Consumer medicine information

Descovy Tablets

Emtricitabine; Tenofovir alafenamide

BRAND INFORMATION

Brand name

Descovy

Active ingredient

Emtricitabine; Tenofovir alafenamide

Schedule

S4

 

Consumer medicine information (CMI) leaflet

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

SUMMARY CMI

DESCOVY®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

▼ This medicine is new or being used differently. Please report side effects. See the full CMI for further details.

1. Why am I using DESCOVY?

DESCOVY contains the active ingredients emtricitabine and tenofovir alafenamide. DESCOVY is used to:

  • treat Human Immunodeficiency Virus-1 (HIV-1) infection in adults and paediatric patients weighing ≥ 25 kg when taken in combination with other anti-HIV medicines
  • to reduce the risk of getting HIV-1 infection in at-risk adults and adolescents weighing ≥ 35 kg

For more information, see Section 1. Why am I using DESCOVY? in the full CMI.

2. What should I know before I use DESCOVY?

Do not use if you have ever had an allergic reaction to DESCOVY or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use DESCOVY? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with DESCOVY and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use DESCOVY?

  • The usual dose is one DESCOVY tablet orally, once daily.
  • Take DESCOVY with or without food.

More instructions can be found in Section 4. How do I use DESCOVY? in the full CMI.

5. What should I know while using DESCOVY?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using DESCOVY.
Things you should not do
  • Do not stop using this medicine suddenly.
  • Do not breastfeed.
  • Avoid doing things that can spread HIV infection.
Driving or using machines
  • Be careful driving or operating machinery until you know how DESCOVY affects you.
Looking after your medicine
  • Keep your DESCOVY tablets in the bottle with the cap tightly closed until you take them.
  • Keep DESCOVY tablets in a cool, dry place where it stays below 30°C.

For more information, see Section 5. What should I know while using DESCOVY? in the full CMI.

6. Are there any side effects?

The most common side effect of DESCOVY is nausea.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

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



FULL CMI

DESCOVY®

Active ingredient(s): emtricitabine, tenofovir alafenamide

Consumer Medicine Information (CMI)

This leaflet provides important information about using DESCOVY. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using DESCOVY.

Where to find information in this leaflet:

1. Why am I using DESCOVY?
2. What should I know before I use DESCOVY?
3. What if I am taking other medicines?
4. How do I use DESCOVY?
5. What should I know while using DESCOVY?
6. Are there any side effects?
7. Product details

1. Why am I using DESCOVY?

DESCOVY contains the active ingredients emtricitabine and tenofovir alafenamide in one tablet.

Emtricitabine and tenofovir alafenamide belong to a group of antiviral medicines known as nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs).

DESCOVY is used to:

  • treat Human Immunodeficiency Virus-1 (HIV-1) infection in adults and paediatric patients weighing ≥ 25 kg when taken in combination with other anti-HIV medicines
  • reduce the risk of getting HIV-1 infection in at-risk adults and adolescents weighing ≥ 35 kg

DESCOVY helps block HIV-1 reverse transcriptase, a viral chemical (enzyme) in your body that is needed for HIV-1 to multiply.

DESCOVY lowers the amount of HIV in the blood (viral load).

DESCOVY may also help to increase the number of T cells (CD4+ cells), allowing your immune system to improve.

Lowering the amount of HIV in the blood lowers the chance of death or infections that happen when your immune system is weak (opportunistic infections).

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

DESCOVY is for people who do not have a resistant HIV virus to DESCOVY.

2. What should I know before I use DESCOVY?

Warnings

Do not use DESCOVY if:

  • you are allergic to emtricitabine or tenofovir alafenamide, or any of the ingredients listed at the end of this leaflet.
  • Always check the ingredients to make sure you can use this medicine.
  • you take:
    - tenofovir disoproxil fumarate (e.g. VIREAD)
    - lamivudine (e.g. Combivir, Zeffix, Kivexa, Trizivir, Triumeq)
    - carbamazepine (e.g. Tegretol)
    - oxcarbazepine (e.g. Trileptal)
    - phenobarbital or phenytoin (e.g. Dilantin)
    - rifabutin (e.g.Mycobutin)
    - rifampicin (e.g. Rifadin/Rimycin)
    - rifapentine (e.g. Priftin)
    - St John's Wort or products containing St John's Wort
    - tipranavir (e.g. Aptivus)
    - boceprevir (e.g. Victrelis)
  • you are also taking adefovir dipivoxil to treat your hepatitis B virus (HBV) infection.

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

Check with your doctor if you:

  • kidney problems or are undergoing kidney dialysis treatment.
    - Your doctor should do blood and urine tests to check your kidneys when starting and during treatment with DESCOVY. Your doctor may tell you to stop taking DESCOVY if you develop new or worse kidney problems.
  • liver problems, including hepatitis B or C virus infection.
  • take any medicines for any other condition

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant. We do not know if DESCOVY can harm your unborn child. You and your doctor will need to decide if DESCOVY is right for you.

Talk to your doctor if you are breastfeeding or intend to breastfeed. You should not breastfeed if you are HIV-positive because of the chance of passing the HIV virus to your baby. At least one of the active substances in this medicine (emtricitabine) have been found in breast milk at low concentrations. It is not known if DESCOVY affects milk production or has effects on the breastfed child. Talk with your doctor about the best way to feed your baby.

Use in Children

DESCOVY is used to treat HIV-1 infection in adults and children weighing ≥ 25 kg.

DESCOVY is used to reduce the risk of getting HIV-1 in adolescents weighing ≥ 35 kg.

DESCOVY has not been studied in children weighing less than 25 kg.

Does DESCOVY cure HIV or AIDS?

DESCOVY does not cure HIV infection or AIDS.

The long-term effects of DESCOVY are not known at this time.

People taking DESCOVY may still get opportunistic infections or other conditions that happen with HIV infection.

Opportunistic infections are infections that develop because the immune system is weakened. Some of these conditions are pneumonia, herpes virus infections, and Mycobacterium avium complex (MAC) infection.

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

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

Does DESCOVY reduce the risk of passing HIV to others?

DESCOVY will substantially reduce the risk of passing HIV to others. However, a residual risk cannot be excluded.

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

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

Never re-use or share needles.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

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

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

For this reason, it is very important to let your doctor or pharmacist know what medications, herbal supplements, or vitamins you are taking.

Know the medicines you take. Keep a list of medicines and show it to your doctor and pharmacist when you get a new medicine.

Your doctor and your pharmacist can tell you if you can take these medicines with DESCOVY.

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

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect DESCOVY.

4. How do I use DESCOVY?

How much to take

  • The usual dose is one DESCOVY tablet orally, once daily.
  • Take DESCOVY with or without food.

If you forget to use DESCOVY

DESCOVY should be used regularly at the same time each day. It is important not to miss a dose of DESCOVY.

If you do miss a dose:

  • If you notice within 18 hours of the time you usually take DESCOVY, you must take the tablet as soon as possible. Then take the next dose as usual.
  • If you notice 18 hours or more after the time you usually take DESCOVY, then do not take the missed dose. Wait and take the next dose at your usual time.

Do not take a double dose to make up for the dose you missed.

Continue with your regular dosing schedule.

When your DESCOVY supply starts to run low, get more from your doctor or pharmacy.

This is very important. If you are taking DESCOVY for HIV-1 treatment, the amount of virus in your blood may increase if the medicine is stopped for even a short time. The virus may develop resistance to DESCOVY and become harder to treat. If you are taking DESCOVY to reduce your risk of getting HIV, you must take DESCOVY every day to protect yourself from getting HIV-1.

If you use too much DESCOVY

If you think that you have used too much DESCOVY, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre by calling 13 11 26 (Australia) and 0800 764 766 (New Zealand), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using DESCOVY?

Things you should do

Remind any doctor, dentist or pharmacist you visit that you are using DESCOVY.

Things you should not do

  • Do not stop using this medicine suddenly.
  • Do not breastfeed.
  • Avoid doing things that can spread HIV infection since DESCOVY does not stop you from passing the HIV infection to others.
    - Do not share needles or other injection equipment.
    - Do not share personal items that can have blood or body fluids on them, like toothbrushes or razor blades.
  • Always practice safer sex by using a latex or polyurethane condom or other barrier to reduce the chance of sexual contact with semen, vaginal secretions, or blood.
  • Do not take DESCOVY if the packaging is torn or shows signs of tampering.

If you are taking DESCOVY to reduce your risk of getting HIV

You must stay HIV-negative to keep taking DESCOVY.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how DESCOVY affects you.

If you are dizzy, have trouble concentrating, or are drowsy, avoid activities that may be dangerous, such as driving or operating machinery.

Looking after your medicine

  • Keep your DESCOVY tablets in the bottle with the cap tightly closed until you take them.
  • Keep DESCOVY tablets in a cool, dry place where it stays below 30°C.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
  • nausea
  • diarrhea
  • fatigue
  • headaches
  • abdominal pain
  • indigestion
  • flatulence
  • rash
  • vomiting
  • abnormal dreams
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Serious Liver Problems
(hepatotoxicity)
  • your skin or the white part of your eyes turns yellow (jaundice)
  • your urine turns dark
  • your bowel movements (stools) turn light in colour
  • you don't feel like eating food for several days or longer
  • you feel sick to your stomach (nausea)
  • you have lower stomach area (abdominal) pain

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

Hepatic Flares

If you have HBV infection you should not stop your DESCOVY treatment without first discussing this with your doctor. Your HBV may get worse (flare-up) if you stop taking DESCOVY. A “flare-up” or “hepatic flare” is when your HBV infection suddenly returns in a worse way than before You may require medical exams and blood tests for several months after stopping treatment. You must discuss your HBV therapy with your doctor.

Signs and symptoms of inflammation

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

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

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

Lactic acidosis can be a medical emergency and may need to be treated in the hospital.
Allergy
Some people are allergic to medicines. If you have any of the following symptoms soon after taking your medicine, DO NOT TAKE ANY MORE DESCOVY and tell your doctor IMMEDIATELY or go to the accident and emergency department at your nearest hospital:
  • skin troubles such as lumpy skin rash or “hives”
  • swelling of the face, lips, mouth or throat which may cause difficulty in swallowing or breathing
  • wheezing, chest pain or tightness
  • fainting
These are very serious effects. If you have them, you may have a serious allergic reaction. You may need urgent medical attention or hospitalisation. Hypersensitivity reactions are very rare.		Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What DESCOVY contains

Active ingredient
(main ingredient)		emtricitabine
tenofovir alafenamide
Other ingredients
(inactive ingredients)

microcrystalline cellulose
croscarmellose sodium
magnesium stearate

Film-coating (200/25 mg tablets)

polyvinyl alcohol
titanium dioxide
polyethylene glycol
talc
indigo carmine aluminum lake

Film-coating (200/10 mg tablets)

polyvinyl alcohol
titanium dioxide
polyethylene glycol
talc
iron oxide black

Potential allergensN/A

Do not take this medicine if you are allergic to any of these ingredients.

What DESCOVY looks like

The 200/25 mg DESCOVY tablets are rectangular-shaped, film-coated and blue in colour.

Each tablet is debossed with “GSI” on one side and the number “225” on the other side.

The 200/10 mg DESCOVY tablets are rectangular-shaped, film-coated and gray in colour.

Each tablet is debossed with “GSI” on one side and the number “210” on the other side

DESCOVY tablets are supplied in bottles containing 30 tablets.

DESCOVY 200/10 mg tablets AUST R 246093

DESCOVY 200/25 mg tablets AUST R 246092

Who distributes DESCOVY

Australia

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

New Zealand

c/- Grant Thornton New Zealand Limited,
L4, 152 Fanshawe Street
Auckland 1010

This leaflet was prepared in June 2022.

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

Published by MIMS August 2022

BRAND INFORMATION

Brand name

Descovy

Active ingredient

Emtricitabine; Tenofovir alafenamide

Schedule

S4

 

1 Name of Medicine

Descovy (200 mg emtricitabine/25 mg tenofovir alafenamide) and Descovy (200 mg emtricitabine/10 mg tenofovir alafenamide) tablets.
The drug substances in Descovy tablets are emtricitabine (FTC) and tenofovir alafenamide (TAF) fumarate.

2 Qualitative and Quantitative Composition

Descovy is available as tablets.
Descovy 200/25 mg tablets contain 200 mg of FTC and TAF fumarate equivalent to 25 mg tenofovir alafenamide.
For the full list of excipients, see Section 6.1 List of Excipients.
Descovy 200/10 mg tablets contain 200 mg of FTC and TAF fumarate equivalent to 10 mg tenofovir alafenamide.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Each 200/25 mg Descovy tablet is rectangular shaped, film-coated and blue in colour. Each tablet is debossed with 'GSI' on one side and the number "225" on the other side.
Each 200/10 mg Descovy tablet is rectangular shaped, film-coated and gray in colour. Each tablet is debossed with 'GSI' on one side and the number "210" on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of HIV-1 infection.

Descovy is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and paediatric patients weighing at least 25 kg. The patients must not have a history of treatment failure or known mutations associated with resistance to the individual components of Descovy (see Section 5.1 Pharmacodynamic Properties).

HIV-1 Pre-exposure prophylaxis.

Descovy is indicated for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 in at-risk adults and adolescents weighing at least 35 kg, excluding individuals at risk from receptive vaginal sex.

4.2 Dose and Method of Administration

Treatment of HIV-1 infection.

In adults and paediatric patients weighing ≥ 25 kg, Descovy is taken orally once daily with or without food.
The recommended dose of Descovy is 200/25 mg.
If Descovy is used in combination with an HIV-1 protease inhibitor that is administered with either ritonavir or cobicistat, the recommended dose of Descovy is 200/10 mg (see Table 1).
Also see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions. For specific dosing recommendations for coadministered antiretroviral agents, refer to their respective product information.
No data are available on which to make a dose recommendation for paediatric patients weighing less than 25 kg.

HIV-1 PrEP.

In HIV-1 uninfected adults and adolescents weighing ≥ 35 kg, Descovy is taken orally once daily with or without food.
The recommended dose of Descovy is 200/25 mg.

Elderly.

No dose adjustment is required for elderly individuals. In clinical trials, 80 of the 97 HIV-infected patients enrolled aged 65 years and over received FTC+TAF given with EVG+COBI as a fixed dose combination tablet. No differences in safety or efficacy have been observed between elderly patients and those between 12 and less than 65 years of age.

Renal impairment.

No dose adjustment of Descovy is required in adult individuals with estimated creatinine clearance ≥ 30 mL/min or in adult patients with end stage renal disease (estimated creatinine clearance < 15 mL/min) on chronic haemodialysis. Descovy should generally be avoided if the CrCl < 15 mL/min but may be used in adults with end stage renal disease (estimated CrCl < 15 mL/min) on chronic haemodialysis if the potential benefits are considered to outweigh the potential risks. On days of haemodialysis, administer the daily dose of Descovy after completion of haemodialysis treatment. Descovy should be avoided in patients with estimated creatinine clearance ≥ 15 and < 30 mL/min, or < 15 mL/min who are not on chronic haemodialysis, as the safety of Descovy has not been established in these populations.
No data are available to make dose recommendations in paediatric patients with renal impairment.

Hepatic impairment.

No dose adjustment of Descovy is required in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment. Descovy has not been studied in patients with severe hepatic impairment (Child-Pugh class C) (see Section 5.2 Pharmacokinetic Properties, Patients with hepatic impairment).

4.3 Contraindications

Descovy is contraindicated in patients with known hypersensitivity to any of the active substances or any other component of the tablets.
Please see Table 2 for established and other potentially significant drug interactions. In addition, prescribing information for any drug coadministered with Descovy should be consulted to exclude significant interaction or contraindication.
Do not use Descovy for PrEP in individuals with unknown or positive HIV-1 status.

4.4 Special Warnings and Precautions for Use

General.

HIV-1 infected patients receiving Descovy or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection, and therefore should remain under close clinical observation by physicians experienced in the treatment of patients with HIV associated diseases.
While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of HIV transmission, a residual risk cannot be excluded. Appropriate precautions must continue to be used. Patients should also be informed that Descovy is not a cure for HIV infection.

Hepatitis B virus (HBV) infection.

Discontinuation of Descovy therapy in individuals infected with HBV may be associated with severe acute exacerbations of hepatitis. Individuals infected with HBV who discontinue Descovy should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, initiation of anti-hepatitis B therapy may be warranted, especially in individuals with advanced liver disease or cirrhosis since post-treatment exacerbation of hepatitis may lead to hepatic decompensation.

Comprehensive management to reduce the risk of sexually acquired infections and development of HIV-1 resistance when Descovy is used for HIV-1 PrEP.

Comprehensive prevention strategy.

Use Descovy for PrEP to reduce the risk of HIV-1 infection. As part of a comprehensive prevention strategy to reduce the risk of sexually acquired infections, counsel individuals on the use of other prevention measures (e.g. consistent and correct condom use, knowledge of partner HIV-1 status, regular testing for sexually transmitted infections that can facilitate HIV-1 transmission). The time from initiation of Descovy for HIV-1 PrEP to maximal protection against HIV-1 infection is unknown.

Risk of resistance with undetected HIV-1 infection.

Descovy should only be used to reduce the risk of acquiring HIV-1 in individuals confirmed to be HIV-negative. Confirm HIV-1 negative status prior to initiating Descovy for PrEP and routinely in individuals taking Descovy for PrEP. HIV-1 resistance substitutions may emerge in individuals with undetected HIV-1 infection who are taking only Descovy, because Descovy alone does not constitute a complete regimen for HIV-1 treatment (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
If clinical symptoms consistent with acute HIV-1 infection are present, and recent (< 1 month) exposures to HIV-1 are suspected, follow local clinical guidelines and use an approved or cleared test to aid in the diagnosis of acute or primary HIV-1 infection.

Importance of adherence.

Counsel HIV-1 uninfected individuals to strictly adhere to the recommended Descovy dosing schedule. The effectiveness of Descovy in reducing the risk of acquiring HIV-1 is strongly correlated with adherence as demonstrated by measurable drug levels. Some individuals, such as adolescents, may benefit from more frequent visits and counselling to support adherence.

Use with other antiretroviral products.

Descovy should not be coadministered with products containing any of the same components, TAF or FTC; or with products containing lamivudine or tenofovir disoproxil fumarate. Descovy should not be administered with adefovir dipivoxil.
Data support use of Descovy with HIV-1 protease inhibitors atazanavir, darunavir and lopinavir for the treatment of HIV (see Table 2). For treatment of HIV and hepatitis C co-infection, Descovy should not be used in conjunction with protease inhibitors that are inhibitors of cathepsin A (such as the anti-hepatitis C agent boceprevir) due to potential drug-drug interactions including altered and/or suboptimal pharmacokinetics of TAF.

Immune reconstitution syndrome.

Immune reconstitution syndrome has been reported in HIV-1 infected patients treated with combination antiretroviral therapy, including FTC, a component of Descovy. In HIV-infected patients with severe immune deficiency at the time of initiation of antiretroviral therapy, an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of antiretroviral therapy. Relevant examples include cytomegalovirus retinitis, generalised and/or focal mycobacterial infections and Pneumocystis jirovecii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.
Autoimmune disorders (such as autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the reported time to onset is more variable, and these events can occur many months after initiation of treatment.

Paediatric use.

The safety, virologic, and immunologic responses in patients who received Descovy were evaluated in 50 treatment-naive, HIV-1 infected patients aged 12 to less than 18 years (≥ 35 kg) through Week 48 and in 23 virologically suppressed patients between the ages of 8 to less than 12 years (≥ 25 kg) through Week 24 in an open-label trial, Study 106 (see Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 5.2 Pharmacokinetic Properties).

Use in the elderly.

In clinical trials, 80 of the 97 patients enrolled aged 65 years and over received FTC and TAF given with EVG and COBI as a fixed dose combination tablet. No differences in safety or efficacy have been observed between elderly patients and those between 12 and less than 65 years of age.

Renal impairment.

Post-marketing cases of renal impairment, including acute renal failure, proximal renal tubulopathy (PRT), and Fanconi syndrome have been reported with tenofovir alafenamide containing products; while most of these cases were characterised by potential confounders that may have contributed to the reported renal events, it is also possible these factors may have predisposed patients to tenofovir-related adverse events.
Patients taking tenofovir prodrugs who have impaired renal function and those taking nephrotoxic agents, including non-steroidal anti-inflammatory drugs, are at increased risk of developing renal-related adverse reactions.
Prior to or when initiating Descovy, and during treatment with Descovy on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus. Discontinue Descovy in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome.
The safety, virologic and immunologic responses of FTC+TAF was evaluated through 144 weeks in an open label clinical study (study 112) in which 248 HIV-1 infected adult patients who were either treatment naïve (N = 6) or virologically suppressed (N = 242) with mild to moderate renal impairment (eGFR by Cockcroft-Gault method 30-69 mL/min) received FTC+TAF in combination with EVG+COBI as a fixed dose combination tablet. The safety profile of FTC+TAF in patients with mild to moderate renal impairment was similar to safety data that from patients with normal renal function.
The safety of FTC+TAF was evaluated through Week 48 in a single arm, open-label clinical study (Study 1825), in which 55 virologically suppressed HIV-1 infected patients with end stage renal disease (eGFR by Cockcroft-Gault method < 15 mL/min) on chronic haemodialysis received FTC+TAF in combination with EVG+COBI as a fixed-dose combination tablet. The safety profile of FTC+TAF in patients with end stage renal disease on chronic haemodialysis was similar to that in patients with normal renal function.
Descovy should generally be avoided if the CrCl < 15 mL/min but may be used in adults with end stage renal disease (estimated CrCl < 15 mL/min) on chronic haemodialysis if the potential benefits are considered to outweigh the potential risks. Descovy should be avoided in patients with estimated creatinine clearance ≥ 15 and < 30 mL/min, or < 15 mL/min who are not on chronic haemodialysis, as the safety of Descovy has not been established in these populations (see Section 4.2 Dose and Method of Administration). No data are available to make dose recommendations in paediatric patients with renal impairment.

Hepatic impairment.

No dose adjustment of Descovy is required in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment. Descovy has not been studied in patients with severe hepatic impairment (Child-Pugh class C) (see Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 5.2 Pharmacokinetic Properties).

Lactic acidosis/severe hepatomegaly with steatosis.

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of antiretroviral nucleoside analogues, including emtricitabine, a component of Descovy and tenofovir disoproxil fumarate, another prodrug of tenofovir, alone or in combination with other antiretrovirals. Treatment with Descovy should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

General.

As Descovy contains FTC any interactions that have been identified with FTC individually may occur with Descovy.

Effects of concomitant drugs on the pharmacokinetics of Descovy.

TAF, a component of Descovy, is transported by P-glycoprotein (P-gp) and BCRP. Drugs that strongly affect P-gp and BCRP activity may lead to changes in TAF absorption (see Table 2). Drugs that induce P-gp activity are expected to decrease the absorption of TAF, resulting in decreased plasma concentration of TAF, which may lead to loss of therapeutic effect of Descovy and development of resistance. Coadministration of Descovy with other drugs that inhibit P-gp and BCRP may increase the absorption and plasma concentration of TAF.

Established and other potentially significant interactions.

Drug interaction information for Descovy with potential concomitant drugs is summarized in Table 2. The drug interactions described are based on studies conducted with Descovy or the components of Descovy (FTC and TAF) as individual agents, or are potential drug interactions that may occur with Descovy.
Table 2 is not all inclusive (see Section 4.3 Contraindications).

Drugs without clinically significant interactions with Descovy.

Based on drug interaction studies conducted with the components of Descovy and the following antiviral agents, no clinically significant drug interactions were observed with dolutegravir, efavirenz, famciclovir, ledipasvir/sofosbuvir, rilpivirine, sofosbuvir, sofosbuvir/velpatasvir, and sofosbuvir/velpatasvir/voxilaprevir. No clinically significant drug interactions are expected when Descovy is combined with maraviroc, nevirapine or raltegravir.
Based on drug interaction studies conducted with the components of Descovy, no clinically significant drug interactions were observed when Descovy was combined with ethinyl estradiol, midazolam, norgestimate, or sertraline. No clinically significant drug interactions are expected when Descovy is combined with buprenorphine, methadone, naloxone, or norbuprenorphine.

4.6 Fertility, Pregnancy and Lactation

Impairment of fertility.

No reproductive toxicity studies have been conducted with FTC and TAF in combination.

Emtricitabine.

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

Tenofovir alafenamide.

There were no effects on fertility, mating performance or early embryonic development when tenofovir alafenamide was administered to male rats at a dose equivalent to 155 times the human dose based on body surface area comparisons for 28 days prior to mating and to female rats for 14 days prior to mating through day seven of gestation.
(Category B3)
There are no adequate and well controlled clinical studies of Descovy or its components in pregnant women. Because animal reproductive studies are not always predictive of human response, Descovy should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Emtricitabine.

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

Tenofovir alafenamide.

Embryofetal development studies performed in rats and rabbits revealed no evidence of embryolethality, fetotoxicity or teratogenicity due to TAF. The embryo-fetal NOAELs in rats and rabbits occurred at TAF exposures (AUC) similar to and 53 times higher than, respectively, the exposure in humans at the recommended daily dose.
 In animal studies it has been shown that tenofovir is secreted into milk. It is not known whether TAF is secreted in human milk. In humans, samples of breast milk obtained from five HIV-1 infected mothers given Truvada (TDF/FTC) show that FTC is secreted in human milk at estimated neonatal concentrations 3 to 12 times higher than the FTC IC50 but 3 to 12 times lower than the Cmin achieved from oral administration of FTC. Breastfeeding infants infected with HIV whose mothers are taking FTC may be at risk for developing viral resistance to FTC. Other FTC associated risks in infants breastfed by mothers who are taking FTC are unknown.
Because of the potential for both HIV transmission and for serious adverse events in nursing infants, HIV-1 infected mothers should be instructed not to breastfeed if they are receiving Descovy.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects of Descovy on the ability to drive and use machines have been performed.

4.8 Adverse Effects (Undesirable Effects)

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.
As Descovy contains FTC, adverse reactions associated with FTC may be expected to occur with the fixed combination tablet.
For additional safety information about Emtriva (FTC), in combination with other antiretroviral agents, consult the product information.

Clinical trials.

Experience from clinical studies in HIV-1 infected treatment naïve patients.

Assessment of adverse reactions is based on pooled data from two 144 week controlled clinical studies (study 104 and study 111) in which 1733 treatment naïve patients received FTC+TAF (N = 866) or FTC+TDF (N = 867), both given with EVG+COBI as a fixed dose combination tablet.
The most common adverse reaction (all grades) and reported in ≥ 10% of patients in the FTC+TAF group was nausea. The proportion of subjects who discontinued treatment with FTC+TAF or FTC+TDF due to adverse events, regardless of severity, was 1.3% and 3.3%, respectively. Table 3 displays the frequency of adverse reactions (all grades) greater than or equal to 5%.
The majority of events presented in Table 3 occurred at severity grade 1.
In addition to the adverse reactions presented in Table 3, abdominal pain, abnormal dreams, dyspepsia, flatulence, rash, and vomiting occurred at a common frequency (≥ 1% and < 10%; frequency based on all adverse events, regardless of relationship to study drug) in the FTC+TAF group.

Laboratory abnormalities.

The frequency of laboratory abnormalities (grades 3-4) occurring in at least 2% of patients receiving FTC+TAF given with EVG+COBI as a fixed dose combination tablet in studies 104 and 111 are presented in Table 4.

Serum lipids.

In the clinical trials of FTC+TAF and FTC+TDF, both given with EVG+COBI as a fixed dose combination tablet, a similar percentage of patients receiving FTC+TAF and FTC+TDF were on lipid lowering agents at baseline (4% and 5%, respectively). While receiving study drug through week 144, an additional 5.5% of FTC+TAF patients were started on lipid lowering agents, compared to 5.8% of FTC+TDF patients.
Changes from baseline in total cholesterol, HDL cholesterol, LDL cholesterol and triglycerides are presented in Table 5.

Experience from clinical studies in HIV-1 infected virologically suppressed patients.

No new adverse reactions to Descovy were identified through week 96 in an open label clinical study (study 109) of virologically suppressed patients who switched treatment from a TDF containing combination regimen to FTC+TAF given with EVG+COBI as a fixed dose combination tablet (N = 959).
No new adverse reactions to Descovy were identified through week 48 in a randomised double blind clinical study (Study 1089) of virologically suppressed patients who switched treatment from a Truvada containing regimen to a Descovy containing regimen (N = 333).
No new adverse reactions to Descovy were identified through Week 48 in a double-blind clinical study (Study 1717) of virologically suppressed patients who switched treatment from an abacavir/lamivudine (ABC/3TC)-containing regimen to a Descovy-containing regimen (FTC/TAF) (N=280).

Experience from clinical studies in HIV-1 infected patients with renal impairment.

The safety of Descovy was evaluated through week 144 in an open label clinical study (study 112) 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 (eGFR by Cockcroft-Gault method 30-69 mL/min) received FTC+TAF in combination with EVG+COBI as a fixed dose combination tablet. The safety profile of FTC+TAF in patients with mild to moderate renal impairment was similar to that from patients with normal renal function (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
In 84 renally impaired patients who switched to FTC+TAF given with EVG+COBI as a fixed dose combination in study 112 from antiviral regimens not containing TDF, mean change from baseline in fasting lipid laboratory tests at week 144 were -19 mg/dL in total cholesterol, -13 mg/dL in LDL cholesterol, -6 mg/dL in HDL cholesterol, 0.2 in total cholesterol to HDL ratio, and -22 mg/dL in triglycerides.

Experience from clinical studies in HIV-1 infected paediatric patients.

The safety of Descovy was evaluated in 50 HIV-infected, treatment-naïve patients between the ages of 12 to < 18 years (≥ 35 kg) through Week 48 and in 23 virologically suppressed patients between the ages of 8 to < 12 years (≥ 25 kg) through Week 24 in an open-label clinical study (Study 106). These patients received FTC+TAF in combination with EVG+COBI as a fixed-dose combination tablet. The safety profile of FTC+TAF in this study was similar to that in adults.

Experience from clinical studies in HIV-1 uninfected adults.

No new adverse reactions to Descovy were identified in a double-blind, randomized, active-controlled study (DISCOVER Study 2055) in which a total of 5387 HIV-1 uninfected adult men or transgender women who have sex with men received Descovy (N=2694) or Truvada (N=2693) once daily for HIV-1 PrEP. Median duration of exposure to Descovy and Truvada was 86 and 87 weeks, respectively.

Post-marketing experience.

In addition to adverse reactions from clinical studies, the following adverse reactions were identified during postapproval use of products containing FTC and/or TAF. Because these reactions were reported voluntarily from a population of unknown size, estimates of frequency cannot be made.

Immune system disorders.

Autoimmune hepatitis (see Section 4.4 Special Warnings and Precautions for Use).

Skin and subcutaneous tissue disorders.

Angioedema, urticaria.

Renal and urinary disorders.

Acute renal failure, proximal renal tubulopathy, Fanconi syndrome.

4.9 Overdose

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

Emtricitabine.

Limited clinical experience is available at doses higher than the therapeutic dose of emtricitabine 200 mg. In one clinical pharmacology study single doses of emtricitabine 1200 mg were administered to 11 patients. No severe adverse reactions were reported. The effects of higher doses are not known.
Haemodialysis treatment removes approximately 30% of the FTC dose over a 3 hour dialysis period starting within 1.5 hours of emtricitabine dosing (blood flow rate of 400 mL/min and a dialysate flow rate of 600 mL/min). It is not known whether emtricitabine can be removed by peritoneal dialysis.

Tenofovir alafenamide.

Limited clinical experience is available at doses higher than the therapeutic dose of TAF. A single supratherapeutic dose of 125 mg TAF was administered to 48 healthy subjects, no serious adverse reactions were reported. The effects of higher doses are unknown. Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antivirals for treatment of HIV infections, combinations, ATC code: J05AF30.

Mechanism of action.

Descovy is a fixed dose combination tablet containing the antiviral drugs FTC and TAF.

Emtricitabine.

FTC is a nucleoside analogue of 2'-deoxycytidine. FTC is phosphorylated by cellular enzymes to form FTC triphosphate. FTC triphosphate inhibits HIV replication through incorporation into viral DNA by the HIV reverse transcriptase, which results in DNA chain termination.
FTC has activity that is specific to human immunodeficiency virus (HIV-1 and HIV-2) and hepatitis B virus. FTC triphosphate is a weak inhibitor of mammalian DNA polymerases that include mitochondrial DNA polymerase γ and there was no evidence of toxicity to mitochondria in vitro and in vivo.

Tenofovir alafenamide.

TAF is a phosphonamidate prodrug of tenofovir (2'-deoxyadenosine monophosphate analogue). TAF is permeable into cells and due to increased plasma stability and intracellular activation through hydrolysis by cathepsin A, TAF is more efficient than tenofovir disoproxil fumarate (TDF) in loading tenofovir into peripheral blood mononuclear cells (PBMCs), including lymphocytes and macrophages. Intracellular tenofovir is subsequently phosphorylated to the pharmacologically active metabolite tenofovir diphosphate. Tenofovir diphosphate inhibits HIV replication through incorporation into viral DNA by the HIV reverse transcriptase, which results in DNA chain termination.
Tenofovir has activity that is specific to human immunodeficiency virus (HIV-1 and HIV-2) and hepatitis B virus (HBV). In vitro studies have shown that both FTC and tenofovir can be fully phosphorylated when combined in cells. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases that include mitochondrial DNA polymerase γ and there is no evidence of mitochondrial toxicity in vitro based on several assays including mitochondrial DNA analyses.

Antiviral activity in vitro.

Emtricitabine.

The in vitro antiviral activity of FTC against laboratory and clinical isolates of HIV was assessed in lymphoblastoid cell lines, the MAGI-CCR5 cell line, and peripheral blood mononuclear cells. The EC50 values for FTC were in the range of 0.0013 to 0.64 microM (0.0003 to 0.158 microgram/mL).
FTC displayed antiviral activity in vitro against HIV-1 clades A, C, D, E, F, and G (EC50 values ranged from 0.007 to 0.075 microM) and showed strain specific activity against HIV-2 (IC50 values ranged from 0.007 to 1.5 microM).
In drug combination studies of FTC with NRTIs (abacavir, 3TC, d4T, zalcitabine, AZT), NNRTIs (delavirdine, efavirenz, nevirapine), and protease inhibitors (PI) (amprenavir, nelfinavir, ritonavir, saquinavir), additive to synergistic effects were observed. No antagonism was observed for these combinations.

Tenofovir alafenamide.

The antiviral activity of TAF against laboratory and clinical isolates of HIV-1 subtype B was assessed in lymphoblastoid cell lines, PBMCs, primary monocyte/macrophage cells and CD4-T lymphocytes. The EC50 values for TAF were in the range of 2.0 to 14.7 nanoM.
TAF displayed antiviral activity in cell culture against all HIV-1 groups (M, N, O), including sub-types A, B, C, D, E, F and G (EC50 values ranged from 0.10 to 12.0 nanoM) and strain specific activity against HIV-2 (EC50 values ranged from 0.91 to 2.63 nanoM).
In a study of TAF with a broad panel of representatives from the major classes of approved anti-HIV agents (NRTIs, NNRTIs, INSTIs and PIs), additive to synergistic effects were observed. No antagonism was observed for these combinations.

Prophylactic activity in a nonhuman primate model of HIV-1 transmission.

Emtricitabine and tenofovir alafenamide.

The prophylactic activity of the combination of daily oral FTC and TAF was evaluated in a controlled study of macaques administered once weekly inoculations of intra-rectal SIV/HIV-1 chimeric virus (SHIV) for up to 19 weeks (n=6) and a controlled study of pigtailed macaques administered once weekly inoculations of intravaginal SHIV for up to 16 weeks (n=6). All 6 macaques and 5 of 6 pigtail macaques that received FTC and TAF at doses resulting in PBMC exposures consistent with those achieved in humans administered a dose of FTC/TAF 200/25 mg remained SHIV antibody seronegative and SHIV RNA negative during all viral challenges.

Drug resistance.

In cell culture.

Emtricitabine.

HIV-1 isolates with reduced susceptibility to FTC have been selected in cell culture. Genotypic analysis of these isolates showed that the reduced susceptibility to FTC was associated with a mutation in the HIV reverse transcriptase gene at codon 184 which resulted in an amino acid substitution of methionine by valine or isoleucine (M184V/I).

Tenofovir alafenamide.

HIV-1 isolates with reduced susceptibility to TAF have been selected in cell culture. HIV-1 isolates selected by TAF expressed a K65R mutation in HIV-1 RT; in addition, a K70E mutation in HIV-1 RT has been transiently observed. HIV-1 isolates with the K65R mutation have low level reduced susceptibility to abacavir, FTC, tenofovir and lamivudine. In vitro drug resistance selection studies with TAF have shown no development of high level resistance after extended culture.
In clinical studies.

In HIV-1 infected treatment naïve patients.

In a pooled analysis of antiretroviral naive patients receiving FTC+TAF given with EVG+COBI as a fixed dose combination tablet in Phase 3 studies 104 and 111, genotyping was performed on plasma HIV-1 isolates from all patients with HIV-1 RNA ≥ 400 copies/mL at confirmed virologic failure, at week 144, or at time of early study drug discontinuation. As of week 144, the development of one or more primary FTC, TAF or EVG resistance associated mutations was observed in 12 of 22 patients with evaluable genotypic data from paired baseline and EVG+COBI+FTC+TAF treatment failure isolates (12 of 866 patients [1.4%]) compared with 12 of 20 treatment failure isolates from patients with evaluable genotypic data in the EVG+COBI+FTC+TDF group (12 of 867 patients [1.4%]). Of the 12 patients with resistance development in the EVG+COBI+FTC+TAF group, the mutations that emerged were M184V/I (N=11) and K65R/N (N = 2) in reverse transcriptase and T66T/A/I/V (N = 2), E92Q (N = 4), Q148Q/R (N = 1), and N155H (N = 2) in integrase. Of the 12 patients with resistance development in the EVG+COBI+FTC+TDF group, the mutations that emerged were M184V/I (N = 9), K65R/N (N = 4), and L210W (N=1) in reverse transcriptase and E92Q/V (N = 4), Q148R (N = 2), and N155H/S (N=3) in integrase. In both treatment groups most patients who developed resistance mutations to EVG developed resistance mutations to both FTC and EVG.
In phenotypic analyses of patients in the resistance analysis population, 8 of 22 patients (36%) receiving EVG+COBI+FTC+TAF had HIV-1 isolates with reduced susceptibility to FTC compared with 7 of 20 patients (35%) receiving EVG+COBI+FTC+TDF. One patient in the EVG+COBI+FTC+TAF group (1 of 22 [4.5%]) and 2 patients in the EVG+COBI+FTC+TDF group (2 of 20 [10%]) had reduced susceptibility to tenofovir. Finally, 7 of 22 patients (32%) had reduced susceptibility to EVG in the EVG+COBI+FTC+TAF group compared with 7 of 20 patients (35%) in the EVG+COBI+FTC+TDF group.

In HIV-1 infected virologically suppressed patients.

In a week 96 analysis of virologically suppressed patients who switched from Truvada to Descovy while maintaining their third antiretroviral agent (Study 1089), 1 of 4 patients analysed in the Descovy+third agent group (1 of 333 [0.3%]) developed M184V in reverse transcriptase in the first 48 weeks, with reduced susceptibility to emtricitabine. In the Truvada+third agent group, 0 of 3 patients analyzed (0 of 330 [0%]) developed resistance to any components of their regimen.
In a week 48 analysis of virologically-suppressed patients who switched from ABC/3TC while maintaining their third antiretroviral agent (Study 1717), 1 of 3 patients analyzed in the Descovy+third agent group (1 of 253 [0.4%]) developed the K65K/R resistance mutation in addition to pre-existing M184V but had no phenotypic resistance to TAF (phenotypic resistance to FTC was present). In the ABC/3TC+third agent group, 1 of 1 patient analyzed (1 of 248 [0.4%]) developed resistance to their third agent (ATV; M46I, I50L, and N88S) in addition to pre-existing reverse transcriptase mutations (multiple TAMs, T69H/N, and M184V) and had phenotypic resistance to FTC and ATV.
In a week 96 analysis of virologically suppressed patients who switched from a regimen containing FTC+TDF+third agent to FTC+TAF given with EVG+COBI in a fixed dose combination tablet (Study 109), 3 of 6 patients analyzed in the EVG+COBI+FTC+TAF group (3 of 959 [0.3%]) developed resistance to study drugs (2 with EVG/FTC resistance, M184I + E92G and M184V + E92Q; and 1 with FTC resistance only, M184M/I). In the FTC+TDF+third agent group, 1 of 2 patients analyzed (1 of 477 [0.2%]) developed resistance to all 3 components of the regimen (multiple TAMs + M184V + T66A/E92Q).

In HIV-1 uninfected adults at risk for HIV-1 infection.

In the DISCOVER Study 2055 of HIV-1 uninfected adult men and transgender women who have sex with men and who are at risk of HIV-1 infection receiving Descovy or Truvada for HIV-1 PrEP, genotyping was performed on participants found to be infected during the study who had HIV-1 RNA ≥ 400 copies/mL (6 of 7 participants receiving Descovy and 13 of 15 participants receiving Truvada). With approximately 4370 and 4386 person-years of follow-up (87 weeks, median) in the Descovy and Truvada groups, respectively, the development of resistance-associated mutations was observed in 0 of 6 HIV-1 infected participants in the Descovy group compared to 4 of 13 HIV-1 infected participants in the Truvada group. The 4 HIV-1 infected participants in the Truvada group had suspected baseline HIV-1 infections, and the study drug mutation that emerged in these participants was M184V.

Cross resistance.

Emtricitabine.

FTC resistant isolates (M184V/I) were cross resistant to 3TC but retained sensitivity to didanosine, d4T, tenofovir and AZT.
Viruses harbouring mutations conferring reduced susceptibility to d4T and AZT thymidine analogue associated mutations (TAMs) (M41L, D67N, K70R, L210W, T215Y/F, K219Q/E) or didanosine (L74V) remained sensitive to FTC. HIV-1 containing the K103N mutation or substitutions associated with resistance to NNRTI were susceptible to FTC.

Tenofovir alafenamide.

The K65R and K70E mutations result in reduced susceptibility to abacavir, didanosine, lamivudine, FTC, and tenofovir, but retain sensitivity to zidovudine.
Multinucleoside resistant HIV-1 with a T69S double insertion mutation or with a Q151M mutation complex including K65R showed reduced susceptibility to TAF.
HIV-1 containing the K103N or Y181C mutations associated with resistance to NNRTIs were susceptible to TAF.
HIV-1 containing mutations associated with resistance to PIs, such as M46I, I54V, V82F/T, and L90M were susceptible to TAF.

Pharmacodynamics.

Effects on electrocardiogram.

In a thorough QT/QTc study in 48 healthy subjects, TAF at the therapeutic dose or at a supratherapeutic dose approximately 5 times the recommended therapeutic dose did not affect the QT/QTc interval and did not prolong the PR interval. The effect of the other component, FTC, or the combination of FTC and TAF on the QT interval is not known.

Clinical trials.

The efficacy and safety of Descovy in HIV-1 infected, treatment naïve adults are based on 144 week data from two randomized, double blind, active controlled studies, GS-US-292-0104 (study 104) and GS-US-292-0111 (study 111) (N = 1733). The efficacy and safety of Descovy in virologically suppressed HIV-1 infected adults is based on 96 week data from a randomized, open label, active controlled study, GS-US-292-0109 (N = 1436) and a randomised, double blind, active controlled study GS-US-311-1089 (study 1089) (N = 663). The efficacy and safety of Descovy in HIV-1 infected, virologically suppressed patients with mild to moderate renal impairment are based on 144 week data from an open label study, GS-US-292-0112 (study 112) (N = 242). The efficacy and safety of Descovy in HIV-1 infected paediatric patients are based on 48-week data in treatment-naïve patients between the ages of 12 to < 18 years (≥ 35 kg) (N=50) and 24-week data in virologically suppressed patients between the ages of 8 to < 12 years (≥ 25 kg) (N=23) from an open-label study, Study 106.
The efficacy and safety of Descovy in HIV-1 uninfected men or transgender women who have sex with men and who are at risk of HIV-1 infection are based on data from a double-blind, randomized, active-controlled study, DISCOVER Study 2055 (N=2670 for efficacy; N=2694 for safety). Participants were followed for a total of 4319 person-years (median, 86 weeks, with approximately 75% of participants having > 84 weeks of follow-up).
HIV-1 infected treatment naïve patients. In both study 104 and study 111, patients were randomized in a 1:1 ratio to receive either Descovy (N = 866) once daily or FTC+TDF (N = 867) once daily, both given with EVG+COBI as a fixed dose combination tablet.
In studies 104 and 111, the mean age was 36 years (range 18-76), 85% were male, 57% were White, 25% were Black, and 10% were Asian. Nineteen percent of patients identified as Hispanic/Latino. The mean baseline plasma HIV-1 RNA was 4.5 log10 copies/mL (range 1.3-7.0). The mean baseline CD4+ cell count was 427 cells/mm3 (range 0-1360) and 13% had CD4+ cell counts less than 200 cells/mm3. Twenty three percent of patients had baseline viral loads greater than 100,000 copies/mL.
In both studies, patients were stratified by baseline HIV-1 RNA (less than or equal to 100,000 copies/mL, greater than 100,000 copies/mL to less than or equal to 400,000 copies/mL, or greater than 400,000 copies/mL), by CD4 count (less than 50 cells/microL, 50-199 cells/microL, or greater than or equal to 200 cells/microL), and by region (US or ex-US).
Treatment outcomes of studies 104 and 111 through 144 weeks are presented in Table 6.
FTC+TAF demonstrated statistical superiority (p=0.021) in achieving HIV-1 RNA < 50 copies/mL when compared to FTC+TDF, both given with EVG+COBI as a fixed dose combination tablet.
The mean increase from baseline in CD4+ cell count at week 144 was 326 cells/mm3 in patients receiving FTC+TAF and 305 cells/mm3 in patients receiving FTC+TDF (p = 0.06).

Bone mineral density.

In the pooled analysis of studies 104 and 111, bone mineral density (BMD) from baseline to week 144 was assessed by dual energy X-ray absorptiometry (DXA) to compare the bone safety of TAF to that of TDF. As shown in Table 7, in patients who had both baseline and week 144 hip or spine measurements (N = 690 and 702 in the FTC+TAF group and N = 683 and 686 in the FTC+TDF group) there were smaller decreases in BMD in patients receiving FTC+TAF as compared with FTC+TDF, both given with EVG+COBI as a fixed dose combination tablet.

Changes in renal laboratory tests.

In the pooled analysis of studies 104 and 111, laboratory tests were performed to compare the effect of TAF, to that of TDF on renal laboratory parameters. As shown in Table 8, statistically significant differences were observed between treatment groups that favored TAF for increases in serum creatinine and changes in proteinuria, including urine protein to creatinine ratio (UPCR), urine albumin to creatinine ratio (UACR), retinol binding protein (RBP) to creatinine ratio, and urine beta-2 microglobulin to creatinine ratio.
HIV-1 infected virologically suppressed patients. Study 109. In study 109, the efficacy and safety of switching from either Atripla, Truvada plus atazanavir (boosted by either COBI or ritonavir), or Stribild to FTC+TAF given with EVG+COBI as a fixed dose combination tablet were evaluated in a randomized, open label trial of virologically suppressed (HIV-1 RNA < 50 copies/mL) HIV-1 infected adults (N = 1436). Patients must have been stably suppressed (HIV-1 RNA < 50 copies/mL) on their baseline regimen for at least 6 months and had no resistance mutations to FTC, TAF or EVG prior to study entry. Patients were randomized in a 2:1 ratio to either switch to FTC+TAF, given with EVG+COBI as a fixed dose combination tablet at baseline (N = 959), or stay on their baseline antiretroviral regimen (N = 477). 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 705 cells/mm3 (range 79-1951).
Patients were stratified by prior treatment regimen. At screening, 42% of patients were receiving Truvada plus atazanavir (boosted by either COBI or ritonavir), 32% of patients were receiving Stribild, and 26% of patients were receiving Atripla.
Treatment outcomes of study 109 through 48 and 96 weeks are presented in Table 9.
At week 96, in patients who had received Atripla as their prior treatment regimen, 90% (227/251) of those who switched to FTC+TAF given with EVG+COBI as a fixed dose combination tablet remained suppressed (HIV-1 RNA < 50 copies/mL) vs. 86% (108/125) of those who stayed on Atripla; in patients who had received Truvada plus boosted atazanavir, 92% (370/402) of those who switched remained suppressed vs. 88% (175/199) of those who stayed on Truvada plus boosted atazanavir; in patients who had received Stribild, 96% (293/306) of those who switched remained suppressed vs. 93% (142/153) of those who stayed on Stribild.
At week 96, switching to FTC+TAF given with EVG+COBI as a fixed dose combination tablet was superior (p=0.017) to staying on a baseline regimen in maintaining HIV-1 RNA < 50 copies/mL.
The mean increase from baseline in CD4+ cell count at week 96 was 60 cells/mm3 in patients who switched and 42 cells/mm3 in those who stayed on their baseline regimen.

Bone mineral density.

In study 109, changes in BMD were assessed by DXA in patients who had both baseline and Week 96 measurements (N=809 and 821 in the FTC+TAF given with EVG+COBI arm and N=396 and 401 in patients who remained on their baseline regimen, for hip and spine, respectively). Results are summarized in Table 10.

Changes in renal laboratory tests.

There were decreases from baseline in proteinuria (UPCR), albuminuria (UACR), and tubular proteinuria (urine RBP to creatinine ratio and urine beta-2 microglobulin to creatinine ratio), and other measures of proximal renal tubular dysfunction (including fractional excretion of uric acid [FEUA]) in patients receiving FTC+TAF given with EVG+COBI as a fixed dose combination tablet, as compared with increases from baseline in patients who stayed on their FTC+TDF containing baseline regimen, collectively indicating the reduced impact of TAF on proximal renal tubular function. At week 96, the median percentage change in UPCR was -26% vs. 9%; in UACR it was -14% vs. 11%. At week 48, the median percentage change in urine RBP to creatinine ratio was -33% vs. 18%; and in urine beta-2 microglobulin to creatinine ratio it was -52% vs. 19% (p < 0.001 for all comparisons).
Study 1089. In study 1089, the efficacy and safety of switching from Truvada to Descovy while maintaining the third antiretroviral agent was evaluated in a randomised, double blind study of virologically suppressed HIV-1 infected adults (N = 663). Patients must have been stably suppressed (HIV-1 RNA < 50 copies/mL) on their baseline regimen for at least 6 months. Patients were randomized in a 1:1 ratio to either switch to Descovy while maintaining their third agent at baseline (N = 333), or stay on their baseline Truvada containing regimen (N = 330). Patients had a mean age of 48 years (range 22-79), 85% were male, 75% were White, and 21% were Black. The mean baseline CD4+ cell count was 679 cells/mm3 (range 79-2201).
Patients were stratified by the class of the third agent in their prior treatment regimen. At baseline, 46% of patients were receiving Truvada in combination with a boosted protease inhibitor and 54% of patients were receiving Truvada in combination with an unboosted third agent.
Treatment outcomes of study 1089 through 48 and 96 weeks are presented in Table 11.
At week 96, in patients who received a boosted protease inhibitor, 86% (133/155) of those who switched from Truvada to Descovy remained suppressed vs. 88% (133/151) of those who stayed on Truvada; in patients who received an unboosted third agent, 91% (162/178) of those who switched from Truvada to Descovy remained suppressed vs. 90% (161/179) of those who stayed on Truvada. Switching to a Descovy containing regimen was non-inferior to staying on a baseline Truvada containing regimen in maintaining HIV-1 RNA < 50 copies/mL. The mean increase from baseline in CD4+ cell count at week 96 was 51 cells/mm3 in patients who switched and 47 cells/mm3 in those who stayed on their baseline Truvada containing regimen.

Bone mineral density.

In study 1089, changes in BMD from baseline to week 96 were assessed by DXA. Results are summarized in Table 12.

Changes in renal laboratory tests.

There were decreases from baseline in proteinuria and tubular proteinuria in patients receiving a regimen containing Descovy, as compared with increases in patients who stayed on a regimen containing Truvada at baseline, collectively indicating the reduced impact of TAF on proximal renal tubular function. At week 96, the median percentage change in UPCR was -26% vs. -3%; in UACR it was -3% vs. 27%; in urine RBP to creatinine ratio it was 4% vs. 43%; and in urine beta-2 microglobulin to creatinine ratio it was -30% vs. 47% (p < 0.001 for all comparisons).
Study 1717. In Study 1717, the efficacy and safety of switching from ABC/3TC to Descovy while maintaining the third antiretroviral agent was evaluated in a randomized, double-blind study of virologically-suppressed (HIV-1 RNA < 50 copies/mL) HIV infected adults (N=556 for safety; N=501 for efficacy). Patients must have been stably suppressed (HIV-1 RNA < 50 copies/mL) on their baseline regimen of ABC/3TC for at least 6 months. Patients were randomized in a 1:1 ratio to either switch to Descovy (N=280) while maintaining their third agent at baseline or stay on their baseline ABC/3TC-containing regimen (N=276). Patients had a mean age of 51 years (range: 20-79), 82% were male, 73% were White and 23% were Black. The mean baseline CD4+ cell count was 715 cells/mm3 (range 43-2010).
Patients were stratified by the class of the third agent in their prior treatment regimen. At baseline, 30% of patients were receiving ABC/3TC in combination with a boosted protease inhibitor and 70% of patients were receiving ABC/3TC in combination with an unboosted third agent.
Treatment outcomes of Study 1717 through 48 weeks are presented in Table 13.
At Week 48, in patients who received a boosted protease inhibitor, 87% (67/77) of those who switched from ABC/3TC to Descovy remained suppressed vs. 91% (68/75) of those who stayed on ABC/3TC; in patients who received an unboosted third agent, 91% (160/176) of those who switched from ABC/3TC to Descovy remained suppressed vs. 94% (162/173) of those who stayed on ABC/3TC.
At Week 48, switching to a Descovy-containing regimen was non-inferior to staying on a baseline ABC/3TC-containing regimen in maintaining HIV-1 RNA < 50 copies/mL.
The mean change from baseline in CD4+ cell count at Week 48 was -29 cells/mm3 in patients who switched and 1 cell/mm3 in those stayed on their baseline ABC/3TC-containing regimen.

Bone mineral density.

In Study 1717, changes in BMD from baseline to Week 48 were assessed by DXA. Results are summarised in Table 14.

Changes in renal laboratory tests.

Measures of tubular proteinuria were similar in patients receiving a regimen containing Descovy compared to patients who stayed on a regimen containing ABC/3TC at baseline. At Week 48, the median percentage change in urine RBP to creatinine ratio was 4% in the Descovy group and 16% in those remaining on an ABC/3TC-containing regimen; and in urine beta-2 microglobulin to creatinine ratio it was 4% vs. 5%.
HIV-1 infected patients with renal impairment. In study 112, the efficacy and safety of FTC+TAF were evaluated in an open label clinical trial in which 242 HIV-1 infected patients with mild to moderate renal impairment (eGFR by Cockcroft-Gault method between 30 to 69 mL/min) switched to FTC+TDF in combination with EVG+COBI as a fixed dose combination tablet. Patients were virologically suppressed (HIV-1 RNA < 50 copies/mL) for at least 6 months before switching.
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. Thirteen percent of patients identified as Hispanic/Latino. At baseline, median eGFR was 56 mL/min, and 33% of patients had an eGFR of 30 to 49 mL/min. The mean baseline CD4+ cell count was 664 cells/mm3 (range 126-1813).
At week 24, 95% (230/242 patients) maintained HIV-1 RNA < 50 copies/mL after switching to FTC+TAF given with EVG+COBI as a fixed dose combination tablet. At week 144, 83.1% (197/237) maintained HIV-1 RNA < 50 copies/mL after switching to FTC+TAF given with EVG+COBI.
In a substudy (N = 32), patients had no change from baseline in their actual glomerular filtration rate at week 24, as measured by iohexol clearance.
Changes from baseline in renal laboratory tests in study 112 are summarized in Table 15.
Multiple assessments of renal function indicate that improvements in renal function occur as early as 1 week after the switch to FTC+TAF given with EVG+COBI as a fixed dose combination tablet and persist through 144 weeks. The prevalence of clinically significant proteinuria (UPCR > 200 mg/g) and albuminuria (UACR ≥ 30 mg/g) decreased from 42% at baseline to 16% at week 144 and 49% at baseline to 32% at week 144, respectively. Other renal assessments, including fractional excretion of uric acid, serum cystatin C, and serum phosphorus showed small changes from baseline through week 144.
In patients whose prior antiretroviral regimen did not include TDF (N = 84), mean change from baseline in serum creatinine at week 144 was 0.01 ± 0.31 mg/dL; 73% of patients had an improvement in proteinuria as measured by urine dipstick; and median percent change in UPCR and UACR were -9% and -4%, respectively. Median percent change in urine RBP to creatinine ratio, and urine beta-2 microglobulin to creatinine ratio at week 144 were 15% and -6%, respectively.
In virologically suppressed patients with renal impairment who switched to FTC+TAF given with EVG+COBI as a fixed dose combination tablet, mean percentage increases from baseline at week 144 were observed in hip and spine BMD. Assessment of BMD using a threshold of 3% for changes from baseline revealed higher percentages of patients had increases versus decreases from baseline in BMD at both hip and spine.
Study 1825. In Study 1825, the efficacy and safety of FTC+TAF given with EVG+COBI were evaluated in a single arm, open-label clinical study in which 55 HIV-1 infected adults with end stage renal disease (eGFR by Cockcroft-Gault method < 15 mL/min) receiving chronic haemodialysis for at least 6 months switched to FTC+TAF in combination with EVG+COBI as a fixed-dose combination tablet. Patients were virologically suppressed (HIV-1 RNA < 50 copies/mL) for at least 6 months before switching.
The mean age was 48 years (range 23-64). Seventy-six percent were male, 82% were Black and 18% were White. Fifteen percent of patients identified as Hispanic/Latino. The mean baseline CD4+ cell count was 545 cells/mm3 (range 205-1473). At Week 48, 81.8% (45/55 patients) maintained HIV-1 RNA < 50 copies/mL after switching to FTC+TAF given with EVG+COBI. There were no clinically significant changes in fasting lipid laboratory tests in patients who switched.
HIV-1 infected paediatric patients. In Study 106, the efficacy, safety, and pharmacokinetics of FTC+TAF, given in combination with EVG+COBI as a fixed-dose combination tablet, in HIV-1-infected patients were evaluated in an open-label trial, in treatment-naïve patients between the ages of 12 to < 18 years (≥ 35 kg) (N=50) and in virologically suppressed patients between the ages of 6 to < 12 years (≥ 25 kg) (N=23).

Cohort 1: treatment-naïve adolescents (12 to < 18 years; ≥ 35 kg).

Patients in cohort 1 had a mean age of 15 years (range: 12 to 17), were 44% male, 12% Asian and 88% Black. At baseline, mean plasma HIV-1 RNA was 4.6 log10 copies/mL, median CD4+ cell count was 456 cells/mm3 (range: 95 to 1110), and median CD4+% was 23% (range: 7% to 45%). Overall, 22% had baseline plasma HIV-1 RNA > 100,000 copies/mL.
Among the patients in cohort 1 at Week 48, 92% (46/50) achieved HIV-1 RNA < 50 copies/mL, similar to response rates in trials of treatment naïve HIV-1 infected adults. The mean increase from baseline in CD4+ cell count at Week 48 was 224 cells/mm3. Three of 50 patients had virologic failure at Week 48; no emergent resistance to FTC+TAF was detected through Week 48.
Among the treatment-naïve adolescent patients in cohort 1 who had both baseline and Week 48 measurements (N=47 and 44 for the lumbar spine and total body less head [TBLH], respectively), mean BMD increased from baseline to Week 48, +4.2% at the lumbar spine and +1.3% for TBLH.

Cohort 2: virologically suppressed children (6 to < 12 years; ≥ 25 kg).

Patients in cohort 2 had a mean age of 10 years (range: 8 to 11), a mean baseline weight of 31.6 kg (range: 26 to 58), 39% were male, 13% were Asian, and 78% were black. At baseline, median CD4+ cell count was 969 cells/mm3 (range: 603 to 1421), and median CD4+% was 39% (range: 30% to 51%).
After switching to FTC+TAF given in combination with EVG+COBI as a fixed-dose combination tablet, 100% (23/23) of patients in cohort 2 remained suppressed (HIV-1 RNA < 50 copies/mL) at Week 24. The mean change from baseline in CD4+ cell count at Week 24 was -150 cells/mm3. No patient qualified for resistance analysis through Week 24.
Among the patients in cohort 2 who had both baseline and Week 24 measurements (N=21 and 23, for lumbar spine and TBLH, respectively), mean BMD increased from baseline to Week 24, +2.9% at the lumbar spine and +1.7% for TBLH.
HIV-1 uninfected adults at risk of HIV-1 infection. The efficacy and safety of Descovy to reduce the risk of acquiring HIV-1 infection were evaluated in a randomized, double-blind multinational study (DISCOVER) comparing once daily Descovy (N=2670 for efficacy; N=2694 for safety) to Truvada (FTC/TDF 200 mg/300 mg; N=2665 for efficacy; N=2693 for safety) in HIV-seronegative men or transgender women who have sex with men and are at risk of HIV-1 infection. Evidence of risk behaviour at entry into the study included at least one of the following: two or more unique condomless anal sex partners in the past 12 weeks or a diagnosis of rectal gonorrhoea/chlamydia or syphilis in the past 24 weeks. The median age of participants was 34 years (range, 18-76); 84% were White, 9% Black, 4% Asian, and 24% Hispanic/Latino.
At baseline, 905 participants (17%) reported receiving Truvada for PrEP, of which 465 were randomized to Descovy.
At Weeks 4, 12, and every 12 weeks thereafter, all participants received local standard of care HIV-1 prevention services, including HIV-1 testing, evaluation of adherence, safety evaluations, risk-reduction counselling, condoms, management of sexually transmitted infections, and assessment of sexual behaviour.
Study participants maintained a high risk of sexual HIV-1 acquisition, with high rates of rectal gonorrhoea (Descovy, 22/100 person-years; Truvada, 21/100 person-years), rectal chlamydia (28/100 person-years in both treatment groups), and syphilis (10/100 person-years in both treatment groups) during the study.
The primary outcome was the incidence of documented HIV-1 infection per 100 person-years in participants randomized to Descovy and Truvada (with a minimum follow-up of 48 weeks and at least 50% of participants having 96 weeks of follow-up). Descovy was non-inferior to Truvada in reducing the risk of acquiring HIV-1 infection (Table 16). The results were similar across the subgroups of age, race, baseline Truvada for PrEP use, and gender identity.
Of the 22 participants with diagnosed HIV-1 infections, 5 had suspected baseline infection prior to study entry (Descovy, 1; Truvada, 4), 15 had undetectable or low drug levels (Descovy, 5; Truvada, 10), and 2 had medium or high drug levels (Descovy, 1; Truvada, 1).

Bone mineral density.

In the DISCOVER study, changes in BMD from baseline were assessed by DXA. Observed changes at Week 48 are summarized in Table 17.

Changes in renal laboratory tests.

In the DISCOVER Study, tests were performed to compare the effect of TAF to that of TDF on renal laboratory parameters. As shown in Table 18, statistically significant differences were observed between treatment groups for changes in glomerular and proximal tubular renal function that favoured TAF.
Participants with renal laboratory data at Week 48 who were receiving Truvada for PrEP at baseline and were randomized to Descovy (N=433) had a mean (±SD) increase in eGFR by Cockcroft-Gault of +3.8 mL/min (14.90), whereas those who were randomized to Truvada (N=400) had a mean decrease in eGFR of -0.6 mL/min (15.98) (p < 0.001).

Changes in lipid laboratory tests.

Minimal declines or no change from baseline was observed in the Descovy treatment group for mean fasting total cholesterol, direct LDL, and HDL, whereas modest declines were observed in the Truvada treatment group at Week 48 (p < 0.002 for the difference between treatment groups for fasting total cholesterol, direct LDL, and HDL). There was no significant change from baseline in the total cholesterol to HDL ratio (Descovy, 0.1 [-0.2, 0.5] and Truvada 0.1 [-0.3, 0.5]) at Week 48, with no differences between Descovy and Truvada.

5.2 Pharmacokinetic Properties

Bioequivalence.

FTC and TAF exposures were bioequivalent when comparing Descovy 200/25 mg to Genvoya (EVG/COBI/FTC/TAF [150/150/200/10 mg] fixed dose combination tablet) following single dose administration to healthy subjects (N = 116) under fed conditions.
FTC and TAF exposures were bioequivalent when comparing Descovy 200/10 mg, administered simultaneously with EVG 150 mg and COBI 150 mg, to Genvoya following single dose administration to healthy subjects (N = 100) under fed conditions.

Absorption and bioavailability.

Following oral administration with food in HIV-1 infected adult patients, peak plasma concentrations were observed 3 hours post-dose for FTC and 1 hour post-dose for TAF (see Table 19 for additional pharmacokinetic parameters).
HIV status has no effect on exposures of emtricitabine and tenofovir in adults.

Effect of food on oral distribution.

Relative to fasting conditions, administration of Descovy with a high fat meal (~ 800 kcal, 50% fat) resulted in a decrease in FTC Cmax and AUClast of 27% and 9%, respectively; and a decrease in TAF Cmax (15-37%) and an increase in AUClast (17-77%). These changes are not considered clinically meaningful and Descovy can be administered without regard to food.

Distribution, metabolism and elimination.

Emtricitabine.

In vitro binding of FTC to human plasma proteins is < 4% and is independent of concentration over the range of 0.02 to 200 microgram/mL. Following administration of radiolabelled FTC approximately 86% is recovered in the urine and 13% is recovered as metabolites. The metabolites of FTC include 3'-sulfoxide diastereomers and their glucuronic acid conjugate. FTC is eliminated by a combination of glomerular filtration and active tubular secretion. Following a single oral dose of Emtriva, the plasma FTC half-life is approximately 10 hours.

Tenofovir alafenamide.

In vitro binding of tenofovir to human plasma proteins is less than 0.7% and is independent of concentration over the range of 0.01 to 25 microgram/mL. Ex vivo binding of TAF to human plasma proteins in samples collected during clinical studies was approximately 80%.
Distribution studies in dogs showed 5.7 to 15-fold higher 14C-radioactivity in lymphoid tissues (iliac, axillary, inguinal and mesenteric lymph nodes, and spleen) 24 hours following administration of an equivalent dose of [14C]-TAF relative to [14C]-TDF.
Metabolism is a major elimination pathway for TAF in humans, accounting for > 80% of an oral dose. In vitro studies have shown that TAF is metabolized 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, TAF is hydrolyzed within cells to form tenofovir (major metabolite), which is phosphorylated to the active metabolite, tenofovir diphosphate. In clinical studies, a 10 mg oral dose of TAF resulted in tenofovir diphosphate concentrations > 4-fold higher in PBMCs and > 90% lower concentrations of tenofovir in plasma as compared to a 300 mg oral dose of TDF.
In vitro, TAF is not metabolized by CYP1A2, CYP2C8, CYP2C9, CYP2C19, or CYP2D6. TAF is minimally metabolized by CYP3A4. Upon coadministration with the moderate CYP3A inducer probe efavirenz, TAF exposure was not significantly affected. TAF is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or UGT1A1 in vitro. TAF is not an inhibitor or inducer of CYP3A in vivo.
TAF is eliminated following metabolism to tenofovir. TAF and tenofovir have a median plasma half-life of 0.51 and 32.37 hours, respectively. Tenofovir is eliminated from the body by the kidneys by both glomerular filtration and active tubular secretion. Renal excretion of intact TAF is a minor pathway with less than 1% of the dose eliminated in urine. The pharmacologically active metabolite, tenofovir diphosphate, has a half-life of 150 to 180 hours within PBMCs.

Age, gender and ethnicity.

No clinically relevant pharmacokinetic differences due to gender or ethnicity have been identified for FTC or TAF.
Pharmacokinetics of FTC and tenofovir have not been fully evaluated in the elderly (65 years of age and older).
Population pharmacokinetics analysis of HIV infected patients in phase 2 and phase 3 studies of FTC+TAF given with EVG+COBI as a fixed dose combination tablet showed that within the age range studied (12 to 82 years), age did not have a clinically relevant effect on exposures of TAF.
Exposures of FTC and TAF achieved in 24 HIV-1 infected paediatric patients aged 12 to < 18 (≥ 35 kg) years were similar to exposures achieved in HIV-1 infected treatment-naïve adults. Exposures of FTC and TAF achieved in 23 HIV-1 infected paediatric patients aged 6 to < 12 years (≥ 25 kg) were generally higher (20-80%) than exposures achieved in HIV-1 infected adults; however, the increase was not considered clinically significant as the safety profiles were similar in adult and paediatric patients.
The pharmacokinetics of emtricitabine and tenofovir are expected to be similar in HIV-1 infected and uninfected adolescents based on the similar exposures of emtricitabine and tenofovir in HIV-1 infected adolescents and adults and on the similar exposures of emtricitabine and tenofovir in HIV-1 infected and uninfected adults.

Patients with renal impairment.

In a Phase 1 study of FTC alone, FTC exposures were increased in subjects with severe renal impairment. The safety of FTC+TAF has not been established in subjects with estimated creatinine clearance ≥ 15 mL and < 30 mL/min.
Exposures of FTC and tenofovir in 12 subjects with end stage renal disease (estimated creatinine clearance < 15 mL/min) on chronic hemodialysis who received FTC+TAF in combination with EVG+COBI as a fixed-dose combination tablet in Study 1825 were significantly higher than in subjects with normal renal function. However, the safety profile of FTC+TAF in subjects with end stage renal disease on chronic haemodialysis in this study was similar to that in subjects with normal renal function. No clinically relevant differences in TAF pharmacokinetics were observed in patients with end stage renal disease as compared to those with normal renal function. There are no pharmacokinetic data on TAF in patients with creatinine clearance < 15 mL/min not on chronic haemodialysis.

Patients with hepatic impairment.

Emtricitabine.

The pharmacokinetics of FTC has not been studied in subjects with hepatic impairment; however, FTC is not significantly metabolized by liver enzymes, so the impact of liver impairment should be limited.

Tenofovir alafenamide.

Clinically relevant changes tenofovir alafenamide or its metabolite tenofovir pharmacokinetics were not observed in patients with mild, moderate or severe hepatic impairment; no TAF dose adjustment is required in patients with hepatic impairment.

Patients with hepatitis B and/or hepatitis C virus co-infection.

Pharmacokinetics of FTC and TAF have not been fully evaluated in hepatitis B and/or C co-infected patients.

Assessment of drug interactions.

Emtricitabine.

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

Tenofovir alafenamide.

TAF is a substrate of P-glycoprotein (P-gp) and BCRP. Drugs that strongly affect P-gp and BCRP activity may lead to changes in TAF absorption.
TAF is not an inhibitor or inducer of CYP3A in vivo.

Drug interaction studies.

Drug-drug interaction studies were conducted with Descovy or the components of Descovy (FTC or TAF) as individual agents.
The effects of coadministered drugs on the exposure of TAF are shown in Table 20. The effects of Descovy or its components on the exposure of coadministered drugs are shown in Table 21.

5.3 Preclinical Safety Data

Genotoxicity.

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

Emtricitabine.

FTC was not mutagenic in bacteria or mouse lymphoma cell assays in vitro nor clastogenic in the mouse micronucleus test in vivo.

Tenofovir alafenamide.

TAF was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma or rat micronucleus assays.

Carcinogenicity.

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

Emtricitabine.

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

Tenofovir alafenamide.

Because there is a lower tenofovir exposure in rats and mice after TAF administration compared to TDF, carcinogenicity studies were conducted only with TDF. Long-term oral carcinogenicity studies of TDF in mice and rats were carried out at exposures up to approximately 10 times (mice) and 4 times (rats) those observed in humans at the 300 mg therapeutic dose of TDF for HIV-1 infection. At the high dose in female mice, liver adenomas were increased at exposures 10 times that in humans. In rats, the study was negative for carcinogenic findings at exposures up to 4 times that observed in humans at the therapeutic dose.

6 Pharmaceutical Particulars

6.1 List of Excipients

Descovy 200/25 mg tablets contain the following ingredients as excipients:

Tablet core.

Microcrystalline cellulose, croscarmellose sodium, and magnesium stearate.

Film-coating.

Polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc and indigo carmine aluminum lake.
Descovy 200/10 mg tablets contain the following ingredients as excipients:

Tablet core.

Microcrystalline cellulose, croscarmellose sodium and magnesium stearate.

Film-coating.

Polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc and iron oxide black.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Descovy should be stored below 30°C.

6.5 Nature and Contents of Container

Descovy is supplied in high density polyethylene (HDPE) bottles containing 30 tablets and a silica gel desiccant and polyester coil and closed with a child resistant closure.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Chemical structure.

FTC is a synthetic nucleoside analog of cytidine. TAF is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5'-monophosphate.

Emtricitabine.

The chemical name of FTC is 5-fluoro-1-(2R,5S)-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine. FTC is the (-) enantiomer of a thio analog of cytidine, which differs from other cytidine analogs in that it has a fluorine in the 5-position.
It has a molecular formula of C8H10FN3O3S and a molecular weight of 247.2. It has the following structural formula:
FTC is a white to off white crystalline powder with a solubility of approximately 112 mg/mL in water at 25°C. The partition coefficient (log p) for emtricitabine is -0.43 and the pKa is 2.65.

Tenofovir alafenamide fumarate.

The chemical name of TAF is L-alanine, N-[(S)-[[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl]phenoxyphosphinyl]-, 1-methylethyl ester, (2E)-2-butenedioate (2:1).
It has an empirical formula of C21H29O5N6P.½(C4H4O4) and a molecular weight of 534.50. It has the following structural formula:
TAF is a white to off-white or tan powder with a solubility of 4.7 mg/mL in water at 20°C.

CAS number.

CAS registry number for emtricitabine: 143491-57-0.
CAS registry number for tenofovir alafenamide: 379270-37-8.
CAS registry number for tenofovir alafenamide fumarate: 1392275-56-7.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes