Consumer medicine information

Eviplera Tablets

Tenofovir disoproxil fumarate; Emtricitabine; Rilpivirine

BRAND INFORMATION

Brand name

Eviplera

Active ingredient

Tenofovir disoproxil fumarate; Emtricitabine; Rilpivirine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Eviplera 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 EVIPLERA 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.

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

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.

What is EVIPLERA

EVIPLERA is used to treat Human Immunodeficiency Virus (HIV-1) infection in adults.

EVIPLERA consists of three medicines:

  • tenofovir disoproxil fumarate, also called tenofovir DF
  • emtricitabine or FTC
  • rilpivirine

These are combined in one tablet to help control Human Immunodeficiency Virus (HIV-1) infection.

Tenofovir disoproxil fumarate and emtricitabine belong to a group of antiviral medicines known as nucleoside and nucleotide reverse transcriptase inhibitors (NRTI).

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

How EVIPLERA works

HIV-1 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.

EVIPLERA helps block HIV-1 reverse transcriptase, a viral chemical in your body (enzyme) that is needed for HIV-1 to multiply. EVIPLERA lowers the amount of HIV-1 in the blood (viral load). EVIPLERA may also help to increase the number of T cells (CD4+ cells), allowing your immune system to improve. Lowering the amount of HIV-1 in the blood lowers the chance of death or infections that happen when your immune system is weak (opportunistic infections).

Use in Children

EVIPLERA is for adults. EVIPLERA has not been studied in children under the age of 18 or adults over the age of 65.

Does EVIPLERA cure HIV OR AIDS

EVIPLERA does not cure HIV-1 infection or AIDS.

The long-term effects of EVIPLERA are not known at this time. People taking EVIPLERA may still get opportunistic infections or other conditions that happen with HIV-1 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-1 infection.

If you wish to continue receiving treatment with EVIPLERA it is important you remain under the care of a hospital or doctor who specialises in the treatment of HIV-1 infection.

Does EVIPLERA reduce the risk of passing HIV to others

EVIPLERA does not stop you from transmitting HIV-1 to others.

For your health and the health of others, it is important to always practice safe 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 EVIPLERA

Who must not take it

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

Do not take EVIPLERA if you are allergic to:

  • tenofovir
  • tenofovir DF
  • emtricitabine,
  • rilpivirine or
  • any of the other ingredients of EVIPLERA

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • rash, itching or hives on the skin
  • swelling of the face, lips, tongue or other parts of the body

Do not take EVIPLERA if you are already taking any other medicines that contain the same active ingredients. The ingredients of EVIPLERA are listed in the product description section of this leaflet.

Do not take EVIPLERA if you are taking other medicines that contain:

  • rilpivirine, unless required for dosage adjustment (e.g. Edurant)
  • lamivudine (e.g. Combivir, Zeffix, Kivexa, Trizivir)
  • efavirenz (e.g. Stocrin)
  • lopinavir/ritonavir (e.g. Kaletra).
  • etravirine (e.g. Intelence)
  • delavirdine (e.g. Rescriptor)
  • nevirapine (e.g. Viramune)
  • didanosine (e.g. Videx, Videx EC)
  • atazanavir sulfate (e.g. Reyataz)
  • tenofovir alafenamide (e.g. Genvoya, Descovy, Odefsey, Biktarvy)

Tell your doctor if you are taking any of the following medicines. Some of these medicines may be obtained without a prescription and some of these may be available under other names. These medicines may alter the amount of EVIPLERA in your blood or EVIPLERA may alter the amount of these medicines in your blood. It is important that you carefully read the package leaflets that are provided with these medicines.

Antiviral Agents (to treat Hepatitis C):

  • ledipasvir/sofosbuvir (e.g. Harvoni)
  • sofosbuvir/velpatasvir (e.g. Epclusa)
  • sofosbuvir/velpatasvir/voxilaprevir (e.g. Vosevi)

Antacids (used to treat stomach ulcers, heartburn or acid reflux):

  • aluminium / magnesium hydroxide
  • calcium carbonate

Anticonvulsants (to treat epilepsy and prevent seizures):

  • carbamazepine (e.g. Tegretol, Teril)
  • oxcarbazepine (e.g. Trieptal)
  • phenobarbital, phenytoin (e.g. Dilantin)

Antimycobacterials (to treat bacterial infections, including tuberculosis [TB]):

  • rifabutin (e.g. Mycobutin)
  • rifampicin (e.g. Rifadin/Rimycin)
  • rifapentine

Corticosteroids (used in a variety of conditions such as inflammation and allergic reactions):

  • dexamethasone when taken by the mouth or injected)

H2-Receptor Antagonists (to treat stomach ulcers or used to relieve heartburn from acid reflux):

  • ranitidine (e.g. Zantac)
  • famotidine (e.g. Pepcidine, Pepzan)
  • cimetidine (e.g. Tagamet, Magicul)
  • nizatidine (e.g. Nizac, Tazac)

Macrolide Antibiotics (to treat bacterial infections):

  • clarithromycin (e.g. Charihexal, Clarac)
  • erythromycin (e.g. E-Mycin, Eryc, EES)
  • troleandomycin

Narcotic Analgesic:

  • methadone (e.g. Biodone, Physeptone)

Proton Pump Inhibitors (prevent or treat stomach ulcers, heartburn or acid reflux disease):

  • omeprazole (e.g. APO-Omeprazole, Meprazol)
  • lansoprazole (e.g. Zoton, Lanzopran)
  • rabeprazole (e.g. Pariet)
  • pantoprazole (e.g. Somac)
  • esomeprazole (e.g. Nexium)

Herbal Products: St. Johns wort (Hypericum perforatum):

  • St. Johns wort (Hypericum perforatum)

Do not take EVIPLERA to treat your HIV-1 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.

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

Before you start to take it

Tell your doctor if you take an antacid medicine (a medicine to treat heartburn from acid reflux) that contains aluminum, magnesium hydroxide, or calcium carbonate. Take antacids at least 2 hours before or at least 4 hours after EVIPLERA.

Tell your doctor if you take an H2-receptor antagonist (medicines use to treat stomach ulcers, heartburn or acid reflux disease such as cimetidine, famotidine, nizatidine or ranitidine). Take the H2-receptor antagonist at least 12 hours before or at least 4 hours after EVIPLERA. Importantly, proton pump inhibitors (such as omeprazole, lansoprazole, rabeprazole, pantoprazole, esomeprazole) also available for these conditions should not be taken with EVIPLERA.

Tell your doctor if you are allergic to foods, dyes, preservatives or any other medicines.

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

Tell your doctor if you are breastfeeding, or plan to breastfeed during your course of medication. You should not breastfeed if you are HIV-1-positive because of the chance of passing the HIV-1 virus to your baby. Two active substances in this medicine (tenofovir disoproxil fumarate and emtricitabine) have been found in breast milk at low concentrations.

Talk with your doctor about the best way to feed your baby.

Tell your doctor if you have kidney problems or are undergoing kidney dialysis treatment.

Tell your doctor if you have bone problems.

Tell your doctor if you have liver problems, including hepatitis B or C virus infection.

Tell your doctor if you have mental health problems.

Taking other medicines

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

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

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

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 EVIPLERA.

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

How to take EVIPLERA

Take the exact amount of EVIPLERA 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 EVIPLERA tablet orally, once daily.

How to take it

Always take EVIPLERA with food. This is important to get the right drug levels in your body.

A nutritional drink alone does not replace food.

If you forget to take EVIPLERA

Do not miss a dose of EVIPLERA.

If you forget to take EVIPLERA within 12 hours of the time you usually take it, take your dose of EVIPLERA with food as soon as possible. Then take your next dose of EVIPLERA at the regularly scheduled time. If you miss a dose of EVIPLERA by more than 12 hours of the time you usually take it, wait and then take the next dose of EVIPLERA at the regularly scheduled time.

Do not take a double dose to make up for a forgotten dose.

When your EVIPLERA 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 EVIPLERA and become harder to treat.

Do not change your dose or stop taking EVIPLERA without first talking to your doctor.

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 EVIPLERA tablets. Do this even if there are no signs of discomfort or poisoning. This may need urgent medical attention.

While you are taking EVIPLERA

Things you must not do

Do not breast-feed. See “Before you start to take it”

Avoid doing things that can spread HIV infection since EVIPLERA does not stop you from passing the HIV-1 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 safe sex by using a latex or polyurethane condom or other barrier to reduce the chance of sexual contact with semen, vaginal secretions, or blood.

Things to be careful of

Be careful driving or operating machinery until you know how EVIPLERA 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, EVIPLERA 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 EVIPLERA, even if you do not think the problems are connected with the medicine or are not listed in this leaflet.

EVIPLERA may cause the following serious side effects:

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) andfat deposits in the liver (steatosis) which sometimes occurs in patients taking anti-HIV-1 medicines.

You may be more likely to get lactic acidosis or liver problems if you are female, very overweight (obese), or have been taking similar nucleoside analog-containing medicines, like EVIPLERA, for a long time.

Hepatic Flares

If you have HIV-1 infection and hepatitis B virus (HBV) infection you should not stop your EVIPLERA treatment without first discussing this with your doctor, as some patients have had blood tests or symptoms indicating a worsening of their hepatitis (“hepatic flare”) after stopping individual components (tenofovir DF, and emtricitabine) of EVIPLERA.

You may require medical exams and blood tests for several months after stopping treatment. EVIPLERA is not approved for the treatment of HBV, so you must discuss your HBV therapy with your doctor.

Kidney Problems

If you have had kidney problems in the past or take other medicines that can cause kidney problems, your doctor should do regular blood tests to check your kidneys.

Symptoms that may be related to kidney problems include a high volume of urine, thirst, muscle pain, and muscle weakness.

Changes in Bone Mineral Density (thinning bones)

Laboratory tests show changes in the bones of patients treated with tenofovir DF, a component of EVIPLERA.

Some HIV-1 positive patients treated with tenofovir disoproxil fumarate developed thinning of the bones (osteopaenia) which could lead to fractures.

If you have had bone problems in the past, your doctor may need to do tests to check your bone mineral density or may prescribe medicines to help your bone mineral density.

Additionally, bone pain and softening of the bone (which may contribute to fractures) may occur as a consequence of kidney problems.

Signs and symptoms of inflammation

In some patients with advanced HIV-1 infection (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV-1 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.

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 EVIPLERA and tell your doctor IMMEDIATELY or go to the accident and emergency department at your nearest hospital.

  • shortness of breath
  • wheezing or difficulty breathing
  • rash, itching or HIV-1es on the skin
  • swelling of the face, lips, tongue or other parts of the body
  • Mouth sores or blisters on your body
  • Inflamed eyes (conjunctivitis)

These are very serious effects. If you have them, you may have a serious allergic reaction. You may need urgent medical attention or hospitalisation.

Pancreatitis

If you have any of the following symptoms after starting your medication, tell your doctor IMMEDIATELY or go to the Accident and Emergency department at your nearest hospital:

  • Severe stomach pain or cramps
  • Nausea
  • Vomiting

These side effects may be due to a condition called pancreatitis which sometimes occurs in patients taking anti-HIV-1 medicines.

Common Side Effects:

Clinical studies have shown the most common side effects of EVIPLERA are:

  • depression
  • diarrhoea

Other side effects include:

  • vomiting
  • nausea
  • intestinal gas
  • dizziness
  • allergic reaction
  • headache
  • sleeping problems (including difficulty to fall asleep or sleepiness)
  • abnormal dreams
  • stomach pain or discomfort
  • indigestion
  • rash
  • skin discolouration (small spots or freckles)
  • pain
  • weakness
  • decreased appetite and
  • fatigue

Marketing experience has shown other side effects reported since emtricitabine and/or tenofovir DF, two components of EVIPLERA, have been marketed include:

  • severe allergic reaction (including swelling of the face, lips, tongue, or throat)
  • inflammation of the pancreas
  • inflammation of the liver
  • shortness of breath
  • fatty liver
  • kidney problems (including decline or failure of kidney function)
  • high volume of urine and thirst caused by kidney problems
  • muscle pain and muscle weakness
  • bone pain, and softening of the bone (which may contribute to fractures) as a consequence of kidney problems have been reported.
  • Rash to severe rash and weight gain have also been reported on EVIPLERA.

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

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

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

After taking EVIPLERA

Storage

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

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

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

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

PRODUCT DESCRIPTION

What the tablets look like

EVIPLERA is the brand name of your medicine.

EVIPLERA tablets are capsule-shaped and purplish-pink in colour.

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

EVIPLERA tablets are supplied in bottles containing 30 tablets.

Ingredients

Each EVIPLERA tablet contains the following active ingredients:

  • tenofovir disoproxil fumarate
  • emtricitabine
  • rilpivirine

Each EVIPLERA tablet also contains the following inactive ingredients:

  • pregelatinized starch
  • lactose
  • cellulose-microcrystalline
  • croscarmellose sodium
  • magnesium stearate
  • povidone
  • polysorbate 20

Film-coating:

  • macrogol 3350
  • hypromellose
  • lactose
  • glycerol triacetate
  • titanium dioxide
  • iron oxide red
  • indigo carmine aluminium lake
  • sunset yellow FCF aluminium lake

SPONSOR

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

Date of preparation: 15 July 2020

AUST R 176537

BIKTARVY, DESCOVY, EPCLUSA, EVIPLERA, GENVOYA, HARVONI, ODEFSEY, VOSEVI and GSI 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 September 2020

BRAND INFORMATION

Brand name

Eviplera

Active ingredient

Tenofovir disoproxil fumarate; Emtricitabine; Rilpivirine

Schedule

S4

 

1 Name of Medicine

Eviplera (tenofovir disoproxil fumarate/emtricitabine/rilpivirine).

2 Qualitative and Quantitative Composition

Each film-coated tablet contains 300 mg tenofovir disoproxil fumarate (tenofovir DF) which is equivalent to 245 mg of tenofovir disoproxil, 200 mg emtricitabine (FTC), and 27.5 mg rilpivirine hydrochloride which is equivalent to 25 mg rilpivirine (RPV).
Tenofovir DF is a white to off-white crystalline powder.
Emtricitabine is a white to off-white crystalline powder.
Rilpivirine hydrochloride is a white to almost white powder.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Each Eviplera tablet is capsule-shaped, film-coated and purplish-pink in colour. Each tablet is debossed with 'GSI' on one side and plain on the other side. The tablets are supplied in bottles with child resistant closures.

