdine, efavirenz, and nevirapine). HIV-1 isolates containing the K65R mutation, selected in vivo by abacavir, didanosine and tenofovir demonstrated reduced susceptibility to inhibition by emtricitabine. Viruses harbouring mutations conferring reduced susceptibility to d4T and AZT (M41L, D67N, K70R, L210W, T215Y/F, K219Q/E) or didanosine (L74V) remained sensitive to emtricitabine. HIV-1 containing the K103N mutation or substitutions associated with resistance to NNRTI were susceptible to emtricitabine.

Elvitegravir.

Elvitegravir resistant viruses show varying degrees of cross resistance to the integrase strand transfer inhibitor raltegravir depending on the type and number of mutations. Viruses expressing the T66I/A mutations maintain susceptibility to raltegravir, while most other patterns showed reduced susceptibility to raltegravir. Viruses expressing elvitegravir or raltegravir resistance mutations maintain susceptibility to dolutegravir.

Effects on electrocardiogram.

The electrocardiographic effects of cobicistat were determined in a study of 48 healthy adult subjects. Cobicistat did not prolong QTcF interval at exposures two and fourfold above the recommended therapeutic dose. A modest increase in PR interval (+9.6 msec) occurred around Cmax, three to five hours after dosing with 250 mg of cobicistat. This finding was not considered to be clinically significant.
In a thorough QT/QTc study in 126 healthy subjects, elvitegravir at the therapeutic or supratherapeutic approximately two times the recommended therapeutic dose did not affect the QT/QTc interval and did not prolong the PR interval.

Clinical trials.

The efficacy of Stribild in HIV-1 infected treatment naïve patients is based on the analyses of 144 week data from two randomised, double blind, active controlled trials study GS-US-236-0102 and study GS-US-236-0103 (N = 1408). The efficacy of Stribild in HIV-1 infected virologically suppressed patients is based on the analyses of 48 week data from two randomised, open label, controlled studies, study GS-US-236-0115, study GS-US-236-0121, and a single group open label study, study GS-US-236-0123, (N = 910) 628 receiving Stribild. Patients in all five studies had estimated creatinine clearance > 70 mL/min at screening.

Treatment naïve patients.

In study GS-US-236-0102, subjects were randomised in a 1:1 ratio to receive either Stribild (tenofovir DF 300 mg/ emtricitabine 200 mg/ elvitegravir 150 mg/ cobicistat 150 mg, N = 348) once daily or Atripla (tenofovir DF 300 mg/ emtricitabine 200 mg/ efavirenz 600 mg, N = 352) once daily. The mean age was 38 years (range 18-67), 89% were male, 63% were white, and 28% were black. The mean baseline plasma HIV-1 RNA was 4.8 log10 copies/mL (range 2.6-6.5). The mean baseline CD4+ cell count was 386 cells/mm3 (range 3-1348) and 13% had CD4+ cell counts < 200 cells/mm3. Thirty three percent of subjects had baseline viral loads > 100,000 copies/mL.
In study GS-US-236-0103, patients were randomised in a 1:1 ratio to receive either Stribild (tenofovir DF 300 mg/ emtricitabine 200 mg/ elvitegravir 150 mg/ cobicistat 150 mg, N = 353) once daily or ATV/r (atazanavir 300 mg + ritonavir 100 mg) + Truvada (tenofovir DF 300 mg/ emtricitabine 200 mg) (N = 355) once daily. The mean age was 38 years (range 19-72), 90% were male, 74% were white, 17% were black, and 5% were Asian. The mean baseline plasma HIV-1 RNA was 4.8 log10 copies/mL (range 1.7-6.6). The mean baseline CD4+ cell count was 370 cells/mm3 (range 5-1132) and 13% had CD4+ cell count < 200 cells/mm3. Forty percent of subjects had baseline viral loads > 100,000 copies/mL.
In both studies, patients were stratified by baseline HIV-1 RNA (≤ 100,000 copies/mL or > 100,000 copies/mL).
Treatment outcomes of study GS-US-236-0102 and study GS-US-236-0103 through 144 weeks are presented in Table 4.
Stribild met the noninferiority criteria in achieving HIV-1 RNA < 50 copies/mL when compared to Atripla and when compared to ATV + RTV + Truvada.
In study GS-US-236-0102, the mean increase from baseline in CD4+ cell count at week 144 was 321 cells/mm3 in the Stribild treated patients and 300 cells/mm3 in the Atripla treated patients. In study GS-US-236-0103, the mean increase from baseline in CD4+ cell count at week 144 was 280 cells/mm3 in the Stribild treated patients and 293 cells/mm3 in the ATV + RTV + Truvada treated patients.

Virologically suppressed patients.

In study GS-US-236-0115 patients had to be on either their first or second antiretroviral regimen with no history of virologic failure, have no current or past history of resistance to the antiretroviral components of Stribild and must have been suppressed (HIV-1 RNA < 50 copies/mL) on a ritonavir boosted PI in combination with Truvada for at least 6 months prior to screening. Patients were randomised in a 2:1 ratio to either switch to Stribild (Stribild arm, N = 293, randomised or dosed) or stay on their baseline antiretroviral regimen for 48 weeks (PI + RTV + Truvada arm, N = 140, randomised or dosed). Patients had a mean age of 41 years (range 21-76), 86% were male, 80% were white, and 15% were black. The mean baseline CD4+ cell count was 610 cells per mm3 (range 74-1919). At screening patients were receiving atazanavir (40%), darunavir (40%), lopinavir (17%), fosamprenavir (3%), or saquinavir (< 1%) as the PI in their regimen.
In study GS-US-236-0121 patients had to be on either their first or second antiretroviral regimen with no history of virologic failure, have no current or past history of resistance to the antiretroviral components of Stribild and must have been suppressed (HIV-1 RNA < 50 copies/mL) on a NNRTI in combination with Truvada for at least 6 months prior to screening. Patients were randomised in a 2:1 ratio to either switch to Stribild (Stribild arm, N = 291, randomised and dosed), or stay on their baseline antiretroviral regimen for 48 weeks (NNRTI + Truvada arm, N = 143, randomised and dosed). Patients had a mean age of 41 years (range 20-72), 93% were male, 78% were white, and 17% were black. The mean baseline CD4+ cell count was 588 cells per mm3 (range 100-1614). Randomisation was stratified by use of efavirenz in the baseline regimen. At screening patients were receiving efavirenz (78%) (predominantly as Atripla [74%]), nevirapine (17%), rilpivirine (4%) (as Eviplera [4%]), or etravirine (1%) as the NNRTI in their regimen.
Virologic outcomes of study GS-US-236-0115 and study GS-US-236-0121 are presented in Table 5. Five treated patients were excluded from the efficacy analysis: in study GS-US-236-0115, three Stribild patients had protocol prohibited documented resistance and one PI + RTV + Truvada patient was not on a protease inhibitor based regimen at screening; in study GS-US-236-0121, one Stribild patient had protocol prohibited documented resistance.
In study GS-US-236-0115, the mean increase from baseline in CD4+ cell count at week 48 was 40 cells per mm3 in the Stribild treated patients and 32 cells per mm3 in the PI + RTV + Truvada treated patients. In study GS-US-236-0121, the mean increase from baseline in CD4+ cell count at week 48 was 56 cells/mm3 in the Stribild treated patients and 58 cells per mm3 in the NNTRI + Truvada treated patients.
In study GS-US-236-0123 patients had to have previously only received raltegravir in combination with Truvada as their first antiretroviral regimen for at least six months. Patients had to be stably suppressed for at least 6 months prior to study entry, have no current or past history of resistance to the antiretroviral components of Stribild, and have HIV-1 RNA < 50 copies/mL at screening. All 48 patients who received at least one dose of Stribild remained suppressed (HIV-1 RNA < 50 copies/mL) through week 48. The mean increase from baseline in CD4+ cell count at week 48 was 23 cells mm3.

