CIPLA TENOFOVIR + EMTRICITABINE 300/200 Tenofovir disoproxil fumarate 300 mg and emtricitabine 200 mg tablet bottle pack

Australia - English - Department of Health (Therapeutic Goods Administration)

Buy It Now

Active ingredient:
emtricitabine,tenofovir disoproxil fumarate
Available from:
Cipla Australia Pty Ltd
Authorization status:
Registered
Authorization number:
327898

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CIPLA TENOFOVIR + EMTRICITABINE 300/200

Tablets

300 mg tenofovir disoproxil fumarate / 200 mg emtricitabine

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

CIPLA TENOFOVIR +

EMTRICITABINE 300/200.

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

CIPLA TENOFOVIR +

EMTRICITABINE 300/200

medicine. You may need to

read it again.

What CIPLA

TENOFOVIR +

EMTRICITABINE

300/200 is used for

What is it used for

to treat Human

Immunodeficiency

Virus-1 (HIV-1)

infection in adults when

taken in combination

with other anti-HIV

medicines;

to help reduce the risk

of getting HIV infection

when used with safer

sex practices in:

HIV-negative men

who have sex with

men, who are at

high risk of getting

infected with HIV-1

through sex.

Male-female sex

partners when one

partner has HIV-1

infection and the

other does not.

How CIPLA TENOFOVIR

+ EMTRICITABINE

300/200 works

CIPLA TENOFOVIR +

EMTRICITABINE 300/200

consists of two medicines

combined in one tablet:

tenofovir disoproxil

fumarate, also called

tenofovir DF

emtricitabine or FTC

These are combined in one

tablet to help control Human

Immunodeficiency Virus

(HIV) infection.

CIPLA TENOFOVIR +

EMTRICITABINE 300/200

contains two active

ingredients that belong to a

group of antiviral medicines

known as nucleoside and

nucleotide reverse

transcriptase inhibitors

(NRTI).

When CIPLA

TENOFOVIR +

EMTRICITABINE 300/200

is used to treat HIV

infection

When used with other HIV-

1 medicines to treat HIV-1

infection, CIPLA

TENOFOVIR +

EMTRICITABINE 300/200

may help:

Reduce the amount of

HIV-1 in your blood.

This is called “viral

load”.

Increase the number of

CD4+ (T) cells in your

blood that help fight off

other infections.

Reducing the amount of

HIV-1 and increasing the

CD4+ (T) cells in your

blood may help improve

your immune system.

This may reduce your risk of

death or infections that can

happen when your immune

system is weak.

Use in Children and

Elderly

CIPLA TENOFOVIR +

EMTRICITABINE 300/200

is for adults.

Do not take CIPLA

TENOFOVIR +

EMTRICITABINE 300/200

if you are under the age of

18 years.

Do not take CIPLA

TENOFOVIR +

EMTRICITABINE 300/200

if you are over the age of 65

before discussing with your

doctor.

Does CIPLA

TENOFOVIR +

EMTRICITABINE

300/200 cure HIV OR

AIDS

CIPLA TENOFOVIR +

EMTRICITABINE

300/200 is not a cure for

HIV infection or AIDS.

While taking CIPLA

TENOFOVIR +

EMTRICITABINE

300/200 you may still

develop infections or other

illnesses associated with

HIV infection.

If you have HIV-1

infection, you must keep

taking HIV-1 medicines to

control HIV-1 infection

and decrease HIV-related

illnesses.

Does CIPLA

TENOFOVIR +

EMTRICITABINE

300/200 reduce the risk of

passing HIV to others

CIPLA TENOFOVIR +

EMTRICITABINE

300/200 does not reduce

the risk of passing HIV to

others through sexual

contact or blood

contamination.

It is important to continue to

take appropriate precautions

to prevent passing HIV to

others.

When CIPLA

TENOFOVIR +

EMTRICITABINE 300/200

is used to reduce the risk of

HIV infection

When used with safer sex

practices, CIPLA

TENOFOVIR +

EMTRICITABINE 300/200

may help to reduce the risk

of getting HIV-1 infection if

you are at high risk of

getting HIV infection.

CIPLA TENOFOVIR +

EMTRICITABINE 300/200

reduces the risk of getting

HIV-1 when you have been

taking it

before

you are

exposed to HIV-1.

Before you take CIPLA

TENOFOVIR +

EMTRICITABINE

300/200

When you must not take it

Together with your doctor,

you need to decide

whether CIPLA

TENOFOVIR +

EMTRICITABINE

300/200 is right for you.

Do not take CIPLA

TENOFOVIR +

EMTRICITABINE

300/200 if you are allergic

to:

tenofovir

tenofovir DF

any of the other

ingredients of CIPLA

TENOFOVIR +

EMTRICITABINE

300/200

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 CIPLA

TENOFOVIR +

EMTRICITABINE

300/200 are listed in the

product description

section of this leaflet.

Do not take CIPLA

TENOFOVIR +

EMTRICITABINE

300/200 if you are already

taking any of the

components of CIPLA

TENOFOVIR +

EMTRICITABINE

300/200 (tenofovir DF or

emtricitabine).

Do not take CIPLA

TENOFOVIR +

EMTRICITABINE

300/200 if you are taking

lamivudine.

Do not take CIPLA

TENOFOVIR +

EMTRICITABINE

300/200 if you are taking

adefovir dipivoxil.

Do not take CIPLA

TENOFOVIR +

EMTRICITABINE

300/200 if you are taking

tenofovir alafenamide.

Do not take CIPLA

TENOFOVIR +

EMTRICITABINE

300/200 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 CIPLA

TENOFOVIR +

EMTRICITABINE

300/200 if the packaging is

torn or shows signs of

tampering.

If you are not sure

whether you should be

taking CIPLA

TENOFOVIR +

EMTRICITABINE

300/200, talk to your

doctor.

For people using CIPLA

TENOFOVIR +

EMTRICITABINE 300/200

to reduce the risk of getting

HIV-1 infection:

CIPLA TENOFOVIR +

EMTRICITABINE 300/200

can only help reduce your

risk of getting HIV-1 before

you are infected.

Do not take CIPLA

TENOFOVIR +

EMTRICITABINE

300/200 to help reduce

your risk of getting HIV-1

if:

you already have HIV-1

infection. If you are

HIV-positive, you need

to take other medicines

with CIPLA

TENOFOVIR +

EMTRICITABINE

300/200 to treat HIV.

CIPLA TENOFOVIR +

EMTRICITABINE

300/200 by itself is not a

complete treatment for

HIV.

you do not know your

HIV-1 infection status.

You may already be

HIV-positive. You need

to take other HIV-1

medicines with CIPLA

TENOFOVIR +

EMTRICITABINE

300/200 to treat HIV-1.

Many HIV-1 tests can

miss HIV-1 infection in

a person who has

recently become

infected. If you have

flu-like symptoms, you

could have recently

become infected with

HIV-1. Tell your

healthcare provider if

you had a flu-like illness

within the last month

before starting CIPLA

TENOFOVIR +

EMTRICITABINE

300/200 or at any time

while taking CIPLA

TENOFOVIR +

EMTRICITABINE

300/200. Symptoms of

new HIV-1 infection

include: tiredness, fever,

joint or muscle aches,

headache, sore throat,

vomiting or diarrhoea,

rash, night sweats or

enlarged lymph nodes in

the neck or groin.

Before you start to take it

Tell your doctor if you are

allergic to foods, dyes,

preservatives or any other

medicines.

Tell your doctor if you are

pregnant, trying to become

pregnant or breast

feeding.

The safe use of CIPLA

TENOFOVIR +

EMTRICITABINE

300/200 in pregnancy has

not been demonstrated.

For this reason, it is

important that women of

child-bearing age receiving

treatment with CIPLA

TENOFOVIR +

EMTRICITABINE

300/200 use an effective

method of contraception to

avoid becoming pregnant

If you are a female who is

taking CIPLA TENOFOVIR

+ EMTRICITABINE

300/200 to reduce the risk of

getting HIV-1 infection and

you become pregnant while

taking CIPLA TENOFOVIR

+ EMTRICITABINE

300/200, talk to your

healthcare provider to

decide if you should keep

taking CIPLA TENOFOVIR

+ EMTRICITABINE

300/200.

The active substances in this

medicine (tenofovir

disoproxil fumarate and

emtricitabine) have been

found in breast milk at low

concentrations.

Consequently, it is

recommended that nursing

mothers do not breast-feed

during treatment with

CIPLA TENOFOVIR +

EMTRICITABINE 300/200.

In general, women infected

with HIV should not breast-

feed their infants in order to

avoid transmission of HIV

to their newborn infant.

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,

sofosbuvir/velpatasvir).

Tell your doctor if you

have kidney problems.

Tell your doctor if you

have or have ever had

abnormal bones or bone

difficulties.

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

CIPLA TENOFOVIR +

EMTRICITABINE

300/200 it is important you

remain under the care of a

hospital or doctor who

specialises in the treatment

of HIV infection.

Avoid doing things that

increase your risk of getting

HIV-1 or spreading HIV-1

to other people:

Do not have any kind of

sex without protection.

Always practice safer

sex. Use latex or non-

latex condoms, except

lambskin, to reduce

contact with semen,

vaginal fluids, or blood.

Do not share personal

items that can have

blood or body fluids on

them, such as

toothbrushes and razor

blades.

Do not share or re-use

needles or other

injection equipment.

Ask your healthcare

provider if you have any

questions about how to

prevent getting HIV-1 or

spreading HIV-1 to other

people.

If you have a long standing

viral infection of your liver

(hepatitis B) it may flare

up when you stop taking

CIPLA TENOFOVIR +

EMTRICITABINE

300/200.

This can cause serious

illness particularly if your

liver is already not working

very well. If you have both

HIV and hepatitis B, when

you start taking CIPLA

TENOFOVIR +

EMTRICITABINE 300/200

and even after you stop,

your doctor is likely to

arrange tests from time to

time to check how well your

liver is working.

CIPLA TENOFOVIR +

EMTRICITABINE

300/200 contains Lactose

Monohydrate

This medicine also contains

lactose monohydrate. If you

have been told by your

doctor that you have an

intolerance to some sugars

(e.g. lactose), talk to your

doctor before taking this

medicine.

Taking other medicines

If you have HIV infection

your doctor will generally

prescribe CIPLA

TENOFOVIR +

EMTRICITABINE

300/200 in combination

with other anti-HIV

medicines.

Tell your doctor if you are

taking any other

medicines, including

medicines you buy without

a prescription from a

pharmacy, supermarket or

health food shop.

Tell your doctor if are

taking:

didanosine (also known

as ddI).

ledipasvir/sofosbuvir

sofosbuvir/velpatasvir

sofosbuvir/velpatasvir/v

oxilaprevir

Some medicines may affect

the way others work. Your

doctor or pharmacist will be

able to tell you what to do

when taking CIPLA

TENOFOVIR +

EMTRICITABINE 300/200

tablets with other medicines.

How to take CIPLA

TENOFOVIR +

EMTRICITABINE

300/200

Take CIPLA

TENOFOVIR +

EMTRICITABINE

300/200 exactly as

prescribed. The usual dose

is one CIPLA

TENOFOVIR +

EMTRICITABINE

300/200 tablet orally once

daily. Take CIPLA

TENOFOVIR +

EMTRICITABINE

300/200 at the same time

each day to keep CIPLA

TENOFOVIR +

EMTRICITABINE

300/200 blood levels

constant.

CIPLA TENOFOVIR +

EMTRICITABINE

300/200 is absorbed

rapidly. Do not take

another CIPLA

TENOFOVIR +

EMTRICITABINE

300/200 dose if vomiting

has occurred unless it

occurs within 1 hour after

taking CIPLA

TENOFOVIR +

EMTRICITABINE

300/200.

How much to take

Take one CIPLA

TENOFOVIR +

EMTRICITABINE

300/200 tablet once daily

or as advised by your

doctor.

If you are not sure how

much CIPLA TENOFOVIR

+ EMTRICITABINE

300/200 you should take,

check with your doctor or

pharmacist. Do not change

the amount of CIPLA

TENOFOVIR +

EMTRICITABINE 300/200

you take unless told to do so

by your doctor.

Your doctor will tell you

how much CIPLA

TENOFOVIR +

EMTRICITABINE 300/200

to take and how often to

take it. You will also find

this information on the label

of your medicine container.

Because your medicine

helps to control your

condition, but does not

cure it, you will need to

take CIPLA TENOFOVIR

+ EMTRICITABINE

300/200 every day. If you

are taking CIPLA

TENOFOVIR +

EMTRICITABINE

300/200 to reduce the risk

of HIV-1 infection, take

CIPLA TENOFOVIR +

EMTRICITABINE

300/200 every day for the

period of time as

prescribed by your doctor.

Do not miss any doses of

CIPLA TENOFOVIR +

EMTRICITABINE

300/200. Missing a dose

lowers the amount of

medicine in your blood.

Do not stop taking CIPLA

TENOFOVIR +

EMTRICITABINE

300/200 without first

talking to your doctor.

When to take it

CIPLA TENOFOVIR +

EMTRICITABINE 300/200

is best taken with a meal or

just afterwards, however

taking it without food

should not reduce the

effectiveness of the

medicine.

If you forget to take CIPLA

TENOFOVIR +

EMTRICITABINE 300/200

It is important to take the

prescribed daily dose in

order to get the maximum

benefit of treatment.

If you forget to take your

daily dose of CIPLA

TENOFOVIR +

EMTRICITABINE 300/200,

take it as soon as you

remember that day, and then

go back to taking your

medicine as you would

normally.

Do not take a double dose

to make up for a forgotten

dose.

Do not take more than one

CIPLA TENOFOVIR +

EMTRICITABINE

300/200 tablet in a day.

If you take too much

(overdose)

Immediately telephone

your doctor or Poisons

Information Centre

(telephone 13 11 26) for

advice, or go to the

accident and emergency

department at your

nearest hospital if you

think you or anyone else

may have taken too many

CIPLA TENOFOVIR +

EMTRICITABINE

300/200 tablets. Do this

even if there are no signs

of discomfort or poisoning.

This may need urgent

medical attention.

While you are taking

CIPLA TENOFOVIR +

EMTRICITABINE

300/200

Things you must do

Tell your doctor or

pharmacist that you are

taking CIPLA

TENOFOVIR +

EMTRICITABINE

300/200 if you are about to

be started on any other

medicines.

Tell your doctor if you

become pregnant or are

trying to become pregnant.

Tell your doctor if for any

reason you have not taken

your medicine exactly as

prescribed.

If you are taking CIPLA

TENOFOVIR +

EMTRICITABINE 300/200

to reduce your risk of

getting HIV

Just taking CIPLA

TENOFOVIR +

EMTRICITABINE

300/200 may not keep you

from getting HIV.

You must continue using

safer sex practices while

you are taking CIPLA

TENOFOVIR +

EMTRICITABINE

300/200 to reduce your

risk of getting HIV.

You must stay HIV-

negative to keep taking

CIPLA TENOFOVIR +

EMTRICITABINE

300/200 to reduce your

risk of infection.

Know your HIV status and

the HIV status of your

partners.

Get tested for HIV at least

every 3 months or when

your healthcare provider

tells you.

Get tested for other sexually

transmitted infections such

as syphilis and gonorrhea.

These infections make it

easier for HIV to infect you.

CIPLA TENOFOVIR +

EMTRICITABINE 300/200

will not stop you from

getting these other

infections.

If you think you were

exposed to HIV, tell your

healthcare provider right

away. They may want to do

more tests to be sure you are

still HIV-negative.

Get information and support

to help reduce risky sexual

behaviour.

Have fewer sex partners.

Do not miss any doses of

CIPLA TENOFOVIR +

EMTRICITABINE

300/200. Missing doses

may increase your risk of

getting HIV infection.

If you do become HIV-

positive, you need more

medicine than CIPLA

TENOFOVIR +

EMTRICITABINE 300/200

alone to treat HIV. CIPLA

TENOFOVIR +

EMTRICITABINE 300/200

by itself is not a complete

treatment for HIV.

If you have HIV and take

only CIPLA TENOFOVIR

+ EMTRICITABINE

300/200, over time your

HIV may become harder to

treat.

Things you must not do

Do not stop taking CIPLA

TENOFOVIR +

EMTRICITABINE

300/200 or change the dose

without first checking with

your doctor.

Do not give this medicine

to anyone else even if their

symptoms seem similar to

yours.

Do not use CIPLA

TENOFOVIR +

EMTRICITABINE

300/200 to treat any other

complaints unless you

doctor says to.

Things to be careful of

Be careful driving or

operating machinery until

you know how CIPLA

TENOFOVIR +

EMTRICITABINE

300/200 affects you.

SIDE EFFECTS

Like all medicines, CIPLA

TENOFOVIR +

EMTRICITABINE 300/200

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 CIPLA

TENOFOVIR +

EMTRICITABINE

300/200, even if you do not

think the problems are

connected with the

medicine or are not listed

in this leaflet.

The most common side

effects in people taking

tenofovir disoproxil

fumarate/emtricitabine to

treat HIV-1 infection

include:

diarrhoea

nausea

tiredness

headache

dizziness

depression

problems sleeping

abnormal dreams

rash

Common side effects in

people who take tenofovir

disoproxil

fumarate/emtricitabine to

reduce the risk of getting

HIV-1 infection include:

stomach-area (abdomen)

pain

headache

decreased weight

Ask your doctor or

pharmacist to answer any

question you may have

about these or other effects.

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 CIPLA

TENOFOVIR +

EMTRICITABINE

300/200 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. All of these

side effects are very rare.

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.

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

Nausea

Stomach-area pains

These side effects may be

due to a condition called

hepatotoxicity with liver

enlargement and fat deposits

in the liver (steatosis) which

sometimes occurs in patients

taking anti-HIV medicines.

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.

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

CIPLA TENOFOVIR +

EMTRICITABINE 300/200,

for a long time.

Hepatic Flares

Your doctor should test

you to see if you have

chronic hepatitis B

infection before you start

taking CIPLA

TENOFOVIR +

EMTRICITABINE

300/200.

If you have chronic

hepatitis B infection you

should not stop your

CIPLA TENOFOVIR +

EMTRICITABINE

300/200 treatment without

first discussing this with

your doctor, as some

patients have had blood

tests or symptoms

indicating a worsening of

their hepatitis (“hepatic

flare”) after stopping

individual components

(tenofovir disoproxil

fumarate and

emtricitabine) of CIPLA

TENOFOVIR +

EMTRICITABINE

300/200.

You may require medical

exams and blood tests for

several months after

stopping treatment.

CIPLA TENOFOVIR +

EMTRICITABINE 300/200

is not approved for the

treatment of hepatitis B, so

you must discuss your

hepatitis B therapy with

your healthcare provider.

Other possible side effects

This list of side effects is not

complete.

CIPLA TENOFOVIR +

EMTRICITABINE 300/200

may cause other serious side

effects. Tell your doctor if

you notice anything else that

is making you feel unwell,

even if it is not on this list.

New and worse kidney

problems

If you have had kidney

problems in the past or need

to take another drug that can

cause kidney problems, your

healthcare provider may

need to perform additional

blood tests to check your

kidneys.

Bone problems

Bone problems can happen

in some people who take

tenofovir disoproxil

fumarate/emtricitabine.

Bone problems include bone

pain, or softening or

thinning of bones, which

may lead to fractures. Your

healthcare provider may

need to do tests to check

your bones.

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.

Some people may get other

side effects while taking

CIPLA TENOFOVIR +

EMTRICITABINE 300/200.

If you are concerned, talk to

your doctor or pharmacist.

Ask your doctor or

pharmacist if you don’t

understand anything in

this list.

Do not be alarmed by this

list of possible side-effects.

Most of them are very rare

and you may not experience

any of them.

Reporting of side effects

If you get any side effects,

talk to your doctor,

pharmacist or nurse. This

includes any possible side

effects not listed in this

leaflet. You can also report

side effects directly at

http://www.tga.gov.au/repor

ting-problems. By reporting

side effects you can help

provide more information on

the safety of this medicine.

After taking CIPLA

TENOFOVIR +

EMTRICITABINE

300/200

Storage

Keep CIPLA

TENOFOVIR +

EMTRICITABINE

300/200 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 CIPLA

TENOFOVIR +

EMTRICITABINE

300/200 tablets in a cool,

dry place where it stays

below 30°C.

Discard any remaining

product 30 days after first

opening of the bottle.

Do not store CIPLA

TENOFOVIR +

EMTRICITABINE

300/200 or any other

medicine in a bathroom or

near a sink.

Do not leave CIPLA

TENOFOVIR +

EMTRICITABINE

300/200 in the car or on a

window sill.

Heat and dampness can

destroy some medicines.

Keep your CIPLA

TENOFOVIR +

EMTRICITABINE

300/200 tablets in the

bottle with the cap tightly

closed until you take them.

If you take CIPLA

TENOFOVIR +

EMTRICITABINE 300/200

tablets out of their pack they

may not keep well.

Disposal

If your doctor tells you to

stop taking CIPLA

TENOFOVIR +

EMTRICITABINE 300/200,

or the tablets have passed

their expiry date, ask your

pharmacist what to do with

any tablets left over.

PRODUCT

DESCRIPTION

What the tablets look like

CIPLA TENOFOVIR +

EMTRICITABINE 300/200

tablets are blue coloured

capsule shaped, biconvex

film coated tablet, plain on

both sides.

CIPLA TENOFOVIR +

EMTRICITABINE 300/200

tablets are supplied in

bottles containing 30 tablets.

Ingredients

Each CIPLA TENOFOVIR

+ EMTRICITABINE

300/200 tablet contains the

following active ingredients:

300 mg tenofovir

disoproxil fumarate

equivalent to tenofovir

disproxil 245 mg

200 mg emtricitabine

Each CIPLA TENOFOVIR

+ EMTRICITABINE

300/200 tablet also contains

the following inactive

ingredients:

croscarmellose sodium

lactose monohydrate

magnesium stearate

microcrystalline

cellulose

pregelatinised starch

Film-coating:

hypromellose

indigo carmine

aluminium lake

lactose monohydrate

titanium dioxide

triacetin

SPONSOR

CIPLA TENOFOVIR +

EMTRICITABINE

300/200 tablets are

supplied in

Australia by:

Cipla Australia Pty Ltd.,

Level 1 / 132-136 Albert

road, South Melbourne Vic

3205

Australian Registration

Number

AUST R 327898

Date of preparation

This leaflet was prepared in

03/2021.

Read the complete document

AUSTRALIA PRODUCT INFORMATION – CIPLA TENOFOVIR + EMTRICITABINE

300/200

(Tenofovir disoproxil fumarate and emtricitabine) tablets

1.

NAME OF THE MEDICINE

Tenofovir disoproxil fumarate/Emtricitabine

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 300 mg tenofovir disoproxil fumarate which is equivalent to 245 mg

of tenofovir disoproxil and 200 mg emtricitabine.

Excipients with known effect: lactose.

For the full list of excipients, see section 6.1 List of excipients.

3.

PHARMACEUTICAL FORM

Film-coated tablets.

The tablets are blue, coloured capsule shaped, biconvex film-coated tablet, plain on both sides.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Treatment of HIV-1 infection

CIPLA TENOFOVIR + EMTRICITABINE 300/200 is indicated for the treatment of HIV infected

adults over the age of 18 years, in combination with other antiretroviral agents.

Pre-exposure prophylaxis

CIPLA TENOFOVIR + EMTRICITABINE 300/200 is indicated in combination with safer sex

practices for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 in adults

at high risk. This indication is based on clinical trials in men who have sex with men (MSM) at high

risk for HIV-1 infection and in heterosexual serodiscordant couples (see section 5.1).

4.2

Dose and method of administration

Recommended dose for treatment of HIV-1 infection

Adults

The recommended dose of CIPLA TENOFOVIR + EMTRICITABINE 300/200 is one tablet

(containing 300 mg tenofovir disoproxil fumarate and 200 mg emtricitabine), taken orally, once daily.

In order to optimise the absorption of tenofovir, it is recommended that CIPLA TENOFOVIR +

EMTRICITABINE 300/200 should be taken with food.

Recommended dose for pre-exposure prophylaxis

Adults

The dose of CIPLA TENOFOVIR + EMTRICITABINE 300/200 in HIV-1 uninfected adults is one

tablet (containing 300 mg tenofovir disoproxil fumarate and 200 mg of emtricitabine), taken orally,

once daily. In order to optimise the absorption of tenofovir, it is recommended that CIPLA

TENOFOVIR + EMTRICITABINE 300/200 should be taken with food.

Children

The safety and efficacy of tenofovir disoproxil fumarate/emtricitabine has not been established in

patients under the age of 18 years. Consequently, CIPLA TENOFOVIR + EMTRICITABINE 300/200

should not be administered to children or adolescents.

Elderly

No data are available on which to make a dose recommendation for patients over the age of 65 years.

Dosage adjustment

Renal impairment

Treatment of HIV-1 infection

Significantly increased drug exposures occurred when tenofovir disoproxil fumarate or emtricitabine

were administered to patients with moderate to severe renal impairment (see tenofovir disoproxil

fumarate and emtricitabine Product Information). Therefore, the dosing interval of tenofovir disoproxil

fumarate/emtricitabine should be adjusted in patients with baseline creatinine clearance <60 mL/min

using the recommendations in Table 1. The safety and effectiveness of these dosing interval

adjustment recommendations have not been clinically evaluated, therefore, clinical response to

treatment and renal function should be closely monitored in these patients.

Table 1. Dosage Adjustment for Patients with Altered Creatinine Clearance

Creatinine Clearance (mL/min)

a

≥60

30–59

<30

(Including Patients

Requiring Haemodialysis)

Recommended Dosing

Interval

Every 24 hours

Every 48 hours

CIPLA TENOFOVIR +

EMTRICITABINE 300/200

should not be administered.

Calculated with Cockcroft Gault equation using ideal (lean) body weight.

Pre-exposure prophylaxis

Do not use CIPLA TENOFOVIR + EMTRICITABINE 300/200 for a PrEP indication in HIV-1

uninfected individuals with estimated creatinine clearance below 60 mL/min (see section 4.4).

Routine monitoring of estimated creatinine clearance should be performed in all individuals with mild

renal impairment. If a decrease in estimated creatinine clearance is observed in uninfected individuals

while using CIPLA TENOFOVIR + EMTRICITABINE 300/200 for PrEP, evaluate potential causes

and re-assess potential risks and benefits of continued use (see section 4.4).

Hepatic impairment

The pharmacokinetics of tenofovir disoproxil fumarate/emtricitabine or emtricitabine have not been

studied in subjects with hepatic impairment. There were no substantial alterations in tenofovir

pharmacokinetics in subjects with hepatic impairment compared with unimpaired subjects. No change

in tenofovir disoproxil fumarate dosing is required in patients with hepatic impairment. Emtricitabine

is not significantly metabolised by liver enzymes, so the impact of hepatic impairment should be

limited.

4.3

Contraindications

CIPLA TENOFOVIR + EMTRICITABINE 300/200 is contraindicated in patients with known

hypersensitivity to tenofovir, tenofovir disoproxil fumarate, emtricitabine or any of the excipients

listed in section 6.1.

CIPLA TENOFOVIR + EMTRICITABINE 300/200 must not be administered to children or

adolescents under the age of 18 years.

CIPLA TENOFOVIR + EMTRICITABINE 300/200 is a fixed-dose combination of tenofovir

disoproxil fumarate and emtricitabine. CIPLA TENOFOVIR + EMTRICITABINE 300/200 should not

be administered concomitantly with other medicinal products containing any of the same active

components: tenofovir disoproxil fumarate or emtricitabine, drugs containing tenofovir alafenamide,

lamivudine or adefovir dipivoxil.

Do not use CIPLA TENOFOVIR + EMTRICITABINE 300/200 for pre-exposure prophylaxis in

individuals with unknown or positive HIV-1 status.

CIPLA TENOFOVIR + EMTRICITABINE 300/200 should be used in HIV-infected patients only in

combination with other antiretroviral agents.

4.4

Special warnings and precautions for use

General

Patients receiving tenofovir disoproxil fumarate/emtricitabine 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 informed that CIPLA TENOFOVIR + EMTRICITABINE 300/200 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 alone or in combination, 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 or uninfected individual with known risk factors for liver disease; however, cases have

also been reported in HIV-1 infected patients with no known risk factors. Treatment with tenofovir

disoproxil fumarate/emtricitabine should be suspended in any patient or uninfected individual 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

Tenofovir and emtricitabine are principally eliminated by the kidney. Renal impairment, including

cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe

hypophosphatemia), has been reported in association with the use of tenofovir disoproxil fumarate (see

section 4.8).

CIPLA TENOFOVIR + EMTRICITABINE 300/200 should be avoided with concurrent or recent use

of a nephrotoxic agent.

It is recommended that creatinine clearance is calculated in all individuals prior to initiating therapy

and, as clinically appropriate, during CIPLA TENOFOVIR + EMTRICITABINE 300/200 therapy. All

individuals at risk for, or with a history of, renal dysfunction, including patients who have previously

experienced renal events while receiving adefovir dipivoxil, should be routinely monitored for

changes in serum creatinine and phosphorus.

Treatment of HIV-1 infection

Dosing interval adjustment of CIPLA TENOFOVIR + EMTRICITABINE 300/200 is required in all

patients with creatinine clearance <60 mL/min (calculated using the Cockcroft Gault equation), (see

section 4.2). Renal function should be closely monitored in these patients. The safety and efficacy of

tenofovir disoproxil fumarate/emtricitabine therapy have not been established in patients with

creatinine clearance between 30 and 59 ml/min, and so the potential benefit of tenofovir disoproxil

fumarate/emtricitabine therapy should be assessed against the potential risk of renal toxicity. CIPLA

TENOFOVIR + EMTRICITABINE 300/200 should not be administered to patients with creatinine

clearance <30 mL/min or patients requiring haemodialysis.

Pre-exposure prophylaxis

CIPLA TENOFOVIR + EMTRICITABINE 300/200 for a PrEP indication should not be used if

estimated creatinine clearance is less than 60 mL/min. If a decrease in estimated creatinine clearance is

observed in uninfected individuals while using CIPLA TENOFOVIR + EMTRICITABINE 300/200

for PrEP, evaluate potential causes and re-assess potential risks and benefits of continued use (see

section 4.2).

Drug interactions

Tenofovir disoproxil fumarate

When tenofovir disoproxil fumarate was administered with didanosine the C

and AUC of

didanosine administered as either the buffered or enteric-coated formulation at a dose of 400 mg daily

increased significantly (see Table 3). The mechanism of this interaction is unknown. Higher

didanosine concentrations could potentiate didanosine-associated adverse events, including

pancreatitis, lactic acidosis and neuropathy. Suppression of CD4 cell counts has been observed in

patients receiving tenofovir disoproxil fumarate with didanosine at a dose of 400 mg daily. In adults

weighing ≥60kg, the didanosine dose should be reduced to 250 mg daily when it is co-administered

with tenofovir disoproxil fumarate/emtricitabine. Data are not available to recommend a dose

adjustment of didanosine for patients weighing <60 kg.

When co-administered, tenofovir disoproxil fumarate/emtricitabine and didanosine EC may be taken

under fasted conditions or with a light meal (<400 kcal, 20% fat). Co-administration of didanosine

buffered tablet formulation with tenofovir disoproxil fumarate/emtricitabine should be under fasted

conditions.

Co-administration of tenofovir disoproxil fumarate/emtricitabine and didanosine

should be undertaken with caution and patients receiving this combination should be monitored

closely for didanosine-associated adverse events. Didanosine should be discontinued in patients

who develop didanosine-associated adverse events.

Ledipasvir/sofosbuvir, sofosbuvir/velpatasvir, and sofosbuvir/velpatasvir/voxilaprevir

Co-administration of tenofovir disoproxil fumarate and ledipasvir/sofosbuvir, sofosbuvir/velpatasvir

or sofosbuvir/velpatasvir/voxilaprevir has been shown to increase tenofovir exposure. Patients

receiving a regimen containing tenofovir disoproxil fumarate concomitantly with

ledipasvir/sofosbuvir, sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevir should be

monitored for adverse reactions associated with tenofovir disoproxil fumarate (see Table 2).

Sofosbuvir

In a drug interaction study of a regimen containing tenofovir disoproxil fumarate given concomitantly

with sofosbuvir, tenofovir C

increased by 25%. Tenofovir AUC and C

were unaltered by

sofosbuvir co-administration. No dose adjustment of efavirenz/emtricitabine/tenofovir disoproxil

fumarate or tenofovir disoproxil fumarate/emtricitabine is required (see Table 2).

Tenofovir disoproxil fumarate affects the pharmacokinetics of atazanavir (see Table 3). Tenofovir

disoproxil fumarate/emtricitabine should only be administered with boosted atazanavir (ATZ

300 mg/Ritonavir 100 mg). The safety and efficacy of this regimen has been substantiated over 48

weeks in a clinical study.

Since tenofovir and emtricitabine are primarily eliminated by the kidneys, co-administration of

tenofovir disoproxil fumarate/emtricitabine with drugs that reduce renal function or compete for active

tubular secretion may increase serum concentrations of tenofovir, emtricitabine, and/or other renally

eliminated drugs.

Bone effects

Bone toxicities including a reduction in bone mineral density have been observed in tenofovir

disoproxil fumarate studies in three animal species. Clinically relevant bone abnormalities have not

been seen in long term clinical studies (>3 years) of tenofovir disoproxil fumarate in HIV-1 infected

adults and were also not seen in studies in HIV-1 uninfected individuals but long term data are lacking

in this population. However, bone abnormalities (infrequently contributing to fractures) may be

associated with proximal renal tubulopathy (see section 4.8). If bone abnormalities are suspected

during therapy then appropriate consultation should be obtained.

Hepatitis B virus (HBV) infection

Individuals should be tested for the presence of chronic hepatitis B virus (HBV) before initiating

tenofovir disoproxil fumarate/emtricitabine. Discontinuation of tenofovir disoproxil

fumarate/emtricitabine therapy in patients infected with HBV may be associated with severe acute

exacerbations of hepatitis. Patients infected with HBV should be closely monitored with both clinical

and laboratory follow-up for at least several months after stopping tenofovir disoproxil

fumarate/emtricitabine treatment. If appropriate, resumption of anti-hepatitis B therapy may be

warranted. In patients with advanced liver disease or cirrhosis, treatment discontinuation is not

recommended since post-treatment exacerbation of hepatitis may lead to hepatic decompensation.

Early virologic failure

Clinical studies in HIV-infected patients have demonstrated that certain regimens that only contain

three nucleoside reverse transcriptase inhibitors (NRTI) are generally less effective than triple drug

regimens containing two NRTIs in combination with either a non-nucleoside reverse transcriptase

inhibitor or a HIV-1 protease inhibitor. In particular, early virological failure and high rates of

resistance mutations have been reported in clinical studies of combinations of tenofovir, lamivudine

and abacavir or tenofovir, lamivudine and didanosine. Triple nucleoside regimens should therefore be

used with caution. Patients on a therapy utilising a triple nucleoside-only regimen should be carefully

monitored and considered for treatment modification.

Immune reconstitution syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiviral

therapy, including emtricitabine and tenofovir disoproxil fumarate. 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 jiroveci

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.

Comprehensive management for use in pre-exposure prophylaxis (PrEP)

Tenofovir disoproxil fumarate/emtricitabine should only be used for PrEP as part of a comprehensive

prevention strategy including other HIV-1 prevention measures, because tenofovir disoproxil

fumarate/emtricitabine is not always effective in preventing the acquisition of HIV-1. Counsel

uninfected individuals about safer sex practices that include consistent and correct use of condoms,

knowledge of their HIV-1 status and that of their partner(s), and regular testing for other sexually

transmitted infections that can facilitate HIV-1 transmission (such as syphilis and gonorrhea). Counsel

uninfected individuals prior to initiation of PrEP about risk and benefits, precautions and limitation of

pre-exposure prophylaxis using tenofovir disoproxil fumarate/emtricitabine.

Tenofovir disoproxil fumarate/emtricitabine should only be used to reduce the risk of acquiring HIV-1

in individuals confirmed to be HIV-negative immediately prior to initiating and routinely reconfirmed

while taking tenofovir disoproxil fumarate/emtricitabine for PrEP. Drug resistant HIV-1 variants have

been identified in individuals with undetected HIV-1 infection who are taking tenofovir disoproxil

fumarate/emtricitabine for a PrEP indication, because tenofovir disoproxil fumarate/emtricitabine

alone does not constitute a complete treatment regimen for HIV-1 infection.

When considering tenofovir disoproxil fumarate/emtricitabine for pre-exposure prophylaxis, the

uninfected individuals should be counselled about the importance of strict adherence to the

recommended tenofovir disoproxil fumarate/emtricitabine dosing schedule. The effectiveness of

tenofovir disoproxil fumarate/emtricitabine in reducing the risk of acquiring HIV-1 is strongly

correlated with patient adherence and detectable drug blood levels.

Many HIV-1 tests, such as rapid tests, detect anti-HIV antibodies and may not identify HIV-1

during the acute stage of infection. Prior to initiating tenofovir disoproxil fumarate/emtricitabine

for a PrEP indication, evaluate seronegative individuals for current or recent signs or symptoms

consistent with acute viral infections (e.g., fever, fatigue, myalgia, skin rash, etc.) and ask about

potential exposure events (e.g., unprotected, or condom broke during sex with an HIV-1 infected

partner) that may have occurred within the last month.

If clinical symptoms consistent with acute viral infection are present and recent (<1 month)

exposures are suspected, delay starting PrEP for at least one month and reconfirm negative

HIV-1 status.

While using tenofovir disoproxil fumarate/emtricitabine for a PrEP indication, HIV-1 screening

tests should be repeated at least every 3 months. If symptoms consistent with acute HIV-1

infection develop following a potential exposure event, PrEP should be discontinued until negative

HIV-1 infection status is confirmed.

Tenofovir disoproxil fumarate/emtricitabine does not reduce the risk of other sexually transmitted

infections and regular monitoring is recommended. Monitoring of renal function, such as with urine

dipstick testing, should be considered for patients at risk for renal disease (see section 4.4).

When considering CIPLA TENOFOVIR + EMTRICITABINE 300/200 for pre-exposure prophylaxis

the following factors may help to identify individuals at high risk of acquiring HIV-1 infection:

has partner(s) known to be HIV-1 infected, or

Engages in high risk sexual behavior (see section 5.1) or sexual activity within a high prevalence

area or social network or has partners from high prevalence areas.

When tenofovir disoproxil fumarate/emtricitabine is used to reduce the risk of acquiring HIV-1, advise

uninfected individuals about the importance of the following:

Confirming that they are HIV-negative before starting to take tenofovir disoproxil

fumarate/emtricitabine to reduce the risk of acquiring HIV-1.

Hepatitis B vaccination should be offered as appropriate.

Tenofovir disoproxil fumarate/emtricitabine should only be used as part of a complete prevention

strategy including other prevention measures. In clinical trials, tenofovir disoproxil

fumarate/emtricitabine only protected some subjects from acquiring HIV-1.

Using condoms consistently and correctly to lower the chance of sexual contact with any body

fluids such as semen, vaginal secretions, or blood.

Knowing their HIV status and the status of their partner(s).

In the case of use of tenofovir disoproxil fumarate/emtricitabine for PrEP in an uninfected partner

in a serodiscordant relationship, the importance of effective antiretroviral treatment of the HIV-1

infected partner in accordance with the current treatment guidelines should be fully explained.

Getting tested regularly (at least every 3 months) for HIV-1 and ask their partner(s) to get tested as

well.

Counselled about the importance of safety risks including monitoring of kidney function.

HIV-1 resistance substitutions may emerge in individuals with undetected HIV-1 infection who

are taking tenofovir disoproxil fumarate/emtricitabine, because tenofovir disoproxil

fumarate/emtricitabine alone does not constitute a complete regimen for HIV-1 treatment (see

sections 4.3 and 4.4).

Reporting any symptoms of acute HIV-1 infection (flu-like symptoms) to their healthcare provider

immediately.

Signs and symptoms of acute infection include: fever, headache, fatigue, arthralgia, vomiting,

myalgia, diarrhea, pharyngitis, rash, night sweats, and adenopathy (cervical and inguinal).

Getting tested for other sexually transmitted infections such as syphilis and gonorrhea that may

facilitate HIV-1 transmission.

Learning about sexual risk behavior and getting support to help reduce sexual risk behaviour.

Taking tenofovir disoproxil fumarate/emtricitabine on a regular dosing schedule and strictly

adhere to the recommended dosing schedule to reduce the risk of acquiring HIV-1. Uninfected

individuals who miss doses are at greater risk of acquiring HIV-1 than those who do not miss

doses (see section 4.4).

Risks and benefits of tenofovir disoproxil fumarate/emtricitabine in women who may be pregnant

or intending to become pregnant.

Use in the elderly

Clinical studies of tenofovir and emtricitabine did not contain sufficient numbers of patients aged

65 years and over to determine whether they respond differently from younger patients. In general,

dose selection for the elderly patient should be cautious, keeping in mind the greater frequency of

decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy (see

section 4.2).

Paediatric use

Safety and effectiveness in paediatric patients have not been established.

Effects on laboratory tests

No data available.

Excipients

CIPLA TENOFOVIR + EMTRICITABINE 300/200 also contains lactose monohydrate. Patients with

rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose

malabsorption should not take this medicinal product.

4.5

Interactions with other medicines and other forms of interactions

The drug interactions described are based on studies conducted with tenofovir disoproxil fumarate or

emtricitabine as individual agents; no drug interaction studies have been conducted using tenofovir

disoproxil fumarate/emtricitabine tablets.

Tenofovir disoproxil fumarate and emtricitabine

The steady state pharmacokinetics of tenofovir and emtricitabine were unaffected when tenofovir

disoproxil fumarate and emtricitabine were administered together versus each agent dosed alone.

In vitro

and clinical pharmacokinetic drug-drug interaction studies have shown the potential for

CYP450 mediated interactions involving tenofovir disoproxil fumarate and emtricitabine with other

medicinal products is low.

Tenofovir and emtricitabine 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, co-administration of tenofovir disoproxil fumarate/emtricitabine with

drugs that are eliminated by active tubular secretion may increase serum concentrations of tenofovir,

emtricitabine, and/or the co-administered drug. Drugs that decrease renal function may increase serum

concentrations of tenofovir and/or emtricitabine.

No clinically significant drug interactions have been observed between tenofovir disoproxil fumarate

and abacavir, efavirenz, emtricitabine, indinavir, lamivudine, lopinavir/ritonavir, methadone,

nelfinavir, saquinavir/ritonavir and oral contraceptives in studies conducted in healthy volunteers. In a

study conducted in healthy volunteers dosed with a single 600 mg dose of ribavirin, no clinically

significant drug interactions were observed between tenofovir disoproxil fumarate and ribavirin.

Similarly, no clinically significant drug interactions have been observed between emtricitabine and

famciclovir, indinavir, d4T, zidovudine and tenofovir disoproxil fumarate.

In drug interaction studies between regimens containing tenofovir disoproxil fumarate and

ledipasvir/sofosbuvir, sofosbuvir, sofosbuvir/velpatasvir, and sofosbuvir/velpatasvir/voxilaprevir

increases in tenofovir exposure were observed. Table 2 summarises the changes in pharmacokinetic

parameters for tenofovir disoproxil fumarate in the presence of sofosbuvir, ledipasvir/sofosbuvir,

sofosbuvir/velpatasvir, and sofosbuvir/velpatasvir/voxilaprevir (see section 4.4).

Table 2. Drug Interactions: Changes in Pharmacokinetic Parameters for Tenofovir

a

in the

Presence of the Co-administered Drug

Co-

administered

Drug

Dose of Co-

administered

Drug (mg)

N

% Change of Tenofovir Pharmacokinetic

Parameters

b

(90% CI)

C

max

AUC

C

min

Ledipasvir/

Sofosbuvir

90/400 once daily

x 10 days

↑47

↑37 to ↑

↑35

↑29 to ↑ 42)

↑47

↑38 to ↑57)

Ledipasvir/

Sofosbuvir

↑64

(↑54 to ↑ 74)

↑50

(↑42 to ↑59)

↑59

(↑49 to ↑ 70)

Ledipasvir/

Sofosbuvir

90/400 once daily

x 14 days

↑79

↑56 to ↑104)

↑98

↑77 to 123)

↑163

↑132 to↑197)

Ledipasvir/

Sofosbuvir

90/400 once daily

x 10 days

↑32

↑25 to ↑39)

↑40

↑31 to ↑50)

↑91

↑74 to ↑110)

Ledipasvir/

Sofosbuvir

↑61

(↑51 to ↑72)

↑65

(↑59 to ↑71)

↑115

(↑105 to ↑126)

Sofosbuvir

400 once daily

↑25

(↑8 to ↑45)

Sofosbuvir/

Velpatasvir

400/100 once

daily

↑55

↑43 to↑68)

↑30

↑24 to↑36)

↑39

↑31 to↑48)

Sofosbuvir/

Velpatasvir

400/100 once

daily

↑55

(↑45 to↑66)

↑39

(↑33 to↑44)

↑52

(↑45 to↑59)

Sofosbuvir/

Velpatasvir

400/100 once

daily

↑77

(↑53 to↑104)

↑81

(↑68 to↑94)

↑121

(↑100 to↑143)

Sofosbuvir/

Velpatasvir

400/100 once

daily

↑36

↑25 to↑47)

↑35

↑29 to↑42)

↑45

↑39 to↑51)

Sofosbuvir/

Velpatasvir

400/100 once

daily

↑44

(↑33 to↑55)

↑40

(↑34 to↑46)

↑84

(↑76 to↑92)

Sofosbuvir/

Velpatasvir

400/100 once

daily

↑46

(↑39 to↑54)

↑40

(↑34 to↑45)

↑70

(↑61 to↑79)

Sofosbuvir/

Velpatasvir/

Voxilaprevir

400 /100 /100+

Voxilaprevir

once daily

↑48

↑36 to↑61)

↑39

↑32to↑46)

↑47

↑38 to↑56)

Subjects received tenofovir disoproxil fumarate 300 mg once daily.

Increase =

↑; Decrease = ↓; No Effect =

Data generated from simultaneous dosing with ledipasvir/sofosbuvir. Staggered administration (12 hours apart)

provided similar results.

Comparison based on exposures when administered as atazanavir/ritonavir + emtricitabine/ tenofovir

disoproxil fumarate.

Comparison based on exposures when administered as darunavir/ritonavir + emtricitabine/ tenofovir disoproxil

fumarate.

Study conducted with efavirenz/emtricitabine/tenofovir disoproxil fumarate co-administered with

ledipasvir/sofosbuvir.

Study conducted with emtricitabine/rilpivirine/tenofovir disoproxil fumarate co-administered with

ledipasvir/sofosbuvir.

Study conducted with tenofovir disoproxil fumarate/emtricitabine + dolutegravir co-administered with

ledipasvir/sofosbuvir.

Study conducted with efavirenz/emtricitabine/tenofovir disoproxil fumarate co-administered with sofosbuvir.

Comparison based on exposures when administered as atazanavir/ritonavir + emtricitabine/tenofovir disoproxil

fumarate.

Comparison based on exposures when administered as darunavir/ritonavir + emtricitabine/tenofovir disoproxil

fumarate.

Study conducted with efavirenz/emtricitabine/tenofovir disoproxil fumarate co-administered with

sofosbuvir/velpatasvir.

Study conducted with elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate co-administered with

sofosbuvir/velpatasvir.

Study conducted with emtricitabine/rilpivirine/tenofovir disoproxil fumarate co-administered with

sofosbuvir/velpatasvir.

Administered as raltegravir + emtricitabine/tenofovir disoproxil fumarate.

Comparison based on exposures when administered as darunavir/ritonavir + emtricitabine/tenofovir disoproxil

fumarate.

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

infected patients.

When unboosted atazanavir (400 mg) was co-administered with tenofovir disoproxil fumarate,

atazanavir increased tenofovir C

by 14% and AUC by 24%. Similarly, lopinavir (400 mg)/ritonavir

(100 mg) increased tenofovir AUC by 32%.

Co-administration of tenofovir disoproxil fumarate with didanosine and atazanavir results in changes

in the pharmacokinetics of didanosine and atazanavir that may be of clinical significance. Concomitant

dosing of tenofovir disoproxil fumarate with didanosine buffered tablets or enteric-coated capsules

significantly increases the C

and AUC of didanosine. When didanosine 250 mg enteric-coated

capsules were administered with tenofovir disoproxil fumarate, systemic exposures of didanosine were

similar to those seen with the 400 mg enteric-coated capsules alone under fasted conditions. The

mechanism of this interaction is unknown. Tenofovir decreases atazanavir concentration. Table 3

summarises the effects of tenofovir disoproxil fumarate on the pharmacokinetics of didanosine and

atazanavir.

Table 3. Drug Interactions: Changes in Pharmacokinetic Parameters for Didanosine and

Atazanavir in the Presence of Tenofovir disoproxil fumarate

Co-

administered

Drug

Dose of Co-

administered Drug

(mg)

N

% Change of Co-administered Drug

Pharmacokinetic Parameters

1

(90% CI)

C

max

AUC

C

min

Didanosine

enteric-coated

capsules

400 once / with or

without food

↑ 48−64%

↑ 25

−↑ 89)

↑ 48−60%

−↑ 79)

250 once /

Simultaneously with

tenofovir disoproxil

fumarate, fasted

↑ 14

(0−↑ 31)

250 once /

Simultaneously with

tenofovir disoproxil

fumarate, fed

2, 4

↓ 29

(↓ 39−↓ 18)

↓ 11

(↓ 23−↑ 2)

Atazanavir

400 once daily

x 14 days

↓ 21

(↓ 27 to ↓ 14)

↓ 25

(↓ 30 to ↓ 19)

↓ 40

(↓ 48 to ↓ 32)

Atazanavir/Ritonavir

300/100 once daily

x 42 days

↓ 28

↓ 50 to ↑ 5)

↓ 25

↓ 42 to ↓ 3)

↓ 23

↓ 46 to ↑ 10)

Increase =

↑; Decrease = ↓; No Effect =

; NC = Not Calculated

Administration with food was with a light meal (~373 kcal, 20% fat).

See section 4.4 regarding use of didanosine with tenofovir disoproxil fumarate.

Relative to 400 mg alone, fasted.

Atazanavir sulfate Prescribing Information (Bristol-Myers Squibb)

In HIV-infected patients, addition of tenofovir disoproxil fumarate to atazanavir 300 mg plus ritonavir 100 mg,

resulted in AUC and C

values of atazanavir that were 2.3- and 4-fold higher than the respective values

observed for atazanavir 400 mg when given alone (Atazanavir sulfate March 2004 United States Package

Insert)

4.6

Fertility, pregnancy and lactation

Effects on fertility

No reproductive toxicity studies have been conducted with tenofovir disoproxil fumarate and

emtricitabine in combination. Male and female rat fertility and mating performance or early embryonic

development were unaffected by an oral tenofovir disoproxil fumarate 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 did not affect fertility in male rats or in female and male mice at respective approximate

exposures (AUC) of 130 and 50-80 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).

Use in pregnancy

Pregnancy Category B3

No clinical data are available for pregnant women being treated with tenofovir disoproxil fumarate or

emtricitabine. No embryofoetal development studies have been conducted with tenofovir disoproxil

fumarate and emtricitabine in combination.

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. 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. Because animal reproduction

studies are not always predictive of human response, tenofovir disoproxil fumarate/emtricitabine

should be used during pregnancy only if clearly needed

.

If an uninfected individual becomes pregnant

while taking tenofovir disoproxil fumarate/emtricitabine for a PrEP indication, careful consideration

should be given to whether use of tenofovir disoproxil fumarate/emtricitabine should be continued,

taking into account the potential increased risk of HIV-1 infection during pregnancy.

Use in lactation

Because of the potential for HIV transmission and for serious adverse reactions in nursing infants,

mothers should be instructed not to breast feed if they are receiving CIPLA TENOFOVIR +

EMTRICITABINE 300/200 for treatment or to reduce the risk of acquiring HIV-1.

Tenofovir disoproxil fumarate:

In humans, samples of breast milk obtained from five HIV-1 infected

mothers show that tenofovir is secreted in human milk at low concentrations (estimated neonatal

concentrations 128 to 266 times lower than the tenofovir IC

(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 disoproxil fumarate are unknown.

Emtricitabine:

Samples of breast milk obtained from five HIV-1 infected mothers show that

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

the emtricitabine IC

but 3 to 12 times lower than the C

(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.

4.7

Effects on ability to drive and use machines

No studies on the effects of tenofovir disoproxil fumarate/emtricitabine on the ability to drive and use

machines have been performed. However, patients should be informed that dizziness has been

reported during treatment with both tenofovir disoproxil fumarate and emtricitabine.

4.8

Adverse effects (Undesirable Effects)

Adverse effects for clinical trials experience in HIV-1 infected patients

Four hundred and forty seven HIV-1 infected patients have received combination therapy with

emtricitabine and tenofovir disoproxil fumarate with either a non-nucleoside reverse transcriptase

inhibitor or protease inhibitor for 48 weeks in ongoing clinical studies.

Study 934 - treatment emergent adverse events

Study 934 was an open-label active-controlled study in which 511 antiretroviral-naïve patients

received either emtricitabine + tenofovir disoproxil fumarate administered in combination with

efavirenz (n=257) or lamivudine/zidovudine administered in combination with efavirenz (n=254).

Adverse events observed in this study were generally consistent with those seen in previous studies in

treatment-experienced or treatment-naïve patients (Table 4). Adverse events leading to study drug

discontinuation occurred in significantly smaller number of patients in the tenofovir disoproxil

fumarate/emtricitabine group compared to the lamivudine/zidovudine group (5% vs 11%, p=0.010).

The most frequently occurring adverse event leading to study drug discontinuation was anaemia

(including decreased haemoglobin), no patient in the tenofovir disoproxil fumarate/emtricitabine

group and 6% of patients in the lamivudine/zidovudine group.

Table 4. Frequency of Adverse Reactions to Emtricitabine and/or Tenofovir disoproxil fumarate

(Grade 2-4) Occurring in

3% of Patients Receiving Emtricitabine and Tenofovir disoproxil

fumarate (or tenofovir disoproxil fumarate/emtricitabine) in Study 934 (0-144 weeks)

1

Adverse Reaction

Tenofovir disoproxil

fumarate/emtricitabine

2

+EFV

N=257

Lamivudine/zidovudine

+EFV

N=254

Gastrointestinal Disorders

Diarrhoea

Nausea

Nervous System Disorders

Headache

Dizziness

Psychiatric Disorders

Insomnia

Abnormal Dreams

Skin and Subcutaneous Tissue Disorders

Rash

Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship

to study drug.

Patients received emtricitabine + tenofovir disoproxil fumarate up to week 96 and switched to tenofovir

disoproxil fumarate/emtricitabine from week 96 to 144.

Laboratory abnormalities

Laboratory abnormalities observed in this study were generally consistent with those seen in previous

studies (Table 5).

Table 5. Grade 3/4 Laboratory Abnormalities Reported in >1% of Patients in Either Treatment

Group, Study 934 (0–144 weeks)

Tenofovir disoproxil

fumarate/emtricitabine

1

+EFV

N=254

Lamivudine/zidovudine

+EFV

N=251

Any ≥ Grade 3 Laboratory Abnormality

Creatine Kinase

(M: >990 U/L)

(F: >845 U/L)

Serum Amylase (>175 U/L)

(M: >180 U/L)

(F: >170 U/L)

(M: >215 U/L)

(F: >170 U/L)

Hyperglycaemia (>250 mg/dL)

Haematuria (>75 RBC/HPF)

Neutrophil (<750/mm

Triglyceride (>750 mg/dL)

Haemoglobin (<7.0 g/dL)

Patients received emtricitabine + tenofovir disoproxil fumarate up to week 96 and switched to

emtricitabine/tenofovir disoproxil fumarate from week 96 to 144.

Tenofovir disoproxil fumarate

From clinical studies

More than 12,000 patients have been treated with tenofovir disoproxil fumarate alone or in

combination with other antiretroviral medicinal products for periods of 28 days to 215 weeks in Phase

I-III clinical trials and expanded access studies. A total of 1,544 patients have received tenofovir

disoproxil fumarate 300 mg once daily in Phase I-III clinical trials; over 11,000 patients have received

tenofovir disoproxil fumarate in expanded access studies.

Treatment-experienced patients

Treatment-emergent adverse events

The most common adverse events that occurred in patients receiving tenofovir disoproxil fumarate

with other antiretroviral agents in clinical trials were mild to moderate gastrointestinal events, such as

nausea, diarrhoea, vomiting and flatulence. Less than 1% of patients discontinued participation in the

clinical studies due to gastrointestinal adverse events (Study 907).

A summary of treatment-emergent adverse events that occurred during the first 48 weeks of Study 907

is provided in Table 6.

Table 6. Selected Treatment-Emergent Adverse Events (Grades 2–4) Reported in ≥3% in Any

Treatment Group in Study 907 (0–48 weeks)

Tenofovir

disoproxil

fumarate

(N=368) (Week

0–24)

Placebo (N=182)

(Week 0–24)

Tenofovir

disoproxil

fumarate

(N=368) (Week

0–48)

Placebo

Crossover to

Tenofovir

disoproxil

fumarate

(N=170) (Week

24–48)

Body as a Whole

Asthenia

Pain

Headache

Abdominal Pain

Back Pain

Chest Pain

Fever

Digestive System

Diarrhoea

Nausea

Vomiting

Anorexia

Dyspepsia

Flatulence

Respiratory

Pneumonia

Nervous System

Depression

Insomnia

Peripheral

Neuropathy

Dizziness

Skin and Appendage

Rash Event

Sweating

Musculoskeletal

Myalgia

Metabolic

Weight Loss

Peripheral neuropathy includes peripheral neuritis and neuropathy.

Rash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, and pustular rash.

Laboratory abnormalities

Laboratory abnormalities observed in this study occurred with similar frequency in the tenofovir

disoproxil fumarate and placebo-treated groups. A summary of Grade 3 and 4 laboratory abnormalities

is provided in Table 7.

Table 7. Grade 3 / 4 Laboratory Abnormalities Reported in

1% of Tenofovir disoproxil

fumarate-Treated Patients in Study 907 (0–48 weeks)

Tenofovir

disoproxil

fumarate

(N=368)

(Week 0–24)

Placebo

(N=182)

(Week 0–24)

Tenofovir

disoproxil

fumarate

(N=368)

(Week 0–48)

Placebo

Crossover to

Tenofovir

disoproxil

fumarate (N=170)

(Week 24–48)

(%)

(%)

(%)

(%)

Any ≥ Grade 3 Laboratory

Abnormality

Triglycerides (>750 mg/dL)

Creatine Kinase

(M: >990U/L)

(F: >845 U/L)

Serum Amylase (>175 U/L)

Urine Glucose (≥3+)

(M: >180 U/L)

(F: >170 U/L)

(M: >215 U/L)

(F: >170 U/L)

Serum Glucose (>250 U/L)

Neutrophils (<750 mg/dL)

Treatment-naïve patients

Treatment-emergent adverse events

The adverse reactions seen in a double-blind active controlled study in which 600 treatment-naïve

patients received tenofovir disoproxil fumarate (N=299) or d4T (N=301) in combination with

lamivudine and efavirenz for 144 weeks (Study 903) were generally consistent, with the addition of

dizziness, with those seen in treatment-experienced patients (Table 8).

Mild adverse events (Grade 1) were common with a similar incidence in both arms, and included

dizziness, diarrhoea and nausea.

Table 8. Selected Treatment-Emergent Adverse Events (Grades 2–4) Reported in ≥5% in Any

Treatment Group in Study 903 (0–144 weeks)

Tenofovir disoproxil

fumarate+3TC+EFV

d4T+3TC+EFV

N=299

N=301

Body as a Whole

Headache

Pain

Back Pain

Fever

Abdominal Pain

Asthenia

Digestive System

Diarrhoea

Nausea

Vomiting

Dyspepsia

Metabolic Disorders

Lipodystrophy

Musculoskeletal

Arthralgia

Myalgia

Nervous System

Depression

Anxiety

Insomnia

Dizziness

Peripheral Neuropathy

Respiratory

Pneumonia

Skin and Appendages

Rash Event

Peripheral neuropathy includes peripheral neuritis and neuropathy

Rash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, and pustular rash

Laboratory abnormalities

With the exception of triglyceride elevations that were more common in the d4T group (14%)

compared with tenofovir disoproxil fumarate (3%), laboratory abnormalities observed in this study

occurred with similar frequency in the tenofovir disoproxil fumarate and d4T treatment arms. A

summary of Grade 3 and 4 laboratory abnormalities is provided in Table 9.

Table 9. Grade 3/4 Laboratory Abnormalities Reported in

1% of Tenofovir disoproxil

fumarate-Treated Patients in Study 903 (0–144 weeks)

Tenofovir disoproxil

fumarate+3TC+EFV

d4T+3TC+EFV

N=299

N=301

Any ≥ Grade 3 Laboratory Abnormality

Creatine Kinase

(M: > 990 U/L)

(F: > 845 U/L)

Serum Amylase (>175 U/L)

(M: >180 U/L)

(F: >170 U/L)

(M: >215 U/L)

(F: >170 U/L)

Haematuria (>100 RBC/HPF)

Neutrophil (<750/mm

Triglyceride (>750 mg/dL)

Adverse reactions from clinical trial experience in HIV-1 uninfected adult subjects

No new adverse reactions to tenofovir disoproxil fumarate/emtricitabine were identified from two

randomised placebo-controlled clinical trials (iPrEx, Partners PrEP) in which 2830 HIV-1 uninfected

adults received tenofovir disoproxil fumarate/emtricitabine once daily for pre-exposure prophylaxis.

Subjects were followed for a median of 71 weeks and 87 weeks, respectively. These trials enrolled

HIV-negative individuals ranging in age from 18 to 67 years. The iPrEx trial enrolled only males or

transgender females of Hispanic/Latino (72%), White (18%), Black (9%) and Asian (5%) race. The

Partners PrEP trial enrolled both males (61-64% across treatment groups) and females in Kenya and

Uganda. Table 10 provides a list of all adverse events that occurred in ≥2% of patients in any

treatment group in the iPrEx and Partners PrEP trials.

Laboratory Abnormalities

Table 11 provides a list of laboratory abnormalities observed in both trials. Six subjects in the TDF-

containing arms of the Partners PrEP trial discontinued participation in the study due to an increase in

blood creatinine compared with no discontinuations in the placebo group. One patient in the tenofovir

disoproxil fumarate/emtricitabine arm of the iPrEx trial discontinued from the study due to an increase

in blood creatinine and another due to low phosphorous.

In addition to the laboratory abnormalities described above, Grade 1 proteinuria (1+) occurred in 6%

of subjects receiving tenofovir disoproxil fumarate/emtricitabine in the iPrEx trial. Grades 2-3

proteinuria (2-4+) and glycosuria (3+) occurred in less than 1% of subjects treated with tenofovir

disoproxil fumarate/emtricitabine in the iPrEx trial and Partners PrEP trial.

Table 10. Selected Adverse Events (All Grades) Reported in

2% in Any Treatment Group in

the iPrEx Trial and Partners PrEP Trial

iPrEx Trial

Partners PrEP Trial

FTC/TDF

(N=1251)

Placebo

(N=1248)

FTC/TDF

(N=1579)

Placebo

(N=1584)

Gastrointestinal Disorders

Diarrhoea

Abdominal pain

Infections and Infestations

Pharyngitis

Urethritis

Urinary tract infection

Syphilis

Secondary syphilis

Anogenital warts

Musculoskeletal and Connective Tissue Disorders

Back pain

Nervous System Disorders

Headache

Psychiatric Disorders

Depression

Anxiety

Reproductive System and Breast Disorders

Genital ulceration

Investigations

Weight decreased

a. Not reported or reported below 2%.

Table 11. Laboratory Abnormalities (Highest Toxicity Grade) Reported for Each Subject in the

iPrEx Trial and Partners PrEP Trial

Grade

b

iPrEx Trial

Partners PrEP Trial

FTC/TDF

N= 1251

Placebo

N= 1248

FTC/TDF

N=1579

Placebo

N=1584

Creatinine

1 (1.1-1.3 X ULN)

27 (2%)

21 (2%)

18 (1%)

12 (<1%)

2-4 (> 1.4 x ULN)

5 (<1%)

3 (<1%)

2 (<1%)

1 (<1%)

Phosphorus

1 (2.5 - <LLN mg/dL)

81 (7%)

110 (9%)

2-4 (<2.0 mg/dL)

123 (10%)

101 (8%)

140 (9%)

136 (9%)

1 (1.25-<2.5 x ULN)

175 (14%)

175 (14%)

20 (1%)

25 (2%)

2-4 (> 2.6 x ULN)

57 (5%)

61 (5%)

10 (<1%)

4 (<1%)

1 (1.25-<2.5 x ULN)

178 (14%)

194 (16%)

21 (1%)

13 (<1%)

2-4 (> 2.6 x ULN)

84 (7%)

82 (7%)

4 (<1%)

6 (<1%)

Hemoglobin

1 (8.5 - 10 mg/dL)

49 (4%)

62 (5%)

56 (4%)

39 (2%)

2-4 (<9.4 mg/dL)

13 (1%)

19 (2%)

28 (2%)

39 (2%)

Neutrophils

1 (1000-1300/mm

23 (2%)

25 (2%)

208 (13%)

163 (10%)

2-4 (<750/mm

7 (<1%)

7 (<1%)

73 (5%)

56 (3%)

Grade 1 phosphorus was not reported for the Partners PrEP trial.

Grading is per DAIDS criteria.

Changes in bone mineral density

In clinical trials of HIV-1 uninfected individuals, decreases in BMD were observed. In the iPrEx trial,

a substudy of 503 subjects found mean changes from baseline in BMD ranging from -0.4% to -1.0%

across total hip, spine, femoral neck, and trochanter in the tenofovir disoproxil fumarate/emtricitabine

group compared with the placebo group, which returned toward baseline after discontinuation of

treatment. Thirteen percent of subjects receiving tenofovir disoproxil fumarate/emtricitabine vs. 6% of

subjects receiving placebo lost at least 5% of BMD at the spine during treatment. Bone fractures were

reported in 1.7% of the tenofovir disoproxil fumarate/emtricitabine group compared with 1.4% in the

placebo group. No correlation between BMD and fractures was noted (see section 5.1). The Partners

PrEP trial found similar fracture rates between treatment and placebo groups (0.8% and 0.6%,

respectively). No BMD evaluations were conducted during this trial (see section 5.1).

Emtricitabine

More than 2000 adult patients with HIV infection have been treated with emtricitabine alone or in

combination with other antiretroviral agents for periods of 10 days to 200 weeks in Phase I-III clinical

trials.

Assessment of adverse reactions is based on data from studies 303 and 301A in which 440 treatment

experienced (303) and 571 treatment naïve (301A) patients received emtricitabine 200 mg (N=580) or

comparator drug (N=431) for 48 weeks.

The most common adverse events that occurred in patients receiving emtricitabine with other

antiretroviral agents in clinical trials were headache, diarrhoea, nausea, and rash, which were generally

of mild to moderate severity. Approximately 1% of patients discontinued participation in the clinical

studies because of to these events. All adverse events were reported with similar frequency in

emtricitabine and control treatment groups with the exception of skin discolouration which was

reported with higher frequency in the emtricitabine treated group.

Skin discolouration, manifested by hyperpigmentation on the palms and/or soles was generally mild

and asymptomatic. The mechanism and clinical significance are unknown.

In addition to the adverse reactions reported in adults, anaemia has been reported commonly and

hyperpigmentation very commonly, in paediatric patients.

A summary of emtricitabine treatment emergent clinical adverse events in studies 303 and 301A is

provided in Table 12.

Table 12. Selected Treatment-Emergent Adverse Events (All Grades, Regardless of Causality)

Reported in

3% of Emtricitabine-Treated Patients in Either Study 303 or 301A (0-48 Weeks)

303

301A

Emtricitabine +

ZDV/d4T +

NNRTI/PI

(N=294)

Lamivudine +

ZDV/d4T +

NNRTI/PI

(N=146)

Emtricitabine +

Didanosine +

Efavirenz

(N=286)

d4T +

Didanosine +

Efavirenz

(N=285)

Body as a Whole

Abdominal Pain

Asthenia

Headache

Digestive System

Diarrhoea

Dyspepsia

Nausea

Vomiting

Musculoskeletal

Arthralgia

Myalgia

Nervous System

Abnormal Dreams

<1%

Depressive

Disorders

Dizziness

Insomnia

Neuropathy/Peripher

al Neuritis

Paresthaesia

Respiratory

Increased Cough

Rhinitis

Skin

Rash Event

1. Rash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, pustular rash, and

allergic reaction.

Laboratory abnormalities

Laboratory abnormalities observed in the emtricitabine studies occurred with similar frequency in the

treatment and placebo-treated/comparator groups.

A summary of Grade 3 and 4 laboratory abnormalities is provided in Table 13.

Table 13. Treatment-Emergent Grade 3/4 Laboratory Abnormalities Reported in

1% of

Emtricitabine-Treated Patients in Either Study 303 or 301A

303

301A

Emtricitabine

+ ZDV/d4T

+ NNRTI/PI (N=294)

Lamivudine +

ZDV/d4T

+ NNRTI/PI

(N=146)

Emtricitabine

+ Didanosine

+ Efavirenz (N=286)

d4T

+ Didanosine

+ Efavirenz

(N=285)

Percentage with

Grade 3 or Grade

4 laboratory

abnormality

ALT (>5.0 x

AST (>5.0 x

ULN)

<1%

Bilirubin (>2.5 x

ULN)

<1%

<1%

Creatine Kinase

(>4.0 x ULN)

Neutrophils

(<750/mm

Pancreatic

Amylase (>2.0 x

ULN)

<1%

Serum Amylase

(>2.0 x ULN)

Serum Glucose

(<40 or >250

mg/dL)

Serum Lipase

(>2.0 x ULN)

<1%

<1%

Triglycerides

(>750 mg/dL)

1. ULN=Upper limit of normal.

From post marketing surveillance

In addition to adverse events reported from clinical trials, the following events have been identified

during post-approval use of tenofovir disoproxil fumarate.

Immune system disorders

Allergic reaction (including angioedema), autoimmune hepatitis (see section 4.4)

Immune Reconstitution Syndrome: In HIV-infected patients with severe immune deficiency at the

time of initiation of antiretroviral therapy, an inflammatory reaction to infectious pathogens (active or

inactive) may arise (see section 4.4).

Metabolism and nutrition disorders

Hypokalaemia, hypophosphataemia, lactic acidosis

Respiratory, thoracic, and mediastinal disorders

Dyspnoea

Gastrointestinal disorders

Increased amylase, abdominal pain, pancreatitis

Hepatobiliary disorders

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

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

Asthaenia

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

disoproxil fumarate therapy in the absence of proximal renal tubulopathy.

Adverse reactions attendant to class

Nephrotoxicity (elevation in serum creatinine and urine protein, and decrease in serum phosphorus) is

the dose-limiting toxicity associated with other nucleotide analogues (cidofovir and high doses of

adefovir dipivoxil evaluated for HIV disease (60 mg and 120 mg)).

Reporting suspected adverse effects

Reporting suspected adverse reactions after registration of the medicinal product is important. It

allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare

professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-

problems.

4.9

Overdose

There is no known antidote for tenofovir disoproxil fumarate/emtricitabine. If overdose occurs the

patient must be monitored for evidence of toxicity, and standard supportive treatment applied as

necessary.

Tenofovir disoproxil fumarate

Clinical experience of doses higher than the therapeutic dose of tenofovir disoproxil fumarate is

available from two studies. In one study, intravenous tenofovir, equivalent to 16.7 mg/kg/day of

tenofovir disoproxil fumarate, was administered daily for 7 days. In the second study, 600 mg of

tenofovir disoproxil fumarate 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 tenofovir disoproxil fumarate, 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 emtricitabine. In

once 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.

For information on the management of overdose, contact the Poisons Information Centre on 131126

(Australia).

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Tenofovir disoproxil fumarate and emtricitabine belong to the nucleoside and nucleotide reverse

transcriptase inhibitors pharmacotherapeutic group (ATC code: J05AF30).

Mechanism of action

Tenofovir disoproxil fumarate

Tenofovir disoproxil fumarate is an acyclic nucleoside phosphonate diester analog of adenosine

monophosphate. Tenofovir disoproxil fumarate 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 reverse transcriptase by competing with the

natural substrate deoxyadenosine 5′-triphosphate and, after incorporation into DNA, by DNA chain

termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases α, β, and

mitochondrial DNA polymerase γ.

Emtricitabine

Emtricitabine, a synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to

form emtricitabine 5'-triphosphate. Emtricitabine 5'-triphosphate inhibits the activity of the HIV-1

reverse transcriptase 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 polymerase α, β, ε and mitochondrial DNA polymerase γ.

Antiviral activity

in vitro

Tenofovir disoproxil fumarate plus Emtricitabine

In combination studies evaluating the

in vitro

antiviral activity of tenofovir and emtricitabine together,

synergistic antiviral effects were observed. Additive to synergistic effects were observed in

combination studies with protease inhibitors, integrase strand transfer inhibitors, and with nucleoside

and non-nucleoside analogue inhibitors of HIV-1 reverse transcriptase.

Tenofovir disoproxil fumarate

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 IC

(50% inhibitory concentration) values for tenofovir were in the range of

0.04

−8.5 μM. In drug combination studies of tenofovir with nucleoside reverse transcriptase inhibitors

(abacavir, didanosine, lamivudine (3TC), stavudine (d4T), zalcitabine, zidovudine (AZT)), non-

nucleoside reverse transcriptase inhibitors (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 (IC

values ranged from 0.5−2.2 μM). In addition, tenofovir has also been shown to be active

in vitro

against HIV-2, with similar potency as observed against HIV-1.

Emtricitabine

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. The IC

value for emtricitabine was in the range of 0.0013

−0.64 μM (0.0003

−0.158 μg/mL). In

drug combination studies of emtricitabine with nucleoside reverse transcriptase inhibitors (abacavir,

3TC, d4T, zalcitabine, AZT), non-nucleoside reverse transcriptase inhibitors (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 (IC

values ranged from 0.007−0.075 μM) and showed strain specific

activity against HIV-2 (IC

values ranged from 0.007

−1.5 μM).

Prophylactic activity in a nonhuman primate model of HIV transmission

Emtricitabine and Tenofovir disoproxil fumarate

The prophylactic activity of the combination of daily oral emtricitabine and tenofovir disoproxil

fumarate was evaluated in a controlled study of macaques inoculated once weekly for 14 weeks with

SIV/HIV-1 chimeric virus (SHIV) applied to the rectal surface. Of the 18 control animals, 17 became

infected after a median of 2 weeks. In contrast, 4 of the 6 animals treated daily with oral emtricitabine

and tenofovir disoproxil fumarate remained uninfected and the two infections that did occur were

significantly delayed until 9 and 12 weeks and exhibited reduced viremia. An M184I-expressing FTC-

resistant variant emerged in 1 of the 2 macaques after 3 weeks of continued drug exposure.

Anti-hepatitis B virus activity

in vitro

Tenofovir disoproxil fumarate

Tenofovir inhibits HBV production in HepG2 2.2.15 with an IC

value of 1.1μM.

Emtricitabine

Emtricitabine inhibits HBV production against laboratory strains of HBV with IC

values in the range

of 0.01 to 0.04 μM.

Drug resistance

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

−4 fold reduction in susceptibility

to tenofovir. In addition, a K70E substitution in HIV-1 reverse transcriptase has been selected by

tenofovir and results in low-level reduced susceptibility to abacavir, emtricitabine, tenofovir and

lamivudine.

Tenofovir-resistant isolates of HIV-1 have also been recovered from some patients treated with

tenofovir disoproxil fumarate in combination with other antiretroviral agents. In treatment-naïve

patients treated with tenofovir disoproxil fumarate + lamivudine + efavirenz through 144 weeks, viral

isolates from 8/47 (17%) patients with virologic failure showed reduced susceptibility to tenofovir. In

treatment-naïve patients treated with emtricitabine + tenofovir disoproxil fumarate + efavirenz through

144 weeks, none of the HIV isolates from 19 patients analysed for resistance showed reduced

susceptibility to tenofovir or the presence of the K65R mutation. In treatment-experienced patients,

14/304 (4.6%) of the tenofovir disoproxil fumarate-treated patients with virologic failure showed

reduced susceptibility to tenofovir. Genotypic analysis of the resistant isolates showed the K65R

mutation in the HIV-1 reverse transcriptase gene.

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).

Emtricitabine-resistant isolates of HIV have been recovered from some patients treated with

emtricitabine alone or in combination with other antiretroviral agents. In a clinical study, viral isolates

from 37.5% of treatment-naïve patients with virologic failure showed reduced susceptibility to

emtricitabine. Genotypic analysis of these isolates showed that the resistance was due to M184V/I

mutations in the HIV reverse transcriptase gene. In a second study in treatment-naïve patients,

genotyping of viral isolates from 2/12 (17%) patients showed development of the M184V/I mutation.

iPrEx Trial:

In a clinical study of HIV-1 seronegative subjects (see section 5.1), no amino acid

substitutions associated with resistance to emtricitabine or tenofovir were detected at the time of

seroconversion among 48 subjects in the tenofovir disoproxil fumarate/emtricitabine group and 83

subjects in the placebo group who became infected with HIV-1 during the trial. Ten subjects were

observed to be HIV-1 infected at time of enrollment. The M184V/I substitutions associated with

resistance to emtricitabine were observed in 3 of the 10 subjects (2 of 2 in the tenofovir disoproxil

fumarate/emtricitabine group and 1 of 8 in the placebo group). One of the two subjects in the tenofovir

disoproxil fumarate/emtricitabine group harbored wild type virus at enrollment and developed the

M184V substitution 4 weeks after enrollment. The other subject had indeterminate resistance at

enrollment but was found to have the M184I substitution 4 weeks after enrollment.

Partners PrEP Trial:

In a clinical study of HIV-1 seronegative subjects (see section 5.1)

,

no variants

expressing amino acid substitutions associated with resistance to emtricitabine or tenofovir were

detected at the time of seroconversion among 12 subjects in the tenofovir disoproxil

fumarate/emtricitabine group, 15 subjects in the tenofovir disoproxil fumarate group, and 51 subjects

in the placebo group. Fourteen subjects were observed to be HIV-1 infected at the time of enrollment

(3 in the tenofovir disoproxil fumarate/emtricitabine group, 5 in the tenofovir disoproxil fumarate

group, and 6 in the placebo group). One of the three subjects in the tenofovir disoproxil

fumarate/emtricitabine group who was infected with wild type virus at enrollment selected an M184V

expressing virus by week 12. Two of the five subjects in the tenofovir disoproxil fumarate group had

tenofovir-resistant viruses at the time of seroconversion; one subject infected with wild type virus at

enrollment developed a K65R substitution by week 16, while the second subject had virus expressing

the combination of D67N and K70R substitutions upon seroconversion at week 60, although baseline

virus was not genotyped and it is unclear if the resistance emerged or was transmitted. Following

enrollment, 4 subjects (2 in the tenofovir disoproxil fumarate

group, 1 in the tenofovir disoproxil

fumarate/emtricitabine group, and 1 in the placebo group) had virus expressing K103N or V106A

substitutions, which confer high-level resistance to NNRTIs but have not been associated with

tenofovir or emtricitabine and may have been present in the infecting virus.

Cross-resistance

Cross-resistance among certain reverse transcriptase inhibitors has been recognised.

Tenofovir disoproxil fumarate

The K65R and K70E substitutions can also be selected by abacavir, or didanosine, and result in

reduced susceptibility to, these agents plus abacavir, didanosine, emtricitabine, tenofovir and

lamivudine. 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 disoproxil fumarate. 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 lamivudine and zalcitabine but

retained sensitivity to abacavir, didanosine, d4T, tenofovir, zidovudine, and NNRTIs (delavirdine,

efavirenz, and nevirapine). HIV-1 isolates containing the K65R mutation, selected

in vivo

by abacavir,

didanosine, tenofovir, and zalcitabine, demonstrated reduced susceptibility to inhibition by

emtricitabine. Viruses harbouring mutations conferring reduced susceptibility to d4T and zidovudine

(M41L, D67N, K70R, L210W, T215Y/F, K219Q/E) or didanosine (L74V) remained sensitive to

emtricitabine. HIV-1 containing the K103N mutation associated with resistance to NNRTIs was

susceptible to emtricitabine.

Clinical trials

Clinical study 934, which demonstrated the safety and efficacy of emtricitabine and tenofovir

disoproxil fumarate in combination with efavirenz in treatment-naïve adults, supports the use of

tenofovir disoproxil fumarate/emtricitabine tablets for the treatment of HIV-1 infection. Additional

supportive data are derived from study 903, in which lamivudine (3TC) and tenofovir were used in

combination in treatment-naïve adults. In clinical study 303 emtricitabine and lamivudine

demonstrated comparable efficacy, safety and resistance patterns as part of multidrug regimens. For

additional information about these trials, please refer to the Product Information for tenofovir

disoproxil fumarate and emtricitabine. The iPrEx study and Partners PrEP study support the use of

tenofovir disoproxil fumarate/emtricitabine to help reduce the risk of acquiring HIV-1.

Tenofovir disoproxil fumarate/emtricitabine

Study 934: Emtricitabine + Tenofovir disoproxil fumarate + Efavirenz compared with Lamivudine /

zidovudine + Efavirenz

Study 934 is a randomised, open-label, active controlled multicentre study comparing two different

dosing regimens in 511 antiretroviral-naïve HIV-1 infected patients. Patients were randomised to

receive either emtricitabine + tenofovir disoproxil fumarate administered in combination with

efavirenz or lamivudine/zidovudine administered in combination with efavirenz. For patients

randomised to receive emtricitabine + tenofovir disoproxil fumarate the two drugs were administered

individually for the first 96 weeks and then switched to tenofovir disoproxil fumarate/emtricitabine

(fixed dose combination) during weeks 96 to 144, without regard to food.

For inclusion in the study, antiretroviral treatment naïve adult patients (≥ 18 years) with plasma HIV

RNA greater than 10,000 copies/mL, must have an estimated glomerular filtration rate as measured by

Cockroft-Gault method of ≥ 50 mL/min, adequate haematologic function, hepatic transaminases and

alanine aminotransferases ≤ 3 ULN, total bilirubin ≤ 1.5 mg/dL, serum amylase ≤ 1.5 ULN and serum

phosphorus ≥ 2.2 mg/dL. Exclusion criteria included: a new AIDS defining condition diagnosed

within 30 days (except on the basis of CD4 criteria), ongoing therapy with nephrotoxic drugs or agents

that interacted with efavirenz, pregnancy/lactation, a history of clinically significant renal / bone

disease or malignant disease other than Kaposi’s sarcoma or basal-cell carcinoma, or a life expectancy

of less than one year. If efavirenz-associated central nervous system toxicities occurred, nevirapine

could be substituted for efavirenz. Patients who were not receiving their originally assigned treatment

regimen after week 48 or 96 and during the 30-day extension study window were not eligible to

continue to weeks 96 or 144 respectively.

Patients had a mean age of 38 years (range 18 to 80), 86% were male, 59% were Caucasian and 23%

were Black. The mean baseline CD4 cell count was 245 cells/mm

(range 2 to 1191) and median

baseline plasma HIV-1 RNA was 5.01 log

copies/mL (range 3.56 to 6.54). Patients were stratified by

baseline CD4 count (< or ≥ 200 cells/mm

); 41% had CD4 cell counts <200 cells/mm

and 51% of

patients had baseline viral loads >100,000 copies/mL Treatment outcomes at 48 and 144 weeks for

those patients who did not have efavirenz resistance at baseline are presented in Table 14.

Table 14. Outcomes of Randomised Treatment at Weeks 48 and 144 (Study 934) in Treatment

Naïve Patients

Outcome at Weeks 48 and 144

WEEK 48

WEEK 144

Emtricitabin

e + Tenofovir

disoproxil

fumarate +

EFV

(N=244)

Lamivudin

e/zidovudin

e

+ EFV

(N=243)

Tenofovir

disoproxil

fumarate/emtricit

abine

4

+ EFV

(N=227)

Lamivudin

e/zidovudin

e

+ EFV

(N=229)

Responder

Virologic failure

Rebound

Never suppressed

Change in antiretroviral regimen

Death

<1%

Patients achieved and maintained confirmed HIV-1 RNA <400 copies/mL.

Includes confirmed viral rebound and failure to achieve confirmed <400 copies/mL.

All deaths were unrelated to study drugs.

Patients received emtricitabine + tenofovir disoproxil fumarate up to week 96 and switched to tenofovir

disoproxil fumarate/emtricitabine from week 96 to 144.

In this study, emtricitabine + tenofovir disoproxil fumarate in combination with efavirenz was

statistically significantly superior to lamivudine/zidovudine in combination with efavirenz with

regards to the primary and secondary endpoints: achieving and maintaining HIV-1 RNA < 400

copies/mL through 48 and 144 weeks (Table 4). The difference in the proportions of responders

between the emtricitabine + tenofovir disoproxil fumarate group and the lamivudine/zidovudine group

was 11.4%, and the 95% CI was 4.3% to 18.6% (p=0.002) at week 48 and a difference of 12.9% (95%

CI was 4.2% to 21.6%, p=0.004) at week 144.

Through 48 weeks of therapy, 80% and 70% of patients in the emtricitabine + tenofovir disoproxil

fumarate and the lamivudine/zidovudine arms, respectively, achieved and maintained HIV-1 RNA <50

copies/mL. The difference in the proportions of responders between the emtricitabine + tenofovir

disoproxil fumarate group and the lamivudine/zidovudine group was 9.1%, and the 95% CI was 1.6%

to 16.6% (p=0.021) at week 48. The proportion of patients responding at 144 weeks of therapy was

higher in the tenofovir disoproxil fumarate/emtricitabine group (64%) compared with the

lamivudine/zidovudine group (56%); p=0.082, a difference of 8.1% and the 95% CI was -0.8% to

17.0%.

The mean increase from baseline in CD4 cell count was 190 cells/mm

and 312 cells/mm

for the

emtricitabine + tenofovir disoproxil fumarate + efavirenz arm, and 158 cells/mm

and 271 cells/mm

for the lamivudine/zidovudine + efavirenz arm (p=0.002 and p = 0.088) at weeks 48 and 144

respectively.

Resistance analysis was performed on HIV isolates from all patients with > 400 copies/mL of HIV-1

RNA at week 144 while on study drug or after treatment switch. Genotypic resistance to efavirenz,

predominantly the K103N mutation, was the most common form of resistance that developed in both

treatment groups. Resistance to efavirenz occurred in 68% (13/19) analysed patients in the tenofovir

disoproxil fumarate/emtricitabine group and in 72% (21/29) analysed patients in the

lamivudine/zidovudine group. The M184V mutation, associated with resistance to emtricitabine and

lamivudine developed significantly less in the analysed patients in the tenofovir disoproxil

fumarate/emtricitabine group 11% (2/19) compared with the analysed patients in the

lamivudine/zidovudine group, 34% (10/29). Two patients in the lamivudine/zidovudine group

developed thymidine analog mutations, specifically D67N or K70R mutations in the reverse

transcriptase gene. No patient in either treatment group developed the K65R mutation, which is

associated with reduced susceptibility to tenofovir disoproxil fumarate.

iPrEx trial

The iPrEx trial was a randomised double-blind placebo-controlled multinational study evaluating

tenofovir disoproxil fumarate/emtricitabine in 2499 HIV-seronegative men or transgender women who

have sex with men and with evidence of high risk behavior for HIV-1 infection. Evidence of high risk

behavior included any one of the following reported to have occurred up to six months prior to study

screening: no condom use during anal intercourse with an HIV-1 positive partner or a partner of

unknown HIV status; anal intercourse with more than 3 sex partners; exchange of money, gifts, shelter

or drugs for anal sex; sex with male partner and diagnosis of sexually transmitted infection; no

consistent use of condoms with sex partner known to be HIV-1 positive.

All subjects received monthly HIV-1 testing, risk-reduction counseling, condoms and management of

sexually transmitted infections. Of the 2499 enrolled, 1251 received tenofovir disoproxil

fumarate/emtricitabine and 1248 received placebo. The mean age of subjects was 27 years, 5% were

Asian, 9% Black, 18% White, and 72% Hispanic/Latino.

Subjects were followed for 4237 person-years. The primary outcome measure for the study was the

incidence of documented HIV seroconversion. At the end of treatment, emergent HIV-1

seroconversion was observed in 131 subjects, of which 48 occurred in the tenofovir disoproxil

fumarate/emtricitabine group and 83 occurred in the placebo group, indicating a 42% (95% CI: 18% to

60%) reduction in risk.

In a post-hoc case control study of plasma and intracellular drug levels in about 10% of study subjects,

risk reduction appeared to be the greatest in subjects with detectable intracellular tenofovir. Efficacy

was therefore strongly correlated with adherence.

Partners PrEP trial

The Partners PrEP trial was a randomised, double-blind, placebo-controlled 3 arm trial conducted in

4758 serodiscordant heterosexual couples in Kenya and Uganda to evaluate the efficacy and safety of

TDF (N=1589) and FTC/TDF (N=1583) versus (parallel comparison) placebo (N=1586), in

preventing HIV-1 acquisition by the uninfected partner.

All subjects received monthly HIV-1 testing, evaluation of adherence, assessment of sexual behavior,

and safety evaluations. Women were also tested monthly for pregnancy. Women who became

pregnant during the trial had study drug interrupted for the duration of the pregnancy and while

breastfeeding. The uninfected partner subjects were predominantly male (61-64% across study drug

groups), and had a mean age of 33-34 years.

Following 7827 person-years of follow up, 82 emergent HIV-1 seroconversions were reported, with an

overall observed seroincidence rate of 1.05 per 100 person-years. Of the 82 seroconversions, 13 and

52 occurred in partner subjects randomised to tenofovir disoproxil fumarate/emtricitabine and placebo,

respectively. Two of the 13 seroconversions in the tenofovir disoproxil fumarate/emtricitabine arm

and 3 of the 52 seroconversions in the placebo arm occurred in women during treatment interruptions

for pregnancy. The risk reduction for tenofovir disoproxil fumarate/emtricitabine relative to placebo

was 75% (95% CI: 55% to 87%). In a post-hoc case control study of plasma drug levels in about 10%

of study subjects, risk reduction appeared to be the greatest in subjects with detectable plasma

tenofovir. Efficacy was therefore strongly correlated with adherence.

Tenofovir disoproxil fumarate

The demonstration of benefit of tenofovir disoproxil fumarate is based on analyses of plasma HIV-1

RNA levels and CD4 cell counts in controlled studies of tenofovir disoproxil fumarate in treatment-

naïve adults and in treatment-experienced adults.

Treatment-experienced patients

Study 907: Tenofovir + Standard Background Therapy (SBT) compared with placebo + SBT

Study 907 was a 24 week, double-blind placebo-controlled multicentre study of tenofovir disoproxil

fumarate added to a stable background regimen of antiretroviral agents in 550 treatment-experienced

patients. After 24 weeks of blinded study treatment, all patients continuing on study were offered

open-label tenofovir disoproxil fumarate for an additional 24 weeks. Patients had a mean baseline

CD4 cell count of 427 cells/mm

(range 23-1385), median baseline plasma HIV RNA of 2340 (range

50–75,000) copies/mL, and mean duration of prior HIV treatment was 5.4 years. Mean age of the

patients was 42 years, 85% were male and 69% were Caucasian, 17% Black and 12% Hispanic.

Changes from baseline in log

copies/mL plasma HIV-1 RNA levels over time up to week 48 are

presented in Figure 1.

Figure 1. Mean Change from Baseline in Plasma HIV-1 RNA (Log

10

Copies/mL) Through Week

48: Study 907 (All Available Data)

The percent of patients with HIV RNA <400 copies/mL and outcomes of patients through 48 weeks

are summarised in Table 15.

Table 15. Outcomes of randomised treatment (Study 907)

Outcomes

0

24 weeks

0

48 weeks

24

48 weeks

Tenofovir

disoproxil

fumarate

(N=368)

%

(95% CI)

Placebo

(N=182)

%

(95% CI)

Tenofovir

disoproxil

fumarate

(N=368)

%

Placebo Crossover

to Tenofovir

disoproxil

fumarate (N=170)

%

HIV RNA <400 copies/mL

(35% to 45%)

(6% to 16%)

Virologic Failure

Discontinued Due to

Adverse Event

Discontinued for Other

Reasons

Patients with HIV RNA <400 copies/mL and no prior study drug discontinuation at weeks 24 and 48

respectively.

Patients with HIV RNA ≥400 copies/mL efficacy failure or missing HIV RNA at weeks 24 and 48

respectively.

Includes lost to follow-up, patient withdrawal, non-compliance, protocol violation and other reasons.

Difference 29% p < 0.001

At 24 weeks of therapy, there was a higher proportion of patients in the tenofovir disoproxil fumarate

arm compared to the placebo arm with HIV RNA <50 copies/mL (19% and 1%, respectively). Mean

change in absolute CD4 counts by week 24 was +12 cells/mm

for the tenofovir group and -5

cells/mm

for the placebo group. Mean change in absolute CD4 counts by week 48 was +4 cells/mm

for the tenofovir disoproxil fumarate group.

Treatment-naïve patients

Study 903: Tenofovir disoproxil fumarate + Lamivudine +Efavirenz compared to Stavudine +

Lamivudine + Efavirenz

Data through 144 weeks are reported for Study 903, a double-blind, active-controlled multicentre

study comparing tenofovir disoproxil fumarate (300 mg once daily) administered in combination with

lamivudine and efavirenz versus d4T, lamivudine, and efavirenz in 600 antiretroviral-naïve patients.

Patients had a mean age of 36 years (range 18–64), 74% were male, 64% were Caucasian and 20%

were Black. The mean baseline CD4 cell count was 279 cells/mm

(range 3–956) and median baseline

plasma HIV-1 RNA was 77,600 copies/mL (range 417–5,130,000). Patients were stratified by baseline

HIV-1 RNA and CD4 count. Forty-three percent of patients had baseline viral loads >100,000

copies/mL and 39% had CD4 cell counts <200 cells/mm

. Treatment outcomes through 144 weeks are

presented in Table 16.

Table 16. Outcomes of Randomised Treatment (Study 903)

Outcomes

At Week 48

At Week 144

Tenofovir

disoproxil

fumarate+

3TC+EFV

(N=299)

d4T+3TC+

EFV

(N=301)

Tenofovir

disoproxil

fumarate+

3TC+EFV

(N=299)

d4T+3TC+E

FV (N=301)

%

%

%

%

Responder

Virologic failure

Rebound

Never suppressed

Added an antiretroviral agent

Death

<1%

<1%

Discontinued due to adverse event

Discontinued for other reasons

Patients achieved and maintained confirmed HIV-1 RNA <400 copies/mL through Weeks 48 and 144.

Includes confirmed viral rebound and failure to achieve confirmed <400 copies/mL through Weeks 48 and

144.

Includes lost to follow-up, patient’s withdrawal, non-compliance, protocol violation and other reasons.

Difference -3.0% (-9.2% to 3.1%) p=0.48. The difference and confidence interval are stratum weighted on

baseline HIV-1 RNA and CD4.

Difference 6.1% (-1.4% to 13.7%) p=0.11. The difference and confidence interval are stratum weighted on

baseline HIV-1 RNA and CD4.

Achievement of plasma HIV-1 RNA concentrations of less than 400 copies/mL at week 144 was

similar between the two treatment groups for the population stratified at baseline on the basis of HIV-1

RNA concentration (≤ or >100,000 copies/mL) and CD4 cell count (< or ≥200 cells/mm

). Through

144 weeks of therapy, 62% and 58% of patients in the tenofovir disoproxil fumarate and d4T arms,

respectively achieved and maintained confirmed HIV-1 RNA <50 copies/mL. The mean increase from

baseline in CD4 cell count was 263 cells/mm

for the tenofovir disoproxil fumarate arm and 283

cells/mm

for the d4T arm.

The proportion of patients who achieved and maintained confirmed HIV RNA <400 using intent-to-

treat analysis through 144 weeks of treatment in study 903 is presented in Figure 2 below.

Genotypic analyses of patients with virologic failure showed development of efavirenz-associated and

lamivudine-associated mutations to occur most frequently and with no difference between the

treatment arms. The K65R mutation occurred in 8 patients on the tenofovir disoproxil fumarate arm

and in 2 patients on the d4T arm. Of the 8 patients who developed K65R in the tenofovir disoproxil

fumarate arm through 144 weeks, 7 of these occurred in the first 48 weeks of treatment and the last

one at week 96. Among these patients, 5/8 patients subsequently gained full virologic control (<50

copies/mL) upon switching to new regimens that included a protease inhibitor in combination with

nucleoside reverse transcriptase inhibitors through a median of 155 weeks of follow-up. From both

genotypic and phenotypic analyses there was no evidence for other pathways of resistance to tenofovir

disoproxil fumarate.

Figure 2. Virologic Response Through Week 144, Study 903*

Genotypic analyses of tenofovir disoproxil fumarate in patients with previous antiretroviral therapy

(Study 902 and 907)

The virologic response to tenofovir disoproxil fumarate therapy has been evaluated with respect to

baseline viral genotype (N=222) in treatment experienced patients participating in trials 902 and 907.

In both of these studies, 94% of the participants evaluated had baseline HIV isolates expressing at

least one NRTI mutation. These included resistance mutations associated with zidovudine (M41L,

D67N, K70R, L210W, T215Y/F or K219Q/E/N), the lamivudine/abacavir-associated mutation

(M184V), and others. In addition the majority of participants evaluated had mutations associated with

either PI or NNRTI use. Virologic responses for patients in the genotype substudy were similar to the

overall results in studies 902 and 907.

Several exploratory analyses were conducted to evaluate the effect of specific mutations and

mutational patterns on virologic outcome. Descriptions of numerical differences in HIV RNA

response are displayed in Table 17. Because of the large number of potential comparisons, statistical

testing was not conducted.

Varying degrees of cross-resistance to tenofovir disoproxil fumarate from pre-existing zidovudine-

associated mutations were observed and appeared to depend on the number and type of mutations.

tenofovir disoproxil fumarate-treated patients whose HIV expressed 3 or more zidovudine-associated

mutations that included either the M41L or L210W reverse transcriptase mutation showed reduced

responses to tenofovir disoproxil fumarate therapy; however, these responses were still improved

compared with placebo. The presence of the D67N, K70R, T215Y/F or K219Q/E/N mutation did not

appear to affect responses to tenofovir disoproxil fumarate therapy. The HIV RNA responses by

number and type of baseline zidovudine-associated mutations are shown in Table 17.

Table 17. HIV RNA Response at Week 24 by Number of Baseline Zidovudine-Associated

Mutations in Studies 902 and 907 (Intent-To-Treat)

1

Number of baseline zidovudine-associated

mutations

2

Change in HIV RNA

3

(N)

Tenofovir disoproxil

fumarate

Placebo

None

-0.80 (68)

-0.11 (29)

-0.50 (154)

0 (81)

1 – 2

-0.66 (55)

-0.04 (33)

≥ 3 including M41L or L210W

-0.21 (57)

+0.01 (29)

≥ 3 without M41L or L210W

-0.67 (42)

+0.07 (19)

Genotypic testing performed by Virco Laboratories and Visible Genetics TruGene

technology

M41L, D67N, K70R, L210W, T215Y/F or K219Q/E/N in RT

Average HIV RNA change from baseline through week 24 (DAVG

) in log

copies/mL

In the protocol defined analyses, virologic response to tenofovir disoproxil fumarate was not reduced

in patients with HIV that expressed the lamivudine/ abacavir-associated M184V mutation. In the

absence of zidovudine-associated mutations, patients with the M184V mutation receiving tenofovir

disoproxil fumarate showed a –0.84 log

copies/mL decrease in their HIV RNA relative to placebo. In

the presence of zidovudine-associated mutations, the M184V mutation did not affect the mean HIV

RNA responses to tenofovir disoproxil fumarate treatment. HIV-1 RNA responses among these

patients were durable through week 48.

There were limited data on patients expressing some primary nucleoside reverse transcriptase inhibitor

mutations and multi-drug resistant mutations at baseline. However, patients expressing mutations at

K65R (N=6), or L74V without zidovudine-associated mutations (N=6) appeared to have reduced

virologic responses to tenofovir disoproxil fumarate.

The presence of at least one HIV protease inhibitor or non-nucleoside reverse transcriptase inhibitor

mutation at baseline did not appear to affect the virologic response to tenofovir disoproxil fumarate.

Cross-resistance between tenofovir disoproxil fumarate and HIV protease inhibitors is unlikely

because of the different enzyme targets involved.

Phenotypic analyses of tenofovir disoproxil fumarate in patients with previous antiretroviral therapy

(Study 902 and 907)

The virologic response to tenofovir disoproxil fumarate therapy has been evaluated with respect to

baseline phenotype (N=100) in treatment experienced patients participating in trials 902 and 907.

Phenotypic analysis of baseline HIV from patients in Studies 902 and 907 demonstrated a correlation

between baseline susceptibility to tenofovir disoproxil fumarate and response to tenofovir disoproxil

fumarate therapy. Table 18 summarises the HIV RNA response by baseline tenofovir disoproxil

fumarate susceptibility.

Table 18. HIV RNA Response at Week 24 by Baseline Tenofovir disoproxil fumarate

Susceptibility in Studies 902 and 907 (Intent-To-Treat)

1

Baseline Tenofovir disoproxil fumarate

Susceptibility

2

Change in HIV RNA

3

(N)

≤ 1

-0.74 (35)

> 1 and ≤ 3

-0.56 (49)

> 3 and ≤ 4

-0.3 (7)

≤ 4

-0.61 (91)

> 4

-0.12 (9)

Tenofovir susceptibility was determined by recombinant phenotypic Antivirogram

assay (Virco)

Fold change in susceptibility from wild-type

Average HIV RNA change from baseline through week 24 (DAVG

) in log

copies/mL

Emtricitabine

Treatment-experienced patients

Study 303: Emtricitabine once daily + Stable Background Therapy (SBT) compared to Lamivudine

twice daily + SBT

Study 303 was a 48 week, open-label, active-controlled multicentre study comparing emtricitabine

(200 mg once daily) to lamivudine, in combination with d4T or zidovudine and a protease inhibitor or

NNRTI in 440 patients who were on a lamivudine-containing triple-antiretroviral drug regimen for at

least 12 weeks prior to study entry and had HIV RNA ≤400 copies/mL.

Patients were randomised 1:2 to continue therapy with lamivudine (150 mg twice daily) or to switch to

emtricitabine (200 mg once daily). All patients were maintained on their stable background regimen.

Patients had a mean age of 42 years (range 22−80), 86% were male, 64% Caucasian, 21% African-

American and 13% Hispanic. Patients had a mean baseline CD4 cell count of 527 cells/mm

(range

37−1909), and a median baseline plasma HIV RNA of 1.7 log

copies/mL (range 1.7−4.0). The

median duration of prior antiretroviral therapy was 27.6 months. Treatment outcomes through

48 weeks are presented in Table 19.

Table 19. Outcomes of randomised treatment at week 48 (Study 303)

Outcome at Week 48

Emtricitabine +

ZDV/d4T + NNRTI/PI

(N=294)

Lamivudine + ZDV/d4T

+ NNRTI/PI

(N=146)

Responder

77% (67%)

82% (72%)

Virologic Failure

Death

<1%

Study Discontinuation Due to Adverse Event

Study Discontinuation For Other Reasons

Patients achieved and maintained confirmed HIV RNA <400 copies/mL (<50 mL) through week 48.

Includes patients who failed to achieve virologic suppression or rebounded after achieving virologic

suppression.

Includes lost to follow-up, patient withdrawal, non-compliance, protocol violation and other reasons.

The mean increase from baseline in CD4 cell count was 29 cells/mm

for the emtricitabine arm and

61 cells/mm

for the lamivudine arm.

Treatment-naïve patients

Study 301A: Emtricitabine once daily + Didanosine once daily + Efavirenz once daily compared to

Stavudine twice daily + Didanosine once daily + Efavirenz once daily

Study 301A was a 48 week double-blind, active-controlled multicentre study comparing emtricitabine

(200 mg once daily) administered in combination with didanosine and efavirenz versus d4T,

didanosine and efavirenz in 571 antiretroviral naïve patients. Patients had a mean age of 36 years

(range 18−69), 85% were male, 52% Caucasian, 16% African-American and 26% Hispanic. Patients

had a mean baseline CD4 cell count of 318 cells/mm

(range 5

−1317) and a median baseline plasma

HIV RNA of 4.9 log

copies/mL (range 2.6−7.0). Thirty-eight percent of patients had baseline viral

loads >100,000 copies/mL and 31% had CD4 cell counts <200 cells/mL. Treatment outcomes through

48 weeks are presented in Table 20.

Table 20. Outcomes of randomised treatment at week 48 (Study 301A)

Outcome at Week 48

Emtricitabine +

Didanosine + Efavirenz

(N=286)

d4T + Didanosine +

Efavirenz

(N=285)

Responder

81% (78%)

68% (59%)

Virologic Failure

Death

<1%

Study Discontinuation Due to Adverse Event

Study Discontinuation For Other Reasons

Patients achieved and maintained confirmed HIV RNA <400 copies/mL (<50 copies/mL) through week 48.

Includes patients who failed to achieve virologic suppression or rebounded after achieving virologic

suppression.

Includes lost to follow-up, patient withdrawal, non-compliance, protocol violation and other reasons.

The mean increase from baseline in CD4 cell count was 168 cells/mm

for the emtricitabine arm and

134 cells/mm

for the d4T arm.

5.2

Pharmacokinetic properties

Pharmacokinetics in adults: Emtricitabine/tenofovir disoproxil fumarate

One tenofovir disoproxil fumarate/emtricitabine Tablet was bioequivalent to one Tenofovir disoproxil

fumarate Tablet (300 mg) plus one Emtricitabine Capsule (200 mg) following single-dose

administration to fasting healthy subjects (N=39).

Tenofovir disoproxil fumarate

The pharmacokinetic properties of tenofovir disoproxil fumarate are summarised in Table 1.

Following oral administration of tenofovir disoproxil fumarate, 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 0.01-25 μg/mL. Approximately

−80% of the in

travenous 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 tenofovir disoproxil fumarate, the terminal elimination half-life of tenofovir is

approximately 17 hours.

Emtricitabine

The pharmacokinetic properties of emtricitabine are summarised in Table 21. Following oral

administration of emtricitabine, emtricitabine is rapidly absorbed with peak plasma concentrations

occurring at 1

−2 hours post

-dose.

In vitro

binding of emtricitabine to human plasma proteins is <4%

and is independent of concentration over the range of 0.02−200 μg/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 emtricitabine, the plasma emtricitabine half-life is

approximately 10 hours.

Table 21. Single Dose Pharmacokinetic Parameters for Tenofovir and Emtricitabine in Adults

1

Tenofovir

Emtricitabine

Fasted Oral Bioavailability (%)

Plasma Terminal Elimination Half-Life (hr)

C

max

(μg/mL)

0.30 ± 0.09

1.8 ± 0.7

AUC (μg*hr/mL)

2.29 ± 0.69

10.0 ± 3.1

CL/F (mL/min)

1043 ± 115

302 ± 94

CLrenal (mL/min)

243 ± 33

213 ± 89

Data presented as mean values.

Data presented as steady state values.

Effects of food on oral absorption

Administration of tenofovir disoproxil fumarate/emtricitabine following a high fat meal

−1000

kcal containing 40

−60% fat) delayed the

time of tenofovir C

by approximately

0.75 hour. An increase in tenofovir AUC of approximately 40% and an increase in C

approximately 14% were observed. Similar findings were observed when tenofovir disoproxil

fumarate/emtricitabine was administered with a light meal. Emtricitabine systemic exposures (AUC

and C

) were unaffected when tenofovir disoproxil fumarate/emtricitabine was administered with

either a high fat or a light meal (see section 4.2).

Age and gender

Children and geriatric patients

Pharmacokinetics of tenofovir and emtricitabine have not been fully evaluated in children (<18 years)

or in the elderly (>65 years) (see section 4.4).

Gender

Tenofovir and emtricitabine pharmacokinetics are similar in male and female patients.

Patients with impaired renal function

The pharmacokinetics of tenofovir and emtricitabine are altered in subjects with renal impairment (see

section 4.4). In subjects with creatinine clearance <50 mL/min, or with end-stage renal disease

(ESRD) requiring dialysis, C

, and AUC

0-∞

of tenofovir and emtricitabine were increased. It is

required that the dosing interval for tenofovir disoproxil fumarate/emtricitabine be modified in HIV-1

infected patients with creatinine clearance <60 mL/min (see section 4.2). Tenofovir disoproxil

fumarate/emtricitabine should not be used in patients with creatinine clearance <30 mL/min and in

patients with end-stage renal disease requiring dialysis (see section 4.4).

Tenofovir disoproxil fumarate/emtricitabine for a PrEP indication should not be used in HIV-1

uninfected individuals with estimated creatinine clearance below 60 mL/min. If a decrease in

estimated creatinine clearance is observed in uninfected individuals while using tenofovir disoproxil

fumarate/emtricitabine for PrEP, evaluate potential causes and re-assess potential risks and benefits of

continued use (see section 4.2).

Patients with hepatic impairment

Tenofovir disoproxil fumarate/emtricitabine

The pharmacokinetics of tenofovir following a 300 mg dose of tenofovir disoproxil fumarate 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 tenofovir disoproxil fumarate/emtricitabine or

emtricitabine have not been studied in patients with hepatic impairment; however, emtricitabine is not

significantly metabolised by liver enzymes, so the impact of liver impairment should be limited.

5.3

Preclinical safety data

Tenofovir and tenofovir disoproxil fumarate 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–

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 data available.

Carcinogenicity

No carcinogenicity studies have been conducted with tenofovir disoproxil fumarate and emtricitabine

in combination. In a long-term carcinogenicity study conducted in mice with tenofovir disoproxil

fumarate 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 gastro-intestinal 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).

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).

Mutagenicity

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

clastogenic in the mouse micronucleus test

in vivo

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

CIPLA TENOFOVIR + EMTRICITABINE 300/200 tablets contain the following ingredients as

excipients:

Tablet core

Croscarmellose sodium,

Lactose monohydrate,

Magnesium stearate,

Microcrystalline cellulose,

Pregelatinised starch.

Film-coating

Hypromellose,

Indigo carmine aluminium lake,

Lactose monohydrate,

Titanium dioxide,

Triacetin.

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

Store below 30°C.

Discard any remaining product 30 days after first opening of the bottle.

6.5

Nature and contents of container

CIPLA TENOFOVIR + EMTRICITABINE 300/200 is supplied in 75 CC white HDPE container with

38 mm white child-resistant PP cap with four silica gel bags of 1 gm each containing 30 tablets.

6.6

Special precautions for disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local

pharmacy.

6.7

Physiochemical properties

Description

Tenofovir disoproxil fumarate is a white to off-white crystalline powder.

Emtricitabine is a white to almost white crystalline powder.

Chemical structure

Tenofovir disoproxil fumarate

Tenofovir disoproxil fumarate is a fumaric acid salt of the

bis

-isopropoxycarbonyloxymethyl ester

derivative of tenofovir. The chemical name of tenofovir disoproxil fumarate is 9-[(

R

[[bis[[(isopropoxycarbonyl)oxy] methoxy]phosphinyl] methoxy]propyl]adenine fumarate (1:1). It has

a molecular formula of C

P C

and a molecular weight of 635.52. It has the following

structural formula:

Emtricitabine

The chemical name of emtricitabine is 5-fluoro-1-(2

R

S

)-[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 C

S and a molecular weight of 247.24. It has the following

structural formula:

CAS number

Tenofovir disoproxil fumarate CAS registry number: 202138-50-9

Emtricitabine CAS registry number: 143491-57-0

7.

MEDICINE SCHEDULE (POISONS STANDARD)

Prescription only medicine (Schedule 4).

8.

SPONSOR

Cipla Australia Pty Ltd.,

Level 1 / 132-136 Albert road,

SOUTH MELBOURNE VIC 3205.

drugsafety@cipla.com

Phone: 1800-569-074

9.

DATE OF FIRST APPROVAL

09 December 2020

10.

DATE OF REVISION

19 March 2021

SUMMARY TABLE OF CHANGES

Section changed

Summary of new information

NA

NA: Not Applicable.

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Public Summary

Summary for ARTG Entry:

327898

CIPLA TENOFOVIR + EMTRICITABINE 300/200 Tenofovir disoproxil fumarate 300 mg and emtricitabine

200 mg tablet bottle pack

ARTG entry for

Medicine Registered

Sponsor

Cipla Australia Pty Ltd

Postal Address

Level 1 / 132-136 Albert Road, SOUTH MELBOURNE, VIC, 3205

Australia

ARTG Start Date

9/12/2020

Product Category

Medicine

Status

Active

Approval Area

Drug Safety Evaluation Branch

Conditions

Conditions applicable to all therapeutic goods as specified in the document "Standard Conditions Applying to Registered or Listed Therapeutic Goods Under

Section 28 of the Therapeutic Goods Act 1989" effective 1 July 1995.

Conditions applicable to the relevant category and class of therapeutic goods as specified in the document "Standard Conditions Applying to Registered or

Listed Therapeutic Goods Under Section 28 of the Therapeutic Goods Act 1989" effective 1 July 1995.

Products

1 . CIPLA TENOFOVIR + EMTRICITABINE 300/200 Tenofovir disoproxil fumarate 300 mg and emtricitabine 200

mg tablet bottle pack

Product Type

Single Medicine Product

Effective Date

9/12/2020

Permitted Indications

No Permitted Indications included on Record

Indication Requirements

No Indication Requirements included on Record

Standard Indications

No Standard Indications included on Record

Specific Indications

<p><b>Treatment of HIV-1 infection: </b>CIPLA TENOFOVIR + EMTRICITABINE 300/200 is indicated for the treatment of HIV infected adults over the age

of 18 years, in combination with other antiretroviral agents.</p> <p><b>Pre-exposure prophylaxis: </b>CIPLA TENOFOVIR + EMTRICITABINE 300/200 is

indicated in combinatin with safer sex practices for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 in adults at high risk. This

indication is based on clinical trials in men who have sex with men (MSM) at high risk for HIV-1 infection and in heterosexual serodiscordant couples.</p>

Warnings

See Product Information and Consumer Medicine Information for this product

Additional Product information

Container information

Type

Material

Life Time

Temperature

Closure

Conditions

Bottle

HDPE

18 Months

Store below 30

degrees Celsius

Child resistant closure

Not recorded

Pack Size/Poison information

Pack Size

Poison Schedule

30 tablets

(S4) Prescription Only Medicine

Components

1 . CIPLA TENOFOVIR + EMTRICITABINE 300/200 Tenofovir disoproxil fumarate 300 mg and emtricitabine 200 mg tablet bottle pack

Dosage Form

Tablet, film coated

Route of Administration

Oral

Visual Identification

Blue coloured capsule shaped, biconvex film-coated tablet, plain on both sides

Active Ingredients

emtricitabine

200 mg

Public Summary

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Visit www.tga.gov.au for contact information

tenofovir disoproxil fumarate

300 mg

Other Ingredients (Excipients)

croscarmellose sodium

hypromellose

indigo carmine aluminium lake

lactose monohydrate

magnesium stearate

microcrystalline cellulose

pregelatinised starch

titanium dioxide

triacetin

© Commonwealth of Australia. This work is copyright. You are not permitted to re-transmit, distribute or commercialise the material without obtaining prior

written approval from the Commonwealth. Further details can be found at http://www.tga.gov.au/about/website-copyright.htm.

Public Summary

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Visit www.tga.gov.au for contact information

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