Odefsey 200mg25mg25mg tablets

United Kingdom - English - MHRA (Medicines & Healthcare Products Regulatory Agency)

Buy It Now

Active ingredient:
Tenofovir alafenamide fumarate; Rilpivirine hydrochloride; Emtricitabine
Available from:
Gilead Sciences International Ltd
INN (International Name):
Tenofovir alafenamide fumarate; Rilpivirine hydrochloride; Emtricitabine
Dosage:
25mg ; 25mg ; 200mg
Pharmaceutical form:
Tablet
Administration route:
Oral
Class:
No Controlled Drug Status
Prescription type:
Never Valid To Prescribe As A VMP
Product summary:
BNF: 05030100

Read the complete document

B. PACKAGE LEAFLET

Package leaflet: Information for the user

Odefsey 200 mg/25 mg/25 mg film-coated tablets

emtricitabine/rilpivirine/tenofovir alafenamide

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

safety information. You can help by reporting any side effects you may get. See the end of section 4

for how to report side effects.

Read all of this leaflet carefully before you start taking this medicine because it contains

important information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or pharmacist.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm them,

even if their signs of illness are the same as yours.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side

effects not listed in this leaflet. See section 4.

What is in this leaflet

What Odefsey is and what it is used for

What you need to know before you take Odefsey

How to take Odefsey

Possible side effects

How to store Odefsey

Contents of the pack and other information

1.

What Odefsey is and what it is used for

Odefsey is an antiviral medicine used to treat infection by the Human Immunodeficiency

Virus (HIV). It is a single tablet that contains a combination of three active substances:

emtricitabine, rilpivirine and tenofovir alafenamide. Each of these active substances works by

interfering with an enzyme called ‘reverse transcriptase’, which is essential for the HIV-1 virus to

multiply.

Odefsey reduces the amount of HIV in your body. This will improve your immune system and reduce

the risk of developing illnesses linked to HIV infection.

Odefsey is used in adults and adolescents aged 12 years and older, who weigh at least 35 kg.

2.

What you need to know before you take Odefsey

Do not take Odefsey:

If you are allergic to emtricitabine, rilpivirine, tenofovir alafenamide or any of the other

ingredients of this medicine (listed in section 6).

If you are currently taking any of the following medicines:

carbamazepine, oxcarbazepine, phenobarbital and phenytoin (used to treat epilepsy

and prevent seizures)

rifabutin, rifampicin and rifapentine (used to treat some bacterial infections such as

tuberculosis)

omeprazole, dexlansoprazole, lansoprazole, rabeprazole, pantoprazole and

esomeprazole (used to prevent and treat stomach ulcers, heartburn, acid reflux disease)

dexamethasone (a corticosteroid medicine used to treat inflammation and suppress the

immune system) when taken by mouth or injected (except as a single dose treatment)

products that contain St. John’s wort (Hypericum perforatum) (a herbal remedy used

for depression and anxiety)

If this applies to you, do not take Odefsey and tell your doctor immediately.

Warnings and precautions

You must remain under the care of your doctor while taking Odefsey.

You can still pass on HIV when taking this medicine, although the risk is lowered by effective

antiretroviral therapy. Discuss with your doctor the precautions needed to avoid infecting other

people. This medicine is not a cure for HIV infection. While taking Odefsey you may still develop

infections or other illnesses associated with HIV infection.

Talk to your doctor before taking Odefsey:

If you have liver problems or a history of liver disease, including hepatitis. Patients with

liver disease including chronic hepatitis B or C, who are treated with antiretrovirals, have a

higher risk of severe and potentially fatal liver complications. If you have hepatitis B infection,

your doctor will carefully consider the best treatment regimen for you.

If you have hepatitis B infection, liver problems may become worse after you stop taking

Odefsey. It is important not to stop taking Odefsey without talking to your doctor: see

section 3, Do not stop taking Odefsey.

If you are taking any medicines that may cause a life-threatening irregular heartbeat (torsades

de pointes).

While you are taking Odefsey

Once you start taking Odefsey, look out for:

Signs of inflammation or infection

Joint pain, stiffness or bone problems

If you notice any of these symptoms, tell your doctor immediately. For more information see

section 4, Possible side effects.

It is possible that in the future, long-term users of Odefsey may get kidney problems.

Children and adolescents

Do not give this medicine to children aged 11 years or under, or weighing less than 35 kg. The

use of Odefsey in children aged 11 years or under or weighing less than 35 kg has not yet been

studied.

Other medicines and Odefsey

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other

medicines. Odefsey may interact with other medicines. As a result, the amounts of Odefsey or other

medicines in your blood may be affected. This may stop your medicines from working properly, or

may make any side effects worse. In some cases, your doctor may need to adjust your dose or check

your blood levels.

Medicines that must never be taken with Odefsey:

carbamazepine, oxcarbazepine, phenobarbital and phenytoin (used to treat epilepsy

and prevent seizures)

rifabutin, rifampicin and rifapentine (used to treat some bacterial infections such as

tuberculosis)

omeprazole, dexlansoprazole, lansoprazole, rabeprazole, pantoprazole and

esomeprazole (used to prevent and treat stomach ulcers, heartburn, acid reflux disease)

dexamethasone (a corticosteroid medicine used to treat inflammation and suppress the

immune system) when taken by mouth or injected (except as a single dose treatment)

products that contain St. John’s wort (Hypericum perforatum) (a herbal remedy used

for depression and anxiety)

If you are taking any of these medicines, do not take Odefsey and tell your doctor immediately.

Other types of medicine:

Talk to your doctor if you are taking:

Any medicines used for treating HIV

Any medicines containing:

tenofovir alafenamide

tenofovir disoproxil

lamivudine

adefovir dipivoxil

Antibiotics used to treat bacterial infections containing:

clarithromycin

erythromycin

These medicines can increase the amount of rilpivirine (a component of Odefsey) in your blood.

Your doctor will give you a different medicine.

Antifungal medicines used to treat fungal infections:

ketoconazole

fluconazole

itraconazole

posaconazole

voriconazole

These medicines can increase the amount of rilpivirine and tenofovir alafenamide (components

of Odefsey) in your blood. Your doctor will give you a different medicine.

Antiviral medicines used to treat hepatitis C containing:

boceprevir

These medicines can decrease the amount of tenofovir alafenamide (a component of Odefsey) in

your blood. Your doctor will give you a different medicine.

Medicines for stomach ulcers, heartburn or acid reflux such as:

antacids (aluminium/magnesium hydroxide or calcium carbonate)

H

2

-antagonists (famotidine, cimetidine, nizatidine or ranitidine)

These medicines can decrease the amount of rilpivirine (a component of Odefsey) in your

blood. If you are taking one of these medicines your doctor will either give you a different

medicine, or recommend how and when you take that medicine:

If you are taking an antacid, take it at least 2 hours before or at least 4 hours after

Odefsey.

If you are taking an H

2

-antagonist, take it at least 12 hours before or at least 4 hours

after Odefsey. H

-antagonists can only be taken once a day if you take Odefsey.

-antagonists should not be taken in a twice a day regimen. Talk to your doctor about

an alternative regimen (see How to take Odefsey).

Ciclosporin, a medicine used to reduce the strength of the body’s immune system:

This medicine can increase the amount of rilpivirine and tenofovir alafenamide (components of

Odefsey) in your blood. Your doctor will give you a different medicine.

Methadone, a medicine used to treat opiate addiction, as your doctor may need to change your

methadone dose.

Dabigatran etexilate, a medicine used to treat heart conditions, as your doctor may need to

monitor the levels of this medicine in your blood.

Tell your doctor if you are taking any of these medicines. Do not stop your treatment without

contacting your doctor.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby,

ask your doctor for advice before taking this medicine.

Use effective contraception while taking Odefsey.

Ask your doctor or pharmacist for advice before taking any medicine when pregnant.

If you have taken Odefsey during your pregnancy, your doctor may request regular blood tests and

other diagnostic tests to monitor the development of your child. In children whose mothers took

nucleoside reverse transcriptase inhibitors (NRTIs) during pregnancy, the benefit from the protection

against HIV outweighed the risk of side effects.

Do not breast-feed during treatment with Odefsey. This is because some of the active substances

in this medicine pass into human breast milk. It is also recommended that you do not breast-feed to

avoid passing the virus to the baby in breast milk.

Driving and using machines

Do not drive or operate machines if you feel tired, sleepy or dizzy after taking your medicine.

Odefsey contains lactose

Tell your doctor if you are lactose intolerant or intolerant to other sugars. Odefsey contains

lactose monohydrate. If you are lactose intolerant, or if you have been told that you have an

intolerance to other sugars, talk to your doctor before taking this medicine.

If any of these applies to you, talk to your doctor before taking Odefsey.

3.

How to take Odefsey

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist

if you are not sure.

The recommended dose is:

Adults: one tablet each day with food

Adolescents 12 years of age and older, who weigh at least 35 kg: one tablet each day with food

Do not chew, crush or split the tablet.

If you are taking an antacid such as aluminium/magnesium hydroxide, or calcium carbonate, take it

at least 2 hours before or at least 4 hours after Odefsey.

If you are taking an H

2

-antagonist such as famotidine, cimetidine, nizatidine or ranitidine, take it at

least 12 hours before or at least 4 hours after Odefsey. H

-antagonists can only be taken once a day if

you take Odefsey. H

-antagonists should not be taken twice a day. Talk to your doctor about an

alternative regimen.

If you take more Odefsey than you should

If you accidentally take more than the recommended dose of Odefsey you may be at increased risk of

experiencing possible side effects with this medicine (see section 4, Possible side effects).

Contact your doctor or nearest emergency department immediately for advice. Keep or take the tablet

bottle with you so that you can easily describe what you have taken.

If you forget to take Odefsey

It is important not to miss a dose of Odefsey.

If you do miss a dose:

If you notice within 12 hours of the time you usually take Odefsey, you must take the tablet as

soon as possible. Always take the tablet with food. Then take the next dose as usual.

If you notice 12 hours or more after the time you usually take Odefsey, then do not take the

missed dose. Wait and take the next dose, with food, at your usual time.

If you vomit less than 4 hours after taking Odefsey, take another tablet with food. If you vomit

more than 4 hours after taking Odefsey you do not need to take another tablet until your next

regularly scheduled tablet.

Do not stop taking Odefsey

Do not stop taking Odefsey without talking to your doctor. Stopping Odefsey can seriously affect

your response to future treatment. If Odefsey is stopped for any reason, speak to your doctor before

you restart taking Odefsey tablets.

When your supply of Odefsey starts to run low, get more from your doctor or pharmacist. This is

very important because the amount of virus may start to increase if the medicine is stopped for even a

short time. The disease may then become harder to treat.

If you have both HIV infection and hepatitis B, it is especially important not to stop your Odefsey

treatment without talking to your doctor first. You may require blood tests for several months after

stopping treatment. In some patients with advanced liver disease or cirrhosis, stopping treatment is not

recommended as this may lead to worsening of your hepatitis, which may be life-threatening.

Tell your doctor immediately about new or unusual symptoms after you stop treatment,

particularly symptoms you associate with hepatitis B infection.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Possible side effects: tell a doctor immediately

Any signs of inflammation or infection. In some patients with advanced HIV infection

(AIDS) and a history of opportunistic infections (infections that occur in people with a weak

immune system), signs and symptoms of inflammation from previous infections may occur soon

after HIV treatment is started. It is thought that these symptoms are due to an improvement in

the body’s immune response, enabling the body to fight infections that may have been present

with no obvious symptoms.

Autoimmune disorders, when the immune system attacks healthy body tissue, may also occur

after you start taking medicines for HIV infection. Autoimmune disorders may occur many

months after the start of treatment. Look out for any symptoms of infection or other symptoms

such as:

muscle weakness

weakness beginning in the hands and feet and moving up towards the trunk of the body

palpitations, tremor or hyperactivity

If you notice these or any symptoms of inflammation or infection, tell your doctor

immediately.

Very common side effects

(may affect more than 1 in 10 people)

difficulty sleeping (insomnia)

headache

dizziness

feeling sick (nausea)

Tests may also show:

increased levels of cholesterol and/or pancreatic amylase (a digestive enzyme) in the blood

increased levels of liver enzymes in the blood

Common side effects

(may affect up to 1 in 10 people)

decreased appetite

depression

abnormal dreams

sleep disorders

depressed mood

feeling sleepy (somnolence)

tiredness

stomach pain or discomfort

being sick (vomiting)

feeling bloated

dry mouth

wind (flatulence)

diarrhoea

rash

Tests may also show:

low white blood cell count (a reduced white blood cell count can make you more prone to

infection)

low platelet count (a type of blood cell involved in clotting blood)

decrease in haemoglobin in your blood

increased fatty acids (triglycerides), bilirubin or lipase in the blood

Uncommon side effects

(may affect up to 1 in 100 people)

signs or symptoms of inflammation or infection

low red blood cell count (anaemia)

severe skin reactions including rash accompanied by fever, swelling and liver problems

problems with digestion resulting in discomfort after meals

swelling of the face, lips, tongue or throat (angioedema)

itching (pruritus)

joint pain (arthralgia)

If any of the side effects get serious tell your doctor.