5.2 Pharmacokinetic Properties

Pharmacokinetics.

Tenofovir disoproxil fumarate, emtricitabine and elvitegravir/ cobicistat.

Following oral administration of Stribild with food in healthy subjects, peak plasma concentrations were observed 4.0 to 4.5 hours postdose for elvitegravir and cobicistat, 2.5 hours postdose for emtricitabine, and three hours for tenofovir following the rapid conversion of tenofovir DF. The steady-state mean Cmax, AUCtau, and Ctrough (mean ± standard deviation [SD]) following multiple doses of Stribild in HIV-1 infected subjects, respectively, were 1.7 ± 0.39 microgram/mL, 23 ± 7.5 microgram.hr/mL, and 0.45 ± 0.26 microgram/mL, respectively for elvitegravir, which provided an inhibitory quotient of ~ 10 (ratio of Ctrough: protein binding adjusted IC95 for wild type HIV-1 virus). Corresponding steady-state mean Cmax, AUCtau, and Ctrough (mean ± SD) were 1.1 ± 0.40 microgram/mL, 8.3 ± 3.8 microgram.hr/mL, and 0.05 ± 0.13 microgram/mL respectively for cobicistat, 1.9 ± 0.5 microgram/mL, 13 ± 4.5 microgram.hr/mL, and 0.14 ± 0.25 microgram/mL respectively for emtricitabine, and 0.45 ± 0.16 microgram/mL, 4.4 ± 2.2 microgram.hr/mL, and 0.1 ± 0.08 microgram/mL respectively for tenofovir.

Tenofovir disoproxil fumarate.

The pharmacokinetic properties of tenofovir DF are summarized in Table 6. Following oral administration of Viread, maximum tenofovir serum concentrations are achieved in 1.0 ± 0.4 hour. In vitro binding of tenofovir to human plasma proteins is < 0.7% and is independent of concentration over the range of 0.01 to 25 microgram/mL. Approximately 70 to 80% of the intravenous dose of tenofovir is recovered as unchanged drug in the urine. Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion. Following a single oral dose of Viread, the terminal elimination half-life of tenofovir is approximately 17 hours.

Emtricitabine.

The pharmacokinetic properties of emtricitabine are summarized in Table 6. Following oral administration of Emtriva, emtricitabine is rapidly absorbed with peak plasma concentrations occurring at 1 to 2 hours postdose. In vitro binding of emtricitabine to human plasma proteins is < 4% and is independent of concentration over the range of 0.02 to 200 microgram/mL. Following administration of radiolabelled emtricitabine approximately 86% is recovered in the urine and 13% is recovered as metabolites. The metabolites of emtricitabine include 3'-sulfoxide diastereomers and their glucuronic acid conjugate. Emtricitabine is eliminated by a combination of glomerular filtration and active tubular secretion. Following a single oral dose of Emtriva, the plasma emtricitabine half-life is approximately 10 hours.

Elvitegravir.

Elvitegravir is 98% to 99% bound to human plasma proteins and binding is independent of drug concentration over the range of 1 nanogram/mL to 1.6 microgram/mL. The mean plasma to blood drug concentration ratio was 1.37. Elvitegravir undergoes primarily oxidative metabolism via CYP3A, and is secondarily glucuronidated via uridine disphosphate glucuronyosyltransferase (UGT) 1A1/3 enzymes. Following oral administration of boosted [14C]elvitegravir, elvitegravir was the predominant species in plasma, representing ~ 94% of the circulating radioactivity. Aromatic and aliphatic hydroxylation or glucuronidation metabolites are present in very low levels, display considerably lower anti-HIV activity and do not contribute to the overall antiviral activity of elvitegravir. 94.8% of the dose was recovered in feces, consistent with the hepatobiliary excretion of elvitegravir; 6.7% of the administered dose was recovered in urine as unchanged elvitegravir. The median terminal plasma half-life of elvitegravir following administration of Stribild is approximately 12.9 hours. Elvitegravir plasma exposures are nonlinear and less than dose proportional, likely due to solubility limited absorption.

Cobicistat.

Cobicistat is 97% to 98% bound to human plasma proteins and the mean plasma to blood drug concentration ratio was 2.
Cobicistat is metabolized via CYP3A (major) and CYP2D6 (minor) mediated oxidation and does not undergo glucuronidation. Following oral administration of [14C]cobicistat, 99% of circulating radioactivity in plasma was unchanged cobicistat. Low levels of metabolites are observed in urine and feces and do not contribute to the CYP3A inhibitory activity of cobicistat. Eighty six percent and 8.2% of the dose were recovered in feces and urine, respectively. The median terminal plasma half-life of cobicistat following administration of Stribild is approximately 3.5 hours and the associated cobicistat exposures provide elvitegravir Ctrough approximately 10-fold above the protein binding adjusted IC95 for wild type HIV-1 virus. Cobicistat exposures are nonlinear and greater than dose proportional over the dose range of 50 to 400 mg, consistent with a mechanism based CYP3A inhibitor.
Effect of food.

Tenofovir disoproxil fumarate, emtricitabine, elvitegravir/ cobicistat.

Relative to fasting conditions, the administration of Stribild with a light meal (~ 373 kcal, 20% fat) or high fat meal (~ 800 kcal, 50% fat) resulted in increased exposures of elvitegravir and tenofovir. For elvitegravir, the Cmax and AUC increased 22% and 36% respectively with a light meal, and 56% and 91% respectively with a high fat meal. The Cmax and AUC of tenofovir increased 20% and 25% respectively with a light meal, while the Cmax was unaffected and AUC increased 25% with a high fat meal. Cobicistat exposures were unaffected by a light meal and although there was a modest decrease of 24% and 18% in Cmax and AUC, respectively with a high fat meal, no difference was observed in its pharmacoenhancing effect on elvitegravir. Emtricitabine exposures were unaffected with light or high fat meal.
Age, gender and ethnicity. No clinically relevant pharmacokinetic differences due to gender or ethnicity have been identified for cobicistat boosted elvitegravir, emtricitabine, or tenofovir DF (see Section 4.4 Special Warnings and Precautions for Use).
The pharmacokinetics of elvitegravir or cobicistat in paediatric patients have not been established. Pharmacokinetics of elvitegravir, cobicistat, emtricitabine and tenofovir have not been fully evaluated in the elderly (65 years of age and older).
No clinically relevant pharmacokinetic differences have been observed between men and women for cobicistat boosted elvitegravir, emtricitabine and tenofovir DF.
Patients with impaired renal function.

Tenofovir disoproxil fumarate and emtricitabine.

The pharmacokinetics of emtricitabine and tenofovir are altered in subjects with renal impairment. In subjects with creatinine clearance below 50 mL/min or with end stage renal disease (ESRD) requiring dialysis, Cmax, and AUC0-∞ of emtricitabine and tenofovir were increased (see Section 4.4 Special Warnings and Precautions for Use).

Elvitegravir and cobicistat.

A study of the pharmacokinetics of cobicistat boosted elvitegravir was performed in non-HIV-1 infected subjects with severe renal impairment (estimated creatinine clearance below 30 mL/min). No clinically relevant differences in elvitegravir or cobicistat pharmacokinetics were observed between subjects with severe renal impairment and healthy subjects.
Patients with hepatic impairment. The pharmacokinetics of Stribild have not been studied in patients with hepatic impairment.

Tenofovir disoproxil fumarate and emtricitabine.

The pharmacokinetics of tenofovir following a 300 mg dose of Viread have been studied in non-HIV infected patients with moderate to severe hepatic impairment. There were no substantial alterations in tenofovir pharmacokinetics in patients with hepatic impairment compared with unimpaired patients. The pharmacokinetics of emtricitabine have not been studied in patients with hepatic impairment; however, emtricitabine is not significantly metabolized by liver enzymes, so the impact of liver impairment should be limited.

Elvitegravir and cobicistat.

Both elvitegravir and cobicistat are primarily metabolized and eliminated by the liver. A study of pharmacokinetics of cobicistat boosted elvitegravir was performed in non-HIV-1 infected subjects with moderate hepatic impairment. No clinically relevant differences in elvitegravir or cobicistat pharmacokinetics were observed between subjects with moderate impairment and healthy subjects. No dosage adjustment of elvitegravir or cobicistat is necessary for patients with mild to moderate hepatic impairment. The effect of severe hepatic impairment on the pharmacokinetics of elvitegravir or cobicistat has not been studied.
Hepatitis B and/or hepatitis C virus coinfection. The pharmacokinetics of tenofovir DF and emtricitabine was not fully evaluated in hepatitis B (HBV) and/or C (HCV) coinfected patients. Limited data from population pharmacokinetic analysis with 24 patients indicated that HBV and/or HCV infection had no clinically relevant effect on the exposure of boosted elvitegravir.
Assessment of drug interactions. The drug interaction studies described were conducted with Stribild, elvitegravir (coadministered with cobicistat or ritonavir), emtricitabine, or tenofovir DF.
As Stribild is indicated for use as a complete regimen for the treatment of HIV-1 infection and should not be administered with other antiretroviral medications, information regarding drug-drug interactions with other antiretrovirals agents is not provided (see Section 4.4 Special Warnings and Precautions for Use).

Elvitegravir.

Elvitegravir is primarily metabolized by cytochrome CYP3A, and drugs that induce or inhibit CYP3A may affect the exposure of elvitegravir. Coadministration of Stribild with drugs that induce CYP3A may result in decreased plasma concentrations of elvitegravir and reduce the therapeutic effect of Stribild (see Section 4.3 Contraindications).
The effects of coadministered drugs on the exposure of elvitegravir are shown in Table 7. The effects of the individual components of Stribild on the exposure of coadministered drugs are shown in Table 8.
In drug interaction studies conducted with elvitegravir, neither famotidine, omeprazole or telaprevir, had clinically significant effect on the Cmax, AUC, or Cmin of elvitegravir.
In drug interaction studies conducted with elvitegravir, there was no clinically significant effect on the Cmax, AUC, or Cmin of R/S-methadone or telaprevir.

Cobicistat.

Cobicistat is an inhibitor of cytochrome P450 (CYP3A), and is also a CYP3A substrate. Agents that are highly dependent on CYP3A metabolism and have high first-pass metabolism are the most susceptible to large increases in exposure when coadministered with cobicistat. Agents that inhibit CYP3A may decrease the clearance of cobicistat, resulting in increased plasma concentration of cobicistat (see Section 4.3 Contraindications).
Cobicistat is an inhibitor of the following transporter: p-glycoprotein (P-gp), BCRP, OATP1B1 and OATP1B3. Coadministration of Stribild with drugs that are substrates of P-gp, BCRP, OATP1B1 and OATP1B3 may result in increased plasma concentrations of such drugs.

Tenofovir disoproxil fumarate and emtricitabine.

In vitro and clinical pharmacokinetic drug-drug interaction studies have shown that the potential for CYP mediated interactions involving emtricitabine and tenofovir with other medicinal products is low.
Emtricitabine and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion. No drug-drug interactions due to competition for renal excretion have been observed; however, coadministration of emtricitabine and tenofovir DF with drugs that are eliminated by active tubular secretion may increase concentrations of emtricitabine, tenofovir, and/or the coadministered drug.
Drugs that decrease renal function may increase concentrations of emtricitabine and/or tenofovir.
In drug interaction studies conducted with emtricitabine and with tenofovir DF, coadministration of emtricitabine and famciclovir had no effect on the Cmax or AUC of either drug, coadministration of tenofovir and entecavir had no effect on the Cmax or AUC of either drug, and coadministration of tenofovir and ribavirin had no effect on the Cmax and AUC of entecavir or ribavirin.

Stribild.

A drug interaction study for Stribild was performed with Epclusa (sofosbuvir/velpatasvir).
The changes in pharmacokinetic parameters for sofosbuvir, GS-331007, and velpatasvir in the presence of Stribild are presented in Table 9.
The changes in pharmacokinetic parameters for Stribild in the presence of Epclusa are presented in Table 10.

5.3 Preclinical Safety Data

Tenofovir disoproxil fumarate.

Tenofovir and tenofovir DF administered in toxicology studies to rats, dogs and monkeys at exposures (based on AUCs) greater than or equal to 6-fold those observed in humans caused bone toxicity. In monkeys the bone toxicity was diagnosed as osteomalacia. Osteomalacia observed in monkeys appeared to be reversible upon dose reduction or discontinuation of tenofovir. In rats and dogs, the bone toxicity manifested as reduced bone mineral density. The mechanism(s) underlying bone toxicity is unknown.
Evidence of renal toxicity was noted in 4 animal species. Increases in serum creatinine, BUN, glycosuria, proteinuria, phosphaturia and/or calciuria and decreases in serum phosphate were observed to varying degrees in these animals. These toxicities were noted at exposures (based on AUCs) 2 to 20 times higher than those observed in humans. The relationship of the renal abnormalities, particularly the phosphaturia, to the bone toxicity is not known.

Genotoxicity.

No genotoxicity studies have been conducted with tenofovir DF, emtricitabine, elvitegravir and cobicistat in combination.
Tenofovir disoproxil fumarate was mutagenic in an in vitro mouse L5178Y lymphoma cell assay (tk locus) and in an ex vivo assay for unscheduled DNA synthesis in rat hepatocytes, but it was negative in in vitro bacterial assays for gene mutation and an in vivo mouse micronucleus test for chromosomal damage.
Emtricitabine was not mutagenic in bacteria or mouse lymphoma cell assays in vitro nor clastogenic in the mouse micronucleus test in vivo.
Elvitegravir showed an equivocal response in an in vitro chromosomal aberration assay in Chinese hamster lung cells, but only in the absence of metabolic activation. No genotoxicity was observed in a test for bacterial reverse mutation in vitro, or in vivo rat micronucleus test.
Cobicistat was not genotoxic in in vitro tests for bacterial reverse gene mutation or gene mutation in mouse lymphoma L5178Y cells (tk locus), or in an in vivo rat micronucleus test.

Carcinogenicity.

No carcinogenicity studies have been conducted with tenofovir DF, emtricitabine, elvitegravir and cobicistat in combination.

Tenofovir disoproxil fumarate.

In a long-term carcinogenicity study conducted in mice with tenofovir DF there was a low incidence of duodenal tumours with the highest dose of 600 mg/kg/day. These were associated with a high incidence of duodenal mucosal hyperplasia, which was also observed with a dose of 300 mg/kg/day. These findings may be related to high local drug concentrations in the gastrointestinal tract, likely to result in much higher exposure margins than that based on the AUC. At therapeutic doses the risk of these duodenal effects occurring in humans is likely to be low. The systemic drug exposure (AUC) with the 600 mg/kg/day dose was approximately 15 times the human exposure at the therapeutic dose of 300 mg/day. No tumourigenic response was observed in rats treated with doses of up to 300 mg/kg/day (5 times the human systemic exposure at the therapeutic dose based on AUC).

Emtricitabine.

In long-term oral carcinogenicity studies conducted with emtricitabine, no drug related increases in tumour incidence were found in mice at doses up to 750 mg/kg/day (32 times the human systemic exposure (AUC) at the therapeutic dose of 200 mg/day) or in rats at doses up to 600 mg/kg/day (38 times the human systemic exposure at the therapeutic dose).

Elvitegravir.

In a long-term carcinogenicity study in mice, no tumourigenic response was seen with doses of up to 2000 mg/kg/day, with the highest dose also being given together with 25 mg/kg/day ritonavir. Respective elvitegravir exposures (AUC) with this dose were approximately 3.1 and 14 times the human exposure with the 150 mg/day dose. No tumourigenic response was seen in a long-term study in rats with doses up to 2000 mg/kg/day (12 times in males and 27 times in females the human exposure (AUC) with the therapeutic dose).

Cobicistat.

In a long-term study in mice with doses of up to 50 mg/kg/day in males and 100 mg/kg/day in females (9-21 times the human exposure (AUC) at 150 mg daily), cobicistat treatment did not result in any increased tumour incidences. In a corresponding study, with doses of up to 50 mg/kg/day in males and 30 mg/kg/day in females (1.9-2.6 times the human exposure with 150 mg daily), treatment resulted in increased incidence of thyroid follicular cell tumours. Hepatocyte hypertrophy was also observed, and this oncogenic response is most likely related to alterations in thyroid hormones and to be specific to species.

6 Pharmaceutical Particulars

6.1 List of Excipients

Stribild tablets contain the following ingredients as excipients:

Tablet core.

Lactose, cellulose-microcrystalline (E460), silicon dioxide, croscarmellose sodium, hyprolose, magnesium stearate (E572), sodium lauryl sulphate.

Film-coating.

Indigo carmine (FD and C blue #2) aluminum lake, macrogol 3350, polyvinyl alcohol, talc, titanium dioxide (E171), yellow iron oxide.

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

Stribild should be stored below 30°C.

6.5 Nature and Contents of Container

Stribild is supplied in high density polyethylene (HDPE) bottles containing 30 tablets and a silica gel desiccant, polyester coil 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.

Tenofovir disoproxil fumarate.

Tenofovir DF is a fumaric acid salt of the bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir. The chemical name of tenofovir DF is 9-[(R)2 [[bis[[(isopropoxycarbonyl)oxy] methoxy]phosphinyl]methoxy]propyl]adenine fumarate (1:1). It has a molecular formula of C19H30N5O10P.C4H4O4 and a molecular weight of 635.52. It has the following structural formula:

Emtricitabine.

The chemical name of emtricitabine is 5-fluoro-1-(2R,5S)-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine. Emtricitabine is the (-) enantiomer of a thio analog of cytidine, which differs from other cytidine analogs in that it has a fluorine in the 5-position.
It has a molecular formula of C8H10FN3O3S and a molecular weight of 247.24. It has the following structural formula:

Elvitegravir.

The chemical name of elvitegravir is 3-quinolinecarboxylic acid, 6-[(3-chloro-2-fluorophenyl)-methyl]- 1,4-dihydro-1-[(1S)-1-(hydroxymethyl)-2-methylpropyl]-7-methoxy-4-oxo-. It has a molecular formula of C23H23ClFNO5 and a molecular weight of 447.9. It has the following structural formula:

Cobicistat.

The chemical name for cobicistat is 1,3-Thiazol-5-ylmethyl [(2R,5R)-5-{[(2S)-2-[(methyl{[2-(propan-2-yl)- 1,3-thiazol-4-yl]methyl}carbamoyl)amino]-4-(morpholin-4-yl) butanoyl]amino}-1,6-diphenylhexan-2-yl]carbamate. It has a molecular formula of C40H53N7O5S2 and a molecular weight of 776.0. It has the following structural formula:

CAS number.

Tenofovir DF CAS registry number: 202138-50-9.
Emtricitabine CAS registry number: 143491-57-0.
Elvitegravir CAS registry number: 697761-98-1.
Cobicistat CAS registry number: 1004316-88-4.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes