Consumer medicine information

Odefsey Tablets

Emtricitabine; Rilpivirine; Tenofovir alafenamide

BRAND INFORMATION

Brand name

Odefsey

Active ingredient

Emtricitabine; Rilpivirine; Tenofovir alafenamide

Schedule

S4

 

Consumer medicine information (CMI) leaflet

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

What is in this leaflet

Read all of this leaflet carefully before you start taking this medicine. This leaflet answers some of the common questions about ODEFSEY tablets. It does not contain all of the available information.

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

This medicine has been prescribed for you personally and you should not pass it on to others. It may harm them, even if their symptoms are the same as yours.

Medicines are sometimes prescribed for conditions that are not mentioned in this leaflet.

Keep this leaflet with your ODEFSEY medicine. You may need to read it again.

What is ODEFSEY

How ODEFSEY works

ODEFSEY tablets consist of the following three medicines:

  • emtricitabine (EMTRIVA®)
  • rilpivirine (EDURANT®)
  • tenofovir alafenamide

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

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

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

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

EMTRIVA® (emtricitabine) belongs to a group of antiviral medicines known as nucleoside and nucleotide reverse transcriptase inhibitors (NRTI).

EDURANT® (rilpivirine) belongs to a group of antiviral medicines known as non-nucleoside reverse transcriptase inhibitors (NNRTI).

Use in children and elderly

ODEFSEY is used to treat HIV-1 infection in adults and children 12 years of age and older.

ODEFSEY has not been studied in children under the age of 12 or weighing less than 35 kg.

Does ODEFSEY cure HIV or AIDS

ODEFSEY does not cure HIV infection or AIDS.

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

People taking ODEFSEY 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 ODEFSEY it is important you remain under the care of a hospital or doctor who specialises in the treatment of HIV infection.

Does ODEFSEY reduce the risk of passing HIV to others

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

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

Never re-use or share needles.

Before you take ODEFSEY

When you must not take it

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

Do not take ODEFSEY if you are allergic to:

  • emtricitabine
  • rilpivirine
  • tenofovir
  • or any of the other ingredients of ODEFSEY.

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

Do not take ODEFSEY if you are already taking any other medicines to treat HIV infection such as:

  • tenofovir disopoxil fumarate
  • emtricitabine
  • lamivudine
  • tenofovir alafenamide
  • rilpivirine

Do not take ODEFSEY if you take:

  • carbamazepine (e.g. Tegretol)
  • oxcarbazepine (e.g. Trileptal)
  • phenobarbital or phenytoin (e.g. Dilantin)
  • rifampicin (e.g. Rifadin/Rimycin)
  • rifapentine (e.g. Priftin)
  • omeprazole (e.g. Losec)
  • esomeprazole (e.g. Nexium)
  • lansoprazole (e.g. Zopral)
  • dexlansoprazole
  • pantoprazole (e.g. Somac)
  • rabeprazole (e.g. Pariet)
  • St John’s Wort or products containing St John’s Wort

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

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

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have, or have had, any of the following medical conditions:

  • kidney problems or are undergoing kidney dialysis treatment.
  • liver problems, including hepatitis B or C virus infection.

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

Tell your doctor if you are breastfeeding, or likely to breastfeed during your course of medication. You should not breastfeed if you are HIV-positive because of the chance of passing the HIV virus to your baby. At least one of the active substances in this medicine (emtricitabine) have been found in breast milk at low concentrations. Talk with your doctor about the best way to feed your baby.

Taking other medicines

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

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

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 ODEFSEY.

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

How to take ODEFSEY

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

Never change the dose on your own.

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

How much to take

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

Take ODEFSEY with food.

If you forget to take it

Do not miss a dose of ODEFSEY.

If you forget to take ODEFSEY, take your missed dose right away unless it is almost time for your next dose.

Do not take a double dose to make up for a forgotten dose. Continue with your regular dosing schedule.

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

If you take too much (overdose)

Immediately telephone your doctor or Poisons Information Centre: 131126 (Australia) and 0800 764 766 (New Zealand) or go to the Accident and Emergency department at your nearest hospital if you think you or anyone else may have taken too many ODEFSEY tablets. Do this even if there are no signs of discomfort or poisoning. This may need urgent medical attention.

While you are taking ODEFSEY

Things you must not do

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

Avoid doing things that can spread HIV infection since ODEFSEY does not stop you from passing the HIV Infection to others.

  • Do not share needles or other injection equipment.
  • Do not share personal items that can have blood or body fluids on them, like toothbrushes or razor blades.
  • Do not have any kind of sex without protection.

Always practice safer sex by using a latex or polyurethane condom or other barrier to reduce the chance of sexual contact with semen, vaginal secretions, or blood.

Do not take ODEFSEY after the expiry or “use by” date (EXP) printed on the bottle. If you take it after the expiry date has passed, it may not work as well.

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

Things to be careful of

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

Side Effects

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

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

Serious side effects

Hepatic Flares

If you have HIV infection and HBV infection you should not stop your ODEFSEY treatment without first discussing this with your doctor. Your HBV may get worse (flare-up) if you stop taking ODEFSEY. 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. ODEFSEY is not approved for the treatment of HBV, so 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

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

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

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

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

Serious Liver Problems (hepatotoxicity)

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

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

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

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 ODEFSEY 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.

Common side effects

The most common side effect of ODEFSEY is nausea.

Other side effects include:

  • diarrhoea
  • fatigue
  • headaches
  • abdominal pain
  • indigestion
  • flatulence
  • dizziness
  • rash
  • vomiting
  • depression
  • weight gain
  • abnormal dreams and sleep issues
  • insomnia
  • decreased appetite

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

This is not a complete list of side effects possible with ODEFSEY.

Ask your doctor or pharmacist for a more complete list of side effects of ODEFSEY and all the medicines you will take.

After taking ODEFSEY

Storage

Keep ODEFSEY tablets where children cannot reach them. A locked cupboard at least one-and-a half metres above the ground is a good place to store them.

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

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

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

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

Product Description

What the tablets look like

The 200/25/25 mg ODEFSEY tablets are oval-shaped, film-coated and grey in colour.

Each tablet is debossed with “GSI” on one side and the number “255” on the other side.

ODEFSEY tablets are supplied in bottles containing 30 tablets.

Ingredients

Each ODEFSEY tablet contains the active ingredients:

  • emtricitabine
  • rilpivirine
  • tenofovir alafenamide

Each ODEFSEY tablet also contains the following inactive ingredients:

  • lactose
  • microcrystalline cellulose
  • povidone
  • polysorbate 20
  • croscarmellose sodium
  • magnesium stearate

Film-coating:

  • polyvinyl alcohol (E1203)
  • titanium dioxide (E171)
  • polyethylene glycol
  • talc (E553b)
  • iron oxide black (E172)

Sponsor

ODEFSEY tablets are supplied in Australia by:

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

In New Zealand:

Gilead Sciences (NZ)
Grant Thornton New Zealand Limited
L4, 152 Fanshawe Street,
Auckland1010
New Zealand

Date of preparation: 14 April 2020

AUST R 260634

ATRIPLA, EMTRIVA, EVIPLERA, GENVOYA, 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 June 2020

BRAND INFORMATION

Brand name

Odefsey

Active ingredient

Emtricitabine; Rilpivirine; Tenofovir alafenamide

Schedule

S4

 

1 Name of Medicine

Odefsey (emtricitabine/rilpivirine/tenofovir alafenamide) tablets for oral use.

6.7 Physicochemical Properties

Chemical structure.

Emtriva is the brand name for FTC, a synthetic nucleoside analog of cytidine. Edurant is the brand name for RPV, a non-nucleoside reverse transcriptase inhibitor. 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 the molecular formula of C8H10FN3O3S and a molecular weight of 247.2. It has the following structural formula:
FTC is a white to off white powder with a solubility of approximately 112 mg/mL in water at 25°C. The partition coefficient (log p) for FTC is -0.43 and the pKa is 2.65.

Rilpivirine.

RPV is available as the hydrochloride salt. The chemical name for RPV hydrochloride is 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl] amino]-2-pyrimidinyl] amino]benzonitrile monohydrochloride. It's molecular formula is C22H18N6.HCl and its molecular weight is 402.88. RPV hydrochloride has the following structural formula:
RPV hydrochloride is a white to almost white powder. RPV hydrochloride is practically insoluble in water and over a wide pH range.

Tenofovir alafenamide.

TAF fumarate is the drug substance. The chemical name pf TAF fumarate 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 the molecular formula: C23H31O7N6P and a molecular weight of 534.5. It has the following structural formula:
TAF fumarate is a white to off white or tan powder with a solubility of 4.7 mg/mL in water at 20°C.

CAS number.

Emtricitabine CAS registry number: 143491-57-0.
Rilpivirine CAS registry number: 700361-47-3.
Tenofovir alafenamide CAS registry number: 379270-37-8.
Tenofovir alafenamide fumarate CAS registry number: 1392275-56-7.

2 Qualitative and Quantitative Composition

Each oral tablet of Odefsey contains 200 mg emtricitabine (FTC), 25 mg rilpivirine (RPV) and 25 mg tenofovir alafenamide (TAF).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Each Odefsey tablet is capsule shaped, film-coated and gray in colour. Each tablet is debossed with 'GSI' on one side and the number "255" on the other side.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antivirals for treatment of HIV infections, combinations. ATC code: J05AR19.

Mechanism of action.

Odefsey is a fixed dose combination of antiretroviral drugs FTC, RPV, and TAF.

Emtricitabine.

A synthetic nucleoside analogue of cytidine, is phosphorylated by cellular enzymes to form FTC 5'-triphosphate. FTC 5'-triphosphate inhibits the activity of the HIV-1 reverse transcriptase (RT) by competing with the natural substrate 2'-deoxycytidine 5'-triphosphate by being incorporated into nascent viral DNA which results in chain termination. FTC 5'-triphosphate is a weak inhibitor of mammalian DNA polymerases α, β, Epsilon and mitochondrial DNA polymerase γ.

Rilpivirine.

RPV is a diarylpyrimidine non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1. RPV activity is mediated by noncompetitive inhibition of HIV-1 reverse transcriptase. RPV does not inhibit the human cellular DNA polymerase α, β, and mitochondrial DNA polymerase γ.

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 IC50 value for FTC was in the range of 0.0013 to 0.64 microM (0.0003 to 0.158 microgram/mL). 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. FTC displayed antiviral activity in vitro against HIV-1 clades A, C, D, E, F, and G (IC50 values ranged from 0.007 to 0.075 microM) and showed strain specific activity against HIV-2 (IC50 values ranged from 0.007 to 1.5 microM).

Rilpivirine.

RPV exhibited activity against laboratory strains of wild type HIV-1 in an acutely infected T cell line with a median 50% effective concentration (EC50) value for HIV-1/IIIB of 0.73 nanoM. Although RPV demonstrated limited in vitro activity against HIV-2 with EC50 values ranging from 2510 to 10,830 nanoM, treatment of HIV-2 infection with RPV is not recommended in the absence of clinical data. RPV demonstrated antiviral activity against a broad panel of HIV-1 group M (subtype A, B, C, D, F, G, H) primary isolates with EC50 values ranging from 0.07 to 1.01 nanoM and group O primary isolates with EC50 values ranging from 2.88 to 8.45 nanoM. RPV showed additive to synergistic antiviral activity in combination with the N(t)RTIs abacavir, didanosine, emtricitabine, 3TC, d4T, tenofovir, and AZT; the PIs amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir and tipranavir; the NNRTIs efavirenz, etravirine and nevirapine; the fusion inhibitor enfuvirtide; the entry inhibitor maraviroc; and the integrase inhibitor raltegravir.

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 subtypes 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.

Drug resistance.

In cell culture.

Emtricitabine.

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

Rilpivirine.

RPV resistant strains were selected in cell culture starting from wild type HIV-1 of different origins and subtypes as well as NNRTI resistant HIV-1. The most commonly observed amino acid substitutions that emerged included: L100I, K101E, V108I, E138K, V179F, Y181C, H221Y, F227C, and M230I.

Tenofovir alafenamide.

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

In clinical studies: in treatment naïve patients.

Emtricitabine and tenofovir alafenamide.

In a pooled analysis of antiretroviral naïve patients receiving FTC + TAF given with EVG + COBI as a fixed dose combination tablet in phase 3 studies 0104 and 0111, 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. 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 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=4), and L210W (N=1) in reverse transcriptase and E92Q/V (N = 4), Q148R (N = 2), and N155H/S (N = 3) in integrase. All patients in both treatment groups who developed resistance mutations to EVG in integrase also developed resistance mutations to FTC in reverse transcriptase.
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. 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. 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.

Rilpivirine containing regimens.

In the cumulative Week 96 pooled resistance analysis for patients receiving RPV in combination with FTC/TDF in clinical studies TMC278-C209 (C209) and TMC278-C215 (C215) (see Section 5.1 Pharmacodynamic Properties, Clinical trials) (N = 550), resistance information was available for 71 of 78 patients who qualified for resistance analysis; 43 of these patients had an amino acid substitution associated with NNRTI (N = 39) or NRTI (N = 41) resistance. Among patients receiving efavirenz in combination with FTC/TDF, resistance information was available for 30 of 37 patients who qualified for resistance analysis; 17 of these patients had an amino acid substitution associated with NNRTI (N = 15) or NRTI (N = 8) resistance.
The NNRTI resistance substitutions that developed most commonly in patients receiving RPV were: V90I, K101E, E138K/Q, V179I, Y181C, V189I, H221Y, and F227C. The presence of the substitutions V90I and V189I at baseline did not affect the virologic response. The E138K substitution emerged most frequently during RPV treatment, commonly in combination with the M184I substitution. The amino acid substitutions associated with NRTI resistance that developed in 3 or more patients were: K65R, K70E, M184V/I, and K219E during the treatment period.
Through Week 96, fewer patients in the RPV arm with baseline viral load ≤ 100,000 copies/mL had emerging resistance associated substitutions and/or phenotypic resistance to RPV (7/288) than patients with baseline viral load > 100,000 copies/mL (30/262). Among those patients who developed resistance to RPV, 4/7 patients with baseline viral load ≤ 100,000 copies/mL and 28/30 patients with baseline viral load > 100,000 copies/mL had cross resistance to other NNRTIs.

In virologically suppressed patients.

Emtricitabine and tenofovir alafenamide.

Three subjects with emergent resistance to FTC and/or EVG were identified (M184M/I; M184I + E92G; M184V + E92Q) as of Week 96 in a clinical study of virologically suppressed patients who switched from a regimen containing FTC + TDF to FTC + TAF given with EVG + COBI in a fixed dose combination tablet (Study 0109, N = 959).

Rilpivirine containing regimens.

Through Week 96, in patients who switched to Odefsey from Eviplera or Atripla (studies 1216 and 1160; N = 754, respectively), resistance information was available for 11 patients. No resistance-associated mutations were detected.

Cross resistance.

In HIV-1 Infected treatment naïve patients or virologically suppressed patients.

Considering all of the available in vitro and in vivo data in treatment naïve patients the following resistance associated substitutions, when present at baseline, may affect the activity of Odefsey: K65R, K70E, K101E, K101P, E138A, E138G, E138K, E138Q, E138R, V179L, Y181C, Y181I, Y181V, M184I, M184V, Y188L, H221Y, F227C, M230I, M230L, and the combination of L100I + K103N.

Emtricitabine.

FTC resistant isolates with the M184V/I substitution were cross resistant to lamivudine and zalcitabine but retained sensitivity to abacavir, didanosine, stavudine, tenofovir, and zidovudone. HIV-1 isolates containing the K65R mutation, selected in vivo by abacavir, didanosine, tenofovir, and zalcitabine, demonstrated reduced susceptibility to inhibition by FTC. Viruses harboring mutations conferring reduced susceptibility to stavudine and zidovudine-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 substitution or other substitutions associated with resistance to NNRTIs was susceptible to FTC.

Rilpivirine containing regimens.

No significant cross resistance has been demonstrated between RPV resistant HIV-1 variants to FTC or tenofovir, or between FTC or tenofovir resistant variants and RPV.

In treatment naïve adult patients.

In the Week 96 pooled analysis for patients receiving RPV in combination with FTC/TDF in clinical studies C209 and C215 (see Section 5.1 Pharmacodynamic Properties, Clinical trials), 66 patients with virologic failure had available phenotypic resistance data at virologic failure, 40 had reduced susceptibility to FTC, 31 had reduced susceptibility to RPV, and 2 had reduced susceptibility to tenofovir. Among these patients, 39 had reduced susceptibility to lamivudine, 31 to etravirine, 28 to efavirenz, and 13 to nevirapine. Reduced susceptibility was observed to abacavir and/or didanosine in some cases. In the RPV group, 6 patients had HIV-1 with reduced susceptibility to abacavir, 9 with reduced susceptibility to didanosine, 3 with reduced susceptibility to stavudine and 2 with reduced susceptibility to zidovudine.

In virologically suppressed adult patients.

In Study GS-US-264-0106, 4 of the 469 patients that switched from a protease inhibitor based regimen to Eviplera had reduced susceptibility to at least one component of Eviplera through week 48. Among these patients, all 4 had reduced susceptibility to FTC and 2 had reduced susceptibility to RPV. Patients with resistance to FTC also were resistant to lamivudine. These patients with resistance to RPV developed phenotypic cross resistance to the other NNRTIs delavirdine, efavirenz, and nevirapine, but remained susceptible to etravirine in 1 of 2 cases.

In vitro.

In a panel of 67 HIV-1 recombinant laboratory strains with one amino acid substitution at RT positions associated with NNRTI resistance, including the most commonly found K103N and Y181C, RPV showed antiviral activity against 64 (96%) of these strains. The single amino acid substitutions associated with a loss of susceptibility to RPV were: K101P and Y181V/I. The K103N substitution did not result in reduced susceptibility to RPV by itself, but the combination of K103N with L100I resulted in a 7-fold reduced susceptibility to RPV. In another study, the Y188L substitution resulted in a reduced susceptibility to RPV of 9-fold for clinical isolates and 6-fold for site directed mutants.

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 was susceptible to TAF. HIV-1 containing mutations associated with resistance to PIs, such as M46I, I54V, V82F/T, and L90M, were susceptible to TAF.

Effects on electrocardiogram.

Rilpivirine.

The effect of RPV at the recommended dose of 25 mg once daily on the QTcF interval was evaluated in a randomized, placebo, and active (moxifloxacin 400 mg once daily) controlled crossover study in 60 healthy adults, with 13 measurements over 24 hours at steady state. RPV at the recommended dose of 25 mg once daily is not associated with a clinically relevant effect on QTc. When supratherapeutic doses of 75 mg once daily and 300 mg once daily of RPV were studied in healthy adults, the maximum mean time matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline correction were 10.7 (15.3) and 23.3 (28.4) ms, respectively. Steady-state administration of RPV 75 mg once daily and 300 mg once daily resulted in a mean Cmax approximately 2.6-fold and 6.7-fold, respectively, higher than the mean steady-state Cmax observed with the recommended 25 mg once daily dose of RPV.

Tenofovir alafenamide.

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.

5.2 Pharmacokinetic Properties

Bioequivalence.

FTC and TAF exposures were bioequivalent when comparing Odefsey 200/25/25 mg to Genvoya (EVG/COBI/FTC/TAF (150/150/200/10 mg) fixed dose combination tablet) following single dose administration to healthy subjects (N = 82) under fed conditions.
RPV exposures were bioequivalent when comparing Odefsey 200/25/25 mg to Edurant (RPV) 25 mg following single dose administration to healthy subjects (N = 95) under fed conditions.

Absorption.

Emtricitabine and tenofovir alafenamide.

Following oral administration with food in HIV-1 infected adult patients, peak plasma concentrations were observed 3 hours postdose for emtricitabine and 1 hour postdose TAF (see Table 6 for additional pharmacokinetic parameters).

Emtricitabine.

Following oral administration of FTC 200 mg capsules, FTC is rapidly absorbed with peak plasma concentrations occurring at 1 to 2 hours postdose. Following a single oral dose of FTC 200 mg capsules, the plasma FTC half-life is approximately 10 hours.

Rilpivirine.

The pharmacokinetic properties of RPV have been evaluated in adult healthy subjects and in adult antiretroviral treatment naïve HIV-1 infected patients (see Table 7). Exposure to RPV was generally lower in HIV-1 infected patients than in healthy subjects. After oral administration, the maximum plasma concentration of RPV is generally achieved within 4 to 5 hours. The absolute bioavailability of RPV hydrochloride is unknown.

Tenofovir alafenamide.

TAF is rapidly absorbed following oral administration, with peak plasma concentrations occurring at 15-45 minutes postdose.

Effect of food on oral distribution.

Emtricitabine.

FTC systemic exposure was unaffected when Odefsey was administered with food.

Rilpivirine.

Relative to fasting conditions, the administration of Odefsey to healthy adult subjects with food resulted in increased RPV exposure (AUC) by 13-73%.

Tenofovir alafenamide.

Relative to fasting conditions, the administration of Odefsey to healthy adult subjects with food resulted in increased TAF exposure (AUC) by 45-54%. These changes are not considered clinically meaningful.
It is recommended that Odefsey be taken with food.

Distribution, metabolism and elimination.

Emtricitabine.

In vitro binding of FTC to human plasma proteins was < 4% and independent of concentration over the range of 0.02 to 200 microgram/mL. At peak plasma concentration, the mean plasma to blood drug concentration ratio was ~ 1.0 and the mean semen to plasma drug concentration ratio was ~ 4.0. In vitro studies indicate that FTC is not an inhibitor of human CYP450 enzymes. Following administration of 14C-FTC, complete recovery of the FTC dose was achieved in urine (~ 86%) and faeces (~ 14%). Thirteen percent of the dose was recovered in the urine as three putative metabolites. The biotransformation of FTC includes oxidation of the thiol moiety to form the 3'-sulfoxide diastereomers (~ 9% of dose) and conjugation with glucuronic acid to form 2'-O-glucuronide (~ 4% of dose). No other metabolites were identifiable.
The plasma FTC half-life was approximately 10 hours. Following FTC dosing, the steady-state mean intracellular half-life of FTC 5'-triphosphate (the active drug moiety) in PBMCs was 39 hours. FTC is primarily excreted by the kidney by both glomerular filtration and active tubular secretion.

Rilpivirine.

RPV is approximately 99.7% bound to plasma proteins in vitro, primarily to albumin. The distribution of RPV into compartments other than plasma (e.g. cerebrospinal fluid, genital tract secretions) has not been evaluated in humans. In vitro experiments indicate that RPV primarily undergoes oxidative metabolism mediated by the cytochrome P450 (CYP) 3A system. The terminal elimination half-life of RPV is approximately 45 hours. After single dose oral administration of 14C-RPV, on average 85% and 6.1% of the radioactivity could be retrieved in faeces and urine, respectively. In faeces, unchanged RPV accounted for on average 25% of the administered dose. Only trace amounts of unchanged RPV (< 1% of dose) were detected in urine.

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 0.01-25 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 human 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. 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 renally eliminated 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 150-180 hours within PBMCs.

Linearity/ nonlinearity.

Emtricitabine.

The multiple dose pharmacokinetics of FTC are dose proportional over the dose range of 25 mg to 200 mg.

Tenofovir alafenamide.

TAF exposures are dose proportional over the dose range of 8 mg to 125 mg.

Pharmacokinetics in special populations.

Age, gender and ethnicity.

No clinically relevant pharmacokinetic differences due to gender or ethnicity have been identified for FTC, RPV, or TAF.
The pharmacokinetics of RPV in antiretroviral treatment naïve HIV-1 infected paediatric patients 12 to less than 18 years of age receiving RPV 25 mg once daily was comparable to that in treatment naïve HIV-1 infected adults receiving RPV 25 mg once daily. There was no impact of bodyweight on RPV pharmacokinetics in paediatric patients in Study C213 (33 to 93 kg), similar to what was observed in adults. Population pharmacokinetic analysis in HIV-1 infected patients showed that RPV pharmacokinetics is not different across the age range (12 to 78 years) evaluated.
Pharmacokinetics of FTC and TAF 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 pediatric patients aged 12 to < 18 years were similar to exposures achieved in treatment naïve adults.

Patients with hepatic impairment.

Emtricitabine.

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

Rilpivirine.

RPV is primarily metabolized and eliminated by the liver. In a study in adults comparing 8 patients with mild hepatic impairment (Child-Pugh score A) to 8 matched controls, and 8 patients with moderate hepatic impairment (Child-Pugh score B) to 8 matched controls, the multiple dose exposure of RPV was 47% higher in patients with mild hepatic impairment and 5% higher in patients with moderate hepatic impairment. No RPV dose adjustment is required in patients with mild or moderate hepatic impairment. RPV has not been studied in patients with severe hepatic impairment (Child-Pugh score C).

Tenofovir alafenamide.

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

Patients with impaired renal function.

Emtricitabine.

FTC is principally eliminated by renal excretion, and the exposure to FTC increases in patients with renal impairment.

Rilpivirine.

The pharmacokinetics of RPV has not been studied in patients with renal insufficiency. Renal elimination of RPV is negligible. Therefore, the impact of renal impairment on RPV elimination is expected to be minimal. As RPV is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis.

Tenofovir alafenamide.

No clinically relevant differences in TAF or tenofovir pharmacokinetics were observed between healthy subjects and patients with severe renal impairment (estimated creatinine clearance less than 30 mL/min) in studies of TAF. There are no pharmacokinetic data on TAF in patients with creatinine clearance < 15 mL/min.
The safety, virologic, and immunologic responses of Odefsey in HIV-1 infected patients with mild to moderate renal impairment (eGFR by Cockcroft-Gault method 30-69 mL/min) are based on an open label trial (Study 0112) that evaluated FTC + TAF given with EVG + COBI as a fixed dose combination tablet in 242 virologically suppressed patients and 6 treatment naïve patients. The safety profile of FTC + TAF in patients with mild to moderate renal impairment was similar to safety data from patients with normal renal function.

Hepatitis B and/or hepatitis C virus coinfection.

Pharmacokinetics of FTC, RPV, and TAF have not been fully evaluated in patients coinfected with hepatitis B and/or C virus. Population pharmacokinetic analysis indicated that hepatitis B and/or C virus coinfection had no clinically relevant effect on the exposure to RPV.

Pregnancy and postpartum.

The exposure to total RPV after intake of RPV 25 mg once daily as part of an antiretroviral regimen was lower during pregnancy (similar for the 2nd and 3rd trimesters) compared with postpartum (see Table 8). The decrease in unbound (i.e. active) RPV pharmacokinetic parameters during pregnancy compared to postpartum was less pronounced than for total RPV.
In women receiving RPV 25 mg once daily during the 2nd trimester of pregnancy, mean intraindividual values for total RPV Cmax, AUC24h, and Cmin values were, respectively, 21%, 29%, and 35% lower as compared to postpartum; during the 3rd trimester of pregnancy, Cmax, AUC24h, and Cmin values were, respectively, 20%, 31%, and 42% lower as compared to postpartum.

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, coadministration of FTC and famciclovir had no effect on the Cmax or AUC of either drug.

Rilpivirine.

RPV is primarily metabolized by cytochrome CYP3A, and drugs that induce or inhibit CYP3A may thus affect the clearance of RPV. Coadministration of Odefsey and drugs that induce CYP3A may result in decreased plasma concentrations of RPV and loss of virologic response and possible resistance. Coadministration of Odefsey and drugs that inhibit CYP3A may result in increased plasma concentrations of RPV. Coadministration of Odefsey with drugs that increase gastric pH may result in decreased plasma concentrations of RPV and loss of virologic response and possible resistance to RPV and to the class of NNRTIs.

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.
In vitro and clinical pharmacokinetic drug-drug interaction studies have shown that the potential for CYP-mediated interactions involving tenofovir alafenamide with other medicinal products is low.
Tenofovir alafenamide is not an inhibitor or inducer of CYP3A in vivo.

Drug interaction studies.

Drug-drug interaction studies were conducted with Odefsey or the components of Odefsey (FTC, RPV, or TAF) as individual agents.
The effects of coadministered drugs on the exposures of RPV and TAF are shown in Tables 9 and 10, respectively. The effects of RPV and TAF on the exposure of coadministered drugs are shown in Tables 11 and 12, respectively.

Clinical trials.

No data are available from clinical studies of Odefsey in HIV infected patients. Clinical efficacy of Odefsey was established from studies conducted with FTC + TAF when given with COBI boosted EVG as a fixed dose combination (Genvoya); and from studies of RPV when given with Truvada (FTC/TDF) as individual components or as a fixed dose combination Eviplera.

Emtricitabine and tenofovir alafenamide containing regimens.

Treatment naïve and virologically suppressed patients.

In both Study 0104 and Study 0111, patients were randomized in a 1:1 ratio to receive either FTC + TAF (N = 866) once daily or FTC + TDF (N = 867) once daily, both given with EVG + COBI as a fixed dose combination tablet.
In Study 0104 and Study 0111, 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).
In Study 0109, 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 study 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 studies 0104 and 0111 through 48 and 144 weeks are presented in Table 13. Treatment outcomes of Study 0109 through 48 and 96 weeks are presented in Table 14.
In studies 0104 and 0111, 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 rate of virologic success was similar across patient subgroups (age, gender, race, baseline HIV-1 RNA, or baseline CD4 count).
In Study 0109, switching to FTC + TAF given with EVG + COBI as a fixed dose combination tablet was superior (p = 0.017) in maintaining HIV-1 RNA < 50 copies/mL when compared to patients who stayed on their baseline regimen. 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.
In studies 0104 and 0111 in treatment naïve patients, 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); and in Study 0109 in virologically suppressed patients, 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.

Bone mineral density (BMD) from baseline to Week 144 in treatment naïve patients and from baseline to Week 96 in virologically suppressed patients was assessed by dual energy x-ray absorptiometry (DEXA) to assess the bone safety of patients receiving FTC + TAF given with EVG + COBI as a fixed dose combination tablet. As shown in Table 15, there were smaller decreases in BMD in treatment naïve patients receiving FTC + TAF as compared with patients receiving FTC + TDF, both given with EVG + COBI as a fixed dose combination tablet. In virologically suppressed patients, there were increases from baseline in mean BMD at the hip and at the spine in the Genvoya group as compared with minimal changes from baseline in both parameters in the FTC/TDF + third agent group.

Renal laboratory parameters.

In the pooled analysis of studies 0104 and 0111 in treatment naïve adult patients, 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), urinary retinol binding protein (RBP) to creatinine ratio, and beta-2 microglobulin to creatinine ratio. The mean ± SD change in serum creatinine after 144 weeks of treatment was 0.04 ± 0.12 mg/dL for the FTC + TAF group and 0.07 ± 0.13 mg/dL for the FTC + TDF group (p < 0.001 for treatment difference). Treatment emergent proteinuria was observed in 40% of patients receiving FTC + TAF and in 45% of patients receiving FTC + TDF (p = 0.027 for treatment difference).
In virologically suppressed patients in Study 0109, there were decreases from baseline in proteinuria (UPCR), albuminuria (UACR), and tubular proteinuria (urinary RBP to creatinine ratio and 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.

Changes in lipid laboratory tests.

Increases from baseline were observed in both treatment groups for the fasting lipid parameters total cholesterol, direct LDL, HDL, and triglycerides at Week 144. As seen in Table 16, the median increase from baseline for these parameters was greater in patients receiving FTC + TAF compared with patients receiving FTC + TDF, both given with EVG + COBI as a fixed dose combination tablet (p < 0.001 for the difference between treatment groups for fasting total cholesterol, direct LDL, HDL, and triglycerides). Median (Q1, Q3) change from baseline at Week 144 in total cholesterol to HDL ratio was 0.2 (-0.3, 0.7) in patients receiving FTC + TAF and 0.1 (-0.4, 0.6) in patients receiving FTC + TDF (p = 0.006 for the difference between treatment groups).

HIV-1 infected patients with renal impairment.

In Study 0112, the efficacy and safety of FTC + TAF were evaluated in an open label clinical study, 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 + 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 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/minute, and 33% of patients had an eGFR of 30 to 49 mL/min. Thirty five percent of patients were on a treatment regimen that did not contain TDF. 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 patients) 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 0112 are summarized in Table 17.
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. These included improvements in proteinuria, albuminuria, and tubular proteinuria, as shown in Table 17. 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.
In 84 renally impaired patients who switched to FTC + TAF given with EVG + COBI as a fixed dose combination tablet in Study 0112 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.

Paediatric patients.

In Study 0106, the efficacy, safety, and pharmacokinetics of FTC + TAF were evaluated in an open label study, in which HIV-1 infected treatment naïve adolescents received FTC + TAF in combination with EVG + COBI as a fixed dose combination tablet. Fifty patients 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.
At week 48, 92% achieved HIV-1 RNA < 50 copies/mL, similar to response rates in studies of treatment naïve HIV-1 infected adults. The mean increase from baseline in CD4+ cell count at week 48 was 224 cells/mm3. Three patients had virologic failure by snapshot at week 48; no emergent resistance to FTC + TAF was detected through week 48. Mean BMD increased from baseline to week 48, +4.2% at the lumbar spine and +1.3% for total body less head.

Rilpivirine containing regimens.

Treatment naïve patients.

Studies C209 and C215.

The efficacy of RPV versus efavirenz in combination with FTC/TDF was evaluated in two randomized, double blind, double dummy, controlled studies (Study C209 and FTC/TDF subset of Study C215) in treatment naïve, HIV-1 infected patients (N = 1368). The studies are identical in design with the exception of the background regimen (BR). Patients were randomized in a 1:1 ratio to receive either RPV 25 mg (N = 686) once daily or efavirenz 600 mg (N = 682) once daily in addition to a BR. In C209 (N = 690), the BR was FTC/TDF. In TMC278-C215 (N = 678), the BR consisted of 2 nucleoside reverse transcriptase inhibitors (NRTIs): FTC + TDF (60%, N = 406) or lamivudine/ zidovudine (30%, N = 204) or abacavir plus lamivudine (10%, N = 68).
For patients who received FTC/TDF (N = 1096) in C209 and C215, the mean age was 37 years (range, 18-78), 78% were male, 62% were white, 24% were black, and 11% were Asian. The mean baseline CD4 cell count was 265 cells/mm3 (range, 1-888) and median baseline plasma HIV-1 RNA was 5 log10 copies/mL (range, 2-7). Patients were stratified by baseline HIV-1 RNA. Fifty percent of patients had baseline viral loads > 100,000 copies/mL and 31% had CD4 cell counts < 200 cells/mm3.
Treatment outcomes through 96 weeks are presented in Table 18. At week 48 and Week 96, RPV administered in combination with FTC/TDF was noninferior in achieving HIV-1 RNA < 50 copies/mL when compared to efavirenz administered in combination with FTC/TDF. The virologic failure rate in the RPV arm at week 48 and at Week 96 was 9% and 11%, respectively, and 4% and 5% in the efavirenz arm. The difference in the rate of new virologic failures from week 48 to Week 96 between RPV and efavirenz arms was not statistically significant (3.6% and 2.1%, respectively, p = 0.242). Discontinuations due to adverse events were higher in the efavirenz arm at Week 96 than the RPV arm.
Virologic outcomes were comparable in males and females in studies C209 and C215.
Based on the pooled data from the C209 and C215 studies the mean CD4 cell count increase from baseline at Week 96 was 226 cells/mm3 for RPV plus FTC/TDF treated patients and 222 cells/mm3 for efavirenz plus FTC/TDF treated patients.

Changes in lipid laboratory tests.

In studies C209 and C215, changes from baseline in total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides are presented in Table 19. The clinical benefit of these findings has not been demonstrated.

Patients coinfected with hepatitis B and/or hepatitis C virus.

In patients coinfected with hepatitis B or C virus receiving RPV in studies C209 and C215, the incidence of hepatic enzyme elevation was higher than in patients receiving RPV who were not coinfected. The same increase was also observed in the efavirenz arm. The pharmacokinetic exposure of RPV in coinfected patients was comparable to that in patients without coinfection.

Virologically suppressed patients.

In study 1216, the efficacy and safety of switching from Eviplera to Odefsey were evaluated in a randomized, double-blind study of virologically suppressed HIV-1 infected adults. Patients must have been stably suppressed (HIV-1 RNA < 50 copies/mL) on their baseline regimen of Eviplera for at least 6 months and had no known resistance mutations to FTC, TAF, or RPV prior to study entry. Patients were randomized in a 1:1 ratio to either switch to Odefsey (N = 316) or stay on Eviplera (N = 314). Patients had a mean age of 45 years (range: 23-72), 90% were male, 75% were White, and 19% were Black. The mean baseline CD4+ cell count was 709 cells/mm3 (range: 104-2527).
In study 1160, the efficacy and safety of switching from Atripla to Odefsey were evaluated in a randomized, double-blind study of virologically suppressed HIV-1 infected adults. Patients must have been stably suppressed (HIV-1 RNA < 50 copies/mL) on their baseline regimen of Atripla for at least 6 months and had no known resistance mutations to FTC, TAF, or RPV prior to study entry. Patients were randomized in a 1:1 ratio to either switch to Odefsey (N = 438) or stay on Atripla (N = 437). Patients had a mean age of 48 years (range: 19-76), 87% were male, 67% were White, and 27% were Black. The mean baseline CD4+ cell count was 700 cells/mm3 (range: 140-1862).
Treatment outcomes of studies 1216 and 1160 are presented in Table 20. At Week 96, switching to Odefsey was noninferior in maintaining HIV-1 RNA < 50 copies/mL when compared to patients who stayed on Eviplera or on Atripla in respective studies.
In study 1216, the mean change from baseline in CD4+ cell count at Week 96 was 12 cells/mm3 in patients who switched to Odefsey and 16 cells/mm3 in those who remained on Eviplera.
In study 1160, the mean change from baseline in CD4+ cell count at Week 96 was 12 cells/mm3 in patients who switched to Odefsey and 6 cells/mm3 in those who stayed on Atripla.

Bone mineral density.

In studies 1216 and 1160, changes in BMD were assessed by DXA in patients who had both baseline and Week 96 measurements (study 1216: N = 160 and 162 in the Odefsey arm, and N = 156 and 158 in the Eviplera arm, for hip and spine, respectively; study 1160: N = 322 and 327 in the Odefsey arm, and N=345 and 344 in the Atripla arm, for hip and spine, respectively). In both studies, there were increases from baseline in mean BMD at the hip and at the spine in the Odefsey groups as compared with minimal changes from baseline in both parameters in the Eviplera and Atripla groups. Results are summarized in Table 21.

Renal laboratory parameters.

In study 1216, there were minimal changes or decreases from baseline in albuminuria (UACR), and tubular proteinuria (urine RBP to creatinine ratio, urine beta-2-microglobulin to creatinine ratio) in patients receiving Odefsey as compared with increases from baseline in patients who stayed on Eviplera. At Week 96, the median percentage change in UACR was 9% vs. 33%; in urine RBP to creatinine ratio, it was 7% vs. 56%; and in urine beta 2-microglobulin to creatinine ratio, it was -16% vs. 44% for the Odefsey and Eviplera groups, respectively (p < 0.001 for the differences between treatment groups).
In study 1160 there were decreases from baseline in albuminuria (UACR), and tubular proteinuria (urine RBP to creatinine ratio, urine beta-2-microglobulin to creatinine ratio) in patients receiving Odefsey as compared with increases from baseline in patients who stayed on Atripla. At Week 96, the median percentage change in UACR was -1% vs. 40%; in urine RBP to creatinine ratio, it was -7.0% vs. 87%; and in urine beta-2-microglobulin to creatinine ratio, it was -32% vs. 68% for the Odefsey and Atripla groups, respectively (p < 0.001 for the differences between treatment groups).

Changes in lipid laboratory tests.

Changes from baseline to Week 96 in the fasting lipid parameters total cholesterol, direct LDL, HDL, and triglycerides for Studies 1216 and 1160 are presented in Table 22. These changes were not considered clinically relevant.

Paediatric patients.

Study C213.

The pharmacokinetics, safety, tolerability, and efficacy of RPV 25 mg once daily, in combination with an investigator-selected background regimen (BR) containing two NRTIs, were evaluated in Study C213, a single-arm, open-label Phase 2 study in antiretroviral treatment-naïve HIV-1 infected paediatric patients 12 to less than 18 years of age and weighing at least 32 kg. This analysis included 36 patients who had completed at least 48 weeks of treatment or discontinued earlier. The median duration of exposure for patients was 63.5 weeks.
The 36 patients had a median age of 14.5 years (range, 12-17 years) and were 55.6% female, 88.9% Black, and 11.1% Asian. The median baseline plasma HIV-1 RNA was 4.8 log10 copies/mL, and the median baseline CD4+ cell count was 414 × 106 cells/L (range, 25-983 x 106 cells/L). The proportion of patients with HIV-1 RNA < 50 copies/mL at week 48 (TLOVR) was 72.2% (26/36). The combination of NRTIs most frequently used together with RPV was FTC/TDF (24 patients [66.7%]), followed by 3TC/TDF (8 patients [22.2%]) and 3TC/AZT (4 patients [11.1%]).
The proportion of responders was higher in patients with a baseline viral load ≤ 100,000 copies/mL (78.6%, 22/28) as compared to those with a baseline viral load > 100,000 copies/mL (50.0%, 4/8).
The proportion of virologic failures was 22.2% (8/36). The proportion of virologic failures was lower in patients with a baseline viral load ≤ 100,000 copies/mL (17.9%, 5/28) as compared to those with a baseline viral load > 100,000 copies/mL (37.5%, 3/8). One patient discontinued due to an adverse event and 1 patient discontinued due to reasons other than an adverse event or virologic failure. At week 48, the mean increase in CD4+ cell count from baseline was 201.2 x 106 cells/L.

5.3 Preclinical Safety Data

Genotoxicity.

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

Emtricitabine.

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

Rilpivirine.

Has tested negative in the in vitro Ames reverse mutation assay, in vitro chromosomal aberration assay in human lymphocyte and in vitro clastogenicity mouse lymphoma assay, tested in the absence and presence of a metabolic activation system. Rilpivirine did not induce chromosomal damage in the in vivo micronucleus test in mice.

Tenofovir alafenamide.

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, RPV 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).

Rilpivirine.

RPV was evaluated for carcinogenic potential by oral gavage administration to mice and rats up to 104 weeks. Daily doses of 20, 60, and 160 mg/kg/day were administered to mice and doses of 40, 200, 500, and 1500 mg/kg/day were administered to rats. An increase in the incidences of hepatocellular adenomas and carcinomas was observed in mice and rats. An increase in the incidences of follicular cell adenomas and/or carcinomas in the thyroid gland was observed in rats. Administration of RPV did not cause a statistically significant increase in the incidence of any other benign or malignant neoplasm in mice or rats. The observed hepatocellular findings in mice and rats are considered to be rodent specific, associated with liver enzyme induction. A similar mechanism does not exist in humans; hence, these tumours are not relevant for humans. The follicular cell findings are considered to be rat specific, associated with increased clearance of thyroxine and are not considered to be relevant for humans. At the lowest tested doses in the carcinogenicity studies, the systemic exposures (based on AUC) to RPV were 21-fold (mice) and 3-fold (rats), relative to those observed in humans at the recommended dose (25 mg once daily).
RPV has tested negative in the in vitro Ames reverse mutation assay, in vitro chromosomal aberration assay in human lymphocyte, and in vitro clastogenicity mouse lymphoma assay, tested in the absence and presence of a metabolic activation system. RPV did not induce chromosomal damage in the in vivo micronucleus test in mice.

Tenofovir alafenamide.

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

4 Clinical Particulars

4.1 Therapeutic Indications

Odefsey is indicated as a complete regimen for the treatment of HIV-1 infection in adults and adolescents (12 years and older with bodyweight at least 35 kg) with plasma HIV-1 RNA ≤ 100,000 copies/mL at the start of therapy. The patients must not have a history of treatment failure or known mutations associated with resistance to the individual components of Odefsey.

4.3 Contraindications

Odefsey is contraindicated in patients with known hypersensitivity to any of the active substances or any other component of the tablets.
Coadministration with the following drugs is contraindicated due to the potential for serious and/or life threatening events or loss of virologic response and possible resistance to Odefsey (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Anticonvulsants: carbamazepine, oxcarbazepine, phenobarbital, phenytoin.
Antimycobacterials: rifampin, rifapentine.
Proton pump inhibitors, such as omeprazole, esomeprazole, lansoprazole, dexlansoprazole, pantoprazole, rabeprazole.
Glucocorticoid systemic dexamethasone, except as a single dose treatment.
Herbal products: St John's wort (Hypericum perforatum).

4.4 Special Warnings and Precautions for Use

General.

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

Virologic failure and development of resistance.

Regardless of HIV-1 RNA level at the start of therapy, more RPV treated patients with CD4+ cell count less than 200 cells/mm3 at the start of therapy experienced virologic failure compared to patients with CD4+ cell count greater than or equal to 200 cells/mm3. More RPV treated patients with HIV-1 RNA greater than 100,000 copies/mL at the start of therapy experienced virologic failure compared to patients with HIV-1 RNA less than 100,000 copies/mL at the start of therapy.
The observed virologic failure rate in RPV treated patients conferred a higher rate of overall treatment resistance and cross resistance to the NNRTI class compared to efavirenz. More patients treated with RPV developed lamivudine/ emtricitabine associated resistance compared to efavirenz (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
Resistance testing and/or historical resistance data should guide the use of Odefsey.

Lactic acidosis/ severe hepatomegaly with steatosis.

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases have been reported with the use of nucleoside analogs, including emtricitabine, a component of Odefsey, and tenofovir DF, another prodrug of tenofovir, alone or in combination with other antiretrovirals. Treatment with Odefsey 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).

HIV and hepatitis B virus (HBV) coinfection.

The safety and efficacy of Odefsey have not been established in patients coinfected with HBV and HIV-1. Discontinuation of Odefsey therapy in patients coinfected with HIV-1 and HBV may be associated with severe acute exacerbations of hepatitis due to the FTC or TAF components of Odefsey. Patients coinfected with HIV-1 and HBV who discontinue Odefsey should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, resumption of antihepatitis B therapy may be warranted. In patients with advanced liver disease or cirrhosis, discontinuation of antihepatitis B therapy is not recommended since post-treatment exacerbation of hepatitis may lead to hepatic decompensation.

Use with other antiretroviral products.

Odefsey is indicated for use as a complete regimen for the treatment of HIV-1 infection and should not be coadministered with other antiretroviral products.
Odefsey should not be used in conjunction with protease inhibitors or non-nucleoside reverse transcriptase inhibitors due to potential drug-drug interactions including altered and/or suboptimal pharmacokinetics of Odefsey, and/or the coadministered antiretroviral products.
Odefsey should not be coadministered with products containing any of the same active components, FTC, RPV or TAF or with products containing lamivudine or TDF, or with adefovir dipivoxil. Caution should be given to prescribing Odefsey with medicinal products that may reduce the exposure of RPV (see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Immune reconstitution syndrome.

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including RPV and FTC components of Odefsey. 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 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 Genvoya were evaluated through week 48 in 50 treatment naïve, HIV-1 infected patients aged 12 to less than 18 years in an open label trial, Study GS-US-292-0106 (Study 0106). The pharmacokinetics, safety, tolerability, and efficacy of RPV were evaluated through week 48 in 36 paediatric patients aged 12 to less than 18 years of age and weighing at least 32 kg in a single arm, open label trial, Study C213 (see Section 5.1 Pharmacodynamic Properties, Clinical trials). Pharmacokinetic parameters, evaluated in 24 patients weighing ≥ 35 kg receiving Genvoya, were similar to adults receiving Genvoya. The pharmacokinetics of RPV in paediatric patients 12 to less than 18 years of age receiving RPV 25 mg once daily was comparable to that in adults. There was no impact of bodyweight on RPV pharmacokinetics in paediatric patients in Study C213, similar to what was observed in adults (see Section 5.2 Pharmacokinetic Properties; Section 4.2 Dose and Method of Administration for dosing recommendations for paediatric patients aged 12 years and older and weighing at least 35 kg). No data are available on which to make a dose recommendation for paediatric patients younger than 12 years or weighing less than 35 kg. The safety profile in adolescent patients who received treatment Genvoya or RPV was similar to that in adults (see Section 4.8 Adverse Effects (Undesirable Effects)).

Use in the elderly.

In general, dose selection for elderly patients should be cautious, keeping in mind the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. In clinical studies, 80 of the 97 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. Clinical studies of RPV did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients (see Section 5.2 Pharmacokinetic Properties).

Renal impairment.

No dose adjustment of Odefsey is required in adult patients with estimated creatinine clearance greater than or equal to 30 mL/min. The safety of Odefsey has not been established in adult patients with estimated creatinine clearance that declines below 30 mL/min or in paediatric patients with renal impairment (see Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 5.2 Pharmacokinetic Properties).
The safety, virologic, and immunologic responses of FTC + TAF was evaluated through 144 weeks in an open label clinical study (Study GS-US-292-0112) [0112]) in which 248 HIV-1 infected adult patients who were either treatment naïve (N = 6) or virologically suppressed (N = 242) with mild to moderate renal impairment (eGFR by Cockcroft-Gault method 30-69 mL/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.
No dose adjustment of RPV is required in patients with mild or moderate renal impairment (see Section 5.2 Pharmacokinetic Properties).
Odefsey should not be initiated in patients with estimated creatinine clearance below 30 mL/min as there is insufficient data available regarding the use of Odefsey in this population (see Section 4.2 Dose and Method of Administration).

Hepatic impairment.

No dose adjustment of Odefsey is required in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment. No pharmacokinetic or safety data are available regarding the use of Odefsey in patients with severe hepatic impairment (Child-Pugh class C).

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

General.

As Odefsey contains FTC, RPV and TAF any interactions that have been identified with these agents individually may occur with Odefsey.

Drugs inducing or inhibiting CYP3A enzymes.

RPV is primarily metabolized by cytochrome P450 (CYP) 3A, and drugs that induce or inhibit CYP3A may thus affect the clearance of RPV.
Coadministration of RPV and drugs that induce CYP3A resulted in decreased plasma concentrations of RPV, which could potentially reduce the therapeutic effect of Odefsey (see Table 1 for drugs studied). Other drugs inducing CYP3A enzymes include carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifapentine, rifampin, dexamethasone, and St John's wort (Hypericum perforatum) (see Section 4.3 Contraindications).
Coadministration of RPV and drugs that inhibit CYP3A resulted in increased plasma concentrations of RPV (see Table 1 for drugs studied).

Drugs inducing or inhibiting P-gp.

TAF, a component of Odefsey, is transported by P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Drugs that strongly affect P-gp and BCRP activity may lead to changes in TAF absorption (see Table 1). 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 Odefsey and development of resistance. Coadministration of Odefsey with drugs that inhibit P-gp and BCRP may increase the absorption and plasma concentration of TAF.

Drugs increasing gastric pH.

Coadministration of RPV with drugs that increase gastric pH (such as proton pump inhibitors, H2-receptor antagonists, and antacids) may decrease plasma concentrations of RPV, which could potentially reduce the therapeutic effect of Odefsey (see Table 1 for drugs studied).

QT prolonging drugs.

There is limited information available on the potential for a pharmacodynamic interaction between RPV and drugs that prolong the QTc interval of the electrocardiogram. In a study of healthy subjects, supratherapeutic doses of RPV (75 mg once daily and 300 mg once daily) have been shown to prolong the QTc interval of the electrocardiogram. Odefsey should be used with caution when coadministered with a drug with a known risk of QTc prolongation.

Established and other potentially significant drug interactions.

Odefsey is indicated for use as a complete regimen for the treatment of HIV-1 infection and should not be coadministered with other antiretroviral products. Therefore, information regarding drug-drug interactions with other antiretroviral products is not provided. Drug interaction information for Odefsey with potential concomitant drugs is summarized in Table 1. The drug interactions described are based on studies conducted with Odefsey or the components of Odefsey (FTC, RPV, and TAF) as individual agents, or are potential drug interactions that may occur with Odefsey. The table is not all inclusive (see Section 4.3 Contraindications).

Drugs without clinically significant interactions with Odefsey.

Based on drug interaction studies conducted with the components of Odefsey, no clinically significant drug interactions have been either observed or expected when Odefsey is combined with the following drugs: acetaminophen, atorvastatin, buprenorphine, digoxin, ledipasvir/ sofosbuvir, metformin, midazolam, naloxone, norbuprenorphine, norethindrone, norgestimate/ ethinylestradiol, sildenafil, simeprevir, and sofosbuvir, sofosbuvir/velpatasvir and sofosbuvir/velpatasvir/voxilaprevir.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

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

Emtricitabine.

FTC 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).

Rilpivirine.

In a study conducted in rats, there were no effects on mating or fertility with RPV up to 400 mg/kg/day, a dose of RPV that showed maternal toxicity. This dose is associated with an exposure that is approximately 40 times higher than the exposure in humans at the recommended dose of 25 mg once daily.

Tenofovir alafenamide.

There were no effects on fertility, mating performance or early embryonic development when TAF was administered to male rats at a dose up to 160 mg/kg/day 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 Odefsey or its components in pregnant women. Because animal reproductive studies are not always predictive of human response, Odefsey 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 FTC exposures (AUC) of 50 and 130-fold the clinical exposure. Impaired weight gain observed in pregnant rabbits at doses resulting in FTC exposures (AUC) at least 33 times the clinical exposure was not associated with any adverse fetal effects.

Rilpivirine.

Lower exposures of rilpivirine were observed during pregnancy; therefore, viral load should be monitored closely.
Rilpivirine in combination with a background regimen was evaluated in a clinical trial of 19 pregnant women during the second and third trimesters, and postpartum. The pharmacokinetic data demonstrate that total exposure (AUC) to rilpivirine as a part of an antiretroviral regimen was approximately 30% lower during pregnancy compared with postpartum (6-12 weeks). Virologic response was preserved throughout the trial period. No mother to child transmission occurred in all 10 infants born to the mothers who completed the trial and for whom the HIV status was available. Rilpivirine was well tolerated during pregnancy and postpartum. There were no new safety findings compared with the known safety profile of rilpivirine in HIV-1 infected adults (see Section 5.2 Pharmacokinetic Properties).
Placental transfer of RPV or its metabolites from dam to fetus was demonstrated in rats. Studies in animals have shown no evidence of relevant embryonic or fetal toxicity or an effect on reproductive function. There was no clinically relevant teratogenicity with RPV in rats and rabbits. The exposures at the embryofetal No Observed Adverse Effect Levels (NOAELs) in rats and rabbits were respectively 15 and 70 times higher than the exposure in humans at the recommended dose of 25 mg RPV once daily.

Tenofovir alafenamide.

Embryofetal development studies have been performed in rats and rabbits revealed no evidence of embryolethality, fetotoxicity or teratogenicity due to TAF. The embryofetal 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.

Emtricitabine.

In humans, samples of breast milk obtained from five HIV-1 infected mothers given Truvada (FTC/TDF) 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 whose mothers are being treated with FTC may be at risk for developing viral resistance to FTC. Other FTC associated risks in infants breastfed by mothers being treated with FTC are unknown.

Rilpivirine.

Studies in lactating rats and their offspring indicate that RPV was present in rat milk. It is not known whether RPV is secreted in human milk.

Tenofovir alafenamide.

In animal studies it has been shown that tenofovir is secreted into milk. It is not known whether TAF is secreted in human milk. Tenofovir associated risks, including the risk of developing viral resistance to tenofovir, in infants breastfed by mothers being treated with TAF are unknown.
Because of the potential for both HIV-1 transmission and for serious adverse events in nursing infants, mothers should be instructed not to breastfeed if they are receiving Odefsey.

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 Odefsey contains FTC, RPV and TAF, adverse reactions associated with these individual antiretroviral agents may be expected to occur with the fixed combination tablet.
For additional safety information about Emtriva (FTC), or Edurant (RPV) in combination with other antiretroviral agents, consult the Product Information for these products.
No data are available from clinical studies of Odefsey in HIV infected patients. The safety of Odefsey is based on studies of FTC + TAF when given with EVG + COBI as the fixed dose combination tablet, Genvoya (EVG/COBI/FTC/TAF); and studies of rilpivirine when given with FTC + TDF as individual components or as the fixed dose combination tablet, Eviplera.

Clinical trials.

Emtricitabine and tenofovir alafenamide-containing regimens.

Experience from clinical studies in treatment naïve patients.

Assessment of adverse reactions is based on pooled data from two 144 week controlled clinical studies (GS-US-292-0104 [0104] and GS-US-292-0111 [0111]) 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 Genvoya group was nausea. The proportion of patients who discontinued treatment with Genvoya or Stribild due to adverse events, regardless of severity, was 1.3% and 3.3%, respectively. Table 2 displays the frequency of adverse reactions (all Grades) greater than or equal to 5%.
The majority of events presented in Table 2 occurred at severity Grade 1.
In addition to the adverse reactions presented in Table 2, abdominal pain, 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 Genvoya group.

Laboratory abnormalities.

The frequency of laboratory abnormalities (grades 3-4) occurring in at least 2% of patients receiving Genvoya in studies 0104 and 0111 are presented in Table 3.

Serum lipids.

In the clinical studies 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 16 (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Experience from clinical studies in virologically suppressed patients.

No new adverse reactions to FTC + TAF were identified through Week 96 in an open label clinical study (Study GS-US-292-0109 [0109]) of virologically suppressed patients who switched from a TDF containing combination regimen to FTC + TAF given with EVG + COBI as a fixed dose combination (N = 959).

Experience from clinical studies in patients with renal impairment.

The safety of FTC + TAF was evaluated through Week 144 in an open label clinical Study 0112, in which 248 HIV-1 infected patients who were either treatment naïve (N = 6) or virologically suppressed (N = 242) with mild to moderate renal impairment (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 from patients with normal renal function (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Experience from clinical studies in paediatric patients.

The safety of FTC + TAF in HIV-1 was evaluated through 48 weeks in a single arm open label study (Study 0106) in which HIV-1 infected, treatment naïve paediatric patients aged 12 to < 18 years received FTC + TAF treatment in combination with EVG + COBI as the fixed dose combination tablet Genvoya. In this study, the safety profile of FTC + TAF in 50 adolescent patients was similar to that in adults.
The safety of RPV was evaluated through Week 48 in a single arm, open label study (Study C213) in 36 paediatric patients 12 to less than 18 years of age and weighing at least 32 kg. No patients discontinued treatment due to adverse reactions. No new adverse reactions were identified compared to those seen in adults.
Most adverse reactions were grade 1 or 2. Adverse reactions (all grades) of very common frequency were headache, depression, somnolence, and nausea. No grade 3 to 4 laboratory abnormalities for AST/ALT or grade 3 to 4 adverse reactions of transaminase increased were reported.

Rilpivirine containing regimens.

Experience from clinical studies in treatment naïve patients.

The safety assessment is based on the Week 96 pooled data from 1368 patients in the controlled studies C209 and C215 in which 80% of antiretroviral treatment naïve HIV-1 infected adult patients received RPV 25 mg once daily in combination with other antiretroviral medicinal products (N = 550). The median duration of exposure for patients in the RPV arm was 104 weeks. No new adverse reaction terms were identified between 48 weeks and 96 weeks. Adverse reactions observed in these studies were generally consistent with those seen in previous studies of the individual components (see Table 4).
The most common adverse reactions (incidence ≥ 3%, grades 2-4) that occurred in patients receiving FTC/TDF, and RPV in clinical studies C209 and C215 were depression, insomnia and headache and diarrhoea.

Laboratory abnormalities.

Laboratory abnormalities observed in studies C209 and C215 were generally consistent with those seen in other studies of the individual components (see Table 5).
RPV was associated with fewer neurological and psychiatric adverse reactions than efavirenz in patients who received FTC/ tenofovir DF in studies C209 and C215.
Additionally, adverse reactions that occurred in up to 2% of patients receiving RPV with other antiretroviral agents in clinical studies include decreased appetite, sleep disorders, abnormal dreams, depressed mood, somnolence, abdominal pain, vomiting, abdominal discomfort and dizziness.

Adrenal function.

In the pooled phase 3 studies of C209 and C215, in patients treated with RPV plus any of the allowed background regimen (N = 686), at Week 96, there was an overall mean change from baseline in basal cortisol of -19.1 nanomol/L in the RVP group, and an increase of -0.6 nanomol/L in the efavirenz group. At Week 96, the mean change from baseline in ACTH stimulated cortisol levels was lower in the RPV group (+18.4 ± 8.36 nanomol/L) than in the efavirenz group (+54.1 ± 7.24 nanomol/L). Mean values for both basal and ACTH stimulated cortisol values at Week 96 were within the normal range. Overall, there were no serious adverse events, deaths, or treatment discontinuations that could clearly be attributed to adrenal insufficiency. Effects on adrenal function were comparable by background N(t)RTIs.

Serum creatinine.

In the pooled phase 3 studies of C209 and C215 studies in patients treated with RPV plus any of the allowed background regimen (N = 686), there was a small increase in serum creatinine over 96 weeks of treatment with RPV. Most of this increase occurred within the first four weeks of treatment; a mean change of 9 micromol/L (range: -26 micromol/L to 53 micromol/L) was observed through Week 96. In patients who entered the trial with mild or moderate renal impairment, the serum creatinine increase observed was similar to that seen in patients with normal renal function. These changes are not considered to be clinically relevant, and no patient discontinued treatment due to increases in serum creatinine. Creatinine increases were comparable by background N(t)RTIs.

Odefsey.

Experience from clinical studies in virologically suppressed patients.

No new adverse reactions to Odefsey were identified through Week 96 in clinical trials of virologically suppressed patients who switched from Eviplera (FTC/RPV/TDF) to Odefsey (Study GS-US-366-1216 [1216], N = 316), or from Atripla (EFV/FTC/TDF) to Odefsey (Study GS-US-366-1160[1160], N = 438).

Postmarketing experience.

In addition to adverse reactions from clinical studies, the following possible adverse reactions have also been identified during postapproval use of Eviplera or products containing tenofovir alafenamide (TAF). Because these events have been reported voluntarily from a population of unknown size, estimates of frequency cannot be made.

The following adverse reactions have been identified during post-approval use of Eviplera.

Metabolism and nutrition disorders.

Weight increased.

Skin and subcutaneous tissue disorders.

Severe skin reactions with systemic symptoms have been reported during postmarketing experience, including rashes accompanied by fever, blisters, conjunctivitis, angioedema, elevated liver function tests, and/or eosinophilia.

The following adverse reactions have been identified during postapproval use of products containing TAF.

Skin and subcutaneous tissue disorders.

Angioedema, urticaria.

4.2 Dose and Method of Administration

In adults and paediatric patients ≥ 12 years of age and weighing ≥ 35 kg, the dose of Odefsey is one tablet taken orally once daily with food.
No data are available on which to make a dose recommendation for children < 12 years of age or weighing < 35 kg.

Elderly.

No dose adjustment is required for elderly patients (see Section 4.4 Special Warnings and Precautions for Use).

Renal impairment.

No dose adjustment of Odefsey is required in adult patients with estimated creatinine clearance greater than or equal to 30 mL/min.
Odefsey should not be initiated in patients with estimated creatinine clearance below 30 mL/min as there are insufficient data available regarding the use of Odefsey in this population.
No data are available to make dose recommendations in paediatric patients with renal impairment.

Hepatic impairment.

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

Pregnancy and postpartum.

Lower exposures of rilpivirine were observed during pregnancy; therefore, viral load should be monitored closely. Alternatively, switching to another ART regimen could be considered (see Section 5.2 Pharmacokinetic Properties; Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).

4.7 Effects on Ability to Drive and Use Machines

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

4.9 Overdose

If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with Odefsey 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 Emtriva. In one clinical pharmacology study single doses of FTC 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 FTC dosing (blood flow rate of 400 mL/min and a dialysate flow rate of 600 mL/min). It is not known whether FTC can be removed by peritoneal dialysis.

Rilpivirine.

There is no specific antidote for overdose with RPV. Human experience of overdose with rilpivirine is limited. Since rilpivirine is highly bound to plasma protein, dialysis is unlikely to result in significant removal of the active substance.

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%.

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Odefsey tablets contain the following ingredients as excipients:

Tablet core.

Lactose, microcrystalline cellulose, povidone, Polysorbate 20, croscarmellose sodium, and magnesium stearate.

Film-coating.

Polyvinyl alcohol (E1203), titanium dioxide (E171), polyethylene glycol, talc (E553b), and iron oxide black (E172).

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

Odefsey should be stored below 30°C.

6.5 Nature and Contents of Container

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

6.6 Special Precautions for Disposal

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

Summary Table of Changes