Other effects that may be seen during HIV treatment

The frequency of the following side effects is not known (frequency cannot be estimated from the

available data).

Bone problems. Some patients taking combination antiretroviral medicines such as Odefsey

may develop a bone disease called osteonecrosis (death of bone tissue caused by loss of blood

supply to the bone). Taking this type of medicine for a long time, taking corticosteroids,

drinking alcohol, having a very weak immune system, and being overweight, may be some of

the many risk factors for developing this disease. Signs of osteonecrosis are:

joint stiffness

joint aches and pains (especially of the hip, knee and shoulder)

difficulty with movement

If you notice any of these symptoms tell your doctor.

During HIV therapy there may be an increase in weight and in levels of blood lipids and glucose. This

is partly linked to restored health and life style, and in the case of blood lipids sometimes to the HIV

medicines themselves. Your doctor will test for these changes.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects

not listed in this leaflet. You can also report side effects directly via the national reporting system:

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple

App Store

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: medsafety@hpra.ie

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

By reporting side effects you can help provide more information on the safety of this medicine.

5.

How to store Odefsey

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and bottle after {EXP}.

The expiry date refers to the last day of that month.

Store in the original package in order to protect from moisture. Keep the bottle tightly closed.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to

throw away medicines you no longer use. These measures will help protect the environment.

6.

Contents of the pack and other information

What Odefsey contains

The active substances are emtricitabine, rilpivirine and tenofovir alafenamide. Each Odefsey tablet

contains 200 mg of emtricitabine, rilpivirine hydrochloride equivalent to 25 mg of rilpivirine and

tenofovir alafenamide fumarate equivalent to 25 mg of tenofovir alafenamide.

The other ingredients are

Tablet core:

Croscarmellose sodium, lactose (as monohydrate), magnesium stearate, microcrystalline cellulose,

polysorbate 20, povidone.

Film-coating:

Macrogol, polyvinyl alcohol, talc, titanium dioxide (E171), iron oxide black (E172).

What Odefsey looks like and contents of the pack

Odefsey is a grey, capsule-shaped, film-coated tablet debossed on one side with “GSI” and “255” on

the other side. Odefsey comes in bottles of 30 tablets and in packs made up of 3 bottles, each

containing 30 tablets. Each bottle contains a silica gel desiccant that must be kept in the bottle to help

protect your tablets. The silica gel desiccant is contained in a separate sachet or canister and should

not be swallowed.

Not all pack sizes may be marketed.

Marketing Authorisation Holder:

Gilead Sciences Ireland UC

Carrigtohill

County Cork, T45 DP77

Ireland

Manufacturer:

Gilead Sciences Ireland UC

IDA Business and Technology Park

Carrigtohill

County Cork

Ireland

For any information about this medicine, please contact the local representative of the Marketing

Authorisation Holder:

België/Belgique/Belgien

Gilead Sciences Belgium SPRL-BVBA

Tél/Tel: + 32 (0) 24 01 35 50

Lietuva

Gilead Sciences Poland Sp. z o.o.

Tel.: +48 22 262 8702

България

Gilead Sciences Ireland UC

Тел.: + 353 (0) 1 686 1888

Luxembourg/Luxemburg

Gilead Sciences Belgium SPRL-BVBA

Tél/Tel: + 32 (0) 24 01 35 50

Česká republika

Gilead Sciences s.r.o.

Tel: + 420 (0) 910 871 986

Magyarország

Gilead Sciences Ireland UC

Tel.: + 353 (0) 1 686 1888

Danmark

Gilead Sciences Sweden AB

Tlf: + 46 (0) 8 5057 1849

Malta

Gilead Sciences Ireland UC

Tel: + 353 (0) 1 686 1888

Deutschland

Gilead Sciences GmbH

Tel: + 49 (0) 89 899890-0

Nederland

Gilead Sciences Netherlands B.V.

Tel: + 31 (0) 20 718 36 98

Eesti

Gilead Sciences Poland Sp. z o.o.

Tel.: +48 22 262 8702

Norge

Gilead Sciences Sweden AB

Tlf: + 46 (0) 8 5057 1849

Ελλάδα

Gilead Sciences Ελλάς Μ.ΕΠΕ.

Τηλ: + 30 (0) 210 8930 100

Österreich

Gilead Sciences GesmbH

Tel: + 43 (0) 1 260 830

España

Gilead Sciences, S.L.

Tel: + 34 (0) 91 378 98 30

Polska

Gilead Sciences Poland Sp. z o.o.

Tel.: +48 22 262 8702

France

Gilead Sciences

Tél: + 33 (0) 1 46 09 41 00

Portugal

Gilead Sciences, Lda.

Tel: + 351 (0) 21 7928790

Hrvatska

Gilead Sciences Ireland UC

Tel: + 353 (0) 1 686 1888

România

Gilead Sciences Ireland UC

Tel: + 353 (0) 1 686 1888

Ireland

Gilead Sciences Ireland UC

Tel: +353 (0) 214 825 999

Slovenija

Gilead Sciences Ireland UC

Tel: + 353 (0) 1 686 1888

Ísland

Gilead Sciences Sweden AB

Sími: + 46 (0) 8 5057 1849

Slovenská republika

Gilead Sciences Slovakia s.r.o.

Tel: + 421 (0) 232 121 210

Italia

Gilead Sciences S.r.l.

Tel: + 39 (0) 02 439201

Suomi/Finland

Gilead Sciences Sweden AB

Puh/Tel: + 46 (0) 8 5057 1849

Κύπρος

Gilead Sciences Ελλάς Μ.ΕΠΕ.

Τηλ: + 30 (0) 210 8930 100

Sverige

Gilead Sciences Sweden AB

Tel: + 46 (0) 8 5057 1849

Latvija

Gilead Sciences Poland Sp. z o.o.

Tel.: +48 22 262 8702

United Kingdom

Gilead Sciences Ltd.

Tel: + 44 (0) 8000 113 700

This leaflet was last revised in 05/2018.

Detailed information on this medicine is available on the European Medicines Agency web site:

http://www.ema.europa.eu.

Read the complete document

Object 1

Odefsey 200 mg/25 mg/25 mg film-coated tablets

Summary of Product Characteristics Updated 30-May-2018 | Gilead Sciences Ltd

This medicinal product is subject to additional monitoring. This will allow quick identification of

new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See

section 4.8 for how to report adverse reactions.

1. Name of the medicinal product

Odefsey 200 mg/25 mg/25 mg film-coated tablets

2. Qualitative and quantitative composition

Each film-coated tablet contains 200 mg of emtricitabine, rilpivirine hydrochloride equivalent to 25 mg of

rilpivirine and tenofovir alafenamide fumarate equivalent to 25 mg of tenofovir alafenamide.

Excipients with known effect

Each tablet contains 189.8 mg lactose monohydrate.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Film-coated tablet.

Grey, capsule-shaped, film-coated tablets, of dimensions 15 mm x 7 mm, debossed with “GSI” on one

side of the tablet and “255” on the other side of the tablet.

4. Clinical particulars

4.1 Therapeutic indications

Odefsey is indicated for the treatment of adults and adolescents (aged 12 years and older with body

weight at least 35 kg) infected with human immunodeficiency virus-1 (HIV-1) without known mutations

associated with resistance to the non-nucleoside reverse transcriptase inhibitor (NNRTI) class, tenofovir

or emtricitabine and with a viral load ≤ 100,000 HIV-1 RNA copies/mL (see sections 4.2, 4.4 and 5.1).

4.2 Posology and method of administration

Therapy should be initiated by a physician experienced in the management of HIV infection.

Posology

Adults and adolescents aged 12 years and older, weighing at least 35 kg

One tablet to be taken once daily with food (see section 5.2).

If the patient misses a dose of Odefsey within 12 hours of the time it is usually taken, the patient should

take Odefsey with food as soon as possible and resume the normal dosing schedule. If a patient misses a

dose of Odefsey by more than 12 hours, the patient should not take the missed dose and simply resume

the usual dosing schedule.

If the patient vomits within 4 hours of taking Odefsey another tablet should be taken with food. If a

patient vomits more than 4 hours after taking Odefsey they do not need to take another dose of Odefsey

until the next regularly scheduled dose.

Elderly

No dose adjustment of Odefsey is required in elderly patients (see section 5.2).

Renal impairment

No dose adjustment of Odefsey is required in adults or in adolescents (aged at least 12 years and of at

least 35 kg body weight) with estimated creatinine clearance (CrCl) ≥ 30 mL/min.

Odefsey should not be initiated in patients with estimated CrCl < 30 mL/min, as there are no data

available regarding the use of Odefsey in this population (see sections 5.1 and 5.2).

Odefsey should be discontinued in patients with estimated creatinine clearance that declines below 30

mL/min during treatment (see sections 5.1 and 5.2).

Hepatic impairment

No dose adjustment of Odefsey is required in patients with mild (Child Pugh Class A) or moderate (Child

Pugh Class B) hepatic impairment. Odefsey should be used with caution in patients with moderate hepatic

impairment. Odefsey has not been studied in patients with severe hepatic impairment (Child Pugh Class

C); therefore, Odefsey is not recommended for use in patients with severe hepatic impairment (see

sections 4.4 and 5.2).

Paediatric population

The safety and efficacy of Odefsey in children younger than 12 years of age, or weighing < 35 kg, have

not yet been established. No data are available.

Pregnancy

Lower exposures of rilpivirine (one of the components of Odefsey) were observed during pregnancy;

therefore viral load should be monitored closely. Alternatively, switching to another antiretroviral

regimen could be considered (see sections 4.4, 4.6, 5.1 and 5.2).

Method of administration

Odefsey should be taken orally, once daily with food (see section 5.2). The film-coated tablet should not

be chewed, crushed or split.

4.3 Contraindications

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

Odefsey should not be co-administered with medicinal products that can result in significant decreases in

rilpivirine plasma concentrations (due to cytochrome P450 [CYP]3A enzyme induction or gastric pH

increase), which may result in loss of therapeutic effect of Odefsey (see section 4.5), including:

Carbamazepine, oxcarbazepine, phenobarbital, phenytoin

Rifabutin, rifampicin, rifapentine

Omeprazole, esomeprazole, dexlansoprazole, lansoprazole, pantoprazole, rabeprazole

Dexamethasone (oral and parenteral doses), except as a single dose treatment

St. John's wort (Hypericum perforatum).

4.4 Special warnings and precautions for use

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

risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should

be taken in accordance with national guidelines.

Virologic failure and development of resistance

There are insufficient data to justify the use in patients with prior NNRTI failure. Resistance testing

and/or historical resistance data should guide the use of Odefsey (see section 5.1).

In the pooled efficacy analysis from the two Phase 3 clinical studies in adults (C209 [ECHO] and C215

[THRIVE]) through 96 weeks, patients treated with emtricitabine/tenofovir disoproxil fumarate +

rilpivirine with a baseline viral load > 100,000 HIV-1 RNA copies/mL had a greater risk of virologic

failure (17.6% with rilpivirine versus 7.6% with efavirenz) compared to patients with a baseline viral load

≤ 100,000 HIV-1 RNA copies/mL (5.9% with rilpivirine versus 2.4% with efavirenz). The virologic

failure rate in patients treated with emtricitabine/tenofovir disoproxil fumarate + rilpivirine at Week 48

and Week 96 was 9.5% and 11.5% respectively, and 4.2% and 5.1% in the emtricitabine/tenofovir

disoproxil fumarate + efavirenz arm. The difference in the rate of new virologic failures from the Week

48 to Week 96 analysis between rilpivirine and efavirenz arms was not statistically significant. Patients

with a baseline viral load > 100,000 HIV-1 RNA copies/mL who experienced virologic failure exhibited a

higher rate of treatment emergent resistance to the NNRTI class. More patients who failed virologically

on rilpivirine than who failed virologically on efavirenz developed lamivudine/emtricitabine associated

resistance (see section 5.1).

Findings in adolescents (12 to less than 18 years of age) in Study C213 were generally in line with these

data (for details see section 5.1).

Only adolescents deemed likely to have good adherence to antiretroviral therapy should be treated with

rilpivirine, as suboptimal adherence can lead to development of resistance and the loss of future treatment

options.

Cardiovascular

At supratherapeutic doses (75 mg once daily and 300 mg once daily), rilpivirine has been associated with

prolongation of the QTc interval of the electrocardiogram (ECG) (see sections 4.5, and 4.9). Rilpivirine at

the recommended dose of 25 mg once daily is not associated with a clinically relevant effect on QTc.

Odefsey should be used with caution when co-administered with medicinal products with a known risk of

Torsade de Pointes.

Patients co-infected with HIV and hepatitis B or C virus

Patients with chronic hepatitis B or C treated with antiretroviral therapy are at an increased risk for severe

and potentially fatal hepatic adverse reactions.

The safety and efficacy of Odefsey in patients co-infected with HIV-1 and hepatitis C virus (HCV) have

not been established.

Tenofovir alafenamide is active against hepatitis B virus (HBV). Discontinuation of Odefsey therapy in

patients co-infected with HIV and HBV may be associated with severe acute exacerbations of hepatitis.

Patients co-infected with HIV and HBV who discontinue Odefsey should be closely monitored with both

clinical and laboratory follow-up for at least several months after stopping treatment.