4 Clinical Particulars

4.1 Therapeutic Indications

Eviplera is indicated for the treatment of HIV infection in treatment naïve adult patients with plasma HIV-1 RNA ≤ 100,000 copies/mL at the start of therapy.
Eviplera is also indicated in certain virologically suppressed (HIV-1 RNA < 50 copies/mL) adult patients on a stable antiretroviral regimen at start of therapy in order to replace their current antiretroviral treatment regimen (see Section 5.1 Pharmacodynamic Properties, Clinical trials). Patients must not have a history of resistance to any of the components of Eviplera (tenofovir DF, FTC or RPV).

4.2 Dose and Method of Administration

Dosage.

Adults.

The recommended dose of Eviplera is one tablet once daily taken orally with food.

Dosage adjustment.

Renal impairment.

Eviplera is not recommended for use in patients with moderate or severe renal impairment (creatinine clearance (CrCl) < 50 mL/min). Patients with moderate or severe renal impairment require dose interval adjustments of tenofovir DF and FTC that cannot be achieved with the combination tablet (see Section 4.4 Special Warnings and Precautions for Use).
When discontinuation of Eviplera is necessary due to one of the components, or when dose modification is necessary, separate preparations of tenofovir DF, FTC and RPV should be used. Please refer to the product information for these products (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Pregnancy and postpartum.

Lower exposures of RPV 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).

4.3 Contraindications

Eviplera is contraindicated in patients with known hypersensitivity to any of the active substances or any other component of the tablets.
Eviplera must not be administered to children or adolescents under the age of 18 years.
Eviplera is a fixed dose combination of tenofovir DF, FTC and RPV. Eviplera should not be administered concurrently with other medicinal products containing any of the same active components: tenofovir DF, FTC, or with medicinal products containing lamivudine, tenofovir alafenamide or adefovir dipivoxil. Eviplera should not be coadministered with RPV unless required for dose adjustment (e.g. with rifabutin, see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Eviplera should not be coadministered with the following medicinal products, as significant decreases in RPV plasma concentrations may occur (due to CYP3A enzyme induction or gastric pH increase), which may result in loss of therapeutic effect of Eviplera:
the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin;
the antimycobacterials rifampicin, rifapentine;
proton pump inhibitors, such as omeprazole, esomeprazole, lansoprazole, dexlansoprazole, pantoprazole, rabeprazole;
the glucocorticoid systemic dexamethasone, except as a single dose treatment;
St. John's wort (Hypericum perforatum).

4.4 Special Warnings and Precautions for Use

General.

Patients receiving Eviplera or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV-1 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 Eviplera, 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 Eviplera is not a cure for HIV-1 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/ FTC 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 Eviplera.

Lactic acidosis/ severe hepatomegaly with steatosis.

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases have been reported with the use of antiretroviral nucleoside analogues including the tenofovir DF component of Eviplera, alone or in combination with other antiretrovirals, in the treatment of HIV-1 infection. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogues to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with Eviplera 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).

Use in renal impairment.

The FTC and tenofovir DF components of Eviplera are primarily excreted by the kidneys; however, RPV is not. Renal failure, renal impairment, elevated creatinine, hypophosphataemia and Fanconi syndrome have been reported with the use of tenofovir DF in clinical practice.
It is recommended that creatinine clearance is calculated in all patients prior to initiating therapy and, as clinically appropriate, during Eviplera therapy. Patients at risk for, or with a history of, renal dysfunction, including patients who have previously experienced renal events while receiving adefovir dipivoxil, should be routinely monitored for changes in serum creatinine and phosphorus.
Eviplera is not recommended for patients with moderate or severe renal impairment (CrCl < 50 mL/min, including patients who require haemodialysis). Patients with moderate or severe renal impairment require a dose adjustment of FTC and tenofovir DF that cannot be achieved with the combination tablet.
Eviplera should be avoided with concurrent or recent use of a nephrotoxic agent.

Use in hepatic impairment.

There is limited information regarding the use of RPV in patients with mild or moderate hepatic impairment, resulting in unexpected variability in the available data. RPV has not been studied in patients with severe hepatic impairment (see Section 5.2 Pharmacokinetic Properties). Eviplera should be used with caution in patients with moderate to severe hepatic impairment (see Section 5.2 Pharmacokinetic Properties).

Bone effects.

Bone toxicity including a reduction in bone mineral density have been observed in tenofovir DF studies in three animal species. Clinically relevant bone abnormalities have not been seen in long-term clinical studies (> 3 years) with Viread. However, bone abnormalities (infrequently contributing to fractures) may be associated with proximal renal tubulopathy (see Section 4.8 Adverse Effects (Undesirable Effects)). If bone abnormalities are suspected during therapy then appropriate consultation should be obtained.

HIV and hepatitis B virus (HBV) coinfection.

Discontinuation of Eviplera therapy in patients coinfected with HIV-1 and HBV may be associated with severe acute exacerbations of hepatitis due to the FTC and tenofovir DF components of Eviplera. Patients coinfected with HIV-1 and HBV should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping Eviplera 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.

Immune reconstitution syndrome.

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

Use in the elderly.

Clinical studies of tenofovir DF, FTC and RPV did not contain sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. Caution should be exercised when prescribing Eviplera to the elderly, keeping in mind the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

Paediatric use.

Eviplera is not recommended for use in children below 18 years of age due to insufficient data on safety and efficacy.

Effects of laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

General.

As Eviplera contains tenofovir DF, FTC and RPV, any interactions that have been identified with these agents individually may occur with Eviplera.
Tenofovir and FTC are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion. No drug-drug interactions due to competition for renal excretion have been observed; however, coadministration of Truvada (FTC/tenofovir DF) with drugs that are eliminated by active tubular secretion may increase serum concentrations of tenofovir, FTC, and/or the coadministered drug. Drugs that decrease renal function may increase serum concentrations of tenofovir and/or FTC.

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 Eviplera (see Table 2 for drugs studied). Other drugs inducing CYP3A enzymes include carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifapentine, 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 2 for drugs studied).

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 Eviplera (see Table 2 for drugs studied) (see Section 4.3 Contraindications).

Didanosine.

Concomitant dosing of tenofovir DF with didanosine buffered tablets or enteric coated capsules significantly increase the Cmax and AUC of didanosine. When didanosine 250 mg enteric coated capsules were administered with tenofovir DF, systemic exposures of didanosine were similar to those seen with the 400 mg enteric coated capsules alone under fasted conditions. The mechanism of this interaction is unknown. Table 1 summarises the effects of tenofovir DF on the pharmacokinetics of didanosine.
As a result of this increased exposure, patients receiving Eviplera and didanosine concomitantly should be carefully monitored for didanosine-associated adverse events, including pancreatitis, lactic acidosis and neuropathy. Suppression of CD4 cell counts has been observed in patients receiving tenofovir DF with didanosine at a dose of 400 mg daily. In adults weighing ≥ 60 kg, the didanosine dose should be reduced to 250 mg daily when it is coadministered with Eviplera. Data are not available to recommend a dose adjustment of didanosine for adults weighing < 60 kg. Didanosine should be discontinued in patients who develop didanosine-associated adverse events.

Atazanavir.

Tenofovir DF decreases exposure to atazanavir and should only be administered with boosted atazanavir (atazanavir 300 mg/ritonavir 100 mg). No data are available to support dosing recommendations for atazanavir or atazanavir/ ritonavir in combination with Eviplera. Table 1 summarises the effects of tenofovir DF on the pharmacokinetics of atazanavir.

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. Eviplera should be used with caution when coadministered with a drug with a known risk of QTc prolongation.

Interactions with other medicinal products.

Caution should be given to prescribing RPV with medicinal products that may reduce the exposure to RPV. For information on interactions with other medicinal products (see Table 2).

Drugs without clinically significant interactions.

The drug interactions described are based on studies conducted with the individual components of Eviplera (FTC, RPV, or tenofovir DF) or Eviplera as a combination product.

Tenofovir disoproxil fumarate.

No clinically significant drug interactions have been observed between tenofovir DF and abacavir, efavirenz, FTC, indinavir, lamivudine, lopinavir/ ritonavir, methadone, nelfinavir, oral contraceptives, ribavirin, saquinavir/ ritonavir, or sofosbuvir.

Emtricitabine.

No clinically significant drug interactions have been observed between FTC and indinavir, zidovudine, stavudine, famciclovir, ledipasvir/sofosbuvir, sofosbuvir/velpatasvir, sofosbuvir/velpatasvir/voxilaprevir, or tenofovir DF.

Rilpivirine.

No clinically significant drug interactions have been observed between RPV and acetaminophen, atorvastatin, didanosine, digoxin, ethinylestradiol, ledipasvir/ sofosbuvir, metformin, norethindrone, raltegravir, sildenafil, sofosbuvir, sofosbuvir/velpatasvir, sofosbuvir/velpatasvir/voxilaprevir, or tenofovir DF.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

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

Tenofovir disoproxil fumarate.

Male and female rat fertility and mating performance or early embryonic development were unaffected by an oral tenofovir DF dose (600 mg/kg/day) that achieved systemic drug exposures that were in excess of the expected value in humans receiving the therapeutic dose (5-fold based on plasma AUC). There was, however, an alteration of the oestrous cycle in female rats.

Emtricitabine.

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.
(Category B3)
There are no well controlled clinical studies of Eviplera in pregnant women. No embryofoetal development studies have been conducted with tenofovir DF, FTC and RPV in combination. Because animal reproductive studies are not always predictive of human response, Eviplera should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
Women of childbearing potential should undergo pregnancy testing before initiation of Eviplera. Women of childbearing potential who are taking Eviplera should use effective contraception throughout treatment.

Tenofovir disoproxil fumarate.

Reproductive toxicity studies performed in rats and rabbits did not reveal any evidence of harm to the foetus due to tenofovir at respective exposures (AUC) of 4-13 and 66-fold the human exposure. Subcutaneous treatment of pregnant rhesus monkeys with a dose of 30 mg/kg/day of the tenofovir base during the last half of pregnancy resulted in reduced foetal serum phosphorus concentrations.

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 foetal effects.

Rilpivirine.

Lower exposures of RPV were observed during pregnancy; therefore, viral load should be monitored closely.
RPV 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 RPV 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. RPV was well tolerated during pregnancy and postpartum. There were no new safety findings compared with the known safety profile of RPV in HIV-1 infected adults (see Section 5.2 Pharmacokinetic Properties).
Placental transfer of RPV or its metabolites from dam to foetus was demonstrated in rats. Studies in animals have shown no evidence of relevant embryonic or foetal toxicity or an effect on reproductive function. There was no clinically relevant teratogenicity with RPV in rats and rabbits. The exposures at the embryofoetal 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.
 Studies in rats have demonstrated that tenofovir and RPV is excreted into milk.
It is not known whether RPV is secreted in human milk. 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 Eviplera.

Tenofovir disoproxil fumarate.

In humans, samples of breast milk obtained from five HIV-1 infected mothers show that tenofovir is secreted in human milk at low concentrations (estimated neonatal concentrations 128 to 266 times lower than the tenofovir IC50) (50% maximal inhibitory concentration). Tenofovir associated risks, including the risk of developing viral resistance to tenofovir, in infants breastfed by mothers being treated with tenofovir DF are unknown.

Emtricitabine.

Samples of breast milk obtained from five HIV-1 infected mothers 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 (minimal expected trough concentrations in adults) 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.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects of Eviplera on the ability to drive and use machines have been performed. However, patients should be informed that dizziness has been reported during treatment with tenofovir DF, FTC, and RPV.

4.8 Adverse Effects (Undesirable Effects)

As Eviplera contains tenofovir DF, FTC and RPV, adverse events associated with these individual antiretroviral agents may be expected to occur with the fixed combination tablet.
For additional safety information about tenofovir DF, FTC or RPV in combination with other antiretroviral agents, consult the product information for these products.

Clinical trials. In treatment naïve HIV-1 infected adults. Studies C209 and C215.

Tenofovir disoproxil fumarate + emtricitabine + rilpivirine.

Treatment emergent adverse reactions.

Studies C209 and C215 were randomised, double-blind, active controlled studies in which 80% of antiretroviral naïve patients received tenofovir DF + FTC administered in combination either with RPV (N = 550) or with efavirenz (N = 546) (see Section 5.1 Pharmacodynamic Properties, Clinical trials). The median duration of exposure for patients in either treatment 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 (Table 3).
The most common adverse reactions (incidence ≥ 3%, grades 2-4) that occurred in patients receiving tenofovir DF, FTC, and RPV in clinical trials 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 (Table 4).
RPV was associated with fewer neurological and psychiatric adverse reactions than efavirenz in patients who received FTC/ tenofovir DF in studies C209 and C215. In addition to the adverse events in studies C209 and C215 (Table 3), the following adverse events were observed in clinical studies of tenofovir DF, FTC and RPV in combination with other antiretroviral agents.
Tenofovir disoproxil fumarate. More than 12,000 patients have been treated with Viread alone or in combination with other antiretroviral medicinal products for periods of 28 days to 215 weeks in phase I-III clinical trials and expanded access studies. A total of 1,544 patients have received Viread 300 mg once daily in phase I-III clinical trials; over 11,000 patients have received Viread in expanded access studies.
The most common adverse events that occurred in patients receiving Viread with other antiretroviral agents in clinical trials were mild to moderate gastrointestinal events, such as nausea, diarrhoea, vomiting and flatulence.
Emtricitabine. More than 2000 adult patients with HIV-1 infection have been treated with Emtriva alone or in combination with other antiretroviral agents for periods of 10 days to 200 weeks in phase I-III clinical trials.
Assessment of adverse reactions is based on data from studies 301A and 303 in which 571 treatment naïve (301A) and 440 treatment experienced (303) patients received Emtriva 200 mg (n = 580) or comparator drug (n = 431) for 48 weeks.
The most common adverse events that occurred in patients receiving Emtriva with other antiretroviral agents in clinical trials were headache, diarrhoea, nausea, and rash, which were generally of mild to moderate severity. Approximately 1% of patients discontinued participation in the clinical studies due to these events. All adverse events were reported with similar frequency in Emtriva and control treatment groups with the exception of skin discolouration which was reported with higher frequency in the Emtriva treated group.
Skin discolouration, manifested by hyperpigmentation on the palms and/or soles was generally mild and asymptomatic. The mechanism and clinical significance are unknown.
In addition to the adverse reactions reported in adults, anaemia has been reported commonly and hyperpigmentation very commonly, in paediatric patients.
Rilpivirine. Adverse reactions that occurred in up to 2% of patients receiving RPV with other antiretroviral agents in clinical trials include decreased appetite, sleep disorders, abnormal dreams, depressed mood, somnolence, abdominal pain, vomiting, abdominal discomfort and dizziness.

