Biktarvy

New Zealand - English - Medsafe (Medicines Safety Authority)

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Active ingredient:
Bictegravir sodium 52.45 mg equivalent to to 50 mg bictegravir;  ; Emtricitabine 200 mg;  ;  ;  ;  ; Tenofovir alafenamide fumarate 28.04 mg equivalent to to 25 mg tenofovir alafenamide;  
Available from:
Gilead Sciences (NZ)
Pharmaceutical form:
Film coated tablet
Composition:
Active: Bictegravir sodium 52.45 mg equivalent to to 50 mg bictegravir   Emtricitabine 200 mg         Tenofovir alafenamide fumarate 28.04 mg equivalent to to 25 mg tenofovir alafenamide   Excipient: Croscarmellose sodium Magnesium stearate Microcrystalline cellulose Opadry brown 85F165072
Prescription type:
Prescription
Therapeutic indications:
BIKTARVY is indicated for the treatment of HIV-1 infection in adults who are antiretroviral therapy (ART)-naive or to replace the current antiretroviral regimen in those who are virologically-supressed (HIV-1 RNA < 50 copied per mL) on a stable antiretroviral regimen at the start of therapy with no history of treatment failure, and no known substitutions associated with resistance to the individual components of BIKTARVY.
Product summary:
Package - Contents - Shelf Life: Bottle, HDPE, 100 mL with CRC PP cap, desiccant and aluminium foil liner - 30 tablets - 24 months from date of manufacture stored at or below 30°C
Authorization number:
TT50-10558
Authorization date:
2019-01-07

BIKTARVY Consumer Medicine Information v1.0 – (15 August 2019) Page 1 of 4

This medicine is subject to additional monitoring. This will allow quick identification of new

safety information. You can help by reporting any side affects you may get. You can report

side effects to your doctor, or directly at www.tga.gov.au/reporting-problems.

BIKTARVY

®

Tablets

(50 mg bictegravir / 200 mg emtricitabine / 25 mg tenofovir alafenamide)

Bictegravir / emtricitabine / tenofovir alafenamide

Consumer Medicine Information

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 BIKTARVY

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.

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.

Medicines are sometimes prescribed

for conditions that are not mentioned

in this leaflet.

Keep this leaflet with your

BIKTARVY medicine.

You may need to read it again.

What is BIKTARVY

How

BIKTARVY works

BIKTARVY tablets consist of the

following medicines:

bictegravir

emtricitabine

tenofovir alafenamide

Bictegravir belongs to a group of

antiretroviral medicine known as

integrase strand transfer inhibitors

(INSTI).

Emtricitabine and tenofovir alafenamide

belong to a group of antiviral medicines

known as nucleoside and nucleotide

reverse transcriptase inhibitors (NRTI)

and (NtRTI) respectively.

These are combined in one tablet to help

control Human Immunodeficiency Virus

1 (HIV-1) infection in adults.

When used to treat HIV-1 infection

BIKTARVY lowers the amount of HIV

in the blood (viral load). BIKTARVY

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).

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.

BIKTARVY is for people who do not

have a resistant HIV virus to

BIKTARVY.

Emtricitabine and tenofovir

alafenamide are also components of

DESCOVY, GENVOYA, ODEFSEY

tablets. VEMLIDY tablets contain

tenofovir alafenamide.

Use in children

BIKTARVY is used to treat HIV-1

infection in adults.

Do not give this medicine to children

and adolescents under 18 years of age.

The use of BIKTARVY in children and

adolescents under 18 years of age has

not yet been studied.

Does BIKTARVY cure

HIV, AIDS or HBV

BIKTARVY does not cure HIV

infection, AIDS or HBV infection.

The long-term effects of BIKTARVY

are not known at this time.

People taking BIKTARVY or any other

medication for HIV 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 BIKTARVY it is

BIKTARVY Consumer Medicine Information v1.0 – (15 August 2019) Page 2 of 4

important you remain under the care

of a hospital or doctor who specialises

in the treatment of HIV infection.

Does BIKTARVY reduce

the risk of passing HIV

to others

You can still pass on HIV when

taking this medicine to other people

through sexual contact, sharing

needles, or being exposed to your

blood, although the risk is lowered by

effective antiretroviral therapy.

Discuss with your doctor the

precautions needed to avoid infecting

other people.

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

BIKTARVY

When you must not take it

Together with your doctor, you need

to decide whether BIKTARVY is

right for you.

Do not take BIKTARVY if you are

allergic to:

bictegravir

emtricitabine

tenofovir

or any of the other ingredients of

BIKTARVY.

The ingredients of BIKTARVY are

listed in the product description

section of this leaflet.

Do not take BIKTARVY if you are

already taking any other medicines

that contain the same active

ingredients.

Do not take BIKTARVY if you taking

other medicines that contain:

tenofovir disoproxil fumarate (e.g.

Viread)

tenofovir alafenamide (e.g. Descovy,

Genvoya, Odefsey, Vemlidy)

emtricitabine (e.g. Descovy, Emtriva

Genvoya, Odefsey)

lamivudine (e.g. Combivir,

Triumeq)

Do not take BIKTARVY to treat your

HIV infection if you are also taking

dofetilide to treat heart conditions.

Do not take BIKTARVY to treat your

HIV infection if you are also taking

rifampicin to treat infections.

Do not take BIKTARVY to treat your

HIV infection if you are also taking

adefovir dipivoxil to treat your

hepatitis B virus (HBV) infection.

Before you start to take it

Tell your doctor if you have allergies

to any other medicines, foods,

preservatives or dyes.

Tell your doctor if you have, or have

had, any of the following medical

conditions:

kidney problems or are undergoing

kidney dialysis treatment.

liver problems, including hepatitis B

or C virus infection.

Tell your doctor if you are pregnant,

or likely to become pregnant during

your course of medication.

We do not know if BIKTARVY can

harm your unborn child. You and your

doctor will need to decide if

BIKTARVY 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. At

least one of the active substances in this

medicine (emtricitabine) has been found

in breast milk at low concentrations.

Talk with your doctor about the best

way to feed your baby.

Taking other medicines

Tell your doctor or pharmacist if you

are taking any other medicines,

including any that you get without a

prescription from your pharmacy,

supermarket or health food shop.

Some medicines and BIKTARVY may

interfere with each other. These include:

carbamazepine (e.g. Tegretol)

oxycarbazepine (e.g. Trileptal)

phenobarbital or phenytoin (e.g.

Dilantin)

rifabutin (e.g.Mycobutin)

rifapentine (e.g. Priftin)

boceprevir (e.g. Victrelis)

St John’s Wort or products

containing St John’s Wort

atazanavir (e.g. Reyataz)

This is not a complete list of medicines

that you should tell your doctor about.

These medicines may be affected by

BIKTARVY or may affect how well it

works. You may need different amounts

of your medicines, or you may need to

take different medicines.

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.

Do not start any new medicines while

you are taking BIKTARVY without

first talking with your doctor or

pharmacist.

BIKTARVY Consumer Medicine Information v1.0 – (15 August 2019) Page 3 of 4

How to take BIKTARVY

Take the exact amount of

BIKTARVY 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 BIKTARVY

tablet orally, once daily.

Take BIKTARVY with or without food.

Do not chew, crush or split the tablet.

When to take it

If you are taking an antacid (such as

aluminium/magnesium hydroxide), a

mineral supplement or vitamin

(containing calcium or iron), ulcer-

healing medication (such as sucralfate),

or a buffered medication (containing

calcium carbonate), take BIKTARVY at

least 2 hours before taking these

medications.

Alternatively, you can take the

medication and BIKTARVY together

with food.

If you forget to take it

Do not miss a dose of BIKTARVY.

If you forget to take BIKTARVY,

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 BIKTARVY 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 BIKTARVY and

become harder to treat.

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

BIKTARVY tablets. Do this even if

there are no signs of discomfort or

poisoning. This may need urgent

medical attention.

While you are taking

BIKTARVY

Things you must not do

Do not breastfeed. See “Before you

start to take it”

Avoid doing things that can spread

HIV infection since BIKTARVY 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.

Do not take BIKTARVY 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 BIKTARVY if the

packaging is torn or shows signs of

tampering.

Things to be careful of

Be careful driving or operating

machinery until you know how

BIKTARVY 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, BIKTARVY 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 BIKTARVY, even if you do not

think the problems are connected with

the medicine or are not listed in this

leaflet.

Hepatic Flares

If you have both HIV infection and

HBV infection you should not stop your

BIKTARVY treatment without first

discussing this with your doctor. Your

HBV may get worse (flare-up) if you

stop taking BIKTARVY. A “flare-up”

or “hepatic flare” is when your HBV

infection suddenly returns in a worse

way than before You may require

medical exams and blood tests for

several months after stopping treatment.

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

BIKTARVY Consumer Medicine Information v1.0 – (15 August 2019) Page 4 of 4

notice any symptoms of infection,

please tell your doctor immediately.

Allergy

Some people are allergic to medicines.

If you have any of the following

symptoms soon after taking your

medicine, DO NOT TAKE ANY

MORE BIKTARVY and tell your

doctor IMMEDIATELY or go to the

accident and emergency department

at your nearest hospital:

skin troubles such as lumpy skin

rash or “hives”

swelling of the face, lips, mouth or

throat which may cause difficulty in

swallowing or breathing

wheezing, chest pain or tightness

fainting

These are very serious effects. If you

have them, you may have a serious

allergic reaction. You may need

urgent medical attention or

hospitalisation. Hypersensitivity

reactions are very rare.

Common side effects

The most common side effects of

BIKTARVY are diarrhoea and

headache.

Other side effects include:

nausea

tiredness (fatigue)

abdominal pain

indigestion

wind (flatulence)

rash

vomiting

Talk to your doctor or pharmacist if

you don’t understand anything in this

list.

This is not a complete list of side effects

possible with BIKTARVY.

Ask your doctor or pharmacist for a

more complete list of side effects of

BIKTARVY and all the medicines

you will take.

After taking BIKTARVY

Storage

Keep BIKTARVY 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 BIKTARVY tablets in a cool,

dry place where it stays below

30 °C.

Do not store BIKTARVY or any

other medicine in a bathroom or near

a sink.

Do not leave BIKTARVY in the car

or on a window sill.

Heat and dampness can destroy some

medicines.

Keep your BIKTARVY tablets in the

bottle with the cap tightly closed until

you take them.

If you take BIKTARVY tablets out of

their pack they may not keep well.

Product Description

What the tablets look like

The 50/200/25 mg BIKTARVY tablets

are capsule-shaped, purplish-brown in

colour and film-coated.

Each tablet is debossed with “GSI” on

one side and the number “9883” on the

other side.

BIKTARVY tablets are supplied in

bottles containing 30 tablets.

Ingredients

Each BIKTARVY tablet contains the

active ingredients:

bictegravir

emtricitabine

tenofovir alafenamide

Each BIKTARVY tablet also contains

the following inactive ingredients:

microcrystalline cellulose

croscarmellose sodium

magnesium stearate

Film-coating

polyvinyl alcohol

titanium dioxide

polyethylene glycol

talc

Opadry II Brown

Sponsor

BIKTARVY tablets are supplied in

Australia by:

Gilead Sciences Pty Ltd

Level 6, 417 St Kilda Road

Melbourne, Victoria 3004

In New Zealand

Gilead

Sciences

(NZ)

Grant

Thornton New Zealand Limited

Level 4, 152 Fanshawe Street

Auckland Central, Auckand1010

New Zealand

Date of preparation: 15 August 2019

BIKTARVY 50/200/25 mg tablets

AUST R 291923

BIKTARVY, GENVOYA, DESCOVY,

ODEFSEY, and VEMLIDY and GSI are

trademarks of Gilead Sciences, Inc., or

its related companies. Other brands

listed are trademarks of their respective

owners and are not trademarks of Gilead

Sciences, Inc.

NEW ZEALAND DATA SHEET

BIKTARVY Data Sheet v1.0 (15 August 2019)

Page 1

1 BIKTARVY

®

(BICTEGRAVIR/EMTRICTABINE/TENOFOVIR ALAFENAMIDE

50/200/25 MG) TABLETS

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Bictegravir 50 mg / Emtricitabine 200 mg / Tenofovir alafenamide 25 mg.

For full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet.

The tablets are film-coated, capsule shaped and purplish-brown in colour. Each tablet is

debossed with ‘GSI’ on one side and the number “9883” on the other side.

4 CLINICAL PARTICULARS

4.1

Therapeutic indications

BIKTARVY is indicated for the treatment of HIV-1 infection in adults who are antiretroviral

therapy (ART)-naïve or to replace the current antiretroviral regimen in those who are

virologically-suppressed (HIV-1 RNA < 50 copies per mL) on a stable antiretroviral regimen

at the start of therapy with no history of treatment failure, and no known substitutions

associated with resistance to the individual components of BIKTARVY.

4.2

Dose and method of administration

BIKTARVY is taken orally once daily with or without food.

Special populations: Dosage adjustment

Children:

Insufficient data are available on which to recommend administration to paediatric

patients less than 18 years of age.

Elderly:

No dose adjustment is required for elderly patients.

Renal impairment:

dose

adjustment

BIKTARVY is

required

adult

patients

with

estimated creatinine clearance greater than or equal to 30 mL per minute.

Initiation of BIKTARVY is not recommended in patients with estimated creatinine clearance

below 30 mL per minute as there are insufficient data available regarding the use of

BIKTARVY in this population.

Hepatic Impairment

:

No dose adjustment of BIKTARVY is required in patients with mild

(Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. BIKTARVY

NEW ZEALAND DATA SHEET

BIKTARVY Data Sheet v1.0 (15 August 2019)

Page 2

has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) (see

Section 5.2 Pharmacokinetic Properties: Pharmacokinetics in Special Populations).

4.3

Contraindications

BIKTARVY is contraindicated in patients with known hypersensitivity to BIC, FTC, TAF or

to any of the excipients.

Coadministration with dofetilide is contraindicated due to the potential for increased

dofetilide plasma concentrations and associated serious and/or life-threatening events.

Coadministration with rifampicin is contraindicated due to decreased BIC plasma

concentrations, which may result in the loss of therapeutic effect and development of

resistance to BIKTARVY.

Please see Table 4 for Established and Other Potentially Significant Drug Interactions. In

addition, prescribing information for any drug coadministered with BIKTARVY should be

consulted to exclude significant interaction or contraindication.

4.4

Special warnings and precautions for use

General

Patients receiving BIKTARVY 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.

While effective viral suppression with antiretroviral therapy has been proven to substantially

reduce the risk of HIV transmission, a residual risk cannot be excluded. Appropriate

precautions must continue to be used. Patients should also be informed that BIKTARVY is

not a cure for HIV infection.

HIV and Hepatitis B Virus (HBV) Co-infection

Discontinuation of BIKTARVY therapy in patients co-infected with HIV-1 and HBV may be

associated with severe acute exacerbations of hepatitis due to the FTC and TAF components

of BIKTARVY. Patients co-infected with HIV-1 and HBV should be closely monitored with

both clinical and laboratory follow-up for at least several months after stopping BIKTARVY

treatment. If appropriate, anti-hepatitis B therapy may be warranted, especially in HBV co-

infected patients with advanced liver disease or cirrhosis since post-treatment exacerbation of

hepatitis may lead to hepatic decompensation.

Use with Other Antiretroviral Products

BIKTARVY should not be coadministered with products containing any of the same

components, BIC, TAF or FTC; or with products containing lamivudine or tenofovir

disoproxil fumarate (TDF). BIKTARVY should not be administered with adefovir dipivoxil.

NEW ZEALAND DATA SHEET

BIKTARVY Data Sheet v1.0 (15 August 2019)

Page 3

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination

antiretroviral therapy, including FTC, a component of BIKTARVY. 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, HBV and

Pneumocystis jirovecii

pneumonia. Any inflammatory symptoms

should be evaluated and treatment instituted when necessary.

Autoimmune disorders 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.

Paediatric Use

Insufficient

data

available

which

recommend

administration

paediatric

patients

less than 18 years of age

Use in the Elderly

No dose adjustment of BIKTARVY is required for elderly patients.

Use in Renal Impairment

No dose adjustment of BIKTARVY is required in adult patients with estimated creatinine

clearance greater than or equal to 30 mL per min.

Initiation of BIKTARVY is not recommended in patients with estimated creatinine clearance

below 30 mL per minute as there are no data available regarding the use of BIKTARVY in

this population (see Section 4.2 Dose and method of administration).

The safety, virologic, and immunologic responses of FTC+TAF was evaluated through 144

weeks in an open-label clinical study GS-US-292-0112 (Study 0112) in which 248 HIV-1

infected adult patients who were either treatment-naïve (N=6) or virologically suppressed

(N=242) with mild to moderate renal impairment (eGFR by Cockcroft-Gault method 30 - 69

mL per min) received FTC+TAF in combination with EVG+COBI as a fixed-dose

combination tablet. The safety profile of FTC+TAF in patients with mild to moderate renal

impairment was similar to safety data that from patients with normal renal function.

Lactic Acidosis/Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been

reported with the use of nucleoside analogs, including emtricitabine, a component of

BIKTARVY, and tenofovir DF, another prodrug of tenofovir, alone or in combination with

NEW ZEALAND DATA SHEET

BIKTARVY Data Sheet v1.0 (15 August 2019)

Page 4

other antiretrovirals. Treatment with BIKTARVY 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).

Co-administration of other medicinal products

Under fasted conditions, BIKTARVY should not be co-administered simultaneously with

magnesium/aluminium-containing antacids due to the expected substantial decrease of BIC

exposure.

Under fasted conditions, BIKTARVY should be administered at least 2 hours before taking

antacids containing magnesium and/or aluminium (see section 4.5).

If taken together with food, BIKTARVY and magnesium/aluminium-containing antacids can

be co-administered simultaneously (see section 4.5).

4.5

Interaction with other medicines and other forms of interaction

General

As BIKTARVY

contains BIC, FTC and TAF any interactions that have been identified with

these agents individually may occur with BIKTARVY.

Bictegravir:

BIC inhibits organic cation transporter 2 (OCT2) and multidrug and toxin

extrusion transporter 1 (MATE1)

in vitro

. Coadministration of BIKTARVY with the OCT2

and MATE1 substrate metformin did not result in a clinically significant increase in

metformin exposure. BIKTARVY may be coadministered with substrates of OCT2 and

MATE1 except dofetilide, which is contraindicated due to the potential for increased

dofetilide plasma concentrations and associated serious and/or life-threatening events (see

Section 4.3 Contraindications).

Bictegravir is a substrate of P-gp and BCRP

in vitro

. However, clinical drug interaction data

show that P-gp/BCRP does not play a clinically significant role in the disposition of

bictegravir.

BIC is primarily eliminated through hepatic metabolism by CYP3A and UGT1A1. Drugs that

are potent inducers of both CYP3A and UGT1A1, such as rifampicin, may significantly

decrease plasma exposures of BIC leading to reduced therapeutic effect of BIC.

Coadministration with rifampicin is contraindicated. Potent inhibitors of both CYP3A and

UGT1A1, such as atazanavir, may significantly increase BIC exposure, and coadministration

is not recommended.

BIC is not an inhibitor or inducer of CYP3A

in vivo

Emtricitabine

In vitro

and clinical pharmacokinetic drug-drug interaction studies have

shown that the potential for CYP-mediated interactions involving FTC with other medicinal

products is low. FTC is 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 FTC with drugs that are

NEW ZEALAND DATA SHEET

BIKTARVY Data Sheet v1.0 (15 August 2019)

Page 5

eliminated by active tubular secretion may increase concentrations of FTC, and/or the

coadministered drug.

Drugs that decrease renal function may increase concentrations of FTC.

In drug interaction studies conducted with FTC and with TDF, coadministration of FTC and

famciclovir had no effect on the C

or AUC of either drug.

Tenofovir Alafenamide:

TAF is a substrate of P-glycoprotein (P-gp) and BCRP. Drugs that

strongly affect P-gp and BCRP activity may lead to changes in TAF absorption. TAF is not

an inhibitor or inducer of CYP3A

in

vivo.

Drug Interaction Studies

Drug-drug interaction studies were conducted with BIKTARVY or various combinations of

the components of BIKTARVY (BIC, FTC or TAF).

The effects of coadministered drugs on the exposure of BIC are shown in Table 1. The effects

of coadministered drugs on the exposure of TAF are shown in Table 2. The effects of BIC

and/or TAF on the exposure of coadministered drugs are shown in Table 3.

Table 1.

Drug Interactions: Changes in Pharmacokinetic Parameters for

BIC in the Presence of the Coadministered Drug

a

Coadministered

Drug

Dose of

Coadministered

Drug (mg)

Bictegravir

(mg)

N

Mean Ratio of Bictegravir

Pharmacokinetic Parameters (90% CI)

b

;

No effect = 1.00

C

max

AUC

C

min

Atazanavir

(fed)

300+150

cobicistat once

daily

75 single

dose

1.31

(1.23, 1.40)

4.06

(3.76, 4.37)

Atazanavir

(fed)

400 once daily

75 single

dose

1.28

(1.23, 1.33)

4.15

(3.81, 4.51)

Darunavir

(fed)

800+150

cobicistat once

daily

75 once daily

1.52

(1.40, 1.64)

1.74

(1.62, 1.87)

2.11

(1.95, 2.29)

Ledipasvir/

Sofosbuvir (fed)

90/400 once daily

75 once daily

0.98

(0.94, 1.03)

1.00

(0.97, 1.03)

1.04

(0.99, 1.09)

Rifabutin

(fasted)

300 once daily

75 once daily

0.80

(0.67, 0.97)

0.62

(0.53, 0.72)

0.44

(0.37, 0.52)

Rifampicin

(fed)

600 once daily

75 single

dose

0.72

(0.67, 0.78)

0.25

(0.22, 0.27)

Sofosbuvir/

velpatasvir/

voxilaprevir (fed)

400/100/100+100

voxilaprevir

once

daily

50 once daily

0.98

(0.94, 1.01)

1.07

(1.03, 1.10)

1.10

(1.05, 1.17)

Voriconazole

(fasted)

300 twice daily

75 single

dose

1.09

(0.96, 1.23)

1.61

(1.41, 1.84)

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Coadministered

Drug

Dose of

Coadministered

Drug (mg)

Bictegravir

(mg)

N

Mean Ratio of Bictegravir

Pharmacokinetic Parameters (90% CI)

b

;

No effect = 1.00

C

max

AUC

C

min

Medications or Oral Supplements Containing Polyvalent Cations

Maximum strength

antacid

(simultaneous

administration,

fasted)

20 mL

single

dose (oral)

50 single

dose

0.20

(0.16, 0.24)

0.21

(0.18, 0.26)

Maximum strength

antacid

(2 hrs after

[BIKTARVY]

fasted)

20 mL

single

dose (oral)

50 single

dose

0.93

(0.88, 1.00)

0.87

(0.81, 0.93)

Maximum strength

antacid

(2 hrs before

[BIKTARVY]

fasted)

20 mL

single

dose (oral)

50 single

dose

0.42

(0.33, 0.52)

0.48

(0.38, 0.59)

Maximum strength

antacid

(simultaneous

administration,

20 mL

single

dose (oral)

50 single

dose

0.51

(0.43, 0.62)

0.53

(0.44, 0.64)

Calcium carbonate

(simultaneous

administration,

fasted)

1200 single dose

50 single

dose

0.58

(0.51, 0.67)

0.67

(0.57, 0.78)

Calcium carbonate

(simultaneous

administration,

1200 single dose

50 single

dose

0.90

(0.78, 1.03)

1.03

(0.89, 1.20)

Ferrous fumarate

(simultaneous

administration,

fasted)

324 single dose

50 single

dose

0.29

(0.26, 0.33)

0.37

(0.33, 0.42)

Ferrous fumarate

(simultaneous

administration,

324 single dose

50 single

dose

0.75

(0.65, 0.87)

0.84

(0.74, 0.95)

NA= Not Available / Not Applicable

a. All interaction studies conducted in healthy volunteers.

b. All No Effect Boundaries are 70% -143%.

c. Evaluated as a potent inhibitor of CYP3A, UGT1A1, and an inhibitor of P-gp.

d. Evaluated as a potent inhibitor of CYP3A and UGT1A1.

e. Evaluated as a potent inhibitor of CYP3A.

f. Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients.

g. Maximum strength antacid contained 80 mg aluminium hydroxide, 80 mg magnesium hydroxide, and 8 mg simethicone, per mL.

h. Reference treatment administered under fasted conditions.

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Page 7

Table 2.

Drug Interactions: Changes in Pharmacokinetic Parameters for

TAF in the Presence of the Coadministered Drug

a

Coadministered

Drug

Dose of

Coadministered

Drug (mg)

Tenofovir

Alafenamide

(mg)

N

Mean Ratio of Tenofovir Alafenamide

Pharmacokinetic Parameters (90%

CI)

b

; No effect = 1.00

C

max

AUC

C

min

Carbamazepine

300 twice daily

25 single dose

0.43

(0.36, 0.51)

0.46

(0.40, 0.54)

Ledipasvir/sofosbuvir

90/400 once daily

25 once daily

1.17

(1.00, 1.38)

1.27

(1.19, 1.34)

Sofosbuvir/

velpastasvir/

voxilaprevir

400/100/100 +100

voxilaprevir

once

daily

25 once daily

1.28

(1.09, 1.51)

1.57

(1.44, 1.71)

NA= Not Available / Not Applicable

All interaction studies conducted in healthy volunteers.

All No Effect Boundaries are 70% -143%.

Study conducted with DESCOVY (emtricitabine/tenofovir alafenamide).

Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients.

Table 3.

Drug Interactions: Changes in Pharmacokinetic Parameters for

Coadministered Drug in the Presence of the Components

BIKTARVY

a

Coadministered

Drug

Dose of

Coadministered

Drug (mg)

Bictegravir

(mg)

Tenofovir

Alafenamide

(mg)

N

Mean Ratio of Coadministered

Drug Pharmacokinetic

Parameters

(90% CI)

b

;

No effect = 1.00

C

max

AUC

C

min

Ledipasvir

90/400 once daily

75 once

daily

25 once daily

0.85

(0.81,

0.90)

0.87

(0.83,

0.92)

0.90

(0.84,

0.96)

Sofosbuvir

1.11

(1.00,

1.24)

1.07

(1.01,

1.13)

GS-331007

1.10

(1.07,

1.13)

1.11

(1.08,

1.14)

1.02

(0.99,

1.06)

Metformin

500 twice daily

50 once

daily

25 once daily

1.28

(1.21,

1.36)

1.39

(1.31,

1.48)

1.36

(1.21,

1.53)

Midazolam

2 single dose

50 once

daily

25 once daily

1.03

(0.87,

1.23)

1.15

(1.00,

1.31)

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Page 8

Coadministered

Drug

Dose of

Coadministered

Drug (mg)

Bictegravir

(mg)

Tenofovir

Alafenamide

(mg)

N

Mean Ratio of Coadministered

Drug Pharmacokinetic

Parameters

(90% CI)

b

;

No effect = 1.00

C

max

AUC

C

min

Norelgestromin

norgestimate

0.180/0.215/0.250

once daily /

ethinyl estradiol

0.025 once daily

75 once

daily

1.23

(1.14,

1.32)

1.08

(1.05,

1.10)

1.10

(1.05,

1.15)

Norgestrel

1.15

(1.10,

1.21)

1.13

(1.07,

1.19)

1.14

(1.06,

1.22)

Ethinyl estradiol

1.15

(1.03,

1.27)

1.04

(0.99,

1.10)

1.05

(0.95,

1.14)

Norelgestromin

norgestimate

0.180/0.215/0.250

once daily /

ethinyl estradiol

0.025 once daily

25 once

daily

1.17

(1.07,1.26)

1.12

(1.07,1.17)

1.16

(1.08,

1.24)

Norgestrel

1.10

(1.02,

1.18)

1.09

(1.01,

1.18)

1.11

(1.03,

1.20)

Ethinyl estradiol

1.22

(1.15,

1.29)

1.11

(1.07,

1.16)

1.02

(0.92,

1.12)

Sertraline

50 single dose

10 once

daily

1.14

(0.94,

1.38)

0.93

(0.77,

1.13)

Sofosbuvir

400/100/100

+100

once daily

50 once

daily

25 once daily

1.14

(1.04,

1.25)

1.09

(1.02,

1.15)

GS-331007

1.03

(0.99,

1.06)

1.03

(1.00,

1.06)

1.01

(0.98,

1.05)

Velpatasvir

0.96

(0.91,

1.01)

0.96

(0.90,

1.02)

0.94

(0.88,

1.01)

Voxilaprevir

0.90

(0.76,

1.06)

0.91

(0.80,

1.03)

0.97

(0.88,

1.06)

NA= Not Available / Not Applicable

All interaction studies conducted in healthy volunteers.

All No Effect Boundaries are 70% -143%.

The predominant circulating nucleoside metabolite of sofosbuvir.

Study conducted with DESCOVY (emtricitabine/tenofovir alafenamide)

Study conducted with GENVOYA (elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide).

Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients.

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Page 9

Effects of concomitant drugs on the Pharmacokinetics of BIKTARVY

BIC, a component of BIKTARVY, is a substrate of CYP3A and UGT1A1. Coadministration

of BIC and drugs that potently induce both CYP3A and UGT1A1 may significantly decrease

plasma concentrations of BIC, which may result in loss of therapeutic effect of BIKTARVY

and development of resistance. Coadministration of BIC with drugs that potently inhibit both

CYP3A and UGT1A1 may significantly increase plasma concentrations of BIC.

TAF,

component

BIKT ARVY,

transpo rted

P-glycoprotein

(P-gp )

BCRP.

Drugs

that

strongly

affect

P-gp

BCRP

activity

lead

changes

absorption

(see

Table

Drugs

that

induce

P-gp

activity

expected

decrease

absorption

T A F ,

r e s u l t i n g

d e c r e a s e d

p l a s m a

c o n c e n t r a t i o n

T A F ,

w h i c h

m a y

l e a d

l o s s

t h e r a p e u t i c

e f f e c t

BIKTARVY

a n d

d e v e l o p m e n t

r e s i s t a n c e .

C o a d m i n i s t r a t i o n

BIKTARVY with

other

drugs

that

inhibit

P-gp

BCRP

increase

absorption

plasma concentration of TAF.

Established and Other Potentially Significant Interactions

B I K T A R V Y

c o m p l e t e

r e g i m e n

f o r

t h e

t r e a t m e n t

H I V - 1

i n f e c t i o n .

T h e r e f o r e ,

c o m p r e h e n s i v e

i n f o r m a t i o n

r e g a r d i n g

d r u g - d r u g

i n t e r a c t i o n s

w i t h

o t h e r

a n t i r e t r o v i r a l

products is not provided.

D r u g

i n t e r a c t i o n

i n f o r m a t i o n

f o r

BIKTARVY

w i t h

p o t e n t i a l

c o n c o m i t a n t

d r u g s

summarised in Table 4. The drug interactions described are based on studies conducted with

BIKTARVY or the components of BIKTARVY (BIC, FTC, and TAF) as individual agents,

or are potential drug interactions that may occur with BIKTARVY.

The table is not all-inclusive (see Section 4.3 Contraindications).

Table 4.

Established and Other Potentially Significant

a

Drug Interactions

Concomitant Drug

Class:

Drug Name

Effect on

Concentration

b

Clinical Comment

Antiarrhythmic:

dofetilide

Effect on dofetilide

concentrations

unknown

Data are not available on the potential interaction of

dofetilide with BIKTARVY. Due to the potential for

serious and/or life-threatening events with increased

dofetilide plasma concentrations, coadministration of

BIKTARVY with dofetilide is contraindicated

(see Section

4.3 Contraindications).

Anticonvulsants:

carbamazepine

oxcarbazepine

phenobarbital

phenytoin

bictegravir

tenofovir

alafenamide

Coadministration of carbamazepine, oxcarbazepine,

phenobarbital, or phenytoin may decrease BIC and TAF

plasma concentrations, which may result in loss of

therapeutic effect and development of resistance.

Alternative anticonvulsants should be considered.

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Page 10

Concomitant Drug

Class:

Drug Name

Effect on

Concentration

b

Clinical Comment

Antimycobacterial:

rifabutin

rifampicin

rifapentine

bictegravir

tenofovir

alafenamide

Coadministration of rifampicin, rifabutin, and rifapentine

may decrease BIC and TAF plasma concentrations, which

may result in loss of therapeutic effect and development of

resistance. Coadministration of BIKTARVY with

rifampicin is contraindicated due to the effect of rifampicin

on the BIC component of BIKTARVY

(see Section 4.3

Contraindications).

Coadministration of BIKTARVY with

rifabutin or rifapentine is not recommended.

HIV-1 Antiviral

Agent:

atazanavir

bictegravir

Coadministration of BIKTARVY with atazanavir, a CYP3A

and UGT1A1 inhibitor, may increase BIC plasma

concentrations. Coadministration of BIKTARVY with

atazanavir is not recommended due to the effect of

atazanavir on the BIC component of BIKTARVY.

Hepatitis C Virus

Antiviral Agent:

boceprevir

Effect on boceprevir,

or tenofovir

alafenamide

concentrations

unknown

Coadministration with boceprevir has the potential to

adversely affect the intracellular activation and clinical

antiviral efficacy of TAF based on

in vitro

data.

Coadministration of BIKTARVY and boceprevir is not

recommended.

Herbal Products:

St. John’s wort

(Hypericum

perforatum)

bictegravir

tenofovir

alafenamide

Coadministration of St. John’s wort may decrease BIC and

TAF plasma concentrations, which may result in loss of

therapeutic effect and development of resistance.

Coadministration of BIKTARVY with St. John’s wort is not

recommended.

Medications or oral

supplements

containing polyvalent

cations (e.g. Mg, Al,

Ca, Fe):

Calcium or iron

supplements

Cation-containing

antacids or laxatives

Sucralfate

Buffered medications

bictegravir

If taken together with food, BIKTARVY and medicinal

products or oral supplements containing polyvalent cations

(e.g. Mg, Al, Ca, Fe) can be taken at the same time.

Under fasted conditions, BIKTARVY should be

administered at least 2 hours before taking medicinal

products or oral supplements containing polyvalent cations.

Table is not all inclusive.

= increase,

= decrease, ↔ = no effect

Drug-drug interaction study was not conducted.

Drugs Without Clinically Significant Interactions with BIKTARVY

Based on drug interaction studies conducted with BIKTARVY or the components of

BIKTARVY, no clinically significant drug interactions were observed or are expected with:

amlodipine, atorvastatin, buprenorphine, drospirenone, ethinyl estradiol, famotidine,

fluticasone, itraconazole, ketoconazole, ledipasvir/sofosbuvir, metformin, methadone,

midazolam, naloxone, norbuprenorphine, norgestimate, omeprazole, sertraline, sofosbuvir,

sofosbuvir/velpatasvir, or sofosbuvir/velpatasvir/voxilaprevir.

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Page 11

Paediatric population

Interaction studies have only been performed in adults.

4.6

Fertility, pregnancy and lactation

Pregnancy

There are no adequate and well controlled clinical studies of BIKTARVY

or its components

in pregnant women. Because animal reproductive studies are not always predictive of human

response, BIKTARVY should be used during pregnancy only if the potential benefit justifies

the potential risk to the fetus.

Bictegravir:

Studies

animals

have

shown

evidence

teratogenicity

effect

r e p r o d u c t i v e

f u n c t i o n .

o f f s p r i n g

f r o m

r a t

a n d

r a b b i t

d a m s

t r e a t e d

w i t h

B I C

d u r i n g

pregnancy,

there

were

toxicologically

significant

effects

developmental

endpoints 36

times (rat) or 1.4 times (rabbit) higher exposures (AUC) than in humans at the recommended

dose of 50 mg BIC in BIKTARVY.

Emtricitabine:

No evidence of embryofoetal toxicity or teratogenicity was observed in mice

r a b b i t s

r e s p e c t i v e

e m t r i c i t a b i n e

e x p o s u r e s

( A U C )

a n d

1 3 0

f o l d

t h e

c l i n i c a l

e x p o s u r e .

I m p a i r e d

w e i g h t

g a i n

o b s e r v e d

p r e g n a n t

r a b b i t s

d o s e s

r e s u l t i n g

emtricitabine exposures (AUC) at least 33 times the clinical exposure was not associated with

any adverse fetal effects.

Tenofovir Alafenamide

E m b r yo fet al

dev el opm ent

studies

performed

rats

rabbits

reveal ed

eviden ce

embr yolethalit y,

fetoto x icit y

te rato genicit y

TAF.

Th e

embryo-fetal NOAELs in rats and rabbits occurred at TAF exposures (AUC) similar to and

53 times higher than, respectively, the exposure in humans at the recommended daily dose.

Breast-feeding

In animal studies, BIC was detected in the plasma of nursing rat pups likely due to the

presence of BIC in milk, without effects on nursing pups at maternal exposures 30 times

higher exposures (AUC) than in humans at the recommended dose of 50 mg BIC in

BIKTARVY. In animal studies it has been shown that tenofovir is secreted into milk. It is not

known whether BIC or TAF is secreted in human milk. In humans, samples of breast milk

obtained from five HIV-1 infected mothers given TRUVADA (TDF/FTC) show that FTC is

secreted in human milk at estimated neonatal concentrations 3 to 12 times higher than the

FTC IC

but 3 to 12 times lower than the C

achieved from oral administration of FTC.

Breastfeeding infants whose mothers are being treated with FTC may be at risk for

developing viral resistance to FTC. Other FTC-associated risks in infants breastfed by

mothers being treated with FTC are unknown.

Because of the potential for both HIV transmission and for serious adverse events in nursing

infants, mothers should be instructed not to breast feed if they are receiving BIKTARVY.

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Page 12

Fertility

No reproductive toxicity studies have been conducted with BIC, FTC and TAF in

combination.

Bictegravir:

BIC did not affect fertility, reproductive performance or embryonic viability in

male and female rats at 29 times higher exposures (AUC) than in humans at the

recommended dose of 50 mg BIC in BIKTARVY.

Emtricitabine:

FTC did not affect fertility in male rats at approximately 140 times or in male

and female mice at approximately 60 times higher exposures (AUC) than in humans given

the recommended 200 mg daily dose in BIKTARVY. Fertility was normal in the offspring of

mice exposed daily from before birth (in utero) through sexual maturity at daily exposures

(AUC) of approximately 60 times higher than human exposures at the recommended 200 mg

daily dose in BIKTARVY.

Tenofovir Alafenamide:

There were no effects on fertility, mating performance or early

embryonic development when TAF was administered to male rats at a dose equivalent to 155

times (25 mg TAF) the human dose based on body surface area comparisons for 28 days prior

to mating and to female rats for 14 days prior to mating through day seven of gestation.

4.7

Effects on ability to drive and use machines

No studies on the effects of BIKTARVY on the ability to drive and use machines have been

performed.

4.8

Undesirable effects

As BIKTARVY contains BIC, FTC, and TAF adverse reactions associated with these

individual antiretrovial agents may be expected to occur with the fixed combination tablet.

Experience from Clinical Studies in Treatment-Naïve Patients

Assessment of adverse reactions is based on pooled data from two 48-week controlled

clinical studies (Study 1489 and Study 1490) in which 1274 treatment-naïve patients received

BIKTARVY (N=634), abacavir (ABC)/DTG/lamivudine (3TC) (N=315) or dolutegravir

(DTG) + FTC/TAF (N=325).

The most common adverse reactions (all Grades) and reported in ≥ 5% of patients in the

BIKTARVY group were diarrhoea and headache. The proportion of subjects who

discontinued treatment with BIKTARVY, ABC/DTG/ lamivudine [3TC]), or DTG +

FTC/TAF due to adverse events, regardless of severity, was 1%, 1%, and <1%, respectively.

Table 5 displays the frequency of adverse reactions (all Grades) greater than or equal to 3%

in the BIKTARVY group.

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Page 13

Table 5.

Adverse Drug Reactions

a

(All Grades) Reported in ≥ 3% of HIV-1

Infected Treatment-Naïve Adults Receiving BIKTARVY in Studies 1489

and 1490 (Week 48 analysis)

BIKTARVY

N=634

ABC/DTG/3TC

N=315

DTG+

FTC/TAF

N=325

GASTROINTESTINAL DISORDERS

Diarrhoea

Nausea

GENERAL DISORDERS AND ADMINISTRATION

SITE CONDITIONS

Fatigue

NERVOUS SYSTEM DISORDERS

Headache

Frequencies of adverse reactions are based on all adverse events attributed to study drugs by the investigator.

No adverse reactions Grade 2 or higher occurred in ≥ 1% of subjects treated with BIKTARVY.

Pooled from Studies 1489 and 1490.

Study 1489

Study 1490

Additional adverse reactions occurring in less than 3% of subjects administered BIKTARVY

in Studies 1489 and 1490 included vomiting, flatulence, dyspepsia, abdominal pain, and rash.

The majority of adverse reactions occurred at severity Grade 1.

Experience from Clinical Studies in Virologically Suppressed Patients

No new adverse reactions to BIKTARVY were identified through Week 48 in a controlled

clinical study (GS-US-380-1844 [“Study 1844”]) of virologically suppressed patients who

switched from regimens of DTG + ABC/3TC or ABC/DTG/3TC to BIKTARVY (N=282).

No new adverse reactions to BIKTARVY were identified through Week 48 in a controlled

clinical study (GS-US-380-1878 [“Study 1878”]) of virologically suppressed patients who

switched from regimens of ritonavir (RTV) or cobicistat (COBI) boosted atazanavir (ATV) or

DRV, plus either FTC/TDF or ABC/3TC, to BIKTARVY (N=290).

Laboratory Abnormalities

The frequency of laboratory abnormalities (Grades 3–4) occurring in at least 2% of subjects

receiving BIKTARVY in Studies 1489 and 1490 are presented in Table 6.

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Table 6.

Laboratory Abnormalities (Grades 3–4) Reported in ≥ 2% of Subjects

Receiving BIKTARVY in Studies 1489 and 1490 (Week 48 analysis)

Laboratory Parameter Abnormality

a

BIKTARVY

N=634

ABC/DTG/3TC

N=315

DTG+

FTC/TAF

N=325

Amylase (>2.0 x ULN)

AST (>5.0 × ULN)

Creatin Kinase (≥10.0 × ULN)

Neutrophils (<750 mm

LDL-cholesterol (fasted) (>190 mg/dL)

ULN = Upper limit of normal

Frequencies are based on treatment-emergent laboratory abnormalities.

Pooled from Studies 1489 and 1490

Study 1489

Study 1490

Changes in Serum Creatinine

been

shown

increase

serum

creatinine

inhibition of tubular secretion of creatinine without affecting renal glomerular function (see

Section 5.2 Pharmacodymanic Properties). Increases in serum creatinine occurred by Week 4

of treatment and remained stable through Week 48. In Studies 1489 and 1490, median (Q1,

Q3) serum creatinine increased by 0.10 (0.03, 0.17) mg per dL, 0.11 (0.03, 0.18) mg per dL,

a n d

0 . 1 1

( 0 . 0 4 ,

0 . 1 9 )

p e r

f r o m

b a s e l i n e

W e e k

t h e

BIKTARVY,

ABC/DTG/3TC, and

DTG+FTC/TAF groups, respectively. There were no discontinuations

due to renal adverse events through Week 48 in BIKTARVY clinical studies.

Changes in Bilirubin:

In Studies 1489 and 1490, total bilirubin increases were observed in

p atients

administered

BIKTARVY through

W ee k

Incr eas es

we re

p rimaril y

Grade

(9%)

Grade

(3%)

(1.0

ULN),

were

associated

with

hepatic

a d v e r s e

r e a c t i o n s

o t h e r

l i v e r

r e l a t e d

l a b o r a t o r y

a b n o r m a l i t i e s .

T h e r e

w e r e

discontinuations

hepatic

adverse

events

through

Week

BIKTARVY clinical

studies.

Experience from Clinical Studies in Patients with Renal Impairment

The safety of FTC + TAF (components of BIKTARVY) was evaluated through 144 weeks in

open-label

clinical

study

(Study

0112)

which

248 HIV-1

infected

patients

were

either

treatment-naïve

(N=6)

virologicall y

suppressed

(N=242)

with

mild

moderate

renal impairment (eGFR by Cockcroft-Gault method 30-69 mL per min) received FTC+TAF

combination

with

EVG+COBI

fixed-dose

combination

tablet.

safety

profile

FTC+TAF

patients

with

mild

moderate

renal

impairment

similar

that

from

patients with normal renal function (see Section 5.1 Clinical Trials).

Experience from Clinical Studies in Patients Coinfected with HIV-1 and Chronic Hepatitis B

The safety of TAF (a component of BIKTARVY) for the treatment of chronic hepatitis B is

based

data

from

randomized,

double-blind,

active-controlled

studies

adults

with

c o m p e n s a t e d

l i v e r

d i s e a s e

( G S - U S - 3 2 0 - 0 1 0 8

a n d

G S - U S - 3 2 0 - 0 1 1 0 )

( s e e

VEMLIDY

(tenofovir alafenamide) Data Sheet).

safety

HIV-suppressed

adults

coinfected

with

chronic

hepatitis

was evaluated through Week 48 in an open-label clinical study (GS-US-292-1249) in which

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Page 15

patients were switched from another antiretroviral regimen to FTC + TAF administered with

elvitegravir

(EVG)

cobicistat

(COBI)

fixed-dose

combination

tablet.

safet y

profile of this regimen in patients coinfected with HIV-1 and chronic hepatitis B was similar

to that in patients with HIV-1 monoinfection (see Section 5.1 Clinical Trials).

HIV/HBV

coinfected

adults

administered

BIKTARVY (n

HIV/HBV

treatment

naïve in Study 1490; n = 8 HIV/HBV suppressed in Study 1878), the adverse effects profile

of BIKTARVY was

similar

that

patients

with

HIV-1

monoinfection. One

patient

Study 1490 developed protocol-defined hepatic flare (ALT > 10 times upper limit of normal).

ALT returned to normal limits without treatment interruption. Given limited data for use of

B I K T A R V Y

H B V

c o i n f e c t i o n ,

c l o s e l y

m o n i t o r

c o i n f e c t e d

p a t i e n t s

( s e e

S e c t i o n

4 . 4

Special warnings and precautions).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It

allows continued monitoring of the benefit/risk balance of the medicine. Healthcare

professionals are asked to report any suspected adverse reactions:

https://nzphvc.otago.ac.nz/reporting/

4.9

Overdose

overdose

occurs

patient

must

monitored

evidence

toxicity.

Treatment

overdose with BIKTARVY 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 National Poisons Centre on

0800 764 766.

Bictegravir:

Limited

clinical

experience

available

doses

higher

than

recommended

dose

BIC.

single

dose

times

dose

BIKTARVY)

administered

healthy

subjects;

serious

adverse

reactions

were

reported.

highl y

bound

plasma

proteins,

unlikel y

that

will

signifi cantl y

removed

hemodialysis or peritoneal dialysis.

Emtricitabine:

Limited clinical experience is available at doses higher than the therapeutic

dose of emtricitabine 200 mg. 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 FTC dose over a 3-hour dialysis

period starting within 1.5 hours of emtricitabine dosing (blood flow rate of 400 mL per min

and a dialysate flow rate of 600 mL per min). It is not known whether emtricitabine can be

removed by peritoneal dialysis.

Tenofovir Alafenamide

: Limited clinical experience is available at doses higher than the

therapeutic dose of TAF. A single supratherapeutic dose of 125 mg TAF was administered to

48 healthy patients, no serious adverse reactions were reported. The effects of higher doses

are unknown. Tenofovir is efficiently removed by hemodialysis with an extraction coefficient

of approximately 54%.

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5 PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group:

Antivirals for treatment of HIV infections, combinations,

ATC code: J05AR20.

Mechanism of action

Bictegravir:

BIC is an integrase strand transfer inhibitor (INSTI) that binds to the integrase

active site and blocks the strand transfer step of retroviral deoxyribonucleic acid (DNA)

integration which is essential for the HIV replication cycle. BIC has activity that is specific to

human immunodeficiency virus (HIV-1 and HIV-2).

Emtricitabine:

FTC is a nucleoside analogue of 2’-deoxycytidine. FTC is phosphorylated by

cellular enzymes to form FTC triphosphate. FTC triphosphate inhibits HIV replication

through incorporation into viral DNA by the HIV reverse transcriptase, which results in DNA

chain-termination.

FTC has activity that is specific to human immunodeficiency virus (HIV-1 and HIV-2) and

hepatitis B virus. FTC triphosphate is a weak inhibitor of mammalian DNA polymerases that

include mitochondrial DNA polymerase γ and there was no evidence of toxicity to

mitochondria

in vitro

in vivo

Tenofovir Alafenamide

: TAF is a phosphonamidate prodrug of tenofovir (2’-deoxyadenosine

monophosphate analogue). TAF is permeable into cells and due to increased plasma stability

and intracellular activation through hydrolysis by cathepsin A, TAF is more efficient than

tenofovir disoproxil fumarate (TDF) in loading tenofovir into peripheral blood mononuclear

cells (PBMCs), including lymphocytes and macrophages. Intracellular tenofovir is

subsequently phosphorylated to the pharmacologically active metabolite tenofovir

diphosphate. Tenofovir diphosphate inhibits HIV replication through incorporation into viral

DNA by the HIV reverse transcriptase, which results in DNA chain-termination.

Tenofovir has activity that is specific to human immunodeficiency virus (HIV-1 and HIV-2)

and hepatitis B virus (HBV).

In vitro

studies have shown that both emtricitabine and

tenofovir can be fully phosphorylated when combined in cells. Tenofovir diphosphate is a

weak inhibitor of mammalian DNA polymerases that include mitochondrial DNA polymerase

γ and there is no evidence of mitochondrial toxicity

in vitro

based on several assays including

mitochondrial DNA analyses.

Antiviral activity in vitro

The triple combination of bictegravir, emtricitabine, and tenofovir alafenamide demonstrated

synergistic antiviral activity in cell culture.

Bictegravir:

The antiviral activity of BIC against laboratory and clinical isolates of HIV-1

was assessed in lymphoblastoid cell lines, PBMCs, primary monocyte/macrophage cells, and

CD4+ T-lymphocytes. The EC

values for BIC for non-resistant strains were in the range of

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<0.05 to 6.6 nM. The protein-adjusted EC

of BIC was 361 nM (0.162 micrograms per mL)

for wild type HIV-1 virus.

BIC displayed antiviral activity in cell culture against HIV-1 groups (M, N, O), including

subtypes A, B, C, D, E, F and G (EC

values ranged from <0.05 and 1.71 nM), and activity

against HIV-2 (EC

= 1.1 nM).

In a study of BIC with representatives from the major classes of approved anti-HIV agents

(NRTIs [nucleoside reverse transcriptase inhibitors], NNRTIs [non-nucleoside reverse

transcriptase inhibitors], INSTIs [integrase strand transfer inhibitors], and PIs [protease

inhibitors]), additive to synergistic antiviral effects were observed. No antagonism was

observed for these combinations.

Emtricitabine:

in vitro

antiviral activity of FTC against laboratory and clinical isolates

of HIV was assessed in lymphoblastoid cell lines, the MAGI-CCR5 cell line, and PBMCs.

The EC

values for FTC were in the range of 0.0013 to 0.64 µM (0.0003 to 0.158 µg per

mL).

FTC displayed antiviral activity

in vitro

against HIV-1 clades A, C, D, E, F, and G (EC

values ranged from 0.007 to 0.075

M) and showed strain specific activity against HIV-2

values ranged from 0.007 to 1.5

In two-drug combination studies of FTC with NRTIs, NNRTIs, and protease inhibitors (PI),

and INSTIs, additive to synergistic effects were observed. No antagonism was observed for

these combinations.

Tenofovir Alafenamide:

The antiviral activity of TAF against laboratory and clinical isolates

of HIV-1 subtype B was assessed in lymphoblastoid cell lines, PBMCs, primary

monocyte/macrophage cells and CD4-T lymphocytes. The EC

values for tenofovir

alafenamide were in the range of 2.0 to 14.7 nM.

TAF displayed antiviral activity in cell culture against all HIV-1 groups (M, N, O), including

sub-types A, B, C, D, E, F, and G (EC

values ranged from 0.10 to 12.0 nM) and strain

specific activity against HIV-2 (EC

values ranged from 0.91 to 2.63 nM).

In a study of TAF with a broad panel of representatives from the major classes of approved

anti-HIV agents (NRTIs, NNRTIs, INSTIs, and PIs), additive to synergistic effects were

observed. No antagonism was observed for these combinations.

Drug Resistance

In Cell Culture

Bictegravir:

HIV-1 isolates with reduced susceptibility to BIC have been selected in cell

culture. In one selection, amino acid substitutions M50I and R263K emerged and phenotypic

susceptibility to BIC was reduced 1.3-, 2.2-, and 2.9-fold for M50I, R263K, and

M50I+R263K, respectively. In a second selection, amino acid substitutions T66I and S153F

emerged and phenotypic susceptibility to BIC was shifted 0.4-, 1.9-, and 0.5-fold for T66I,

S153F, and T66I+S153F, respectively.

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Emtricitabine:

HIV-1 isolates with reduced susceptibility to FTC have been selected in cell

culture

.

Genotypic analysis of these isolates showed that the reduced susceptibility to FTC

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).

Tenofovir Alafenamide:

HIV-1 isolates with reduced susceptibility to TAF have been

selected in cell culture. HIV-1 isolates selected by TAF expressed a K65R mutation in HIV-1

RT; in addition, a K70E mutation in HIV-1 RT has been transiently observed. HIV-1 isolates

with the K65R mutation have low-level reduced susceptibility to abacavir, FTC, tenofovir,

and lamivudine.

In vitro

drug resistance selection studies with TAF have shown no

development of high-level resistance after extended culture.

In Clinical Studies

In Treatment-Naïve Patients:

patient

receiving

BIKTARVY had

HIV-1

with

treatment

emergent genotypic or phenotypic resistance to BIC, FTC, or TAF in the resistance analysis

population

with

HIV-1 RNA ≥ 200 copies/mL at the time of confirmed virologic

f a i l u r e ,

W e e k

4 8 ,

e a r l y

s t u d y

d r u g

d i s c o n t i n u a t i o n )

p o o l e d

a n a l y s i s

6 3 4

antiretroviral-naïve patients through Week 48 (Studies 1489 and 1490).

In Virologically Suppressed Patients:

patient

receiving

BIKTARVY had

HIV-1

with

treatment emergent genotypic or phenotypic resistance to BIC, FTC, or TAF in the resistance

analysis

population

with

HIV-1 RNA ≥ 200 copies/mL at the time of confirmed

v i r o l o g i c

f a i l u r e ,

W e e k

4 8 ,

e a r l y

s t u d y

d r u g

d i s c o n t i n u a t i o n )

2 8 2

virologically-

suppressed patients who switched from DTG + ABC/3TC or ABC/DTG/3TC to BIKTARVY

(Study 1844).

p a t i e n t

r e c e i v i n g

BIKTARVY

h a d

H I V - 1

w i t h

t r e a t m e n t

e m e r g e n t

g e n o t y p i c

phenotypic resistance to BIC, FTC, or TAF in the resistance analysis population (n = 1 with

HIV-1 RNA ≥ 200 copies/mL at the time of confirmed virologic failure, Week 48, or early

s t u d y

d r u g

d i s c o n t i n u a t i o n )

2 9 0

v i r o l o gi c a l l y- s u p p r e s s e d

p a t i e n t s

w h o

s w i t c h e d

f r o m

regimens

COBI

boosted

DRV,

plus

either

FTC/TDF

ABC/3TC,

BIKTARVY (Study 1878).

In Patients Coinfected with HIV-1 and Chronic Hepatitis B:

In a clinical study of patients

coinfected with HIV-1 and chronic hepatitis B who received FTC + TAF in combination with

EVG+COBI as a fixed-dose combination tablet for 48 weeks (GS-US-292-1249, N = 72), no

subject had HIV or HBV emergent resistance to FTC, TAF, or EVG.

Cross-resistance

Bictegravir

Integrase Strand Transfer Inhibitor-resistant Mutant HIV-1 Strains

: The susceptibility of

BIC was tested against 64 INSTI-resistant clinical isolates (20 with single substitutions and

44 with 2 or more substitutions). Fifty of the 64 INSTI-resistant clinical isolates had ≤ 2.5-

fold phenotypic change to BIC and were assessed as sensitive. All single and double mutants

of these isolates lacking Q148H/K/R, and 10 of 24 Q148H/K/R containing isolates with or

without additional INSTI resistance associated substitutions also had ≤ 2.5-fold reduced

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susceptibility to BIC. Reduced susceptibility to BIC of > 2.5 fold was found for 14 of the 24

Q148H/R/K containing isolates that also had G140A/C/S substitutions in integrase; 9 of those

14 isolates had additional mutations at L74M, T97A, or E138A/K. In addition, site-directed

mutants with G118R and T97A+G118R had 3.4- and 2.8-fold reduced susceptibility to BIC,

respectively. A clinical isolate carrying the T66I+E138K+Q148K triple mutation conferred

substantial resistance to bictegravir (44-fold)

in vitro

Reverse Transcriptase Inhibitor- and Protease Inhibitor-resistant Strains

: BIC demonstrated

equivalent antiviral activity against 5 NNRTI-resistant, 3 NRTI-resistant, and 4 PI-resistant

HIV-1 mutant clones compared with the wild-type strain.

Emtricitabine:

FTC-resistant

isolates

(M184V/I)

were

cross-resistant

retained

sensitivity to didanosine, d4T, tenofovir and AZT.

Viruses harbouring mutations conferring reduced susceptibility to d4T and AZT - thymidine

analogue-associated mutations - TAMs (M41L, D67N, K70R, L210W, T215Y/F, K219Q/E)

didanosine

(L74V)

remained

sensitive

emtricitabine.

HIV-1

containing

K103N

mutation or substitutions associated with resistance to NNRTI were susceptible to FTC.

Tenofovir Alafenamide:

K65R

K70E

mutations

result

reduced

susceptibility

abacavir, didanosine, lamivudine, FTC, and tenofovir, but retain sensitivity to zidovudine.

Multinucleoside

resistant

HIV-1

with

T69S

double

insertion

mutation

with

Q151M

mutation complex including K65R showed reduced susceptibility to TAF.

HIV-1

containing

K103N

Y181C

mutations

associated

with

resistance

NNRTIs

were susceptible to TAF.

HIV-1 containing mutations associated with resistance to PIs, such as M46I, I54V, V82F/T,

and L90M were susceptible to TAF.

Effects on the electrocardiogram

Bictegravir:

In a thorough QT/QTc study in 48 healthy subjects, BIC at supratherapeutic

doses of 1.5 and 6 times the recommended therapeutic dose did not affect the QT/QTc

interval and did not prolong the PR interval.

Tenofovir Alafenamide:

thorough

QT/QTc

study

healthy

subjects,

t h e r a p e u t i c

d o s e

s u p r a t h e r a p e u t i c

d o s e

ap p r o x i m at el y

t i m e s

t h e

r e c o m m en d e d

therapeutic dose did not affect the QT/QTc interval and did not prolong the PR interval.

effect of the other component, FTC, or the combination of FTC and TAF on the QT interval is

not known.

Effects on Serum Creatinine

The effect of BIC on renal function was evaluated in a randomized, blinded, parallel,

placebo-controlled trial in 40 healthy subjects who received BIC 75 mg (n = 20) or placebo

(n = 20) once daily with food for 14 days. Mean change from baseline in serum creatinine in

the BIC group was 0.1 mg per dL on Days 7 and 14. BIC did not have a clinically significant

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effect on the estimated glomerular filtration rate or on the actual glomerular filtration rate

(determined by the clearance of probe drug, iohexol) compared with placebo.

Clinical Data

The efficacy and safety of BIKTARVY in HIV-1 infected, treatment-naïve adults are based

on 48-week data from two randomized, double-blind, active-controlled studies, GS-US-380-

1489 (“Study 1489”) (N=629) and GS-US-380-1490 (“Study 1490”) (N=645).

The efficacy and safety of BIKTARVY in virologically-suppressed HIV-1 infected adults are

based on 48-week data from a randomized, double-blind, active-controlled study,

GS-US-380-1844 (“Study 1844”) (N = 563); and a randomized, open label, active-controlled

study, GS-US-380-1878 (“Study 1878”) (N=577).

The efficacy and safety of FTC + TAF (components of BIKTARVY) in HIV-1 infected,

virologically-suppressed patients with mild to moderate renal impairment is based on 144-

week data from an open-label study, Study 0112 (N=242).

The efficacy and safety of FTC+TAF (components of BIKTARVY) in adult patients

coinfected with HIV-1 and chronic hepatitis B are based on 48-week data from an open-label

study, GS-US-292-1249 (“Study 1249”) (N=72). The efficacy and safety of BIKTARVY in

adult patients coinfected with HIV-1 and chronic hepatitis B are also supported by 48-week

data in 8 HIV/HBV coinfected adults treated with BIKTARVY in Study 1490 and 8

HIV/HBV coinfected adults treated with BIKTARVY in Study 1878.

Treatment-Naïve Patients

Study 1489 and 1490

In Study 1489, patients were randomized in a 1:1 ratio to receive either BIKTARVY (N=314)

or ABC/DTG/3TC (600/50/300 mg) (N=315) once daily. In Study 1490, patients were

randomized in a 1:1 ratio to receive either BIKTARVY (N=320) or DTG + FTC/TAF

(50+200/25 mg) (N=325) once daily.

In Studies 1489 and 1490, the mean age was 35 years (range 18-77), 89% were male, 58%

were White, 33% were Black, and 3% were Asian. 24% percent of patients identified as

Hispanic/Latino. The mean baseline plasma HIV-1 RNA was 4.4 log

copies/mL (range 1.3-

6.6). The mean baseline CD4+ cell count was 460 cells/mm

(range 0-1636) and 11% had

CD4+ cell counts less than 200 cells/mm

. 18% of patients had baseline viral loads greater

than 100,000 copies/mL. In Study 1490, 14 patients had HIV/HBV coinfection and 10

patients had HIV/HCV coinfection at baseline. In Study 1489, 4 patients had HIV/HCV

coinfection at baseline. In both studies, patient randomisation were stratified by baseline

HIV-1 RNA (less than or equal to 100,000 copies/mL, greater than 100,000 copies/mL to less

than or equal to 400,000 copies/mL, or greater than 400,000 copies/mL), by CD4 count (less

than 50 cells/μL, 50-199 cells/μL, or greater than or equal to 200 cells/μL), and by region

(US or ex-US).

Treatment outcomes of Studies 1489 and 1490 through Week 48 are presented in Table 7.

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Table 7.

Pooled Virologic Outcomes of Studies 1489 and 1490 at Week 48 in

Treatment-Naïve Patients

a

BIKTARVY

(N=634)

ABC/DTG/3TC

(N=315)

DTG + FTC/TAF

(N=325)

HIV-1 RNA < 50 copies/mL

Treatment Difference (95% CI)

BIKTARVY vs. Comparator

-2.1% (-5.9% to

1.6%)

-1.9% (-5.6% to

1.8%)

HIV-1 RNA ≥ 50 copies/mL

e

No Virologic Data at Week 48

Window

Discontinued Study Drug Due to

AE or Death

<1%

Discontinued Study Drug Due to

Other Reasons and Last

Available HIV-1 RNA

<50 copies/mL

Missing Data During Window

but on Study Drug

<1%

Week 48 window was between Day 295 and 378 (inclusive).

Pooled from Study 1489 (N=314) and Study 1490 (N=320).

Study 1489

Study 1490

Includes patients who had ≥ 50 copies/mL in the Week 48 window; patients who discontinued early due to lack or loss of efficacy;

patients

discontinued

reasons

other

than

adverse

event

(AE),

death

lack

loss

ef ficacy

time

discontinuation had a viral value of ≥ 50 copies/mL.

Includes patients who discontinued due to AE or death at any time point from Day 1 through the time window if this resulted in no

virologic data on treatment during the specified window.

Includes

patients

discontinued

reasons

other

than

death

lack

loss

efficacy,

e.g.,

withdrew

consent,

loss

follow-up, etc.

BIKTARVY was

noninferior

achieving

HIV-1

< 50

copies/mL

Week

when

compared

ABC/DTG/3TC

DTG+FTC/TAF,

respectively.

Treatment

outcomes

were

similar among treatment groups across subgroups by age, sex, race, baseline viral load, and

baseline CD4+ cell count.

In Studies 1489 and 1490, the mean increase from baseline in CD4+ count at Week 48 was

207, 229, and 201 cells per mm

in the pooled BIKTARVY, ABC/DTG/3TC, and

DTG+FTC/TAF groups, respectively.

Bone Mineral Density:

In Study 1489, bone mineral density (BMD) change from baseline to

Week 48 was assessed by dual-energy X-ray absorptiometry (DXA). In patients who had

both baseline and Week 48 hip and lumbar spine BMD measurements (N= 257 and 267 in the

BIKTARVY group and N= 270 and 274 in the ABC/DTG/3TC group, for hip and lumbar

spine, respectively), mean percentage changes in BMD were similar in the BIKTARVY

group compared to the ABC/DTG/3TC group for hip (−0.8% vs. −1.0%) and lumbar spine

(−0.8% vs.−0.6%).

Patients Coinfected with HIV-1 and Chronic Hepatitis B:

In Study 1490, 7 of 8 patients

with HIV/HBV coinfection at baseline who were randomized to receive BIKTARVY were

HBV suppressed (HBV DNA < 29 IU/mL) and had HIV-1 RNA <50 copies/mL at Week 48.

One patient had missing HBV DNA data at Week 48.

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Virologically-Suppressed Patients

Study 1844 and Study 1878

In Study 1844, the efficacy and safety of switching from a regimen of DTG + ABC/3TC or

ABC/DTG/3TC to BIKTARVY were evaluated in a randomized, double-blind study of

virologically-suppressed (HIV-1 RNA <50 copies/mL) HIV-1 infected adults (N=563).

Patients must have been stably suppressed (HIV-1 RNA <50 copies/mL) on their baseline

regimen for at least 3 months prior to study entry. Patients were randomized in a 1:1 ratio to

either switch to BIKTARVY at baseline (N=282), or stay on their baseline antiretroviral

regimen (N=281). Patients had a mean age of 45 years (range 20-71), 89% were male, 73%

were White, and 22% were Black. 17% of patients identified as Hispanic/Latino. The mean

baseline CD4+ cell count was 723 cells/mm

(range 124-2444).

In Study 1878, the efficacy and safety of switching from either ABC/3TC or FTC/TDF

(200/300 mg) plus ATV or DRV (boosted by either COBI or RTV) to BIKTARVY were

evaluated in a randomized, open-label study of virologically-suppressed HIV-1 infected

adults (N=577). Patients must have been stably suppressed on their baseline regimen for at

least 6 months and must not have been previously treated with any INSTI. Patients were

randomized in a 1:1 ratio to either switch to BIKTARVY (N=290), or stay on their baseline

antiretroviral regimen (N=287). Patients had a mean age of 46 years (range 20-79), 83% were

male, 66% were White, and 26% were Black. 19% of patients identified as Hispanic/Latino.

The mean baseline CD4+ cell count was 663 cells/mm

(range 62-2582). Patients were

stratified by prior treatment regimen. At screening, 15% of patients were receiving ABC/3TC

plus ATV or DRV (boosted by either COBI or RTV) and 85% of patients were receiving

FTC/TDF plus ATV or DRV (boosted by either COBI or RTV).

Treatment outcomes of Studies 1844 and 1878 through Week 48 are presented in Table 8.

Table 8.

Virologic Outcomes of Studies 1844 and 1878 at Week 48

a

Study 1844

Study 1878

BIKTARVY

(N=282)

ABC/DTG/3TC

(N=281)

BIKTARVY

(N=290)

Baseline ATV- or

DRV-based

regimen (N=287)

HIV-1 RNA < 50 copies/mL

Treatment Difference

(95% CI)

-1.4% (-5.5% to 2.6%)

3.2% (-1.6% to 8.2%)

HIV-1 RNA ≥ 50 copies/mL

b

<1%

Treatment Difference

(95% CI)

0.7% (-1.0% to 2.8%)

0.0% (-2.5% to 2.5%)

No Virologic Data at Week

48 Window

Discontinued Study Drug

Due to AE or Death and

Last Available HIV-1 RNA

< 50 copies/mL

Discontinued Study Drug

Due to Other Reasons and

Last Available HIV-1 RNA

< 50 copies/mL

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Study 1844

Study 1878

BIKTARVY

(N=282)

ABC/DTG/3TC

(N=281)

BIKTARVY

(N=290)

Baseline ATV- or

DRV-based

regimen (N=287)

Missing Data During

Window but on Study Drug

Week 48 window was between Day 295 and 378 (inclusive).

Includes patients who had ≥ 50 copies/mL in the Week 48 window; patients who discontinued early due to lack or loss of efficacy;

patients who discontinued for reasons other than lack or loss of efficacy and at the time of discontinuation had a viral value of ≥ 50

copies/mL.

Includes

patients

discontinued

reasons

other

than

death

lack

loss

efficacy,

e.g.,

withdrew

consent,

loss

follow-up, etc.

Study

1844,

Week

switching

BIKTARVY was

noninferior to

remaining

ABC/DTG/3TC.

percentages

patients

with

HIV-1 RNA ≥ 50 copies/mL and who

m a i n t a i n e d

H I V - 1

R N A

<

c o p i e s / m L

w e r e

s i m i l a r

b e t w e e n

t h e

BIKTARVY

ABC/DTG/3TC

groups.

Treatment

outcomes

between

treatment

groups

were

similar

across

subgroups by age, sex, race, baseline viral load, and baseline CD4+ count. The mean change

from baseline in CD4+ count at Week 48 was -31 cells per mm

in patients who switched to

BIKTARVY and 4 cells per mm

in patients who stayed on ABC/DTG/3TC.

Bone Mineral Density

: In Study 1844, BMD change from baseline to Week 48 was assessed

by DXA. In patients who had both baseline and Week 48 hip and lumbar spine BMD

measurements (N=229 and 233 in the BIKTARVY group and N=242 and 244 in the

ABC/DTG/3TC group, for hip and lumbar spine, respectively), mean percentage increases in

BMD were similar in the BIKTARVY group compared to the ABC/DTG/3TC group for hip

(0.2% vs. 0.3%) and lumbar spine (0.7% vs.0.4%).

Study

1878,

Week

switching

BIKTARVY was

noninferior

remaining

ATV- or DRV-based regimen. The percentages of patients with HIV-1 RNA ≥ 50 copies/mL

and who maintained HIV-1 RNA < 50 copies/mL were similar between the BIKTARVY and

ATV- or

DRV-based

regimen

groups.

Treatment

outcomes

between

treatment

groups

were

similar across subgroups by age, sex, race, baseline viral load, and baseline CD4+ count. The

mean change from baseline in CD4+ count at Week 48 was 25 cells per mm

in patients who

switched

BIKTARVY and

cel l s

p er

pat i ent s

s t a yed

their

baseline

regimen.

Patients Coinfected with HIV-1 and Chronic Hepatitis B

: In Study 1878, at Week 48, 100%

(8/8) of the patients coinfected with HIV/HBV at baseline in the BIKTARVY maintained

HBV DNA < 29 IU/mL (missing = excluded analysis) and HIV RNA < 50 copies/mL.

NEW ZEALAND DATA SHEET

BIKTARVY Data Sheet v1.0 (15 August 2019)

Page 24

5.2

Pharmacokinetic properties

The pharmacokinetic (PK) properties of BIKTARVY components are provided in Table 9.

Table 9.

Pharmacokinetic Properties of the Components of BIKTARVY

Bictegravir (BIC)

Emtricitabine (FTC)

Tenofovir

Alafenamide (TAF)

Absorption

2.0–4.0

1.5–2.0

0.5–2.0

Effect of high-fat

meal

(relative to

fasting)

AUC ratio

1.24 (1.16, 1.33)

0.96 (0.93, 0.99)

1.63 (1.43, 1.85)

ratio

1.13 (1.06, 1.20)

0.86 (0.78, 0.93)

0.92 (0.73, 1.14)

Distribution

% bound to human plasma

proteins

>99

<4

Blood-to-plasma ratio

0.64

Elimination

17.3 (14.8, 20.7)

10.4 (9.0, 12.0)

0.51 (0.45, 0.62)

Metabolism

Metabolic pathway(s)

CYP3A

UGT1A1

Not significantly

metabolized

Cathepsin A

(PBMCs)

CES1 (hepatocytes)

Excretion

Major route of elimination

Metabolism

Glomerular filtration and

active tubular secretion

Metabolism

% of dose excreted in urine

<1

% of dose excreted in feces

60.3

13.7

31.7

PBMCs=peripheral blood mononuclear cells; CES1=carboxylesterase 1

a. Values reflect administration of BIKTARVY with or without food.

b. Values refer to geometric mean ratio [high-fat meal/ fasting] in PK parameters and (90% confidence interval). High fat

meal is approximately 800 kcal, 50% fat.

values refer to median (Q1, Q3) terminal plasma half-life. Note that the active metabolite of TAF, tenofovir

diphosphate, has a half-life of 150-180 hours within PBMCs.

In vivo

, TAF is hydrolyzed within cells to form tenofovir (major metabolite), which is phosphorylated to the active

metabolite, tenofovir diphosphate.

In vitro

studies have shown that TAF is metabolized to tenofovir by cathepsin A in

PBMCs and macrophages; and by CES1 in hepatocytes.

e. Dosing in mass balance studies: single dose administration of [

C] BIC; single dose administration of [

C] FTC after

multiple dosing of FTC for ten days; single dose administration of [

C] TAF.

T h e

m u l t i p l e

d o s e

p h a r m a c o k i n e t i c

p a r a m e t e r s

t h e

c o m p o n e n t s

BIKTARVY

provided in Table 10.

NEW ZEALAND DATA SHEET

BIKTARVY Data Sheet v1.0 (15 August 2019)

Page 25

Table 10.

Multiple Dose PK Parameters of BIC, FTC, and TAF Following Oral

Administration of BIKTARVY With or Without Food in HIV-Infected

Adults

Parameter

Mean (%CV)

BIC

a

FTC

b

TAF

c

(microgram/mL)

6.15 (22.9)

2.13 (34.7)

0.121(15.4)

(microgram.h/mL)

102 (26.9)

12.3 (29.2)

0.142 (17.3)

trough

(microgram/mL)

2.61 (35.2)

0.096 (37.4)

CV=Coefficient of Variation; NA = Not Applicable

a. From Population PK analysis in Studies 1489, 1490, 1844, and 1878; N=1193.

b. From Intensive PK analysis in Studies 1489, 1490, 1844, and 1878; N=77.

c. From Population PK analysis in Studies 1489 and 1490; N=486.

Special Populations

Age, Gender, and Ethnicity

Population analyses using pooled pharmacokinetic data from adult trials did not identify any

clinically relevant differences due to age, gender or race on the exposures of BIC, FTC, or

TAF.

Patients with Impaired Renal Function

dose

adjustment

BIKTARVY is

required

adult

patients

with

estimated

creatinine

clearance greater than or equal to 30 mL per minute.

Initiation of BIKTARVY is not recommended in patients with estimated creatinine clearance

below 30 mL per minute as there are insufficient data available regarding the use of

BIKTARVY in this population.

Patients with Hepatic Impairment

Bictegravir:

Clinically relevant changes in the pharmacokinetics of BIC were not observed in

subjects with moderate hepatic impairment.

Emtricitabine

: The

pharmacokinetics

been

studied

subjects

with

hepatic

impairment; however, FTC is not significantly metabolized by liver enzymes, so the impact

of liver impairment should be limited.

Tenofovir Alafenamide

Clinically

relevant

changes

pharmacokinetics

metabolite

tenofovir

were

observed

patients

with

mild,

moderate,

severe

hepatic

impairment; no TAF dose adjustment is required in patients with hepatic impairment.

NEW ZEALAND DATA SHEET

BIKTARVY Data Sheet v1.0 (15 August 2019)

Page 26

Hepatitis B and/or Hepatitis C Virus Co-infection

Pharmacokinetics of BIC, FTC and TAF have not been fully evaluated in hepatitis B and/or C

co-infected patients.

5.3

Preclinical safety data

Genotoxicity

No genotoxicity studies have been conducted with BIC, FTC and TAF in combination.

Bictegravir:

BIC was not mutagenic in bacteria or clastogenic in human lymphocytes in vitro

and in a rat micronucleus test in vivo

Emtricitabine:

was not mutagenic in bacteria or mouse lymphoma cell assays

in vitro

nor clastogenic in the mouse micronucleus test

in vivo

Tenofovir Alafenamide:

TAF was not genotoxic in the reverse mutation bacterial test (Ames

test), mouse lymphoma or rat micronucleus assays.

Carcinogenicity

No carcinogenicity studies have been conducted with BIC, FTC and TAF in combination.

Bictegravir:

BIC was not carcinogenic in a 6-month rasH2 transgenic mouse study at doses

of up to 100 mg/kg/day in males and 300 mg/kg/day in females, respectively. This resulted in

exposures of approximately 15 (males) and 23 (females) timesthe exposure in humans at the

recommended dose. Bictegravir was also not carcinogenic in a 104 week rat study at doses up

to 300 mg/kg/day. This resulted in an exposure of approximately 31 times the exposure in

humans at the recommended dose.

Emtricitabine:

In long-term oral carcinogenicity studies conducted with FTC, 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).

Tenofovir Alafenamide:

Because there is a lower tenofovir exposure in rats and mice after

TAF administration compared to TDF, carcinogenicity studies were conducted only with

TDF. Long-term oral carcinogenicity studies of TDF in mice and rats were carried out at

exposures up to approximately 10 times (mice) and 4 times (rats) those observed in humans

at the 300 mg therapeutic dose of TDF for HIV-1 infection. At the high dose in female mice,

liver adenomas were increased at tenofovir exposures 10 times (300 mg TDF) and 151 times

(BIKTARVY) the exposure observed in humans. In rats, the study was negative for

carcinogenic findings.

NEW ZEALAND DATA SHEET

BIKTARVY Data Sheet v1.0 (15 August 2019)

Page 27

6 PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Tablet core

Croscarmellose sodium

Magnesium stearate

Microcrystalline cellulose

Film-coating

Iron oxide black

Iron oxide red

Polyethylene glycol

Polyvinyl alcohol

Talc

Titanium dioxide

6.2

Incompatibilities

Not applicable

6.3

Shelf life

2 years

6.4

Special precautions for storage

BIKTARVY should be stored below 30 °C.

6.5

Nature and contents of container

BIKTARVY tablets are supplied in white, high density polyethylese (HDPE) bottles with a

polypropylene continuous-thread, child resistant cap, lined with an induction activated

aluminium foil liner. Each bottle contains 30 tablets and silica gel desiccant and polyester

coil.

6.6

Special precautions for disposal

Any unused medicine or waste material should be disposed of in accordance with local

requirements.

7 MEDICINE SCHEDULE

Prescription Medicine

NEW ZEALAND DATA SHEET

BIKTARVY Data Sheet v1.0 (15 August 2019)

Page 28

8 SPONSOR

Gilead Sciences (NZ)

c/- Grant Thornton New Zealand Limited

Level 4, 152 Fanshawe Street

Auckland Central, Auckand1010

New Zealand

Tel: 0800 443 933

9 DATE OF FIRST APPROVAL

15 August 2019

10 DATE OF REVISION OF THE TEXT

Not applicable

BIKTARVY, DESCOVY, GENVOYA, GILEAD, GSI, and TRUVADA are registered trademarks of Gilead

Sciences, Inc., or its related companies. All other trademarks referenced herein are the property of their

respective owners.

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