Liver disease

The safety and efficacy of Odefsey in patients with significant underlying liver disorders have not been

established.

Patients with pre-existing liver dysfunction, including chronic active hepatitis, have an increased

frequency of liver function abnormalities during combination antiretroviral therapy (CART) and should

be monitored according to standard practice. If there is evidence of worsening liver disease in such

patients, interruption or discontinuation of treatment must be considered.

Weight and metabolic parameters

An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy.

Such changes may in part be linked to disease control and life style. For lipids, there is in some cases

evidence for a treatment effect, while for weight gain there is no strong evidence relating this to any

particular treatment. For monitoring of blood lipids and glucose reference is made to established HIV

treatment guidelines. Lipid disorders should be managed as clinically appropriate.

Mitochondrial dysfunction following exposure

in utero

Nucleos(t)ide analogues may impact mitochondrial function to a variable degree, which is most

pronounced with stavudine, didanosine and zidovudine. There have been reports of mitochondrial

dysfunction in HIV negative infants exposed in utero and/or postnatally to nucleoside analogues; these

have predominantly concerned treatment with regimens containing zidovudine. The main adverse

reactions reported are haematological disorders (anaemia, neutropenia) and metabolic disorders

(hyperlactatemia, hyperlipasemia). These events have often been transitory. Late onset neurological

disorders have been reported rarely (hypertonia, convulsion, abnormal behaviour). Whether such

neurological disorders are transient or permanent is currently unknown. These findings should be

considered for any child exposed in utero to nucleos(t)ide analogues, who present with severe clinical

findings of unknown etiology, particularly neurologic findings. These findings do not affect current

national recommendations to use antiretroviral therapy in pregnant women to prevent vertical

transmission of HIV.

Immune Reactivation Syndrome

In HIV infected patients with severe immune deficiency at the time of institution of CART, 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 CART. Relevant examples include cytomegalovirus retinitis,

generalised and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia. Any

inflammatory symptoms should be evaluated and treatment instituted when necessary.

Autoimmune disorders (such as Graves' disease) have also been reported to occur in the setting of

immune reactivation; however, the reported time to onset is more variable and these events can occur

many months after initiation of treatment.

Opportunistic infections

Patients receiving Odefsey 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.

Osteonecrosis

Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol

consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been

reported particularly in patients with advanced HIV disease and/or long-term exposure to CART. Patients

should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or

difficulty in movement.

Nephrotoxicity

A potential risk of nephrotoxicity resulting from chronic exposure to low levels of tenofovir due to dosing

with tenofovir alafenamide cannot be excluded (see section 5.3).

Pregnancy

Lower exposures of rilpivirine were observed when rilpivirine 25 mg once daily was taken during

pregnancy. In the Phase 3 studies (C209 and C215), lower rilpivirine exposure, similar to that seen during

pregnancy, has been associated with an increased risk of virological failure, therefore viral load should be

monitored closely (see sections 4.6, 5.1 and 5.2). Alternatively, switching to another antiretroviral

regimen could be considered.

Co-administration of other medicinal products

Some medicinal products should not be co-administered with Odefsey (see sections 4.3 and 4.5).

Odefsey should not be co-administered with other antiretroviral medicinal products (see section 4.5).

Odefsey should not be co-administered with other medicinal products containing tenofovir alafenamide,

lamivudine, tenofovir disoproxil or adefovir dipivoxil (see section 4.5).

Excipients

Odefsey contains lactose monohydrate. Consequently, patients with rare hereditary problems of galactose

intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this

medicinal product.

4.5 Interaction with other medicinal products and other forms of interaction

Odefsey is indicated for use as a complete regimen for the treatment of HIV-1 infection and should not be

co-administered with other antiretroviral medicinal products. Therefore, information regarding drug-drug

interactions with other antiretroviral medicinal products is not provided. Interaction studies have only

been performed in adults.

Emtricitabine

In vitro and clinical pharmacokinetic drug-drug interaction studies have shown that the potential for CYP-

mediated interactions involving emtricitabine with other medicinal products is low. Co-administration of

emtricitabine with medicinal products that are eliminated by active tubular secretion may increase

concentrations of emtricitabine, and/or the co-administered medicinal product. Medicinal products that

decrease renal function may increase concentrations of emtricitabine.

Rilpivirine

Rilpivirine is primarily metabolised by CYP3A. Medicinal products that induce or inhibit CYP3A may

thus affect the clearance of rilpivirine (see section 5.2). Rilpivirine inhibits P-glycoprotein (P-gp) in vitro

(50% inhibitory concentration [IC

] is 9.2 µM). In a clinical study, rilpivirine did not significantly affect

the pharmacokinetics of digoxin. Additionally, in a clinical drug-drug interaction study with tenofovir

alafenamide, which is more sensitive to intestinal P-gp inhibition, rilpivirine did not affect tenofovir

alafenamide exposures when administered concurrently, indicating that rilpivirine is not a P-gp inhibitor

in vivo.

Rilpivirine is an in vitro inhibitor of the transporter MATE-2K with an IC

of < 2.7 nM. The clinical

implications of this finding are currently unknown.

Tenofovir alafenamide

Tenofovir alafenamide is transported by P-gp and breast cancer resistance protein (BCRP). Medicinal

products that affect P-gp and BCRP activity may lead to changes in tenofovir alafenamide absorption (see

Table 1). Medicinal products that induce P-gp activity (e.g., rifampicin, rifabutin, carbamazepine,

phenobarbital) are expected to decrease the absorption of tenofovir alafenamide, resulting in decreased

plasma concentration of tenofovir alafenamide, which may lead to loss of therapeutic effect of Odefsey

and development of resistance. Co-administration of Odefsey with other medicinal products that inhibit

P-gp and BCRP activity (e.g., ketoconazole, fluconazole, itraconazole, posaconazole, voriconazole,

ciclosporin) is expected to increase the absorption and plasma concentration of tenofovir alafenamide.

Based on data from an in vitro study, co-administration of tenofovir alafenamide and xanthine oxidase

inhibitors (e.g., febuxostat) is not expected to increase systemic exposure to tenofovir in vivo.

Tenofovir alafenamide is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or

CYP2D6 in vitro. Tenofovir alafenamide is not an inhibitor or inducer of CYP3A in vivo. Tenofovir

alafenamide is a substrate of organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 in vitro.

The distribution of tenofovir alafenamide in the body may be affected by the activity of OATP1B1 and

OATP1B3.

Concomitant use contraindicated

Co-administration of Odefsey and medicinal products that induce CYP3A has been observed to decrease

the plasma concentrations of rilpivirine which could potentially lead to loss of virologic response to

Odefsey (see section 4.3) and possible resistance to rilpivirine and to the NNRTI class.

Co-administration of Odefsey with proton pump inhibitors has been observed to decrease the plasma

concentrations of rilpivirine (due to an increase in gastric pH) which could potentially lead to loss of

virologic response to Odefsey (see section 4.3) and possible resistance to rilpivirine and to the NNRTI

class.

Concomitant use where caution is recommended

CYP enzyme inhibitors

Co-administration of Odefsey with medicinal products that inhibit CYP3A enzyme activity has been

observed to increase rilpivirine plasma concentrations.

QT prolonging medicinal products

Odefsey should be used with caution when co-administered with a medicinal product with a known risk

of Torsade de Pointes (see section 4.4).

Other interactions

Tenofovir alafenamide is not an inhibitor of human uridine diphosphate glucuronosyltransferase (UGT)

1A1 in vitro. It is not known whether emtricitabine, or tenofovir alafenamide are inhibitors of other UGT

enzymes. Emtricitabine did not inhibit the glucuronidation reaction of a non-specific UGT substrate in

vitro.

Interactions between Odefsey or its individual component(s) and co-administered medicinal products are

listed in Table 1 below (increase is indicated as “↑”, decrease as “↓” and no change as “↔”).

Table 1: Interactions between Odefsey or its individual component(s) and other medicinal products

Medicinal product by therapeutic

areas

Effects on medicinal product

levels.

Mean percent change in AUC,

C

max

, C

min

Recommendation concerning

co-administration with Odefsey

ANTI-INFECTIVES

Antifungals

Ketoconazole (400 mg once daily)/

Rilpivirine

Ketoconazole:

AUC: ↓ 24%

: ↓ 66%

: ↔

Rilpivirine:

AUC: ↑ 49%

: ↑ 76%

: ↑ 30%

Inhibition of CYP3A

Expected:

Tenofovir Alafenamide:

AUC: ↑

: ↑

Inhibition of P-gp

Interaction not studied with

tenofovir alafenamide. Co-

administration of ketoconazole is

expected to increase plasma

concentrations of tenofovir

alafenamide (inhibition of P-gp).

Co-administration is not

recommended.

Fluconazole

Itraconazole

Posaconazole

Voriconazole

Interaction not studied with any of

the components of Odefsey. Co-

administration of these antifungal

agents is expected to increase

plasma concentrations of rilpivirine

(inhibition of CYP3A) and

tenofovir alafenamide (inhibition of

P-gp).

Co-administration is not

recommended.

Antimycobacterials

Rifampicin/ Rilpivirine

Rifampicin:

AUC: ↔

: N/A

: ↔

25-desacetyl-rifampicin:

AUC: ↓ 9%

: N/A

: ↔

Rilpivirine:

AUC: ↓ 80%

: ↓ 89%

: ↓ 69%

Induction of CYP3A

Expected:

Tenofovir Alafenamide:

AUC: ↓

: ↓

Induction of P-gp

Interaction not studied with

tenofovir alafenamide. Co-

administration is likely to cause

significant decreases in the plasma

concentrations of tenofovir

Co-administration is

contraindicated.

alafenamide (induction of P-gp).

Rifapentine

Interaction not studied with any of

the components of Odefsey. Co-

administration is likely to cause

significant decreases in the plasma

concentrations of rilpivirine

(induction of CYP3A) and

tenofovir alafenamide (induction of

P-gp).

Co-administration is

contraindicated.

Rifabutin (300 mg once daily)/

Rilpivirine

Rifabutin (300 mg once daily)/

Rilpivirine

Rifabutin:

AUC: ↔

: ↔

: ↔

25-O-desacetyl-rifabutin:

AUC: ↔

: ↔

: ↔

Rilpivirine:

AUC: ↓ 42%

: ↓ 48%

: ↓ 31%

Induction of CYP3A

Expected:

Tenofovir Alafenamide:

AUC: ↓

: ↓

Induction of P-gp

Interaction not studied with

tenofovir alafenamide. Co-

administration is likely to cause

significant decreases in the plasma

concentrations of tenofovir

Co-administration is

contraindicated.

alafenamide (induction of P-gp).

Macrolide antibiotics

Clarithromycin

Erythromycin

Interaction not studied with any of

the components of Odefsey. The

combination of Odefsey with these

macrolide antibiotics may cause an

increase in the plasma

concentrations of rilpivirine

(inhibition of CYP3A) and

tenofovir alafenamide (inhibition of

P-gp).

Co-administration is not

recommended.

Antiviral agents

Boceprevir

Interaction not studied with any of

the components of Odefsey.

Co-administration is not

recommended.

Boceprevir has the potential to

adversely affect the intracellular

activation and clinical antiviral

efficacy of tenofovir alafenamide

based on in vitro data.

Ledipasvir/Sofosbuvir (90 mg/400

mg once daily)/ Rilpivirine

Ledipasvir:

AUC: ↑ 2%

: ↑ 2%

: ↑ 1%

Sofosbuvir:

AUC: ↑ 5%

: ↓ 4%

Sofosbuvir metabolite GS-331007:

AUC: ↑ 8%

: ↑ 10%

: ↑ 8%

Rilpivirine:

AUC: ↓ 5%

: ↓ 7%

No dose adjustment is required.

: ↓ 3%

Ledipasvir/Sofosbuvir (90 mg/400

mg once daily)/ Tenofovir

alafenamide

Tenofovir alafenamide:

AUC: ↑ 32%

: ↑ 3%

Sofosbuvir/Velpatasvir (400

mg/100 mg once daily)/

Rilpivirine

Sofosbuvir:

AUC: ↔

: ↔

Sofosbuvir metabolite GS-331007:

AUC: ↔

: ↔

: ↔

Velpatasvir:

AUC: ↔

: ↔

: ↔

Rilpivirine:

AUC: ↔

: ↔

: ↔

No dose adjustment is required.

Sofosbuvir/Velpatasvir/Voxilaprevi

r (400 mg/100 mg/100 mg + 100

mg once daily)

Emtricitabine/Rilpivirine/Tenofovir

alafenamide (200 mg/25 mg/25 mg

once daily)

Sofosbuvir:

AUC: ↔

: N/A

: ↔

Sofosbuvir metabolite GS-331007:

AUC: ↔

No dose adjustment is required.

: N/A

: ↔

Velpatasvir:

AUC: ↔

: ↔

: ↔

Voxilaprevir:

AUC: ↔

: ↔

: ↔

Emtricitabine:

AUC: ↔

: ↔

: ↔

Rilpivirine:

AUC: ↔

: ↔

: ↔

Tenofovir alafenamide:

AUC: ↑ 52%

: N/A

: ↑ 32%

Sofosbuvir (400 mg once daily)/

Rilpivirine (25 mg once daily)

Sofosbuvir:

AUC: ↔

: ↑ 21%

No dose adjustment is required.

Sofosbuvir metabolite GS-331007:

AUC: ↔

: ↔

Rilpivirine:

AUC: ↔

: ↔

: ↔

Simeprevir (150 mg once daily)/

Rilpivirine

Simeprevir:

AUC: ↑ 6%

: ↓ 4%

: ↑ 10%

Rilpivirine:

AUC: ↑ 12%

: ↑ 25%

: ↑ 4%

No dose adjustment is required.

ANTICONVULSANTS

Carbamazepine

Oxcarbazepine

Phenobarbital

Phenytoin

Interaction not studied with any of

the components of Odefsey. Co-

administration may cause

significant decreases in the plasma

concentrations of rilpivirine

(induction of CYP3A) and

tenofovir alafenamide (induction of

P-gp).

Co-administration is

contraindicated.

GLUCOCORTICOIDS

Dexamethasone (systemic, except

for single dose use)

Interaction not studied with any of

the components of Odefsey.

Significant dose dependent

decreases in rilpivirine plasma

concentrations are expected

(induction of CYP3A).

Co-administration is

contraindicated.

PROTON PUMP INHIBITORS

Omeprazole (20 mg once daily)/

Rilpivirine

Omeprazole:

AUC: ↓ 14%

: N/A

: ↓ 14%

Rilpivirine:

AUC: ↓ 40%

: ↓ 33%

: ↓ 40%

Reduced absorption, increase in

gastric pH

Co-administration is

contraindicated.

Lansoprazole

Rabeprazole

Pantoprazole

Esomeprazole

Dexlansoprazole

Interaction not studied with any of

the components of Odefsey.

Significant decreases in rilpivirine

plasma concentrations are expected

(reduced absorption, increase in

gastric pH).

Co-administration is

contraindicated.

HERBAL PRODUCTS

St. John's wort (Hypericum

perforatum)

Interaction not studied with any of

the components of Odefsey. Co-

administration may cause

significant decreases in the plasma

concentrations of rilpivirine

(induction of CYP3A) and

tenofovir alafenamide (induction of

P-gp).

Co-administration is

contraindicated.

H

2

-RECEPTOR ANTAGONISTS

Famotidine (40 mg single dose

taken 12 hours before rilpivirine)/

Rilpivirine

Famotidine (40 mg single dose

taken 2 hours before rilpivirine)/

Rilpivirine:

AUC: ↓ 9%

: N/A

: ↔

Rilpivirine:

Only H

-receptor antagonists that

can be dosed once daily should

be used. A strict dosing schedule

with intake of the H

-receptor

antagonists at least 12 hours

before or at least 4 hours after

Odefsey should be used.

Rilpivirine

Famotidine (40 mg single dose

taken 4 hours after rilpivirine)/

Rilpivirine

AUC: ↓ 76%

: N/A

: ↓ 85%

Reduced absorption, increase in

gastric pH

Rilpivirine:

AUC: ↑ 13%

: N/A

: ↑ 21%

Cimetidine

Nizatidine

Ranitidine

Interaction not studied with any of

the components of Odefsey. Co-

administration may cause

significant decreases in rilpivirine

plasma concentrations (reduced

absorption, increase in gastric pH).

ANTACIDS

Antacids (e.g., aluminium or

magnesium hydroxide, calcium

carbonate)

Interaction not studied with any of

the components of Odefsey. Co-

administration may cause

significant decreases in rilpivirine

plasma concentrations (reduced

absorption, increase in gastric pH).

Antacids should only be

administered either at least 2

hours before or at least 4 hours

after Odefsey.

ORAL CONTRACEPTIVES

Ethinylestradiol (0.035 mg once

daily)/ Rilpivirine

Norethindrone (1 mg once daily)/

Rilpivirine

Ethinylestradiol:

AUC: ↔

: ↔

: ↑ 17%

Norethindrone:

AUC: ↔

: ↔

: ↔

No dose adjustment is required.

Rilpivirine:

AUC: ↔*

: ↔*

: ↔*

*based on historic controls

Norgestimate (0.180/0.215/0.250

mg once daily)/ Ethinylestradiol

(0.025 mg once daily)/

Emtricitabine/Tenofovir

alafenamide (200/25 mg once

daily)

Norelgestromin:

AUC: ↔

: ↔

: ↔

Norgestrel:

AUC: ↔

: ↔

: ↔

Ethinylestradiol:

AUC: ↔

: ↔

: ↔

No dose adjustment is required.

NARCOTIC ANALGESICS

Methadone (60-100 mg once daily,

individualised dose)/ Rilpivirine

R(-) methadone:

AUC: ↓ 16%

: ↓ 22%

: ↓ 14%

S(+) methadone:

AUC: ↓ 16%

: ↓ 21%

No dose adjustments are

required.

Clinical monitoring is

recommended as methadone

maintenance therapy may need to

be adjusted in some patients.

: ↓ 13%

Rilpivirine:

AUC: ↔*

: ↔*

: ↔*

*based on historic controls

ANALGESICS

Paracetamol (500 mg single dose)/

Rilpivirine

Paracetamol:

AUC: ↔

: N/A

: ↔

Rilpivirine:

AUC: ↔

: ↑ 26%

: ↔

No dose adjustment is required.

ANTIARRHYTHMICS

Digoxin/ Rilpivirine

Digoxin:

AUC: ↔

: N/A

: ↔

No dose adjustment is required.

ANTICOAGULANTS

Dabigatran etexilate

Interaction not studied with any of

the components of Odefsey.

A risk for increases in dabigatran

plasma concentrations cannot be

excluded (inhibition of intestinal P-

gp).

Co-administration should be used

with caution.

IMMUNOSUPPRESSANTS

Ciclosporin

Interaction not studied with any of

the components of Odefsey. Co-

administration of ciclosporin is

expected to increase plasma

concentrations of rilpivirine

(inhibition of CYP3A) and

tenofovir alafenamide (inhibition of

P-gp).

Co-administration is not

recommended.

ANTIDIABETICS

Metformin (850 mg single dose)/

Rilpivirine

Metformin:

AUC: ↔

: N/A

: ↔

No dose adjustment is required.

HMG CO-A REDUCTASE INHIBITORS

Atorvastatin (40 mg once daily)/

Rilpivirine

Atorvastatin:

AUC: ↔

: ↓ 15%

: ↑ 35%

Rilpivirine:

AUC: ↔

: ↔

: ↓ 9%

No dose adjustment is required.

PHOSPHODIESTERASE TYPE 5 (PDE-5) INHIBITORS

Sildenafil (50 mg single dose)/

Rilpivirine

Sildenafil:

AUC: ↔

: N/A

: ↔

Rilpivirine:

AUC: ↔

: ↔

: ↔

No dose adjustment is required.

Vardenafil

Tadalafil

Interaction not studied with any of

the components of Odefsey. These

are medicinal products within class

where similar interactions could be

predicted.

No dose adjustment is required.

HYPNOTICS/SEDATIVES

Midazolam (2.5 mg, orally, single

dose)/ Tenofovir alafenamide

Midazolam (1 mg, intravenously,

single dose)/ Tenofovir

alafenamide

Midazolam:

AUC: ↑ 12%

: N/A

: ↑ 2%

Midazolam:

AUC: ↑ 8%

: N/A

: ↓ 1%

No dose adjustment is required.

N/A = not applicable

This interaction study has been performed with a dose higher than the recommended dose for rilpivirine

hydrochloride assessing the maximal effect on the co-administered medicinal product. The dosing

recommendation is applicable to the recommended dose of rilpivirine of 25 mg once daily.

Study conducted with emtricitabine/rilpivirine/tenofovir disoproxil fumarate fixed-dose combination

tablet.

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

HCV-infected patients.

Studies conducted with other medicinal products

Based on drug-drug interaction studies conducted with the components of Odefsey, no clinically

significant interactions are expected when Odefsey is combined with the following medicinal products:

buprenorphine, naloxone, norbuprenorphine and norgestimate/ethinylestradiol.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential/contraception in males and females

The use of Odefsey should be accompanied by the use of effective contraception (see section 4.5).

Pregnancy

There are no adequate and well-controlled studies of Odefsey or its components in pregnant women.

There are a limited amount of data (less than 300 pregnancy outcomes) from the use of rilpivirine and

tenofovir alafenamide in pregnant women (see sections 4.4, 5.1 and 5.2). Lower exposures of rilpivirine

were observed during pregnancy; therefore viral load should be monitored closely. A large amount of

data on pregnant women (more than 1,000 exposed outcomes) indicate no malformative nor

foetal/neonatal toxicity associated with emtricitabine.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see

section 5.3) with the components of Odefsey.

As a precautionary measure, it is preferable to avoid the use of Odefsey during pregnancy.

Breast-feeding

Emtricitabine is excreted in human milk. It is not known whether rilpivirine or tenofovir alafenamide are

excreted in human milk. In animal studies it has been shown that tenofovir is excreted in milk.

There is insufficient information on the effects of all the components of Odefsey in newborns/infants,

therefore Odefsey should not be used during breast-feeding.

In order to avoid transmission of HIV to the infant it is recommended that HIV infected women do not

breast-feed their infants under any circumstances.

Fertility

No human data on the effect of Odefsey on fertility are available. Animal studies do not indicate harmful

effects of emtricitabine, rilpivirine hydrochloride or tenofovir alafenamide on fertility (see section 5.3).

4.7 Effects on ability to drive and use machines

Patients should be informed that fatigue, dizziness and somnolence have been reported during treatment

with the components of Odefsey (see section 4.8). This should be considered when assessing a patient's

ability to drive or operate machinery.

4.8 Undesirable effects

Summary of the safety profile

The most frequently reported adverse reactions in clinical studies of treatment-naïve patients taking

emtricitabine + tenofovir alafenamide in combination with elvitegravir + cobicistat were nausea (11%),

diarrhoea (7%), and headache (6%). The most frequently reported adverse reactions in clinical studies of

treatment-naïve patients taking rilpivirine hydrochloride in combination with emtricitabine + tenofovir

disoproxil fumarate were nausea (9%), dizziness (8%), abnormal dreams (8%), headache (6%), diarrhoea

(5%) and insomnia (5%).

No new adverse reactions were identified through Week 96 in 2 clinical studies of virologically

suppressed patients who switched from emtricitabine/rilpivirine/tenofovir disoproxil fumarate

(FTC/RPV/TDF) to Odefsey (Study GS-US-366-1216) or from efavirenz/emtricitabine/tenofovir

disoproxil fumarate (EFV/FTC/TDF) to Odefsey (Study GS-US-366-1160).

Tabulated summary of adverse reactions

Assessment of adverse reactions is based on safety data from across all Phase 2 and 3 studies in which

2,396 patients received emtricitabine + tenofovir alafenamide given with elvitegravir + cobicistat as a

fixed-dose combination tablet, pooled data from 686 patients who received rilpivirine 25 mg once daily in

combination with other antiretroviral medicinal products in the controlled studies TMC278-C209 and

TMC278-C215, 754 patients who received Odefsey in Studies GS-US-366-1216 and GS-US-366-1160,

and on post-marketing experience with FTC/RPV/TDF.

The adverse reactions in Table 2 are listed by system organ class and highest frequency observed.

Frequencies are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥

1/1,000 to < 1/100) or rare (≥ 1/10,000 to < 1/1,000).

Table 2: Tabulated list of adverse reactions

Frequency

Adverse reaction

Blood and lymphatic system disorders

Common:

decreased white blood cell count

, decreased haemoglobin

, decreased platelet

count

Uncommon:

anaemia

Immune system disorders

Uncommon:

immune reactivation syndrome

Metabolism and nutrition disorders

Very common:

increased total cholesterol (fasted)

, increased LDL-cholesterol (fasted)

Common:

decreased appetite

, increased triglycerides (fasted)

Psychiatric disorders

Very common:

insomnia

Common:

depression

, abnormal dreams

1, 3

, sleep disorders

, depressed mood

Nervous system disorders

Very common:

headache

1, 3

, dizziness

1, 3

Common:

somnolence

Gastrointestinal disorders

Very common:

nausea

1, 3

, increased pancreatic amylase

Common:

abdominal pain

1, 3

, vomiting

1, 3

, increased lipase

, abdominal discomfort

, dry

mouth

, flatulence

, diarrhoea

Uncommon:

dyspepsia

Hepatobiliary disorders

Very common:

increased transaminases (AST and/or ALT)

Common:

increased bilirubin

Skin and subcutaneous tissue disorders

Common:

rash

1, 3

Uncommon:

severe skin reactions with systemic symptoms

4, 5

, angioedema

2, 6

, pruritus

Musculoskeletal and connective tissue disorders

Uncommon:

arthralgia

General disorders and administration site conditions

Common:

fatigue

1, 3

Adverse reactions identified from rilpivirine clinical studies.

This adverse reaction was not observed in the Phase 3 studies of emtricitabine + tenofovir alafenamide

in combination with elvitegravir + cobicistat or in the Phase 3 studies with Odefsey but identified from

clinical studies or post-marketing experience of emtricitabine when used with other antiretrovirals.

Adverse reactions identified from emtricitabine + tenofovir alafenamide clinical studies.

Adverse reaction identified through post-marketing surveillance of emtricitabine/rilpivirine/tenofovir

disoproxil fumarate

This adverse reaction was not observed in randomised controlled clinical studies for

emtricitabine/rilpivirine/tenofovir disoproxil fumarate, so the frequency category was estimated from a

statistical calculation based on the total number of patients exposed to emtricitabine/rilpivirine/tenofovir

disoproxil fumarate or all of its components in randomised controlled clinical studies (n = 1261). See

description of selected adverse reactions.

This adverse reaction was identified through post-marketing surveillance for emtricitabine but was not

observed in randomised controlled clinical studies in adults or paediatric HIV clinical studies of

emtricitabine. The frequency category of uncommon was estimated from a statistical calculation based on

the total number of patients exposed to emtricitabine in these clinical studies (n = 1,563).

Laboratory abnormalities

Changes in serum creatinine for rilpivirine-containing regimens

The pooled data from the Phase 3 TMC278-C209 and TMC278-C215 studies of treatment-naïve patients

also demonstrate that serum creatinine increased and estimated glomerular filtration rate (eGFR)

decreased over 96 weeks of treatment with rilpivirine. Most of this increase in creatinine and decrease in

eGFR occurred within the first four weeks of treatment. Over 96 weeks of treatment with rilpivirine mean

changes of 0.1 mg/dL (range: -0.3 mg/dL to 0.6 mg/dL) for creatinine and -13.3 mL/min/1.73 m

(range:

-63.7 mL/min/1.73 m

to 40.1 mL/min/1.73 m

) for eGFR were observed. In patients who entered the

studies with mild or moderate renal impairment, the serum creatinine increase observed was similar to

that seen in patients with normal renal function. These increases do not reflect a change in actual

glomerular filtration rate (GFR).

Changes in lipid laboratory tests

In studies in treatment-naïve patients receiving emtricitabine + tenofovir alafenamide (FTC + TAF) or

emtricitabine + tenofovir disoproxil fumarate (FTC + TDF), both given with elvitegravir + cobicistat as a

fixed-dose combination tablet, increases from baseline were observed in both treatment groups for the

fasting lipid parameters total cholesterol, direct low-density lipoprotein (LDL)- and high-density

lipoprotein (HDL)-cholesterol, and triglycerides at Week 144. The median increase from baseline for

these parameters was greater in patients receiving FTC + TAF compared with patients receiving FTC +

TDF (p < 0.001 for the difference between treatment groups for fasting total cholesterol, direct LDL- and

HDL-cholesterol, and triglycerides). Median (Q1, Q3) change from baseline at Week 144 in total

cholesterol to HDL-cholesterol ratio was 0.2 (-0.3, 0.7) in patients receiving FTC + TAF and 0.1 (-0.4,

0.6) in patients receiving FTC + TDF (p = 0.006 for the difference between treatment groups).

Switching from a TDF-based regimen to Odefsey may lead to slight increases in lipid parameters. In a

study of virologically suppressed patients switching from FTC/RPV/TDF to Odefsey (Study GS-US-366-

1216), increases from baseline were observed in fasting values of total cholesterol, direct LDL

cholesterol, HDL cholesterol, and triglycerides in the Odefsey arm; and no clinically relevant changes

from baseline in median fasting values for total cholesterol to HDL ratio were observed in either

treatment arm at Week 96. In a study of virologically suppressed patients switching from EFV/FTC/TDF

to Odefsey (Study GS-US-366-1160), decreases from baseline were observed in the fasting values of total

cholesterol and HDL cholesterol in the Odefsey arm; no clinically relevant changes from baseline in

median fasting values for total cholesterol to HDL ratio, direct LDL cholesterol or triglycerides were

observed in either treatment arm at Week 96.

Cortisol

In the pooled Phase 3 TMC278-C209 and TMC278-C215 studies of treatment-naïve patients, at Week 96,

there was an overall mean change from baseline in basal cortisol of -19.1 (-30.85; -7.37) nmol/L in the

rilpivirine arm and of -0.6 (-13.29; 12.17) nmol/L in the efavirenz arm. At Week 96, the mean change

from baseline in ACTH-stimulated cortisol levels was lower in the rilpivirine arm (+18.4 ± 8.36 nmol/L)

than in the efavirenz arm (+54.1 ± 7.24 nmol/L). Mean values for the rilpivirine arm for both basal and

ACTH-stimulated cortisol at Week 96 were within the normal range. These changes in adrenal safety

parameters were not clinically relevant. There were no clinical signs or symptoms suggestive of adrenal

or gonadal dysfunction in adults.

Description of selected adverse reactions

Metabolic parameters

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section 4.4).

Immune Reactivation Syndrome

In HIV infected patients with severe immune deficiency at the time of initiation of CART, an

inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune

disorders (such as Graves' disease) have also been reported; however, the reported time to onset is more

variable and these events can occur many months after initiation of treatment (see section 4.4).

Osteonecrosis

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk

factors, advanced HIV disease or long-term exposure to CART. The frequency of this is unknown (see

section 4.4).

Severe skin reactions

Severe skin reactions with systemic symptoms have been reported during post-marketing experience of

emtricitabine/rilpivirine/tenofovir disoproxil fumarate including rashes accompanied by fever, blisters,

conjunctivitis, angioedema, elevated liver function tests, and/or eosinophilia.

Paediatric population

The safety of emtricitabine + tenofovir alafenamide was evaluated through 48 weeks in an open-label

clinical study (GS-US-292-0106) in which 50 HIV-1 infected, treatment-naïve paediatric patients aged 12

to < 18 years received emtricitabine + tenofovir alafenamide in combination with elvitegravir + cobicistat

as a fixed-dose combination tablet. In this study, the safety profile in adolescent patients was similar to

that in adults (see section 5.1).

The safety assessment of rilpivirine is based on Week 48 data from one single-arm open-label study

(TMC278-C213) in 36 paediatric patients 12 to < 18 years and weighing at least 32 kg. No patients

discontinued rilpivirine due to adverse reactions. No new adverse reactions were identified compared to

those seen in adults. Most adverse reactions were Grade 1 or 2. Adverse reactions (all grades) of very

common frequency were headache, depression, somnolence and nausea. No Grade 3-4 laboratory

abnormalities for AST/ALT or Grade 3-4 adverse reactions of transaminase increased were reported (see

section 5.1).

Other special populations

Patients with renal impairment

The safety of emtricitabine + tenofovir alafenamide was evaluated through 144 weeks in an open-label

clinical study (GS-US-292-0112), in which 248 HIV-1 infected patients who were either treatment-naïve

(n = 6) or virologically suppressed (n = 242) with mild to moderate renal impairment (estimated

glomerular filtration rate by Cockcroft-Gault method [eGFR

]: 30-69 mL/min) received emtricitabine +

tenofovir alafenamide in combination with elvitegravir + cobicistat as a fixed-dose combination tablet.

The safety profile in patients with mild to moderate renal impairment was similar to that in patients with

normal renal function (see section 5.1).

Patients co-infected with HIV and HBV

The safety of emtricitabine + tenofovir alafenamide in combination with elvitegravir and cobicistat as a

fixed-dose combination tablet (elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide [E/C/F/TAF])

was evaluated in 72 HIV/HBV co-infected patients receiving treatment for HIV in an open-label clinical

study (GS-US-292-1249), through Week 48, in which patients were switched from another antiretroviral

regimen (which included TDF in 69 of 72 patients) to E/C/F/TAF. Based on these limited data, the safety

profile of emtricitabine + tenofovir alafenamide in combination with elvitegravir and cobicistat as a fixed-

dose combination tablet, in patients with HIV/HBV co-infection, was similar to that in patients with HIV-

1 monoinfection.

In patients co-infected with hepatitis B or C virus receiving rilpivirine, the incidence of hepatic enzyme

elevation was higher than in patients receiving rilpivirine who were not co-infected. The pharmacokinetic

exposure of rilpivirine in co-infected patients was comparable to that in patients without co-infection.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the national reporting system:

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

or search for MHRA Yellow Card in the Google Play or Apple App Store

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: [email

protected]

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

4.9 Overdose

If overdose occurs the patient must be monitored for evidence of toxicity (see section 4.8), and standard

supportive treatment applied as necessary including observation of the clinical status of the patient and

monitoring of vital signs and ECG (QT interval).

There is no specific antidote for overdose with Odefsey. Up to 30% of the emtricitabine dose can be

removed by haemodialysis. Tenofovir is efficiently removed by hemodialysis with an extraction

coefficient of approximately 54%. It is not known whether emtricitabine or tenofovir can be removed by

peritoneal dialysis. Since rilpivirine is highly protein bound, dialysis is unlikely to result in significant

removal of the active substance.

Administration of activated charcoal may also be used to aid in removal of unabsorbed rilpivirine

hydrochloride.

5. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antiviral for systemic use; antivirals for treatment of HIV infections,

combinations, ATC code: J05AR19

Mechanism of action and pharmacodynamic effects

Emtricitabine is a nucleoside reverse transcriptase inhibitor (NRTI) and analogue of 2'-deoxycytidine.

Emtricitabine is phosphorylated by cellular enzymes to form emtricitabine triphosphate. Emtricitabine

triphosphate competitively inhibits HIV-1 reverse transcriptase (RT), resulting in deoxyribonucleic acid

(DNA) chain termination. Emtricitabine has activity against HIV-1, HIV-2, and HBV.

Rilpivirine is a diarylpyrimidine NNRTI of HIV-1. Rilpivirine activity is mediated by non-competitive

inhibition of HIV-1 RT. Rilpivirine does not inhibit the human cellular DNA polymerases α, β and

mitochondrial DNA polymerase γ.

Tenofovir alafenamide is a nucleotide reverse transcriptase inhibitor (NtRTI) and prodrug of tenofovir

(2'-deoxyadenosine monophosphate analogue). Due to increased plasma stability and intracellular

activation through hydrolysis by cathepsin A, tenofovir alafenamide is more efficient than tenofovir

disoproxil fumarate in loading tenofovir into peripheral blood mononuclear cells (PBMCs) (including

lymphocytes and other HIV target cells) and macrophages. Intracellular tenofovir is subsequently

phosphorylated to the active metabolite tenofovir diphosphate. Tenofovir diphosphate inhibits HIV RT,

resulting in DNA chain termination. Tenofovir has activity against HIV-1, HIV-2 and HBV.

Antiviral activity

in vitro

The combinations of emtricitabine, rilpivirine, and tenofovir alafenamide were not antagonistic and

showed synergistic effects with each other in cell culture combination antiviral activity assays.

The antiviral activity of emtricitabine against laboratory and clinical isolates of HIV-1 was assessed in

lymphoblastoid cell lines, the MAGI CCR5 cell line, and PBMCs. The 50% effective concentration

) values for emtricitabine were in the range of 0.0013 to 0.64 µM. Emtricitabine displayed antiviral

activity in cell culture against HIV-1 subtype A, B, C, D, E, F, and G (EC

values ranged from 0.007 to

0.075 µM) and showed activity against HIV-2 (EC

values ranged from 0.007 to 1.5 µM).

Rilpivirine exhibited activity against laboratory strains of wild-type HIV-1 in an acutely infected T-cell

line with a median EC

value for HIV-1/IIIB of 0.73 nM (0.27 ng/mL). Rilpivirine also demonstrated

antiviral activity against a broad panel of HIV-1 group M (subtype A, B, C, D, F, G, H) primary isolates

with EC

values ranging from 0.07 to 1.01 nM (0.03 to 0.37 ng/mL), group O primary isolates with EC

values ranging from 2.88 to 8.45 nM (1.06 to 3.10 ng/mL), and showed limited in vitro activity against

HIV-2 with EC

values ranging from 2,510 to 10,830 nM (920 to 3,970 ng/mL).

The antiviral activity of tenofovir alafenamide against laboratory and clinical isolates of HIV-1 subtype B

was assessed in lymphoblastoid cell lines, PBMCs, primary monocyte/macrophage cells, and CD4+-T

lymphocytes. The EC

values for tenofovir alafenamide were in the range of 2.0 to 14.7 nM. Tenofovir

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

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

values ranged from 0.10 to 12.0 nM) and showed activity against

HIV-2 (EC

values ranged from 0.91 to 2.63 nM).

Resistance

Considering all of the available in vitro data and data generated in treatment-naïve patients, the following

resistance-associated mutations in HIV-1 RT, when present at baseline, may affect the activity of

Odefsey: K65R, K70E, K101E, K101P, E138A, E138G, E138K, E138Q, E138R, V179L, Y181C, Y181I,

Y181V, M184I, M184V, Y188L, H221Y, F227C, M230I, M230L and the combination of L100I and

K103N.

A negative impact by NNRTI mutations other than those listed above (e.g., mutations K103N or L100I as

single mutations) cannot be excluded, since this was not studied in vivo in a sufficient number of patients.

As with other antiretroviral medicinal products, resistance testing and/or historical resistance data should

guide the use of Odefsey (see section 4.4).

In vitro

Reduced susceptibility to emtricitabine is associated with M184V/I mutations in HIV-1 RT.

Rilpivirine-resistant strains were selected in cell culture starting from wild-type HIV-1 of different origins

and subtypes as well as NNRTI-resistant HIV-1. The most commonly observed amino acid substitutions

that emerged included: L100I, K101E, V108I, E138K, V179F, Y181C, H221Y, F227C, and M230I.

HIV-1 isolates with reduced susceptibility to tenofovir alafenamide expressed a K65R mutation in HIV-1

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

In treatment-naïve adult patients

In the Week 144 pooled analysis of antiretroviral-naïve patients receiving

elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) in the Phase 3 studies GS-US-

292-0104 and GS-US-292-0111, the development of one or more primary resistance-associated mutations

was observed in HIV-1 isolates from 12 of 866 (1.4%) patients treated with E/C/F/TAF. Among these 12

HIV-1 isolates, the mutations that emerged were M184V/I (n = 11) and K65R/N (n = 2) in RT and

T66T/A/I/V (n = 2), E92Q (n = 4), Q148Q/R (n = 1), and N155H (n = 2) in integrase.

In the Week 96 pooled analysis for patients receiving emtricitabine/tenofovir disoproxil fumarate

(FTC/TDF) + rilpivirine hydrochloride in the Phase 3 clinical studies TMC278-C209 and TMC278-C215,

HIV-1 isolates from 43 patients had an amino acid substitution associated with NNRTI (n = 39) or NRTI

(n = 41) resistance. The NNRTI resistance-associated mutations that developed most commonly were:

V90I, K101E, E138K/Q, V179I, Y181C, V189I, H221Y and F227C. The presence of V90I and V189I at

baseline did not affect the response. Fifty-two percent of HIV-1 isolates with emergent resistance in the

rilpivirine arm developed concomitant NNRTI and NRTI mutations, most frequently E138K and M184V.

The mutations associated with NRTI resistance that developed in 3 or more patient isolates were: K65R,

K70E, M184V/I and K219E.

Through Week 96, fewer patients in the rilpivirine arm with baseline viral load ≤ 100,000 copies/mL had

emerging resistance-associated substitutions and/or phenotypic resistance to rilpivirine (7/288) than

patients with baseline viral load > 100,000 copies/mL (30/262).

In virologically suppressed patients

One patient with emergent resistance (M184M/I) was identified in a clinical study of virologically

suppressed patients who switched from a regimen containing emtricitabine + tenofovir disoproxil

fumarate to E/C/F/TAF in a fixed-dose combination (FDC) tablet (GS-US-292-0109, n = 959).

Through Week 96, in patients who switched to Odefsey from emtricitabine/rilpivirine/tenofovir

disoproxil fumarate (FTC/RPV/TDF) or efavirenz/emtricitabine/tenofovir disoproxil fumarate

(EFV/FTC/TDF) (Studies GS-US-366-1216 and GS-US-366-1160; n = 754), no treatment-emergent

resistance-associated mutations were detected.

In patients co-infected with HIV and HBV

In a clinical study of HIV virologically suppressed patients co-infected with chronic hepatitis B, who

received E/C/F/TAF for 48 weeks (GS-US-292-1249, n = 72), 2 patients qualified for resistance analysis.

In these 2 patients, no amino acid substitutions associated with resistance to any of the components of

E/C/F/TAF were identified in HIV-1 or HBV.

Cross-resistance

Emtricitabine-resistant viruses with the M184V/I substitution were cross-resistant to lamivudine, but

retained sensitivity to didanosine, stavudine, tenofovir, and zidovudine.

In a panel of 67 HIV-1 recombinant laboratory strains with one resistance-associated mutation at RT

positions associated with NNRTI resistance, the only single resistance-associated mutations associated

with a loss of susceptibility to rilpivirine were K101P and Y181V/I. The K103N substitution alone did

not result in reduced susceptibility to rilpivirine, but the combination of K103N and L100I resulted in a 7-

fold reduced susceptibility to rilpivirine. In another study, the Y188L substitution resulted in a reduced

susceptibility to rilpivirine of 9-fold for clinical isolates and 6-fold for site-directed mutants.

In patients receiving rilpivirine hydrochloride in combination with FTC/TDF in Phase 3 studies

(TMC278-C209 and TMC278-C215 pooled data), most HIV-1 isolates with emergent phenotypic

resistance to rilpivirine had cross-resistance to at least one other NNRTI (28/31).

The K65R and also the K70E substitution result in reduced susceptibility to abacavir, didanosine,

lamivudine, emtricitabine, and tenofovir, but retain sensitivity to zidovudine.

Clinical data

Clinical efficacy of Odefsey was established from studies conducted with emtricitabine + tenofovir

alafenamide when given with elvitegravir + cobicistat as an E/C/F/TAF FDC tablet, from studies

conducted with rilpivirine when given with FTC/TDF as individual components or as a FTC/RPV/TDF

FDC tablet, and from studies conducted with Odefsey.

Emtricitabine + tenofovir alafenamide containing regimens

Treatment-naïve and virologically suppressed HIV-1 infected adult patients

In Study GS-US-292-0104 and Study GS-US-292-0111, patients received either E/C/F/TAF (n = 866) or

elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (E/C/F/TDF) (n = 867) once daily, both

given as FDC tablets.

The mean age was 36 years (range 18-76), 85% were male, 57% were White, 25% were Black, and 10%

were Asian. The mean baseline plasma HIV-1 RNA was 4.5 log

copies/mL (range 1.3-7.0) and 23% of

patients had baseline viral loads > 100,000 copies/mL. The mean baseline CD4+ cell count was 427

cells/mm

(range 0-1,360) and 13% had CD4+ cell counts < 200 cells/mm

In Studies GS-US-292-0104 and GS-US-292-0111, E/C/F/TAF demonstrated statistical superiority in

achieving HIV-1 RNA < 50 copies/mL when compared to E/C/F/TDF at Week 144. The difference in

percentage was 4.2% (95% CI: 0.6% to 7.8%). Pooled treatment outcomes at 48 and 144 weeks are

shown in Table 3.

In Study GS-US-292-0109, the efficacy and safety of switching from either EFV/FTC/TDF, FTC/TDF

plus atazanavir (boosted by either cobicistat or ritonavir), or E/C/F/TDF to E/C/F/TAF FDC tablet were

evaluated in a randomised, open-label study of virologically suppressed (HIV-1 RNA < 50 copies/mL)

HIV-1 infected adults (n = 959 switching to E/C/F/TAF, n = 477 Stayed on Baseline Regimen [SBR]).

Patients had a mean age of 41 years (range 21-77), 89% were male, 67% were White, and 19% were

Black. The mean baseline CD4+ cell count was 697 cells/mm

(range 79-1,951).

In Study GS-US-292-0109, switching from a tenofovir disoproxil fumarate-based regimen to E/C/F/TAF

was superior in maintaining HIV-1 RNA < 50 copies/mL compared to staying on the baseline regimen.

Pooled treatment outcomes at 48 weeks are shown in Table 3.

Table 3: Virologic outcomes of Studies GS-US-292-0104, GS-US-292-0111 at Week 48 and Week

144

a

, and GS-US-292-0109 at Week 48

a

Treatment-naïve adults in Studies GS-US-292-0104 and

GS-US-292-0111

b

Virologically

suppressed adults in

Study GS-US-292-0109

Week 48

Week 144

Week 48

E/C/F/TAF

(n = 866)

E/C/F/TDF

(n = 867)

E/C/F/TAF

(n = 866)

E/C/F/TDF

(n = 867)

E/C/F/TAF

(n = 959)

Baseline

regimen

(n = 477)

HIV-1 RNA < 50

copies/mL

Treatment

difference

2.0% (95% CI: -0.7% to

4.7%)

4.2% (95% CI: 0.6% to

7.8%)

4.1% (95% CI: 1.6% to

6.7%, p < 0.001

HIV-1 RNA ≥ 50

copies/mL

d

No virologic data

in Week 48 or 144

window

Discontinued study

drug due to AE or

Discontinued study

drug due to other

reasons and last

available HIV-1

RNA < 50

copies/mL

Missing data

during window but

on study drug

< 1%

<1%

HIV-1 RNA < 20

copies/mL

Treatment

difference

0.4% (95% CI: -3.0% to

3.8%)

5.4% (95% CI: 1.5% to

9.2%)

Proportion (%) of

patients with

HIV-1 RNA < 50

copies/mL by

prior treatment

regimen

d

EFV/FTC/TDF

FTC/TDF plus

boosted atazanavir

E/C/F/TDF

a Week 48 window was between Day 294 and 377 (inclusive); Week 144 window was between Day 966

and 1049 (inclusive).

b In both studies, patients were stratified by baseline HIV-1 RNA (≤ 100,000 copies/mL, > 100,000

copies/mL to ≤ 400,000 copies/mL, or > 400,000 copies/mL), by CD4+ cell count (< 50 cells/µL, 50-199

cells/µL, or ≥ 200 cells/µL), and by region (US or ex US).

c P-value for the superiority test comparing the percentages of virologic success was from the CMH

(Cochran-Mantel-Haenszel) test stratified by the prior treatment regimen (EFV/FTC/TDF, FTC/TDF plus

boosted atazanavir, or E/C/F/TDF).

d Included patients who had ≥ 50 copies/mL in the Week 48 or 144 window; patients who discontinued

early due to lack or loss of efficacy; patients who discontinued for reasons other than an adverse event

(AE), death or lack or loss of efficacy and at the time of discontinuation had a viral value of ≥ 50

copies/mL.

e Included patients who discontinued due to AE or death at any time point from Day 1 through the time

window if this resulted in no virologic data on treatment during the specified window.

f Included patients who discontinued for reasons other than an AE, death, or lack or loss of efficacy; e.g.,

withdrew consent, loss to follow-up, etc.

In Studies GS-US-292-0104 and GS-US-292-0111, the rate of virologic success was similar across

patient subgroups (age, gender, race, baseline HIV-1 RNA, or baseline CD4+ cell count).

The mean increase from baseline in CD4+ cell count was 230 cells/mm

in E/C/F/TAF-treated patients

and 211 cells/mm

in E/C/F/TDF-treated patients (p = 0.024) at Week 48 and 326 cells/mm

E/C/F/TAF-treated patients and 305 cells/mm

in E/C/F/TDF-treated patients (p = 0.06) at Week 144.

Rilpivirine-containing regimens

Treatment-naïve HIV-1 infected adult patients

The efficacy of rilpivirine is based on the analyses of 96 weeks data from two randomised, double-blind,

controlled studies in treatment-naïve patients (TMC278-C209 and emtricitabine + tenofovir disoproxil

fumarate subset of TMC278-C215).

In the pooled analysis for TMC278-C209 and TMC278-C215 of 1096 patients who received a

background regimen (BR) of FTC/TDF, demographic and baseline characteristics were balanced between

the rilpivirine and efavirenz (EFV) arms. The median age was 36 years, 78% were male and 62% White

and 24% Black/African American. Median plasma HIV-1 RNA was 5.0 log

copies/mL and median

CD4+ cell count was 255 cells/mm

Overall response and a subgroup analysis of the virologic response (< 50 HIV-1 RNA copies/mL) at both

48 weeks and 96 weeks, and virologic failure by baseline viral load (pooled data from the two Phase 3

clinical studies, TMC278-C209 and TMC278-C215, for patients receiving the FTC/TDF BR) is presented

in Table 4.

Table 4: Virologic outcomes of randomised treatment of Studies TMC278-C209 and TMC278-C215

(pooled data for patients receiving rilpivirine hydrochloride or efavirenz in combination with

FTC/TDF) at Week 48 (primary) and Week 96

RPV + FTC/TDF

(n = 550)

EFV + FTC/TDF

(n = 546)

RPV + FTC/TDF

(n = 550)

EFV + FTC/TDF

(n = 546)

Week 48

Week 96

Overall response

(HIV-1 RNA < 50

copies/mL

(TLOVR

83.5% (459/550)

82.4% (450/546)

76.9% (423/550)

77.3% (422/546)

By baseline viral load (copies/mL)

100,000

89.6% (258/288)

84.8% (217/256)

83.7% (241/288)

80.8% (206/255)

> 100,000

76.7% (201/262)

80.3% (233/290)

69.5% (182/262)

74.2% (216/291)

Non-response

Virologic failure

(all patients)

9.5% (52/550)

4.2% (23/546)

11.5% (63/550)

5.1% (28/546)

By baseline viral load (copies/mL)

100,000

4.2% (12/288)

2.3% (6/256)

5.9% (17/288)

2.4% (6/255)

> 100,000

15.3% (40/262)

5.9% (17/290)

17.6% (46/262)

7.6% (22/291)

Death

0.2% (1/546)

0.7% (4/546)

Discontinued due

to adverse event

(AE)

2.2% (12/550)

7.1% (39/546)

3.6% (20/550)

8.1% (44/546)

Discontinued for

non-AE reason

4.9% (27/550)

6.0% (33/546)

8% (44/550)

8.8% (48/546)

EFV = efavirenz; RPV = rilpivirine

a ITT TLOVR = Intention to treat time to loss of virologic response.

b The difference of response rate at Week 48 is 1% (95% confidence interval -3% to 6%) using normal

approximation.

c There were 17 new virologic failures between the Week 48 primary analysis and Week 96 (6 patients

with baseline viral load ≤ 100,000 copies/mL and 11 patients with baseline viral load > 100,000

copies/mL). There were also reclassifications in the Week 48 primary analysis with the most common

being reclassification from virologic failure to discontinued for non-AE reasons.

d There were 10 new virologic failures between the Week 48 primary analysis and Week 96 (3 patients

with baseline viral load ≤ 100,000 copies/mL and 7 patients with baseline viral load > 100,000

copies/mL). There were also reclassifications in the Week 48 primary analysis with the most common

being reclassification from virologic failure to discontinued for non-AE reasons.

e e.g., lost to follow up, non-compliance, withdrew consent.

FTC/TDF + rilpivirine hydrochloride was non-inferior in achieving HIV-1 RNA < 50 copies/mL

compared to FTC/TDF + efavirenz.

Odefsey regimen

Virologically suppressed HIV-1 infected adult patients

In Study GS-US-366-1216, the efficacy and safety of switching from FTC/RPV/TDF to Odefsey were

evaluated in a randomised, double-blind study of virologically suppressed HIV-1 infected adults. Patients

had a mean age of 45 years (range 23−72), 90% were male, 75% were White, and 19% were Black. The

mean baseline CD4+ cell count was 709 cells/mm

(range: 104-2,527).

In Study GS-US-366-1160, the efficacy and safety of switching from EFV/FTC/TDF to Odefsey were

evaluated in a randomised, double-blind study of virologically suppressed HIV-1 infected adults. Patients

had a mean age of 48 years (range 19−76), 87% were male, 67% were White, and 27% were Black. The

mean baseline CD4+ cell count was 700 cells/mm

(range 140−1,862).

Treatment outcomes of Studies GS-US-366-1216 and GS-US-366-1160 are presented Table 5.

Table 5: Virologic outcomes of Studies GS-US-366-1216 and GS-US-366-1160 at Weeks 48

a

and 96

b

GS-US-366-1216

GS-US-366-1160

Week 48

Week 96

Week 48

Week 96

ODE

(n =

316)

FTC/RPV

/TDF (n =

313)

c

ODE (n

= 316)

FTC/RPV

/TDF (n =

313)

c

ODE

(n =

438)

EFV/FTC

/TDF

(n = 437)

ODE (n

= 438)

EFV/FTC/

TDF

(n = 437)

HIV-1 RNA < 50

copies/mL

d

Treatment

difference

-0.3% (95% CI:

-4.2% to 3.7%)

0.7% (95% CI:

-4.3% to 5.8%)

-2.0% (95% CI:

-5.9% to 1.8%)

0% (95% CI:

-4.8% to 4.8%)

HIV-1 RNA ≥ 50

copies/mL

d

No virologic data

in Week 48 or 96

window

Discontinued study

drug due to AE or

death and last

available HIV-1

RNA < 50

copies/mL

Discontinued study

drug due to other

reasons and last

available HIV-1

RNA < 50

copies/mL

Missing data

during window but

on study drug

< 1%

<1%

ODE = Odefsey

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

b Week 96 window was between Day 631 and 714 (inclusive).

c One patient who was not on FTC/RPV/TDF prior to screening was excluded from the analysis.

d Included patients who had ≥ 50 copies/mL in the Week 48 or Week 96 window; patients who

discontinued early due to lack or loss of efficacy; patients who discontinued for reasons other than lack or

loss of efficacy and at the time of discontinuation had a viral value of ≥ 50 copies/mL.

e Included patients who discontinued for reasons other than an AE, death, or lack or loss of efficacy; e.g.,

withdrew consent, loss to follow-up, etc.

At Week 96, switching to Odefsey was noninferior in maintaining HIV-1 RNA < 50 copies/mL when

compared to patients who stayed on FTC/RPV/TDF or on EFV/FTC/TDF in respective studies.

In Study GS-US-366-1216, the mean change from baseline in CD4+ cell count at Week 96 was 12

cells/mm

in patients who switched to Odefsey and 16 cells/mm

in those who remained on

FTC/RPV/TDF. In Study GS-US-366-1160, the mean change from baseline in CD4+ cell count at Week

96 was 12 cells/mm

in patients who switched to Odefsey and 6 cells/mm

in those who stayed on

EFV/FTC/TDF.

HIV-1 infected adult patients with mild to moderate renal impairment

In Study GS-US-292-0112, the efficacy and safety of E/C/F/TAF FDC tablet were evaluated in an open-

label clinical study of 242 HIV-1 infected, virologically suppressed patients with mild to moderate renal

impairment (eGFR

: 30-69 mL/min).

The mean age was 58 years (range 24-82), with 63 patients (26%) who were ≥ 65 years of age. Seventy-

nine percent were male, 63% were White, 18% were Black, and 14% were Asian. Thirty-five percent of

patients were on a treatment regimen that did not contain tenofovir disoproxil fumarate. At baseline,

median eGFR

was 56 mL/min, and 33% of patients had an eGFR

from 30 to 49 mL/min. The mean

baseline CD4+ cell count was 664 cells/mm

(range 126-1,813).

At Week 144, 83.1% (197/237 patients) maintained HIV-1 RNA < 50 copies/mL after switching to

E/C/F/TAF FDC tablet.

Patients co-infected with HIV and HBV

In open-label Study GS-US-292-1249, the efficacy and safety of E/C/F/TAF were evaluated in adult

patients co-infected with HIV-1 and chronic hepatitis B. Sixty-nine of the 72 patients were on prior TDF-

containing antiretroviral therapy. At the start of treatment with E/C/F/TAF, the 72 patients had been HIV-

suppressed (HIV-1 RNA < 50 copies/mL) for at least 6 months with or without suppression of HBV DNA

and had compensated liver function. The mean age was 50 years (range 28-67), 92% of patients were

male, 69% were White, 18% were Black, and 10% were Asian. The mean baseline CD4+ cell count was

636 cells/mm

(range 263-1498). Eighty-six percent of patients (62/72) were HBV suppressed (HBV

DNA < 29 IU/mL) and 42% (30/72) were HBeAg positive at baseline.

Of the patients who were HBeAg positive at baseline, 1/30 (3.3%) achieved seroconversion to anti-HBe

at Week 48. Of the patients who were HBsAg positive at baseline, 3/70 (4.3%) achieved seroconversion

to anti-HBs at Week 48.

At Week 48, 92% of patients (66/72) maintained HIV-1 RNA < 50 copies/mL after switching to

E/C/F/TAF. The mean change from baseline in CD4+ cell count at Week 48 was -2 cells/mm

. Ninety-

two percent (66/72 patients) had HBV DNA < 29 IU/mL using missing = failure analysis at Week 48. Of

the 62 patients who were HBV suppressed at baseline, 59 remained suppressed and 3 had missing data.

Of the 10 patients who were not HBV suppressed at baseline (HBV DNA ≥ 29 IU/mL), 7 became

suppressed, 2 remained detectable, and 1 had missing data. Alanine aminotransferase (ALT)

normalisation was achieved in 40% (4/10) of subjects with ALT greater than upper limit of normal (ULN)

at baseline.

There are limited clinical data on the use of E/C/F/TAF in HIV/HBV co-infected patients who are

treatment-naïve.

Changes in measures of bone mineral density

In studies in treatment-naïve adult patients, E/C/F/TAF was associated with smaller reductions in bone

mineral density (BMD) compared to E/C/F/TDF through 144 weeks of treatment as measured by dual

energy X ray absorptiometry (DXA) analysis of hip (mean change: −0.8% vs −3.4%, p < 0.001) and

lumbar spine (mean change: −0.9% vs −3.0%, p < 0.001).

Small improvements in BMD were noted at 48 weeks after switching to E/C/F/TAF compared to

maintaining the tenofovir disoproxil fumarate-containing regimen.

In Odefsey studies in virologically suppressed adult patients, increases in BMD were noted at 96 weeks

after switching to Odefsey compared to minimal changes with maintaining FTC/RPV/TDF or

EFV/FTC/TDF at the hip (mean change 1.6% for Odefsey vs -0.6% for FTC/RPV/TDF, p<0.001; 1.8%

for Odefsey vs -0.6% for EFV/FTC/TDF, p<0.001) and the spine (mean change 2.0% for Odefsey vs

-0.3% for FTC/RPV/TDF, p<0.001; 1.7% for Odefsey vs 0.1% for EFV/FTC/TDF; p<0.001).

Changes in measures of renal function

In studies in treatment-naïve adult patients, E/C/F/TAF was associated with lower impact on renal safety

parameters (as measured after 144 weeks treatment by eGFR

and urine protein to creatinine ratio

[UPCR] and after 96 weeks treatment by urine albumin to creatinine ratio [UACR]) compared to

E/C/F/TDF. Through 144 weeks of treatment, no subject discontinued E/C/F/TAF due to a treatment-

emergent renal adverse event compared with 12 subjects who discontinued E/C/F/TDF (p < 0.001). In

studies in virologically suppressed adult patients, through 96 weeks of treatment there were minimal

changes or decreases in albuminuria (UACR) in patients receiving Odefsey compared with increases from

baseline in patients who stayed on FTC/RPV/TDF or EFV/FTC/TDF. See also section 4.4.

Paediatric population

Emtricitabine + tenofovir alafenamide regimen

In Study GS-US-292-0106, the efficacy, safety, and pharmacokinetics of E/C/F/TAF FDC tablet were

evaluated in an open-label study of 50 HIV-1 infected, treatment-naïve adolescents. Patients had a mean

age of 15 years (range 12-17), were 56% female, 12% Asian, and 88% Black. At baseline, median plasma

HIV-1 RNA was 4.7 log

copies/mL, median CD4+ cell count was 456 cells/mm

(range 95 to 1,110),

and median CD4+% was 23% (range 7-45). Overall, 22% had baseline plasma HIV-1 RNA > 100,000

copies/mL.

At 48 weeks, 92% (46/50) achieved HIV-1 RNA < 50 copies/mL, similar to response rates in studies of

treatment-naïve HIV-1 infected adults. No emergent resistance to E/C/F/TAF was detected through Week

Rilpivirine-containing regimen

The pharmacokinetics, safety, tolerability, and efficacy of rilpivirine 25 mg once daily, in combination

with an investigator-selected BR containing two NRTIs, were evaluated in Study TMC278-C213, a

single-arm, open-label Phase 2 study in antiretroviral-naïve HIV-1 infected paediatric patients 12 to < 18

years of age and weighing at least 32 kg. The median duration of exposure for patients was 63.5 weeks.

Thirty-six patients had a median age of 14.5 years and were 55.6% female, 88.9% Black, and 11.1%

Asian. The median baseline plasma HIV-1 RNA was 4.8 log

copies/mL, and the median baseline CD4+

cell count was 414 cells/mm

. The proportion of patients with HIV-1 RNA < 50 copies/mL at Week 48

(TLOVR) was 72.2% (26/36). The combination of NRTIs most frequently used together with rilpivirine

was FTC/TDF (24 subjects [66.7%]).

The proportion of responders was higher in subjects with a baseline viral load ≤ 100,000 copies/mL

(78.6%, 22/28) as compared to those with a baseline viral load > 100,000 copies/mL (50.0%, 4/8). The

proportion of virologic failures was 22.2% (8/36).

The European Medicines Agency has deferred the obligation to submit the results of studies with Odefsey

in one or more subsets of the paediatric population in the treatment of human HIV-1 infection (see section

4.2 for information on paediatric use).

Pregnancy

Rilpivirine (one of the components of Odefsey) in combination with a background regimen was evaluated

in Study TMC114HIV3015 in 19 pregnant women during the 2

and 3

trimesters, and postpartum. The

pharmacokinetic data demonstrate that total exposure (AUC) to rilpivirine as a part of an antiretroviral

regimen was approximately 30% lower during pregnancy compared with postpartum (6-12 weeks). The

virologic response was generally preserved throughout the study: of the 12 patients that completed the

study, 10 patients were suppressed at the end of the study; in the other 2 patients an increase in viral load

was observed only postpartum, for at least 1 patient due to suspected suboptimal adherence. No mother to

child transmission occurred in all 10 infants born to the mothers who completed the trial and for whom

the HIV status was available. Rilpivirine was well tolerated during pregnancy and postpartum. There

were no new safety findings compared with the known safety profile of rilpivirine in HIV-1 infected

adults (see sections 4.2, 4.4 and 5.2).

5.2 Pharmacokinetic properties

Absorption

Odefsey: Emtricitabine and tenofovir alafenamide exposures were bioequivalent when comparing one

Odefsey 200/25/25 mg film-coated tablet to elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide

(150/150/200/10 mg) fixed-dose combination tablet following single dose administration to healthy

subjects (n = 82) under fed conditions. Rilpivirine exposures were bioequivalent when comparing

Odefsey 200/25/25 mg to one rilpivirine (as hydrochloride) 25 mg film-coated tablet following single

dose administration to healthy subjects (n = 95) under fed conditions.

Emtricitabine is rapidly and extensively absorbed following oral administration with peak plasma

concentrations occurring at 1 to 2 hours post-dose. Following multiple dose oral administration of

emtricitabine to 20 HIV-1 infected subjects, the (mean ± SD) area-under the plasma concentration-time

curve over a 24-hour dosing interval (AUC) was 10.0 ± 3.1 hµg/mL. The mean steady-state plasma

trough concentration at 24 hours post-dose was equal to or greater than the mean in vitro IC

value for

anti-HIV-1 activity. The absolute bioavailability of emtricitabine from 200 mg hard capsules was

estimated to be 93%. Emtricitabine systemic exposure was unaffected when emtricitabine was

administered with food.

After oral administration, the maximum plasma concentration of rilpivirine is generally achieved within 4

to 5 hours. The absolute bioavailability of rilpivirine is unknown. Relative to fasting conditions, the

administration of Odefsey to healthy adult subjects with food resulted in increased rilpivirine exposure

(AUC) by 13-72%.

Tenofovir alafenamide is rapidly absorbed following oral administration, with peak plasma

concentrations occurring at 15-45 minutes post-dose. Relative to fasting conditions, the administration of

Odefsey to healthy adult subjects with food resulted in increased tenofovir alafenamide exposure (AUC)

by 45-53%.

It is recommended that Odefsey be taken with food.

Distribution

In vitro binding of emtricitabine to human plasma proteins was < 4% and independent of concentration

over the range of 0.02-200 µg/mL.

In vitro binding of rilpivirine to human plasma proteins is approximately 99.7%, primarily to albumin.

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. Ex vivo binding of tenofovir alafenamide to human plasma proteins in

samples collected during clinical studies was approximately 80%.

Biotransformation

The biotransformation of emtricitabine includes oxidation of the thiol moiety to form the 3'-sulfoxide

diastereomers (approximately 9% of dose) and conjugation with glucuronic acid to form 2'-O-glucuronide

(approximately 4% of dose). Emtricitabine did not inhibit in vitro drug metabolism mediated by any of

the major human CYP isoforms involved in drug biotransformation. Also, emtricitabine did not inhibit

uridine-5'-diphosphoglucuronyl transferase (UGT), the enzyme responsible for glucuronidation.

In vitro experiments indicate that rilpivirine hydrochloride primarily undergoes oxidative metabolism

mediated by the CYP3A system.

Metabolism is a major elimination pathway for tenofovir alafenamide in humans, accounting for > 80%

of an oral dose. In vitro studies have shown that tenofovir alafenamide is metabolised to tenofovir (major

metabolite) by cathepsin A in PBMCs (including lymphocytes and other HIV target cells) and

macrophages; and by carboxylesterase-1 in hepatocytes. In vivo, tenofovir alafenamide is hydrolysed

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

tenofovir diphosphate. In human clinical studies, a 10 mg oral dose of tenofovir alafenamide given with

emtricitabine, cobicistat and elvitegravir resulted in tenofovir diphosphate concentrations > 4-fold higher

in PBMCs and > 90% lower concentrations of tenofovir in plasma as compared to a 245 mg oral dose of

tenofovir disoproxil (as fumarate) given with emtricitabine, cobicistat and elvitegravir.

In vitro, tenofovir alafenamide is not metabolised by CYP1A2, CYP2C8, CYP2C9, CYP2C19, or

CYP2D6. Tenofovir alafenamide is minimally metabolised by CYP3A4. Upon co-administration with the

moderate CYP3A inducer probe efavirenz, tenofovir alafenamide exposure was not significantly affected.

Following administration of tenofovir alafenamide, plasma [

C] -radioactivity showed a time-dependent

profile, with tenofovir alafenamide as the most abundant species in the initial few hours and uric acid in

the remaining period.

Elimination

Emtricitabine is primarily excreted by the kidneys with complete recovery of the dose achieved in urine

(approximately 86%) and faeces (approximately 14%). Thirteen percent of the emtricitabine dose was

recovered in urine as three metabolites. The systemic clearance of emtricitabine averaged 307 mL/min.

Following oral administration, the elimination half-life of emtricitabine is approximately 10 hours.

The terminal elimination half-life of rilpivirine is approximately 45 hours. After single dose oral

administration of [

C]-rilpivirine, on average 85% and 6.1% of the radioactivity could be retrieved in

faeces and urine, respectively. In faeces, unchanged rilpivirine accounted for on average 25% of the

administered dose. Only trace amounts of unchanged rilpivirine (< 1% of dose) were detected in urine.

Renal excretion of intact tenofovir alafenamide is a minor pathway with < 1% of the dose eliminated in

urine. Tenofovir alafenamide fumarate is mainly eliminated following metabolism to tenofovir. Tenofovir

is renally eliminated by both glomerular filtration and active tubular secretion.

Pharmacokinetics in special populations

Age, gender and ethnicity

No clinically relevant pharmacokinetic differences due to age, gender or ethnicity have been identified for

emtricitabine, rilpivirine or tenofovir alafenamide.

Paediatric population

The pharmacokinetics of rilpivirine in antiretroviral-naïve HIV-1 infected paediatric patients 12 to < 18

years of age receiving rilpivirine 25 mg once daily was comparable to that in treatment-naïve HIV-1

infected adults receiving rilpivirine 25 mg once daily. There was no impact of body weight on rilpivirine

pharmacokinetics in paediatric patients in Study C213 (33 to 93 kg), similar to what was observed in

adults. The pharmacokinetics of rilpivirine in paediatric patients < 12 years of age is under investigation.

Exposures of emtricitabine and tenofovir alafenamide given with elvitegravir + cobicistat achieved in 24

paediatric patients aged 12 to < 18 years were similar to exposures achieved in treatment-naïve adults

(Table 6).

Table 6: Pharmacokinetics of emtricitabine, and tenofovir alafenamide in antiretroviral-naïve

adolescents and adults

Adolescents

Adults

Emtricitabine + tenofovir alafenamide

Emtricitabine + tenofovir alafenamide

(ngh/mL)

14,424.4 (23.9)

242.8 (57.8)

275.8 (18.4)

11,714.1 (16.6)

206.4 (71.8)

292.6 (27.4)

(ng/mL)

2,265.0 (22.5)

121.7 (46.2)

14.6 (20.0)

2,056.3 (20.2)

162.2 (51.1)

15.2 (26.1)

(ng/mL)

102.4 (38.9)

10.0 (19.6)

95.2 (46.7)

10.6 (28.5)

FTC = emtricitabine; TAF = tenofovir alafenamide; TFV = tenofovir, N/A = not applicable

Data are presented as mean (%CV).

a n = 24 adolescents (GS-US-292-0106); n = 19 adults (GS-US-292-0102)

b n = 23 adolescents (GS-US-292-0106, population PK analysis)

c n = 539 (TAF) or 841 (TFV) adults (GS-US-292-0111 and GS-US-292-0104, population PK analysis)

Renal impairment

Emtricitabine is principally eliminated by renal excretion and the exposure to emtricitabine increases in

patients with renal impairment. Mean systemic emtricitabine exposure was higher in patients with severe

renal impairment (CrCl < 30 mL/min) (33.7 µgh/mL) than in subjects with normal renal function (11.8

µgh/mL).

The pharmacokinetics of rilpivirine have not been studied in patients with renal insufficiency. Renal

elimination of rilpivirine is negligible. In patients with severe renal impairment or end-stage renal disease,

plasma concentrations may be increased due to alteration of drug absorption, distribution and/or

metabolism secondary to renal dysfunction. As rilpivirine is highly bound to plasma proteins, it is

unlikely that it will be significantly removed by haemodialysis or peritoneal dialysis (see section 4.9).

No clinically relevant differences in tenofovir alafenamide, or tenofovir pharmacokinetics were observed

between healthy subjects and subjects with severe renal impairment (estimated CrCl from 15 to < 30

mL/min) in studies of cobicistat-boosted elvitegravir or of tenofovir alafenamide, respectively.

Hepatic impairment

The pharmacokinetics of emtricitabine have not been studied in patients with varying degrees of hepatic

insufficiency; however emtricitabine is not significantly metabolised by liver enzymes, so the impact of

liver impairment should be limited.

Rilpivirine hydrochloride is primarily metabolised and eliminated by the liver. In a study comparing 8

patients with mild hepatic impairment (Child-Pugh Class A) to 8 matched controls and 8 patients with

moderate hepatic impairment (Child-Pugh Class B) to 8 matched controls, the multiple dose exposure of

rilpivirine was 47% higher in patients with mild hepatic impairment and 5% higher in patients with

moderate hepatic impairment. However, it may not be excluded that the pharmacologically active,

unbound, rilpivirine exposure is significantly increased in moderate impairment. Rilpivirine has not been

studied in patients with severe hepatic impairment (Child Pugh Class C) (see section 4.2).

Clinically relevant changes in the pharmacokinetics of tenofovir alafenamide or its metabolite tenofovir

were not observed in patients with mild or moderate hepatic impairment. In patients with severe hepatic

impairment, total plasma concentrations of tenofovir alafenamide and tenofovir are lower than those seen

in subjects with normal hepatic function. When corrected for protein binding, unbound (free) plasma

concentrations of tenofovir alafenamide in severe hepatic impairment and normal hepatic function are

similar.

Hepatitis B and/or hepatitis C virus co-infection

The pharmacokinetics of emtricitabine, rilpivirine and tenofovir alafenamide have not been fully

evaluated in patients co-infected with hepatitis B and/or C virus.

Pregnancy and postpartum

After taking rilpivirine 25 mg once daily as part of an antiretroviral regimen, the total exposure of

rilpivirine was lower during pregnancy (similar for the 2

and 3

trimester) compared with postpartum.

The decrease in the unbound free fraction of rilpivirine exposure (ie, active) during pregnancy compared

to postpartum was less pronounced than for total exposure of rilpivirine.

In women receiving rilpivirine 25 mg once daily during the 2

trimester of pregnancy, mean intra-

individual values for total rilpivirine C

, AUC

and C

values were 21%, 29% and 35% lower,

respectively, as compared to postpartum; during the 3

trimester of pregnancy, C

, AUC

and C

values were 20%, 31% and 42% lower, respectively, as compared to postpartum.

5.3 Preclinical safety data

Non-clinical data on emtricitabine reveal no special hazard for humans based on conventional studies of

safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction

and development.

Non-clinical data on rilpivirine hydrochloride reveal no special hazard for humans based on studies of

safety pharmacology, drug disposition, genotoxicity, carcinogenic potential, toxicity to reproduction and

development. Liver toxicity associated with liver enzyme induction was observed in rodents. In dogs

cholestasis-like effects were noted.

Carcinogenicity studies with rilpivirine in mice and rats revealed tumorigenic potential specific for these

species, but are regarded as of no relevance for humans.

Non-clinical studies of tenofovir alafenamide in rats and dogs revealed bone and kidney as the primary

target organs of toxicity. Bone toxicity was observed as reduced bone mineral density in rats and dogs at

tenofovir exposures at least four times greater than those expected after administration of Odefsey. A

minimal infiltration of histiocytes was present in the eye in dogs at tenofovir alafenamide and tenofovir

exposures of approximately 4- and 17-times greater, respectively, than those expected after administration

of Odefsey.

Tenofovir alafenamide was not mutagenic or clastogenic in conventional genotoxicity assays.

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

alafenamide compared to tenofovir disoproxil fumarate, carcinogenicity studies and a rat peri-postnatal

study were conducted only with tenofovir disoproxil fumarate. No special hazard for humans was

revealed in conventional studies of carcinogenic potential and toxicity to reproduction and development.

Reproductive toxicity studies in rats and rabbits showed no effects on mating, fertility, pregnancy or

foetal parameters. However, tenofovir disoproxil fumarate reduced the viability index and weight of pups

in a peri-postnatal toxicity study at maternally toxic doses.

6. Pharmaceutical particulars

6.1 List of excipients

Tablet core

Croscarmellose sodium

Lactose (as monohydrate)

Magnesium stearate

Microcrystalline cellulose

Polysorbate 20

Povidone

Film-coating

Macrogol

Polyvinyl alcohol

Talc

Titanium dioxide (E171)

Iron oxide black (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Store in the original package in order to protect from moisture. Keep the bottle tightly closed.

6.5 Nature and contents of container

High density polyethylene (HDPE) bottle with a polypropylene continuous-thread, child-resistant cap,

lined with an induction activated aluminium foil liner containing 30 film-coated tablets. Each bottle

contains silica gel desiccant and polyester coil.

The following pack sizes are available: outer cartons containing 1 bottle of 30 film-coated tablets and

outer cartons containing 90 (3 bottles of 30) film-coated tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

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

requirements.

7. Marketing authorisation holder

Gilead Sciences Ireland UC

Carrigtohill

County Cork, T45 DP77

Ireland

8. Marketing authorisation number(s)

EU/1/16/1112/001

EU/1/16/1112/002

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 21 June 2016

10. Date of revision of the text

05/2018

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.

Company Contact Details

Gilead Sciences Ltd

Address

Gilead Medical Information (UK & Eire), 280 High Holborn, London, WC1V 7EE, UK

E-mail

Prod complaints: [email

protected]

Medical Information Direct Line

08000 113 700 (UK)

Customer Care direct line

+44 (0)203 681 4681

Telephone

+44 (0)203 681 4500

Medical Information Direct Line

+353 214 825 999 (Ireland)

Medical Information e-mail

[email

protected]

Similar products

Search alerts related to this product

View documents history

Share this information