Adrenal function.

In the pooled phase 3 trials 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 RPV 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 trials of C209 and C215 trials 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 subject discontinued treatment due to increases in serum creatinine. Creatinine increases were comparable by background N(t)RTIs.

Serum lipids.

Changes from baseline in total cholesterol, LDL cholesterol, HDL cholesterol and triglycerides are presented in Table 5. The mean changes from baseline were smaller in the RPV arm versus the efavirenz arm. The impact of such 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.

In virologically supressed HIV-1 infected patients. Studies GS-US-264-0106 and GS-US-264-0111.

No new adverse reactions to Eviplera were identified in clinical trials of virologically suppressed patients who switched from a regimen containing a ritonavir boosted protease inhibitor (GS-US-264-0106, N = 469) or from Atripla (GS-US-264-0111, N = 49) to Eviplera.

Postmarketing surveillance.

In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of Eviplera, or products containing emtricitabine (FTC) and/or tenofovir disoproxil fumarate (tenofovir DF). Because these events have been reported voluntarily from a population of unknown size, estimates of frequency cannot be made.

Immune system disorders.

Allergic reaction (including angioedema), autoimmune hepatitis (see Section 4.4 Special Warnings and Precautions for Use).
Immune Reconstitution Syndrome: In HIV-infected patients with severe immune deficiency at the time of initiation of antiretroviral therapy, an inflammatory reaction to infectious pathogens (active or inactive) may arise (see Section 4.4 Special Warnings and Precautions for Use).

Metabolism and nutrition disorders.

Hypokalaemia, hypophosphataemia, lactic acidosis.

Respiratory, thoracic and mediastinal disorders.

Dyspnoea.

Gastrointestinal disorders.

Increased amylase, abdominal pain, pancreatitis.

Hepatobiliary disorders.

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

Skin and subcutaneous tissue disorders.

Rash.

Musculoskeletal and connective tissue disorders.

Rhabdomyolysis, muscular weakness, myopathy, osteomalacia (manifested as bone pain and infrequently contributing to fractures).

Renal and urinary disorders.

Increased creatinine, renal insufficiency, renal failure, acute renal failure, Fanconi syndrome, proximal renal tubulopathy, nephrogenic diabetes insipidus, proteinuria, acute tubular necrosis, polyuria, interstitial nephritis (including acute cases).

General disorders and administration site conditions.

Asthaenia.
The following adverse reactions, listed under the body system headings above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia (manifested as bone pain and infrequently contributing to fractures), hypokalaemia, muscular weakness, myopathy, hypophosphataemia. These events are not considered to be causally associated with tenofovir DF therapy in the absence of proximal renal tubulopathy.

Exacerbations of hepatitis after discontinuation of treatment.

In HIV-1 infected patients coinfected with HBV, clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of treatment (see Section 4.4 Special Warnings and Precautions for Use).
Eviplera.

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.

Metabolism and nutrition disorders.

Weight increased.

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 www.tga.gov.au/reporting-problems.

4.9 Overdose

If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with Eviplera 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.

Tenofovir disoproxil fumarate.

Clinical experience of doses higher than the therapeutic dose of Viread 300 mg is available from two studies. In one study, intravenous tenofovir, equivalent to 16.7 mg/kg/day of tenofovir DF, was administered daily for 7 days. In the second study, 600 mg of tenofovir DF was administered to patients orally for 28 days. No unexpected or severe adverse reactions were reported in either study. The effects of higher doses are not known.
Tenofovir is efficiently removed by haemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of Viread, a four hour haemodialysis session removed approximately 10% of the administered tenofovir dose.

Emtricitabine.

Limited clinical experience is available at doses higher than the therapeutic dose of 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 RPV is limited. Since RPV is highly bound to plasma protein, dialysis is unlikely to result in significant removal of the active substance.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group.

Antivirals for treatment of HIV infections, combinations, ATC code: J05AR06.

Mechanism of action.

Tenofovir disoproxil fumarate.

An acyclic nucleoside phosphonate diester analogue of adenosine monophosphate. Tenofovir DF requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate. Tenofovir diphosphate inhibits the activity of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) by competing with the natural substrate deoxyadenosine 5'-triphosphate and, after incorporation into deoxyribonucleic acid (DNA), by DNA chain termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases α, β, and mitochondrial DNA polymerase γ.

Emtricitabine.

A synthetic nucleoside analogue of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate. Emtricitabine 5'-triphosphate inhibits the activity of the HIV-1 RT by competing with the natural substrate deoxycytidine 5'-triphosphate by being incorporated into nascent viral DNA which results in chain termination. Emtricitabine 5'-triphosphate is a weak inhibitor of mammalian DNA polymerases α, β, ε 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 RT. RPV does not inhibit the human cellular DNA polymerase α, β, and mitochondrial DNA polymerase γ.

Antiviral activity in vitro.

Tenofovir disoproxil fumarate, emtricitabine and rilpivirine.

The triple combination of tenofovir, FTC and RPV demonstrated synergistic antiviral activity in cell culture.

Tenofovir disoproxil fumarate.

The in vitro antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, primary monocyte/ macrophage cells and peripheral blood lymphocytes. The IC50 (50% inhibitory concentration) values for tenofovir were in the range of 0.04 to 8.5 micromolar. In drug combination studies of tenofovir with nucleoside analogue reverse transcriptase inhibitors (NRTIs) (abacavir, didanosine, lamivudine (3TC), stavudine (d4T), zalcitabine, zidovudine (AZT)), NNRTIs (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir, saquinavir), additive to synergistic effects were observed. Tenofovir displayed antiviral activity in vitro against HIV-1 clades A, B, C, D, E, F, G and O (IC50 values ranged from 0.5 to 2.2 micromolar). In addition, tenofovir has also been shown to be active in vitro against HIV-2, with similar potency as observed against HIV-1.

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 micromolar (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 (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 micromolar) and showed strain specific activity against HIV-2 (IC50 values ranged from 0.007 to 1.5 micromolar).

Rilpivirine.

RPV exhibited activity against laboratory strains of wild type HIV-1 in an acutely infected T cell line with a median EC50 value for HIV-1/IIIB of 0.73 nanomolar. Although RPV demonstrated limited in vitro activity against HIV-2 with EC50 values ranging from 2510 to 10830 nanomolar, 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 nanomolar and group O primary isolates with EC50 values ranging from 2.88 to 8.45 nanomolar. RPV showed additive to synergistic antiviral activity in combination with the N(t)RTIs abacavir, didanosine, FTC, 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.

Drug resistance.

In cell culture.

Tenofovir disoproxil fumarate.

HIV-1 isolates with reduced susceptibility to tenofovir have been selected in vitro. These viruses expressed a K65R mutation in reverse transcriptase and showed a 2 to 4-fold reduction in susceptibility to tenofovir. In addition, a K70E substitution in HIV-1 reverse transcriptase has been selected by tenofovir and results in low level reduced susceptibility to abacavir, FTC, tenofovir and lamivudine.

Emtricitabine.

FTC resistant isolates of HIV 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 reverse transcriptase 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.
In clinical studies: treatment naïve patients.

Studies C209 and C215: tenofovir disoproxil fumarate, emtricitabine, and rilpivirine.

In the cumulative week 96 pooled resistance analysis for patients receiving RPV in combination with FTC/ tenofovir DF in clinical trials C209 and 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/ tenofovir DF, 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 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.
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 Eviplera: K65R, K70E, K101E, K101P, E138A, E138G, E138K, E138Q, E138R, V179L, Y181C, Y181I, Y181V, M184I, M184V, Y188L, H221Y, F227C, M230I, M230L and the combination of L1001 + K103N.
In clinical studies: virologically suppressed patients.

Study GS-US-264-0106.

Of the 469 Eviplera treated patients (317 patients who switched to Eviplera at baseline and 152 patients who switched at week 24), a total of 7 patients were analysed for resistance development and all had genotypic and phenotypic data available. Through week 24, two patients who switched to Eviplera at baseline (2 of 317 patients, 0.6%) developed genotypic and/or phenotypic resistance to study drugs. After week 24, 2 additional patients in the Eviplera arm developed resistance by week 48 (total of 4 of 469 patients, 0.9%). The most common emergent resistance mutations in Eviplera treated patients were M184V/I and E138K in reverse transcriptase. All patients remained susceptible to tenofovir.
Of the 24 patients treated with Eviplera that had the NNRTI associated K103N substitution pre-existing at baseline, 17 of 18 patients in the Eviplera arm and 5 of 6 patients in the SBR arm maintained virologic suppression after switching to Eviplera through 48 weeks and 24 weeks of treatment, respectively.

Study GS-US-264-0111.

Through week 48, no emergent resistance developed among patients that switched to Eviplera from Atripla (0 of 49 patients).

Cross resistance.

Tenofovir disoproxil fumarate, emtricitabine and rilpivirine.

No significant cross resistance has been demonstrated between RPV resistant HIV-1 variants and FTC or tenofovir, or between FTC or tenofovir resistant variants and RPV.
In clinical studies: treatment naïve patients. In the 96 week pooled resistance analysis of the HIV-1 from patients receiving RPV in combination with tenofovir DF/ FTC in clinical trials C209 and C215 (see Section 5.1 Pharmacodynamic Properties, Clinical trials), 66 patients had available HIV-1 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 DF. Among these patients, 39 had HIV-1 with reduced susceptibility to 3TC, 31 with reduced susceptibility to etravirine, 28 with reduced susceptibility to efavirenz, and 13 with reduced susceptibility to nevirapine. 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 clinical studies: virologically suppressed 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 reduced susceptibility to FTC also had reduced susceptibility to lamivudine. These patients with reduced susceptibility to RPV developed phenotypic cross resistance to the other NNRTIs delavirdine, efavirenz, and nevirapine, but remained susceptible to etravirine in 1 of 2 cases.

Tenofovir disoproxil fumarate.

The K65R and K70E mutations selected by tenofovir are also selected in some HIV-1 infected patients treated with abacavir, didanosine, or zalcitabine. HIV isolates with this mutation result in reduced susceptibility to abacavir, didanosine, FTC and 3TC. Therefore, cross resistance among these drugs may occur in patients whose virus harbours the K65R mutation. Patients with HIV-1 expressing three or more thymidine analogue associated mutations (TAMs) that included either the M41L or L210W reverse transcriptase mutation showed reduced susceptibility to tenofovir DF. Multinucleoside resistant HIV-1 with a T69S double insertion mutation in the reverse transcriptase showed reduced susceptibility to tenofovir. HIV-1 containing the substitutions associated with NNRTI resistance K103N and Y181C, or RPV associated substitutions were susceptible to tenofovir.

Emtricitabine.

FTC resistant isolates (M184V/I) were cross resistant to 3TC and zalcitabine but retained sensitivity to abacavir, didanosine, d4T, tenofovir, AZT, and NNRTIs (delavirdine, efavirenz, and nevirapine). HIV-1 isolates containing the K65R mutation, selected in vivo by abacavir, didanosine, tenofovir, and zalcitabine, demonstrated reduced susceptibility to inhibition by FTC. Viruses harbouring mutations conferring reduced susceptibility to d4T and AZT (M41L, D67N, K70R, L210W, T215Y/F, K219Q/E) or didanosine (L74V) remained sensitive to FTC. HIV-1 containing the substitutions associated with NNRTI resistance K103N or RPV associated substitutions were susceptible to FTC.

Rilpivirine.

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, Y181I and Y181V. 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.

Effects on electrocardiogram.

The effect of RPV at the recommended dose of 25 mg once daily on the QTcF interval was evaluated in a randomised, 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.

Clinical trials.

In treatment naïve HIV-1 infected adults.

Studies C209 and C215.

The data available to support the efficacy of Eviplera tablets include the available data for each individual agent, the data from clinical studies C209 and C215 where the three agents were used concurrently, and the demonstration of bioequivalence between Eviplera tablets and the three individual agents coadministered under fed conditions. No new clinical efficacy or safety studies have been conducted with the Eviplera tablet.
The efficacy of Eviplera is analysed at week 48 and week 96 from two randomised, double-blind, controlled studies C209 and 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 randomised 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 tenofovir DF/ FTC. In C215 (N = 678), the BR consisted of 2 NRTIs: tenofovir DF/ FTC (60%, N = 406) or lamivudine/ zidovudine (30%, N = 204) or abacavir plus lamivudine (10%, N = 68).
For patients who received tenofovir DF/ FTC (N = 1096) in C209 and C215, the mean age was 37 years (range 18 to 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 to 888) and 31% had CD4+ cell counts < 200 cells/mm3. The median baseline plasma HIV-1 RNA was 5 log10 copies/mL (range 2 to 7).
At week 48, RPV administered in combination with tenofovir DF/ FTC has been shown to be noninferior (with 12% noninferiority margin) in achieving the primary efficacy outcome of HIV-1 RNA < 50 copies/mL when compared to efavirenz administered in combination with tenofovir DF/ FTC. The response rate (HIV-1 RNA < 50 copies/mL) at week 96 was comparable between the RPV arm and the efavirenz arm. The incidence of virologic failure was higher in the RPV arm than the efavirenz arm at week 96; however, most of the virologic failures occurred within the first 48 weeks of treatment. The virological 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. Low rates of new virologic failure, similar between the treatment arms, were observed between the week 48 and the week 96 analysis (see Table 6). Discontinuations due to adverse events were higher in the efavirenz arm at week 96 than the RPV arm.
Patients were stratified by baseline HIV-1 RNA. Fifty percent of patients had baseline viral loads ≤ 100,000 copies/mL, 39% of patients had baseline viral load between 100,000 copies/mL to 500,000 copies/mL and 11% of patients had baseline viral load > 500,000 copies/mL. A subgroup analysis of the virologic response (< 50 HIV-1 RNA copies/mL) at week 48 and week 96 and virologic failure by baseline viral load (pooled data from the two phase 3 clinical studies C209 and C215, for patients receiving the tenofovir DF/ FTC background regimen) is presented in Table 6.
Virologic outcomes were comparable in males and females in studies C209 and C215.
Based on the pooled data from the C209 and C215 trials the mean CD4 cell count increase from baseline at week 96 was 226 cells/mm3 for RPV plus tenofovir DF/ FTC treated patients and 222 cells/mm3 for efavirenz plus tenofovir DF/ FTC treated patients.
In virologically suppressed HIV-1 infected patients.

Study GS-US-264-0106.

The efficacy and safety of switching from a ritonavir boosted protease inhibitor in combination with two NRTIs to Eviplera was evaluated in a randomised, open label study in virologically suppressed HIV-1 infected adults. Patients had to be on either their first or second antiretroviral regimen with no history of virologic failure, have no current or past history of resistance to any of the three components of Eviplera, and must have been stably suppressed (HIV-1 RNA < 50 copies/mL) for at least 6 months prior to screening. Patients were randomised in a 2:1 ratio to either switch to Eviplera at baseline (Eviplera, N = 317), or stay on their baseline antiretroviral regimen for 24 weeks (SBR, N = 159) before switching to Eviplera for an additional 24 weeks (N = 152). Patients had a mean age of 42 years (range 19-73), 88% were male, 77% were white, 17% were black, and 17% were Hispanic/ Latino. The mean baseline CD4 cell count was 584 cells/mm3 (range 42-1484). Randomisation was stratified by use of tenofovir DF and/or lopinavir/ ritonavir in the baseline regimen.
Treatment outcomes through 24 weeks are presented in Table 7. Switching to Eviplera was noninferior in maintaining HIV-1 RNA < 50 copies/mL when compared to patients who stayed on a ritonavir boosted protease inhibitor in combination with two NRTIs (treatment difference (95% CI): + 3.8% (-1.6% to 9.1%)).
The mean CD4+ cell count increase from baseline to week 24 was 10 cells/mm3 for the Eviplera arm and 22 cells/mm3 for the SBR arm. The difference in median CD4+ cell count change between the Eviplera arm and the SBR arm was not statistically significant at week 24 (p = 0.28).
Among patients in the SBR arm who maintained their baseline regimen for 24 weeks and then switched to Eviplera, 92% (140/152) of patients had HIV-1 RNA < 50 copies/mL after 24 weeks of Eviplera, consistent with the week 24 results for patients who switched to Eviplera at baseline.
At week 48, 89% (283/317) of patients randomised to switch to Eviplera at baseline (Eviplera) had HIV-1 RNA < 50 copies/mL, 3% (8/317) were considered virologic failures (HIV RNA ≥ 50 copies/mL), and 8% (26/317) did not have data available in the week 48 window. Of the 26 patients without data available at week 48, 7 patients discontinued due to adverse event or death, 16 patients discontinued for other reasons, and 3 patients were missing data but remained on study drug. The median CD4+ cell count change at week 48 was +17 cells/mm3 in the on-treatment analysis.

Study GS-US-264-0111.

The efficacy, safety, and pharmacokinetics of switching from Atripla to Eviplera were evaluated in an open label study in virologically suppressed HIV-1 infected adults. Patients had to have previously only received Atripla as their first antiretroviral regimen for at least three months, and wished to switch regimens due to efavirenz intolerance. Patients had to be stably suppressed for at least 8 weeks prior to study entry, have no current or past history of resistance to any of the three components of Eviplera, and have HIV-1 RNA < 50 copies/mL at screening. The majority of subjects were male (92%), with an overall mean age of 38 years (range 24-57 years); most were white (82%) or black (12%) and non-Hispanic/ Latino (80%). The mean baseline CD4 cell count was 656 cells/mm3 (range 188 to 1528 cells/mm3).
Patients were switched from Atripla to Eviplera without a washout period. Among 49 patients who received at least one dose of Eviplera, 100% of patients remained suppressed (HIV-1 RNA < 50 copies/mL) at week 12 and week 24. At week 48, 94% (46/49) of patients remained suppressed, and 4% (2/49) were considered virologic failures (HIV-1 RNA ≥ 50 copies/mL). One patient (2%) did not have data available in the week 48 window; study drug was discontinued due to a protocol violation (i.e. reason other than AE or death) and the last available HIV-1 RNA was < 50 copies/mL.

5.2 Pharmacokinetic Properties

One Eviplera tablet is bioequivalent to one tenofovir DF 300 mg tablet plus one FTC 200 mg capsule plus one RPV 25 mg tablet following single-dose administration to fed healthy subjects (N = 34).
The separate pharmaceutical forms of tenofovir DF, FTC and RPV were used to determine the pharmacokinetics of tenofovir DF, FTC and RPV in HIV-1 infected patients.

Tenofovir disoproxil fumarate.

The pharmacokinetic properties of tenofovir DF are summarized in Table 1. Following oral administration of tenofovir DF, maximum tenofovir serum concentrations are achieved in 1.0 ± 0.4 hour. In vitro binding of tenofovir to human plasma proteins is < 0.7% and is independent of concentration over the range of 0.01 to 25 microgram/mL. Approximately 70 to 80% of the intravenous dose of tenofovir is recovered as unchanged drug in the urine. Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion. Following a single oral dose of tenofovir DF, the terminal elimination half-life of tenofovir is approximately 17 hours.

Emtricitabine.

The pharmacokinetic properties of FTC are summarized in Table 8. Following oral administration of FTC 200 mg capsules, FTC is rapidly absorbed with peak plasma concentrations occurring at 1 to 2 hours postdose. In vitro binding of FTC to human plasma proteins is < 4% and is independent of concentration over the range of 0.02 to 200 microgram/mL. Following administration of radiolabelled FTC approximately 86% is recovered in the urine and 13% is recovered as metabolites. The metabolites of FTC include 3'-sulfoxide diastereomers and their glucuronic acid conjugate. FTC is eliminated by a combination of glomerular filtration and active tubular secretion. Following a single oral dose of 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. 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 mean C0h and AUC24h values in HIV-1 infected patients were 0.080 ± 0.037 microgram/mL and 2.40 ± 1.03 microgram.hr/mL, respectively. The absolute bioavailability of RPV is unknown. RPV is approximately 99.7% bound to plasma proteins in vitro, primarily to albumin. In vitro experiments indicate that RPV primarily undergoes oxidative metabolism mediated by the cytochrome CYP3A 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.

Effect of food.

The administration of Eviplera to healthy adult subjects with either a light meal or a standard meal resulted in increased exposures of RPV and tenofovir relative to fasting conditions. The Cmax and AUC of RPV increased by 34% and 9% (light meal) and 26% and 16% (standard meal), respectively. The Cmax and AUC for tenofovir increased by 12% and 28% (light meal) and 32% and 38% (standard meal), respectively. FTC exposures were not affected by food. Eviplera must be administered with food to ensure optimal absorption.

Additional information on special populations.

Age, gender and ethnicity. Pharmacokinetic studies with Eviplera have not been fully evaluated in children (< 18 years) or in the elderly (over 65 years) (see Section 4.4 Special Warnings and Precautions for Use).
Population pharmacokinetic analysis in HIV-1 infected patients showed that RPV pharmacokinetics are not different across the age range (18 to 78 years) evaluated.
No clinically important pharmacokinetic differences due to gender or ethnicity have been identified.
Patients with impaired renal function. Eviplera is not recommended for patients with moderate or severe renal impairment (CrCl < 50 mL/min).

Tenofovir disoproxil fumarate and emtricitabine.

Patients with moderate or severe renal impairment require dose interval adjustment of FTC and tenofovir DF that cannot be achieved with the combination tablet (see Section 4.4 Special Warnings and Precautions for Use).

Rilpivirine.

The pharmacokinetics of RPV have 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 haemodialysis or peritoneal dialysis.
Patients with hepatic impairment. The pharmacokinetics of Eviplera have not been studied in patients with hepatic impairment.

Tenofovir disoproxil fumarate and emtricitabine.

The pharmacokinetics of tenofovir following a 300 mg dose of tenofovir DF have been studied in non-HIV infected patients with moderate to severe hepatic impairment. There were no substantial alterations in tenofovir pharmacokinetics in patients with hepatic impairment compared with unimpaired patients. The pharmacokinetics of FTC have not been studied in patients with moderate to severe 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 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).
Hepatitis B and/or hepatitis C virus coinfection. Pharmacokinetics of tenofovir DF and FTC have not been fully evaluated in hepatitis B and/or C coinfected patients. Population pharmacokinetic analysis indicated that hepatitis B and/or C virus coinfection had no clinically relevant effect on the exposure to RPV.

Switching from an efavirenz containing regimen.

The pharmacokinetics of RPV and efavirenz were evaluated in 49 virologically suppressed, HIV-1 infected patients following the switch from an efavirenz containing regimen to Eviplera (study GS-US-264-0111). Consistent with the established half-life for efavirenz, efavirenz concentrations remained above its protein binding adjusted IC90 (10 nanogram/mL) for 4 weeks postswitch. Despite the expected CYP3A induction by efavirenz, RPV mean trough concentrations achieved levels that were in the range of historical data starting 2 weeks postswitch. The efficacy data from study GS-US-264-0111 (see Section 5.1 Pharmacodynamic Properties, Clinical trials) indicates that the brief period of lower RPV exposure following the switch from an efavirenz containing regimen does not impact antiviral efficacy. No dose adjustment is required following the switch from an efavirenz containing regimen.

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 9). 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 intra-individual 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.

5.3 Preclinical Safety Data

Genotoxicity.

No genotoxicity studies have been conducted with tenofovir DF, FTC and RPV in combination.
Tenofovir disoproxil fumarate was mutagenic in an in vitro mouse L5178Y lymphoma cell assay (tk locus) and in an ex vivo assay for unscheduled DNA synthesis in rat hepatocytes, but it was negative in in vitro bacterial assays for gene mutation and an in vivo mouse micronucleus test for chromosomal damage.
Emtricitabine was not mutagenic in bacteria or mouse lymphoma cell assays in vitro 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. RPV did not induce chromosomal damage in the in vivo micronucleus test in mice.

Carcinogenicity.

No carcinogenicity studies have been conducted with tenofovir DF, FTC and RPV in combination.

Tenofovir disoproxil fumarate.

In a long-term carcinogenicity study conducted in mice with tenofovir DF there was a low incidence of duodenal tumours with the highest dose of 600 mg/kg/day. These were associated with a high incidence of duodenal mucosal hyperplasia, which was also observed with a dose of 300 mg/kg/day. These findings may be related to high local drug concentrations in the gastrointestinal tract, likely to result in much higher exposure margins than that based on the AUC. At therapeutic doses the risk of these duodenal effects occurring in humans is likely to be low. The systemic drug exposure (AUC) with the 600 mg/kg/day dose was approximately 15 times the human exposure at the therapeutic dose of 300 mg/day. No tumourigenic response was observed in rats treated with doses of up to 300 mg/kg/day (5 times the human systemic exposure at the therapeutic dose based on AUC).

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 1,500 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 tumors 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).

Animal toxicology.

Tenofovir disoproxil fumarate.

Tenofovir and tenofovir DF administered in toxicology studies to rats, dogs and monkeys at exposures (based on AUCs) greater than or equal to 6-fold those observed in humans caused bone toxicity. In monkeys the bone toxicity was diagnosed as osteomalacia. Osteomalacia observed in monkeys appeared to be reversible upon dose reduction or discontinuation of tenofovir. In rats and dogs, the bone toxicity manifested as reduced bone mineral density. The mechanism(s) underlying bone toxicity is unknown.
Evidence of renal toxicity was noted in 4 animal species. Increases in serum creatinine, BUN, glycosuria, proteinuria, phosphaturia and/or calciuria and decreases in serum phosphate were observed to varying degrees in these animals. These toxicities were noted at exposures (based on AUCs) 2 to 20 times higher than those observed in humans. The relationship of the renal abnormalities, particularly the phosphaturia, to the bone toxicity is not known.

6 Pharmaceutical Particulars

6.1 List of Excipients

Eviplera tablets contain the following ingredients as excipients:

Tablet core.

Pregelatinized starch, lactose, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, povidone, polysorbate 20.

Film coating.

Macrogol 3350, hypromellose, lactose, glycerol triacetate, titanium dioxide, iron oxide red, indigo carmine aluminium lake, sunset yellow FCF aluminium lake.

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

Eviplera should be stored below 30°C.

6.5 Nature and Contents of Container

Eviplera is supplied in high density polyethylene (HDPE) bottles containing 30 tablets and a desiccant (silica gel canister or sachet), 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.

6.7 Physicochemical Properties

Chemical structure.

Tenofovir disoproxil fumarate.

Tenofovir DF is a fumaric acid salt of the bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir. The chemical name of tenofovir DF is 9-[(R)-2[[bis [[(isopropoxycarbonyl)oxy] methoxy]phosphinyl]methoxy] propyl]adenine fumarate (1:1). It has a molecular formula of C19H30N5O10P.C4H4O4 and a molecular weight of 635.52. It has the following structural formula:

Emtricitabine.

The chemical name of FTC is 5-fluoro-1-(2R,5S)-[2-(hydroxymethyl)- 1,3-oxathiolan-5-yl]cytosine. FTC is the (-) enantiomer of a thio analog of cytidine, which differs from other cytidine analogs in that it has a fluorine in the 5-position. It has a molecular formula of C8H10FN3O3S and a molecular weight of 247.24. It has the following structural formula:

Rilpivirine.

RPV is present in Eviplera tablets as the hydrochloride salt. The chemical name for rilpivirine hydrochloride is 4-[[4-[[4-[(E)-2-cyanoethenyl]- 2,6-dimethylphenyl]amino]- 2-pyrimidinyl]amino]benzonitrile monohydrochloride. Its molecular formula is C22H18N6.HCl and its molecular weight is 402.88. Rilpivirine hydrochloride has the following structural formula:

CAS number.

Tenofovir DF CAS registry number: 202138-50-9.
FTC CAS registry number: 143491-57-0.
RPV CAS registry number: 700361-47-3.
Tenofovir DF has a solubility of 13.4 mg/mL in water at 25°C. The partition coefficient (log p) for tenofovir disoproxil is 1.25 and the pKa is 3.75.
FTC has 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.
RPV hydrochloride is practically insoluble in water and over a wide pH range.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes