Consumer medicine information

Tenofovir Disoproxil/Emtricitabine/Efavirenz Viatris 300/200/600

Tenofovir disoproxil maleate; Emtricitabine; Efavirenz

BRAND INFORMATION

Brand name

Tenofovir Disoproxil/Emtricitabine/Efavirenz Viatris 300/200/600

Active ingredient

Tenofovir disoproxil maleate; Emtricitabine; Efavirenz

Schedule

SUMMARY CMI

TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600

Consumer Medicine Information (CMI) summary

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

1. Why am I using TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600?

TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600 contains the active ingredient tenofovir disoproxil maleate, emtricitabine and efavirenz. This medicine is used to treat Human Immunodeficiency Virus (HIV-1) infection in adults. See Section 1. Why am I using TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600? in the full CMI.

2. What should I know before I use TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600?

Do not use if you have ever had an allergic reaction to tenofovir disoproxil maleate, emtricitabine and efavirenz or any of the ingredients listed at the end of the CMI.
Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.
For more information, see Section 2. What should I know before I use TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with this medicine and affect how it works. A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600?

The usual dose of TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600 is one tablet once a day.

Details are in Section 4. How do I use TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600? in the fullCMI.

5. What should I know while using TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600?

Things you should do	Remind any doctor or pharmacist you visit that you are using this medicine. When your medicine supply starts to run low, get more from your doctor or pharmacy.
Things you should not do	Do not stop using this medicine suddenly. Avoid doing things that can spread HIV infection.
Driving or using machines	Be careful driving or operating machinery until you know how this medicine affects you. If you are dizzy, have trouble concentrating, or are drowsy, avoid activities that may be dangerous.
Drinking alcohol	Taking this medicine with alcohol or other medicines causing similar side effects such as drowsiness, may increase those side effects.
Looking after your medicine	Keep this medicine and all other medications out of reach of children. Store this medicine in a cool, dry place where it stays below 25°C.

For more information, see Section 5. What should I know while using TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600? in the full CMI.

6. Are there any side effects?

The common side effects are dizziness, headache, trouble sleeping, drowsiness, trouble concentrating, unusual dreams, rash, tiredness, upset stomach, vomiting, gas and diarrhoea. Tell your doctor right away if any of these side effects bother you. For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

FULL CMI

TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600

Active ingredients: tenofovir disoproxil maleate, emtricitabine, efavirenz

Consumer Medicine Information (CMI)

This leaflet provides important information about using TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600.

Where to find information in this leaflet:

1. Why am I using TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600?
2. What should I know before I use TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600?
3. What if I am taking other medicines?
4. How do I use TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600?
5. What should I know while using TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600?
6. Are there any side effects?
7. Product details

1. Why am I using TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600?

TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600 contains the active ingredients tenofovir disoproxil maleate, emtricitabine and efavirenz. These are combined in one tablet to help control Human Immunodeficiency Virus (HIV-1) infection.

Tenofovir disoproxil and emtricitabine belong to a group of antiviral medicines known as nucleoside and nucleotide reverse transcriptase inhibitors (NRTI). Efavirenz belongs to a group of antiviral medicines known as non-nucleoside reverse transcriptase inhibitors (NNRTI).

TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600 is used to treat HIV-1 infection in adults. This medicine can be taken alone or in combination with other anti-HIV medicines.

Do not take TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600 if you are under the age of 18 years.

Do not take TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600 if you are over the age of 65 before discussing with your doctor.

How TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600 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.

TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600 helps block HIV-1 reverse transcriptase, a viral chemical in your body (enzyme) that is needed for HIV-1 to multiply. TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600 lowers the amount of HIV-1 in the blood (viral load). TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600 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).

TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600 does not cure HIV-1 infection or AIDS.

The long-term effects of TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600 are not known at this time. People taking TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600 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 weak.

Some of these conditions are:

pneumonia,
herpes virus infections, and
Mycobacterium avium complex (MAC) infections.

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 TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600, it is important you remain under the care of a hospital or doctor who specialises in the treatment of HIV-1 infection.

TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600 has not been shown to lower your chance of passing HIV to others through sexual contact, sharing needles, or being exposed to your blood.

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.

2. What should I know before I use TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600?

Warnings

Do not use TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600 if:

you are allergic to tenofovir disoproxil maleate, tenofovir disoproxil fumarate, emtricitabine, efavirenz or any of the ingredients listed at the end of this leaflet.
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.
Always check the ingredients to make sure you can use this medicine.
Do not use TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600 for a condition for which it was not prescribed.
Do not share TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600 with other people even if they have the same symptoms that you have. It may harm them.

Check with your doctor if you have:

kidney problems or are undergoing kidney dialysis treatment
bone problems
liver problems, including Hepatitis B Virus (HBV) infection
HIV infection. Your doctor may want to do tests to check your liver while you take TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600
ever had mental illness or are using recreational drugs or alcohol
ever had seizures or are taking medicine for seizures
ever had a serious allergic drug reaction involving the skin (e.g. Stevens Johnson syndrome)
any medical conditions.

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

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Women taking TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600 should not become pregnant. Serious birth defects have been seen in the babies of animals and women treated with efavirenz (a component of TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600) during pregnancy. It is not known whether efavirenz caused these defects.

Women of child-bearing age receiving treatment with TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600 should not rely only on hormone-based birth control, such as pills, injections or implants.

TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600 may make these contraceptives ineffective. Women must use a reliable form or barrier contraception (such as a condom or diaphragm), even if they also use other methods of birth control.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

Do not breast-feed if you are taking TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600.

It is recommended that nursing mothers do not breast-feed during treatment with TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600. In general, women infected with HIV should not breast-feed their infants in order to avoid transmission of HIV to their newborn infant.

The active substances in this medicine (tenofovir and emtricitabine and efavirenz) have been found in breast milk at low concentrations.

Do not breast-feed if you have HIV or HBV.

If you are a woman who has or will have a baby, talk with your doctor or pharmacist about the best way to feed your baby. If your baby does not already have HIV or HBV, there is a chance that the baby can get HIV or HBV through breast-feeding. In general, women infected with HIV should not breast-feed their infants in order to avoid transmission of HIV to their newborn infant.

3. What if I am taking other medicines?

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

TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600 may change the effect of other medicines, including the ones for HIV-1 and may cause serious side effects.

Your doctor may change your other medicines or change their doses. Other medicines, including herbal products may affect TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600.

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

Do not take any other medicines, including prescription or non-prescription medicines and herbal products, without checking with your doctor.

The following medicines may cause serious or life-threatening side effects when taken with TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600.

Do not take elbasvir/grazoprevir with TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600.

It may lose its effect and reduce your response to elbasvir/grazoprevir.

Do not take St. Johns wort (Hypericum perforatum) or products containing St. Johns wort with TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600.

St. John's wort is a herbal product sold as a dietary supplement. Talk to your doctor or pharmacist if you are taking or are planning to take St. John's wort. Taking St. John's wort may decrease TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600 levels and lead to increased viral load and possible resistance to TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600 or cross-resistance to other anti-HIV drugs.

Voriconazole should not be taken with TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600.

It may lose its effect or may increase the chance of having side effects from TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600.

Do not take TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600 if you are already taking any other medicines that contain the same active ingredients.

Do not take TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600 if you are taking other medicines that contain:

Efavirenz
Lamivudine

Do not take TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600 to treat your HIV infection if you are also taking adefovir dipivoxil.

It is also important to tell your doctor if you are taking any of the following:

Bepridil, cisapride (e.g. Prepulsid), midazolam (e.g. Hypnovel), pimozide (e.g. Orap), triazolam (e.g. Halcion), ergot medications (e.g. Cafergot).
Saquinavir (e.g. Invirase), clarithromycin (e.g. Klacid); these medicines may need to be replaced with another medicine when taken with TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600.
Calcium channel blockers such as diltiazem (e.g. Vasocardol) and others; indinavir (e.g. Crixivan); methadone, rifabutin (e.g. Mycobutin), rifampin (e.g. Rifadin).
Lipid-lowering medicines such as atorvastatin (e.g. Lipitor), pravastatin (e.g. Pravachol) or simvastatin (e.g. Zocor).
Antidepressant medicines such as sertraline (e.g. Zoloft) or bupropion (e.g. Zyban); immunosuppressant medicines cyclosporine (e.g. Neoral), tacrolimus (e.g. Prograf) or sirolimus (e.g. Rapamune); these medicines may need to have their dose changed when taken with TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600.
Didanosine (also known as ddI or Videx); tenofovir disoproxil (a component of TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600) may increase the amount of didanosine in your blood, which could result in more side effects. You may need to be monitored more carefully if you are taking didanosine and TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600 together. Also, the dose of didanosine may need to be changed.
Atazanavir sulphate (e.g. Reyataz) or lopinavir/ritonavir (e.g. Kaletra); these medicines may increase the amount of tenofovir disoproxil (a component of TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600) in your blood which could result in more side effects. Atazanavir sulphate is not recommended with TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600. You may need to be monitored more carefully if you are taking TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600 and lopinavir/ritonavir together. Also, the dose of lopinavir/ritonavir may need to be changed.
Other HIV medications including amprenavir (e.g. Agenerase), ritonavir (e.g. Norvir), fosamprenavir calcium (e.g. Telzir), raltegravir (e.g. Isentress), ritonavir or maraviroc (e.g. Celsentri), Also, the dose of maraviroc may need to be changed.
Medicine for seizures such as phenytoin (e.g. Dilantin), carbamazepine (e.g. Tegretol) or phenobarbital (phenobarbitone); your doctor may want to switch you to another medicine or check drug levels in your blood from time to time.
Antifungal medications such as itraconazole (e.g. Sporanox) and posaconazole (e.g. Noxafil); these medicines may need to be replaced with another medicine when taken with TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600.
Hepatitis C antiviral agents such as ledipasvir/sofosbuvir (e.g. HARVONI), or sofosbuvir/velpatasvir (e.g. EPCLUSA), sofosbuvir/velpatasvir/voxilapreir (e.g. VOSEVI), simeprevir (e.g Olysio), bocepravir (e.g. Victrelis) and telaprevir (e.g. Incivek).
Antimalarial Agents such as artemether/lumefantrine (Coartem/Riamet).

These are not all the medicines that may cause problems if you take TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600. Be sure to tell your healthcare provider about all medicines that you take.

It is a good idea to keep a complete list of all the medicines that you take.

Make a new list when medicines are added or stopped. Give copies of this list to your doctor or pharmacist every time you visit your doctor or fill a prescription.

4. How do I use TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600?

How much to take

The usual dose of TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600 is one tablet once a day.
Take the exact amount of TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600 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.
Stay under a doctor's care when taking TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600.
Do not change your treatment or stop treatment without first talking with your doctor.

When to take TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600

Taking TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600 at bedtime may make some side effects less bothersome.

How to take TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600

Always take TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600 on an empty stomach.
Swallow TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600 with water.

If you forget to use TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600

It is important that you do not miss any doses of TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600.

If you miss a dose of TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600, take the missed dose as soon as possible and then take your next scheduled dose at its regular time.

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

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

If you think that you have used too much TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600, you may need urgent medical attention.

You should immediately:

phone the Poisons Information Centre (Australia telephone 13 11 26) for advice, or
contact your doctor, or
go to the Emergency Department at your nearest hospital.

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

5. What should I know while using TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600?

Things you should do

Tell your doctor or pharmacist that you are taking TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600 if you are about to be started on any other medicines.

Your doses may need adjustment.

When your TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600 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 TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600 and become harder to treat.

Things you should not do

Avoid doing things that can spread HIV infection since TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600 does not stop you from passing the HIV infection to others.

Do not take TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600 if the packaging is torn or shows signs of tampering.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600 affects you.

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

Drinking alcohol

Tell your doctor if you drink alcohol.

Taking TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600 with alcohol or other medicines causing similar side effects as TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600, such as drowsiness, may increase those side effects.

Looking after your medicine

Keep your TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600 tablets in the bottle with the cap tightly closed until you take them.

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

Store it in a cool dry place below 25°C away from moisture, heat or sunlight; for example, do not store it:

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

Keep it where young children cannot reach it.

A locked cupboard at least one-and-a half metres above the ground is a good place to store them.

Getting rid of any unwanted medicine

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

Do not use this medicine after the expiry date.

6. Are there any side effects?

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

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

Common side effects

Common side effects

What to do

These side effects may be reduced if you take TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600 at bedtime on an empty stomach. They also tend to go away after you have taken the medicine for a few weeks. If you have these common side effects, such as dizziness, it does not mean that you will also have serious psychiatric problems, such as severe depression, strange thoughts or angry behaviour.
It is possible that these symptoms may be more severe if TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600 is used with alcohol or mood altering (recreational) drugs.

dizziness
headache
trouble sleeping
drowsiness
trouble concentrating
unusual dreams

Other common side effects:

Rash. Rashes usually go away without any change in treatment. In a small number of patients, rash may be serious. If you develop a rash, call your doctor immediately.
Tiredness
Upset stomach
Vomiting
Gas and diarrhoea

Speak to your doctor if you have any of these common side effects and they worry you.

Other possible side effects:

Changes in body fat develop in some people receiving anti HIV-1 therapy. These changes may include an increased amount of fat in the upper back and neck ('buffalo hump'), in the breasts and around the trunk. Loss of fat from the legs, arms and face may also happen. The cause and long-term health effects of these fat changes are not known.

Sleeping problems (including difficulty to fall asleep or sleepiness).

Skin discolouration (small spots or freckles) may also occur with TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600.

Serious side effects

Serious side effects

What to do

Lactic Acidosis (build-up of an acid in the blood):

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

Serious Liver Problems
(hepatotoxicity):

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

These side effects may be due to a condition called hepatotoxicity with liver enlargement (hepatomegaly) and fat deposits in the liver (steatosis) which sometimes occurs in patients taking anti HIV-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 TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600, for a long time.
Pancreatitis:

Severe stomach pain or cramps
Nausea
Vomiting

Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Hepatic Flares

If you have HIV-1 infection and hepatitis B virus (HBV) infection you should not stop your TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600 treatment without first discussing this with your doctor, as some patients have had blood tests or symptoms indicating a worsening of their hepatitis ("hepatic flare") after stopping individual components (tenofovir disoproxil, and emtricitabine) of TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600.

You may require medical exams and blood tests for several months after stopping treatment. TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600 is not approved for the treatment of HBV, so you must discuss your HBV therapy with your doctor.

Serious Psychiatric Problems

A small number of patients may experience severe depression, strange thoughts, or angry behaviour while taking TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600.

Some patients have thoughts of suicide and a few have actually committed suicide.

These problems may occur more often in patients who have had mental illness.

Contact your doctor right away if you think you are having these psychiatric problems, so your doctor can decide if you should continue to take TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600.

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.

Changes in Bone Mineral Density (thinning bones)

It is not known whether long-term use of TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600 will cause damage to your bones. 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.

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 Tenofovir TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600 and tell your doctor IMMEDIATELY or go to the accident and emergency department at your nearest hospital.

Skin troubles such as lumpy skin rash or "hives"
Swelling of the face, lips, mouth or throat which may cause difficulty in swallowing or breathing
Wheezing, chest pain or tightness
Fainting

These are very serious side effects. If you have them, you may have a serious allergic reaction.

You may need urgent medical attention or hospitalisation. Hypersensitivity reactions are very rare.

Contact your doctor before stopping TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600 because of side effects or for any other reason.

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

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

Reporting side effects

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

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

7. Product details

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

What TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600 contains

Active ingredient (main ingredient)	tenofovir disoproxil maleate emtricitabine efavirenz
Other ingredients (inactive ingredients)	colloidal anhydrous silica croscarmellose sodium ferric oxide hyprolose lactose monohydrate magnesium stearate microcrystalline cellulose OPADRY II complete film coating system 85F540043 PINK sodium metabisulfite
Potential allergens	sugars as lactose traces of sulfites

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

What TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600 looks like

TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600 is capsule shaped and pink in colour. Each tablet is debossed with "M" on one side of the tablet and "TEE" on the other side. (AUST R 280721).

Who distributes TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600

Alphapharm Pty Ltd trading as Viatris
Level 1, 30 The Bond
30-34 Hickson Road
Millers Point NSW 2000
www.viatris.com.au
Phone: 1800 274 276

This leaflet was prepared in April 2024.

TENOFOVIR DISOPROXIL/EMTRICITABINE/EFAVIRENZ VIATRIS 300/200/600_cmi\Apr24/00

Published by MIMS June 2024

BRAND INFORMATION

Brand name

Tenofovir Disoproxil/Emtricitabine/Efavirenz Viatris 300/200/600

Active ingredient

Tenofovir disoproxil maleate; Emtricitabine; Efavirenz

Schedule

1 Name of Medicine

Tenofovir disoproxil maleate, emtricitabine and efavirenz.

2 Qualitative and Quantitative Composition

Each Tenofovir Disoproxil/Emtricitabine/Efavirenz Viatris 300/200/600 tablet contains 300 mg of tenofovir disoproxil maleate (equivalent to 245 mg of tenofovir disoproxil), 200 mg of emtricitabine and 600 mg of efavirenz.

Excipients with known effect.

Sugars as lactose and traces of sulfites.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Tenofovir Disoproxil/Emtricitabine/Efavirenz Viatris 300/200/600 tablets are capsule shaped, pink film-coated, biconvex, beveled edge tablets debossed with "M" on one side of the tablet and "TEE" on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Tenofovir Disoproxil/Emtricitabine/Efavirenz Viatris 300/200/600 is indicated for the treatment of HIV infected adults over the age of 18 years. This indication is based on analyses of plasma HIV-1 RNA levels and CD4 cell counts in controlled studies of Viread, Emtriva and Stocrin in treatment-naïve and treatment experienced adults.

4.2 Dose and Method of Administration

Adults.

The recommended dose of Tenofovir/Emtricitabine/Efavirenz is one tablet once daily taken orally on an empty stomach. Dosing at bedtime may improve the tolerability of nervous system symptoms.

Children and adolescents.

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

Elderly.

Tenofovir/Emtricitabine/Efavirenz should be administered with caution to elderly patients (see Section 4.4 Special Warnings and Precautions for Use).

Renal impairment.

Tenofovir/Emtricitabine/Efavirenz is not recommended for 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 disoproxil and emtricitabine that cannot be achieved with the combination tablet (see Section 4.4 Special Warnings and Precautions for Use).
The safety and efficacy of once daily dosing of tenofovir disoproxil with emtricitabine in patients with mild renal impairment (CrCl 50 to 80 mL/min), have been demonstrated in clinical studies. No dosage adjustment is recommended for patients with renal impairment who receive efavirenz. Therefore no dosage adjustment is required for Tenofovir/Emtricitabine/Efavirenz in patients with mild renal impairment.

Hepatic impairment.

Tenofovir/Emtricitabine/Efavirenz is not recommended for patients with moderate to severe hepatic impairment because of insufficient data to determine whether dose adjustment of efavirenz is necessary. Patients with mild hepatic impairment may be treated with Tenofovir/Emtricitabine/Efavirenz, however caution should be exercised in administering Tenofovir/Emtricitabine/Efavirenz to these patients (see Section 4.4 Special Warnings and Precautions for Use).
Where discontinuation of Tenofovir/Emtricitabine/Efavirenz is necessary due to one of the components, or where dose modification is necessary, separate preparations of tenofovir disoproxil, emtricitabine and efavirenz are available. Please refer to the product information for these products.
It is expected that tenofovir exposure will be approximately 35% lower following administration of Tenofovir/Emtricitabine/Efavirenz on an empty stomach as compared to the individual component tenofovir disoproxil when taken with food. Administration of Tenofovir/Emtricitabine/Efavirenz on an empty stomach may decrease tenofovir exposure and may lead to a decrease in the efficacy of Tenofovir/Emtricitabine/Efavirenz. Patients should therefore be monitored carefully to detect any sign of virological failure and/or emergence of resistance to tenofovir disoproxil.

4.3 Contraindications

Tenofovir/Emtricitabine/Efavirenz is contraindicated in patients with known hypersensitivity to any of the active substances or any other component of the tablets.
Tenofovir/Emtricitabine/Efavirenz should not be used with elbasvir/grazoprevir due to the expected significant decreases in plasma concentrations of elbasvir and grazoprevir. This effect is due to induction of CYP3A4 by efavirenz, and may result in loss of therapeutic effect of elbasvir/grazoprevir (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Tenofovir/Emtricitabine/Efavirenz should not be administered concurrently with voriconazole because efavirenz significantly decreases voriconazole plasma concentrations (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

St John's wort.

Tenofovir/Emtricitabine/Efavirenz should not be used with St. John's wort (Hypericum perforatum) or St. John's wort containing products since it is expected to result in reduced plasma concentrations of efavirenz.
This effect is due to an induction of CYP3A4 and may result in loss of therapeutic effect and development of resistance.

4.4 Special Warnings and Precautions for Use

Tenofovir/Emtricitabine/Efavirenz is a fixed-dose combination of tenofovir disoproxil, emtricitabine and efavirenz and should not be administered concomitantly with other medicinal products containing any of the same active components, tenofovir disoproxil, emtricitabine, efavirenz [unless dose-adjustment is required, e.g. with rifampicin (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions), or with medicinal products containing lamivudine, tenofovir alafenamide or with adefovir dipivoxil.

General.

Patients receiving Tenofovir/Emtricitabine/Efavirenz or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection, and therefore should remain under close clinical observation by physicians experienced in the treatment of patients with HIV associated diseases.
Patients should be advised that antiretroviral therapies, including Tenofovir/Emtricitabine/Efavirenz, 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 Tenofovir/Emtricitabine/Efavirenz is not a cure for HIV infection.
Efavirenz plasma concentrations may be altered by substrates, inhibitors, or inducers of CYP3A4. Likewise, efavirenz may alter plasma concentrations of drugs metabolized by CYP3A4 or CYP2B6. The prominent effect of efavirenz at steady-state is induction of CYP3A4 and CYP2B6. However, efavirenz has demonstrated CYP3A4 inhibitory effects in vitro; therefore, the theoretical potential exists for efavirenz to increase the levels of CYP3A4 substrates. Caution should be used during the first days of Tenofovir/Emtricitabine/Efavirenz therapy in patients taking a CYP3A4 substrate with both a narrow therapeutic index and the potential for serious and/or life-threatening adverse reactions (e.g. cardiac arrhythmias, prolonged sedation, or respiratory depression). Caution should be exercised for agents such as ergot derivatives (dihydroergotamine, ergonovine, ergotamine, methylergonovine), midazolam, triazolam, bepridil, cisapride, and pimozide (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Use in hepatic impairment.

Tenofovir/Emtricitabine/Efavirenz is not recommended for patients with moderate or severe hepatic impairment because of insufficient data to determine whether dose adjustment of efavirenz is necessary. Because of the extensive cytochrome P450 (CYP450)-mediated metabolism of efavirenz and limited clinical experience in patients with chronic liver disease, caution should be exercised in administering Tenofovir/Emtricitabine/Efavirenz to patients with hepatic impairment. Patients should be monitored carefully for adverse events and, laboratory tests should be performed to evaluate their liver disease at periodic intervals.
In patients with underlying liver disease including hepatitis B or C infection and in patients treated with other medications associated with liver toxicity monitoring of liver enzymes is recommended. A few of the postmarketing reports of hepatic failure occurred in patients with no pre-existing hepatic disease or other identifiable risk factors (see Section 4.8 Adverse Effects (Undesirable Effects)). Liver enzyme monitoring should also be considered for patients without pre-existing hepatic dysfunction or other risk factors. In patients with persistent elevations of serum transaminases to greater than five times the upper limit of the normal range, the benefit of continued therapy with Tenofovir/Emtricitabine/Efavirenz needs to be weighed against the unknown risks of significant liver toxicity (see Section 4.8 Adverse Effects (Undesirable Effects)).

Use in renal impairment.

The emtricitabine and tenofovir disoproxil components of Tenofovir/Emtricitabine/Efavirenz are primarily excreted by the kidneys. Renal failure, renal impairment, elevated creatinine, hypophosphataemia and Fanconi syndrome have been reported with the use of tenofovir disoproxil in clinical practice.
It is recommended that creatinine clearance is calculated in all patients prior to initiating therapy and, as clinically appropriate, during Tenofovir/Emtricitabine/Efavirenz 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.
Tenofovir/Emtricitabine/Efavirenz is not recommended for patients with moderate or severe renal impairment (CrCl < 50 mL/min). Patients with moderate or severe renal impairment require a dose adjustment of emtricitabine and tenofovir disoproxil that cannot be achieved with the combination tablet.
Tenofovir/Emtricitabine/Efavirenz should be avoided with concurrent or recent use of a nephrotoxic agent.

Use in the elderly.

Clinical studies of tenofovir disoproxil, emtricitabine and efavirenz 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 Tenofovir/Emtricitabine/Efavirenz 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.

Tenofovir/Emtricitabine/Efavirenz is not recommended for use in children below 18 years of age due to insufficient data on safety and efficacy.
Undesirable effects with an altered frequency have been observed in paediatric patients following the administration of efavirenz or emtricitabine.
Undesirable effects in children receiving efavirenz were generally similar to those of adult patients; however, rash was reported more frequently in children and was more often of higher grade than in adults. Rash was reported in 59 of 182 children (32%) treated with efavirenz. In addition to the adverse reactions reported in adults, anaemia was common and hyperpigmentation was very common in paediatric patients receiving emtricitabine in a clinical study.

Effects on laboratory tests.

No data available.

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 disoproxil component of Tenofovir/Emtricitabine/Efavirenz, alone or in combination with other antiretrovirals, in the treatment of HIV infection. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogues to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with Tenofovir/Emtricitabine/Efavirenz 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).

Bone effects.

Bone toxicity including a reduction in bone mineral density have been observed in tenofovir disoproxil 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 Tenofovir/Emtricitabine/Efavirenz therapy in patients co-infected with HIV and HBV may be associated with severe acute exacerbations of hepatitis due to the emtricitabine and tenofovir disoproxil components of Tenofovir/Emtricitabine/Efavirenz. Patients co-infected with HIV and HBV should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping Tenofovir/Emtricitabine/Efavirenz treatment. If appropriate, initiation of anti-hepatitis B therapy may be warranted. In patients with advanced liver disease or cirrhosis, discontinuation of anti-hepatitis B therapy is not recommended since post-treatment exacerbation of hepatitis may lead to hepatic decompensation.

QTc prolongation.

QTc prolongation has been observed with the use of efavirenz (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Consider alternatives to Tenofovir/Emtricitabine/Efavirenz when coadministered with a drug with a known risk of Torsade de Pointes or when administered to patients at higher risk of Torsade de Pointes.

Psychiatric symptoms.

Serious psychiatric adverse reactions including severe depression, suicidal ideation, nonfatal suicide attempts, aggressive behaviour, paranoid reactions, and manic reactions have been reported in patients treated with efavirenz (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients with a history of psychiatric disorders appear to be at greater risk of these serious psychiatric adverse experiences. There have been reports (approximately 1 to 2 per 1000 efavirenz-treated patients) of delusions and inappropriate behaviour, predominately in patients with a history of mental illness or substance abuse. Severe acute depression (including suicidal ideation/attempts) has also been infrequently reported in both efavirenz-treated and control-treated patients). There have been occasional postmarketing reports of death by suicide, delusions and psychosis-like behaviour and catatonia; although a causal relationship to the use of efavirenz cannot be determined from these reports. Patients should be advised that if they experience these symptoms they should contact their doctor immediately to assess the possibility that the symptoms may be related to the use of Tenofovir/Emtricitabine/Efavirenz, and if so, to determine whether the risks of continued therapy outweigh the benefits.

Nervous system symptoms.

Symptoms including, but were not limited to, dizziness, insomnia, somnolence, impaired concentration and abnormal dreaming are frequently reported adverse events in patients receiving efavirenz 600 mg daily in clinical studies (see Section 4.8 Adverse Effects (Undesirable Effects)). Nervous System Symptoms usually begin during the first or second day of therapy and generally resolve after the first two to four weeks. Dosing at bedtime or on an empty stomach may improve the tolerability of these symptoms. Patients should be informed that these common nervous system symptoms are likely to improve with continued therapy and are not predictive of subsequent onset of any of the less frequent psychiatric symptoms. Patients receiving efavirenz should be alerted to the potential for additive central nervous system effects when efavirenz is used concomitantly with alcohol or psychoactive drugs.

Convulsions.

Convulsions have been observed rarely in patients receiving efavirenz, including in the presence of a known medical history of seizures. Patients who are receiving concomitant anticonvulsant medications primarily metabolised by the liver, such as carbamazepine, phenytoin and phenobarbital (phenobarbitone), may require periodic monitoring of plasma levels (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Caution must be taken in any patients with a history of seizures.

Skin rash.

Mild to moderate rash has been reported in clinical studies with efavirenz and usually resolves with continued therapy. Appropriate antihistamines and/or corticosteroids may improve the tolerability and hasten the resolution of rash. Severe rash associated with blistering, moist desquamation or ulceration has been reported in less than 1% of patients treated with efavirenz. The incidence of Grade 4 rashes (e.g. erythema multiforme or Stevens-Johnson syndrome) was approximately 0.14%. Efavirenz should be discontinued if severe rash associated with blistering, desquamation, mucosal involvement or fever develops. Efavirenz is not recommended for patients who have had a life threatening cutaneous reaction (e.g. Stevens-Johnson syndrome).
Rash was reported in 59 of 182 children (32%) treated with efavirenz in three clinical trials for a median 123 weeks in six patients.
Rashes are usually mild-to-moderate maculopapular skin eruptions that occur within the first two weeks of initiating therapy with efavirenz. In most patients, rash resolves with continuing therapy with efavirenz within one month. Tenofovir/Emtricitabine/Efavirenz can be reinitiated in patients interrupting therapy because of rash. Use of appropriate antihistamines and/or corticosteroids is recommended when Tenofovir/Emtricitabine/Efavirenz is restarted.
Experience with efavirenz in patients who discontinued other antiretroviral agents of the NNRTI class is limited.

Lipodystrophy.

Combination antiretroviral therapy has been associated with the redistribution of body fat (lipodystrophy) in HIV patients. The long-term consequences of these events are currently unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and protease inhibitors and lipoatrophy and nucleoside reverse transcriptase inhibitors has been hypothesised. A higher risk of lipodystrophy has been associated with individual factors such as older age, and with drug related factors such as longer duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should include evaluation for physical signs of fat redistribution. Consideration should be given to the measurement of fasting serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate.

Immune reconstitution syndrome.

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

Effect of food.

The administration of Tenofovir/Emtricitabine/Efavirenz with food may increase efavirenz exposure (see Section 5.2 Pharmacokinetic Properties) and may lead to an increase in frequency of undesirable effects. It is recommended that Tenofovir/Emtricitabine/Efavirenz be taken on an empty stomach, preferably at bedtime.

Animal toxicology.

Tenofovir.

Tenofovir and tenofovir disoproxil 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.

4.5 Interactions with Other Medicines and Other Forms of Interactions

General.

As Tenofovir/Emtricitabine/Efavirenz contains tenofovir disoproxil, emtricitabine and efavirenz, any interactions that have been identified with these agents individually may occur with Tenofovir/Emtricitabine/Efavirenz.

Tenofovir and emtricitabine.

Tenofovir and emtricitabine are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion. No drug-drug interactions due to competition for renal excretion have been observed; however, co-administration of tenofovir disoproxil and emtricitabine with drugs that are eliminated by active tubular secretion may increase serum concentrations of tenofovir, emtricitabine, and/or the co-administered drug. Drugs that decrease renal function may increase serum concentrations of tenofovir and/or emtricitabine.
No clinically significant drug interactions have been observed between tenofovir disoproxil and abacavir, efavirenz, emtricitabine, indinavir, 3TC, lopinavir/ritonavir, methadone, nelfinavir, oral contraceptives, ribavirin, saquinavir/ritonavir, sofosbuvir and tacrolimus (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Immunosuppressants) in studies conducted in healthy volunteers. In a study conducted in healthy volunteers dosed with a single 600 mg dose of ribavirin, no clinically significant drug interactions were observed between tenofovir disoproxil and ribavirin. Similarly, no clinically significant drug interactions have been observed between emtricitabine and famciclovir, indinavir, stavudine, zidovudine and tenofovir disoproxil.

Efavirenz.

The prominent effect of efavirenz at steady-state is induction of CYP3A and CYP2B6. Other compounds that are substrates of CYP3A4 or CYP2B6 may have decreased plasma concentrations when coadministered with efavirenz. Drugs that induce CYP3A4 activity may be expected to increase the clearance of efavirenz. In vitro studies have demonstrated that efavirenz inhibits P450 isozymes 2C9, 2C19, and 3A4 in the range of observed efavirenz plasma concentrations.
Tenofovir/Emtricitabine/Efavirenz should not be administered concurrently with voriconazole (see Section 4.3 Contraindications). Caution should be exercised when administering Tenofovir/Emtricitabine/Efavirenz concurrently with terfenadine, astemizole, cisapride, midazolam, triazolam, bepridil, pimozide, voriconazole or ergot derivatives (see Section 4.4 Special Warnings and Precautions for Use).

Concomitant antiretroviral agents.

Amprenavir.

Although efavirenz (600 mg once daily) was seen to decrease the AUC, C_max and C_min of amprenavir (1200 mg every 12 hours) in HIV infected patients, the clinical significance of decreased amprenavir concentrations has not been established, the possibility of this interaction should be taken into consideration before choosing a regimen containing both efavirenz and amprenavir.

Fosamprenavir calcium.

Appropriate doses of fosamprenavir (unboosted) and Tenofovir/Emtricitabine/Efavirenz with respect to safety and efficacy have not been established. An additional 100 mg/day (300 mg total) of ritonavir is recommended when Tenofovir/Emtricitabine/Efavirenz is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when Tenofovir/Emtricitabine/Efavirenz is administered with fosamprenavir plus ritonavir twice daily.

Atazanavir/ritonavir.

Insufficient data are available to make a dosing recommendation for atazanavir/ritonavir in combination of Tenofovir/Emtricitabine/Efavirenz. Therefore coadministration of atazanavir/ritonavir and Tenofovir/Emtricitabine/Efavirenz is not recommended.
Coadministration of efavirenz 600 mg with atazanavir in combination with low dose ritonavir resulted in substantial decreases in atazanavir exposure, necessitating dosage adjustment of atazanavir.
Tenofovir disoproxil affects the pharmacokinetics of atazanavir (see Table 1). Tenofovir should only be administered with boosted atazanavir (ATZ 300 mg/RTV 100 mg). The safety and efficacy of this regimen has been substantiated over 48 weeks in a clinical study. When unboosted atazanavir (400 mg) was coadministered with tenofovir disoproxil, atazanavir increased tenofovir C_max by 14% and AUC by 24%.

Indinavir.

Insufficient data are available to make a dosing recommendation with Tenofovir/Emtricitabine/Efavirenz. When indinavir at an increased dose (1,000 mg every eight hours) was given with efavirenz in uninfected volunteers, the indinavir AUC and Ctrough were decreased on average by 33% to 46% and 39% to 57%, respectively (ranges represent diurnal variation), compared to when indinavir was given alone at the standard dose (800 mg every 8 hours). Similar differences in indinavir AUC and Ctrough were also observed in HIV infected patients who received indinavir (1,000 mg every 8 hours) with efavirenz compared to indinavir given alone (800 mg every 8 hours). While the clinical significance of decreased indinavir concentrations has not been established, the magnitude of the observed pharmacokinetic interaction should be taken into consideration when choosing a regimen containing both efavirenz and indinavir.

Lopinavir/ritonavir.

Insufficient data are available to make a dosing recommendation with Tenofovir/Emtricitabine/Efavirenz. When tenofovir disoproxil was administered with lopinavir (400 mg)/ritonavir (100 mg), the tenofovir AUC increased by 32%. Coadministration of lopinavir/ritonavir with efavirenz resulted in a substantial decrease in lopinavir exposure, necessitating dosage adjustment of lopinavir/ritonavir. When used in combination with efavirenz and two NRTIs in multiple protease inhibitor experienced subjects, increasing the dose of lopinavir/ritonavir 33.3% from 400/100 mg (three soft capsules) twice daily, to 533/133 mg (four soft capsules) twice daily yielded similar lopinavir plasma concentrations as compared to historical data of lopinavir/ritonavir 400/100 mg twice daily.

Raltegravir.

The AUC, C_max, and C_min of raltegravir (400 mg single dose) were decreased by 36%, 36%, and 21%, respectively, when given with efavirenz (600 mg once daily) compared to raltegravir alone. The mechanism of the interaction is induction of the UGT1A1 enzyme by efavirenz. No dose adjustment is necessary for raltegravir.

Ritonavir.

When efavirenz 600 mg (given once daily at bedtime) and ritonavir 500 mg (given every 12 hours) were studied in uninfected volunteers, the combination was not well tolerated and was associated with a higher frequency of adverse clinical experiences (e.g. dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes).
Sufficient data on the tolerability of efavirenz with low-dose ritonavir (100 mg, once or twice daily), are not available. When using efavirenz in a regimen including low-dose ritonavir, the possibility of an increase in the incidence of efavirenz-associated adverse events should be considered, namely due to a possible pharmacodynamic interaction.
Monitoring of liver enzymes is recommended when Tenofovir/Emtricitabine/Efavirenz is used in combination with ritonavir.

Saquinavir.

When saquinavir soft gelatin capsules (1,200 mg every eight hours) was given with efavirenz to uninfected volunteers, saquinavir AUC and C_max were decreased by 62% and 45 to 50%, respectively. Saquinavir should not be used as sole protease inhibitor in combination with Tenofovir/Emtricitabine/Efavirenz. No data are available on the potential interactions of efavirenz with the combination of saquinavir and ritonavir.

Didanosine.

Concomitant dosing of tenofovir disoproxil with didanosine buffered tablets or enteric coated capsules significantly increase the C_max and AUC of didanosine. When didanosine 250 mg enteric-coated capsules were administered with tenofovir disoproxil, 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 disoproxil on the pharmacokinetics of didanosine. As a result of this increased exposure, patients receiving Tenofovir/Emtricitabine/Efavirenz and didanosine 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 disoproxil 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 Tenofovir/Emtricitabine/Efavirenz.
Data are not available to recommend a dose adjustment of didanosine for patients weighing < 60 kg. When coadministered, Tenofovir/Emtricitabine/Efavirenz and didanosine EC may be taken under fasted conditions or with a light meal (< 400 kcal, 20% fat). Coadministration of didanosine buffered tablet formulation with Tenofovir/Emtricitabine/Efavirenz should be under fasted conditions. Co-administration of Tenofovir/Emtricitabine/Efavirenz and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse events. Didanosine should be discontinued in patients who develop didanosine-associated adverse events.

Maraviroc.

The AUC₁₂ and C_max of maraviroc (100 mg twice daily) are decreased by 45% and 51%, respectively, when given with efavirenz (600 mg once daily) compared to maraviroc administered alone. Refer to the prescribing information for maraviroc for guidance on coadministration with efavirenz.

Hepatitis C antiviral agents.

Boceprevir.

The C_min of boceprevir (800 mg 3 times daily) was decreased by 44% when given with efavirenz (600 mg once daily) compared to boceprevir alone. The mechanism of the interaction is induction of CYP3A. Refer to the prescribing information for boceprevir for guidance on coadministration with efavirenz.

Telaprevir.

Concomitant administration of telaprevir and efavirenz resulted in reduced steady-state exposures to telaprevir and efavirenz. When telaprevir 1125 mg every 8 hours was administered with efavirenz 600 mg once daily, the AUC, C_max, and C_min of telaprevir were decreased by 18%, 14%, and 25% relative to telaprevir 750 mg every 8 hours administered alone and the AUC, C_max, and C_min of efavirenz were decreased by 18%, 24%, and 10%. The mechanism of the effect on telaprevir is induction of CYP3A by efavirenz. Refer to the prescribing information for telaprevir for guidance on coadministration with efavirenz.

Simeprevir.

Concomitant administration of simeprevir with efavirenz resulted in significantly decreased plasma concentrations of simeprevir due to CYP3A induction by efavirenz, which may result in loss of therapeutic effect of simeprevir. Coadministration of simeprevir with Tenofovir/Emtricitabine/Efavirenz is not recommended. Refer to the prescribing information for simeprevir for more information.

Ledipasvir/sofosbuvir.

Concomitant administration of ledipasvir/sofosbuvir with Tenofovir/Emtricitabine/Efavirenz resulted in increases in tenofovir AUC, C_max and C_min of approximately 98%, 79% and 163%, respectively, compared with Tenofovir/Emtricitabine/Efavirenz alone. No dose adjustment of Tenofovir/Emtricitabine/Efavirenz or ledipasvir/sofosbuvir is required. Patients receiving Tenofovir/Emtricitabine/Efavirenz with ledipasvir/sofosbuvir should be monitored for adverse reactions associated with tenofovir disoproxil fumarate.

Sofosbuvir/velpatasvir and sofosbuvir/velpatasvir/voxilaprevir.

Coadministration of efavirenz with a HCV treatment regimen containing velpatasvir has been shown to decrease velpatasvir exposure. Concomitant administration of sofosbuvir/velpatasvir with Tenofovir/Emtricitabine/Efavirenz increased tenofovir AUC, C_max, and C_min by 81%, 77%, and 121%, respectively, compared with Tenofovir/Emtricitabine/Efavirenz alone, and decreased velpatasvir AUC, C_max, and C_min by 53%, 47%, and 57%, respectively, compared with sofosbuvir/velpatasvir alone. Similarly, tenofovir exposure is expected to increase and velpatasvir and voxilaprevir are expected to decrease upon coadministration of sofosbuvir/velpatasvir/voxilaprevir and Tenofovir/Emtricitabine/Efavirenz. Coadministration of Tenofovir/Emtricitabine/Efavirenz with sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevir is not recommended.

Sofosbuvir.

Concomitant administration of sofosbuvir with Tenofovir/Emtricitabine/Efavirenz resulted in increases in tenofovir C_maxby 25%, compared with Tenofovir/Emtricitabine/Efavirenz alone. Tenofovir AUC and C_min were unaltered by sofosbuvir coadministration. No dose adjustment of Tenofovir/Emtricitabine/Efavirenz or sofosbuvir is required.

Elbasvir/grazoprevir.

Coadministration of efavirenz with elbasvir/grazoprevir reduced elbasvir AUC and C_max by 54% and 45%, respectively, and reduced grazoprevir AUC and C_max by 83% and 87%, respectively, compared to elbasvir/grazoprevir alone. Concomitant administration of Tenofovir/Emtricitabine/Efavirenz with elbasvir/grazoprevir is contraindicated (see Section 4.3 Contraindications) because it may lead to loss of virologic response to elbasvir/grazoprevir. This loss is due to significant decreases in elbasvir and grazoprevir plasma concentrations caused by CYP3A4 induction. Refer to the product information for elbasvir/grazoprevir for more information.

Glecaprevir/pibrentasvir.

Concomitant administration of glecaprevir/pibrentasvir with efavirenz may significantly decrease plasma concentrations of glecaprevir and pibrentasvir, leading to reduced therapeutic effect. Coadministration of glecaprevir/pibrentasvir with Tenofovir/Emtricitabine/Efavirenz is not recommended. Refer to the prescribing information for glecaprevir/pibrentasvir for more information.

Concomitant antimicrobial agents.

Macrolide antibiotics.

Clarithromycin.

Coadministration of efavirenz 400 mg once daily with clarithromycin given as 500 mg every 12 hours for seven days resulted in a significant effect of efavirenz on the pharmacokinetics of clarithromycin. The AUC and C_max of clarithromycin decreased 39 and 26%, respectively, while the AUC and C_max of the active clarithromycin hydroxymetabolite were increased 34 and 49%, respectively, when used in combination with efavirenz. The clinical significance of these changes in clarithromycin plasma levels is not known. In uninfected volunteers, 46% developed rash while receiving efavirenz and clarithromycin. No dose adjustment of efavirenz is recommended when given with clarithromycin. Alternatives to clarithromycin should be considered.
Rifamycins.

Rifabutin.

Coadministration of rifabutin (300 mg once daily for 14 days) and efavirenz (600 mg once daily for 14 days) in uninfected volunteers, reduced the C_maxand AUC of rifabutin by 32% and 38% respectively. Rifabutin clearance was increased when rifabutin was given with efavirenz. The daily dose of rifabutin should be increased by 50% when coadministered with Tenofovir/Emtricitabine/Efavirenz. For regimens where rifabutin is given 2 or 3 times a week, a doubling of the rifabutin dose should be considered. The possibility of this interaction should been taken into consideration before choosing a regimen containing both efavirenz and rifabutin.

Rifampicin.

Rifampicin reduced efavirenz AUC by 26% and C_max by 20% in uninfected volunteers. An additional 200 mg/day (total 800 mg/day) of efavirenz is recommended when rifampicin is coadministered with Tenofovir/Emtricitabine/Efavirenz to patients weighing 50 kg or more.

Concomitant antifungal agents.

Itraconazole.

Coadministration of efavirenz (600 mg once daily) with itraconazole (200 mg orally every 12 hours) in uninfected volunteers decreased the steady-state AUC, C_max and C_min of itraconazole. Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered.

Voriconazole.

Voriconazole increased efavirenz AUC and C_max by 44% and 38%, respectively while efavirenz decreased voriconazole AUC and C_max by 77% and 61% respectively in uninfected volunteers. Coadministration of Tenofovir/Emtricitabine/Efavirenz and voriconazole is contraindicated (see Section 4.3 Contraindications).

Posaconazole.

Coadministration of efavirenz (400 mg orally once daily) with posaconazole (400 mg orally twice daily) decreased the AUC and C_max of posaconazole by 50% and 45%, respectively, compared to posaconazole administered alone. Concomitant use of posaconazole and Tenofovir/Emtricitabine/Efavirenz should be avoided unless the benefit to the patient outweighs the risk.

Antimalarial agents.

Artemether/lumefantrine.

Coadministration of efavirenz (600 mg once daily) with artemether 20 mg/lumefantrine 120 mg tablets (6 4-tablet doses over 3 days) resulted in a decrease in exposures (AUC) to artemether, dihydroartemisinin (active metabolite of artemether), and lumefantrine by approximately 51%, 46%, and 21%, respectively. Exposure to efavirenz was not significantly affected. Since decreased concentrations of artemether, dihydroartemisinin, or lumefantrine may result in a decrease of antimalarial efficacy, caution is recommended when Tenofovir/Emtricitabine/Efavirenz and artemether/lumefantrine tablets are coadministered.

Atovaquone/proguanil.

Efavirenz (600 mg once daily) was coadministered with atovaquone and proguanil 250/100 mg to HIV-infected and healthy subjects. After adjustment for potential confounding parameters (race, age, smoking status, body weight and height, CYP2C19 genotype) in the multiple variable linear regression analysis, geometric mean atovaquone AUC and C_max were reduced 75% and 44%, respectively, while proguanil AUC was reduced approximately 43%.
Reduced therapeutic effect of antimalarial drugs may result from the substantial decrease in plasma concentrations of atovaquone. Coadministration of atovaquone/proguanil with Tenofovir/Emtricitabine/Efavirenz should be avoided whenever possible.

Concomitant anticonvulsant agents.

Carbamazepine.

Coadministration of efavirenz (600 mg orally once daily) with carbamazepine (400 mg once daily) in uninfected volunteers resulted in a two-way interaction. The steady-state AUC, C_max, and C_min of carbamazepine decreased by 27%, 20% and 35%, respectively, while the steady-state AUC, C_max, and C_min of efavirenz decreased by 36%, 21%, and 47%, respectively. The steady-state AUC, C_max, and C_min of the active carbamazepine epoxide metabolite remained unchanged. Carbamazepine plasma levels should be monitored periodically. There are no data on the coadministration of higher doses of either medicinal product; therefore, no dose recommendation can be made, and alternative anticonvulsant treatment should be considered.

Other anticonvulsants.

When efavirenz is administered concomitantly with phenytoin, phenobarbital (phenobarbitone), or other anticonvulsants that are substrates of CYP450 isozymes, there is the potential for reduction or increase in the plasma concentrations of each agent; therefore, periodic monitoring of plasma levels should be conducted.

Lipid-lowering agents.

Coadministration of efavirenz with the HMG-CoA reductase inhibitors atorvastatin, pravastatin, or simvastatin has been shown to reduce the plasma concentration of the statin in uninfected volunteers. Dosage adjustments of statins may be required (refer to the prescribing information for the statin).

Atorvastatin.

Coadministration of efavirenz (600 mg orally once daily) with atorvastatin (10 mg orally once daily) in uninfected volunteers decreased the steady-state AUC and C_max of atorvastatin by 43% and 12%, respectively, of 2-hydroxy atorvastatin by 35% and 13%, respectively, of 4-hydroxy atorvastatin by 4% and 47%, respectively, and of total active atorvastatin by 34% and 20%, respectively, compared to atorvastatin administered alone.

Pravastatin.

Coadministration of efavirenz (600 mg orally once daily) with pravastatin (40 mg orally once daily) in uninfected volunteers decreased the steady-state AUC and C_max of pravastatin by 40% and 18%, respectively, compared to pravastatin administered alone.

Simvastatin.

Coadministration of efavirenz (600 mg orally once daily) with simvastatin (40 mg orally once daily) in uninfected volunteers decreased the steady-state AUC and C_max of simvastatin by 69% and 76%, respectively, of simvastatin acid by 58% and 51%, respectively, of total active HMG-CoA reductase inhibitors by 60% and 70%, respectively, compared to simvastatin administered alone.
Coadministration of efavirenz with atorvastatin, pravastatin, or simvastatin did not affect efavirenz AUC or C_max values. No dosage adjustment is necessary for efavirenz.

Concomitant calcium channel blockers.

Diltiazem.

Coadministration of efavirenz (600 mg orally once daily) with diltiazem (240 mg orally once daily) in uninfected volunteers decreased the steady-state AUC, C_max and C_min of diltiazem. Diltiazem dose adjustments should be guided by clinical response (refer to the product information for diltiazem). Pharmacokinetic parameters for efavirenz were slightly increased (11% to 16%). No dosage adjustment of efavirenz is necessary when administered with diltiazem.

Other calcium channel blockers.

No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of CYP3A4 enzyme (e.g. verapamil, felodipine, nifedipine). When efavirenz is administered concomitantly with one of these agents, there is potential for reduction in the plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the product information for the calcium channel blocker).

Other interactions.

Antidepressants.

Sertraline.

The C_max, C24 and AUC of sertraline were decreased when given with efavirenz. The possibility of this interaction should be taken into consideration before choosing a regimen containing both efavirenz and sertraline. Sertraline dose increases should be guided by clinical response.

Bupropion.

Coadministration of efavirenz (600 mg orally once daily) with bupropion (150 mg single dose, sustained release) in uninfected volunteers decreased the AUC and C_max of bupropion by 55% and 34%, respectively, compared to bupropion alone. Hydroxybupropion AUC was unchanged and hydroxybupropion C_max was increased by 50%. The effect of efavirenz on bupropion exposure is thought to be due to the induction of bupropion metabolism. Increases in bupropion dose may be necessary when taken in combination with efavirenz and should be guided by clinical response, but should not exceed the maximum recommended dose. No adjustment of efavirenz is required.

Narcotic analgesics.

Methadone.

Coadministration of efavirenz with methadone resulted in decreased plasma levels of methadone and signs of opiate withdrawal in a study of HIV-infected patients with a history of injection drug use. The methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms.

Immunosuppressants.

When an immunosuppressant metabolized by CYP3A4 (e.g. cyclosporine, tacrolimus, or sirolimus) is administered with efavirenz, decreased exposure of the immunosuppressant may be expected due to CYP3A4 induction. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with Tenofovir/Emtricitabine/Efavirenz. Immunosuppressants metabolized by CYP3A4 are not anticipated to affect exposure of efavirenz. There were no clinically significant pharmacokinetic interactions when tenofovir disoproxil/ emtricitabine was coadministered with tacrolimus.

Hormonal contraceptives.

A reliable method of barrier contraception must be used in addition to hormonal contraceptives.

Oral.

When an oral contraceptive (ethinyl estradiol 0.035 mg/norgestimate 0.25 mg once daily) and efavirenz (600 mg once daily) were coadministered for 14 days, efavirenz had no effect on ethinyl estradiol concentrations, but plasma concentrations of norelgestromin and levonorgestrel, active metabolites of norgestimate, were markedly decreased in the presence of efavirenz (64%, 46%, and 82% decrease in norelgestromin AUC, C_max, and C_min, respectively, and 83%, 80%, and 86% decrease in levonorgestrel AUC, C_max and C_min, respectively). The clinical significance of these effects is not known. No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentration was observed.

Implant.

Decreased exposure of etonogestrel may be expected (CYP3A4 induction), and there have been occasional postmarketing reports of contraceptive failure with etonogrestrel in efavirenz-exposed patients.

QT prolonging drugs.

There is limited information available on the potential for a pharmacodynamics interaction between efavirenz and drugs that prolong the QTc interval. QTc prolongation has been observed with the use of efavirenz (see Section 5.1 Pharmacodynamic Properties). Consider alternatives to Tenofovir/Emtricitabine/Efavirenz when coadministered with a drug with a known risk of Torsade de Pointes.

St. John's wort (Hypericum perforatum).

See Section 4.3 Contraindications.

Cannabinoid test interaction.

Efavirenz does not bind to cannabinoid receptors. False positive urine cannabinoid test results have been reported with some screening assays in uninfected and HIV infected subjects receiving efavirenz. Confirmation of positive screening tests for cannabinoids by a more specific method such as gas chromatography/mass spectrometry is recommended.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No reproductive toxicity studies have been conducted with tenofovir disoproxil, emtricitabine and efavirenz in combination.

Tenofovir.

Male and female rat fertility and mating performance or early embryonic development were unaffected by an oral tenofovir disoproxil 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.

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

Efavirenz.

Efavirenz did not impair mating or fertility of male or female rats, and did not affect sperm or offspring of treated male rats. The reproductive performance of offspring born to female rats given efavirenz was not affected. As a result of the rapid clearance of efavirenz in rats, systemic drug exposures achieved in these studies were below those achieved in humans given therapeutic doses of efavirenz.
(Category D)
Efavirenz may cause foetal harm when administered during the first trimester to pregnant women. Pregnancy should be avoided in women receiving Tenofovir/Emtricitabine/Efavirenz. Barrier contraception must always be used in combination with other methods of contraception (e.g. oral or other hormonal contraceptives). Women of childbearing potential should undergo pregnancy testing before initiation of Tenofovir/Emtricitabine/Efavirenz. If a woman takes Tenofovir/Emtricitabine/Efavirenz during the first trimester of pregnancy, or becomes pregnant whilst taking Tenofovir/Emtricitabine/Efavirenz, she should the informed of the potential harm to the foetus. Because of the long half-life of efavirenz, use of adequate contraceptive measures for 12 weeks after discontinuation of Tenofovir/Emtricitabine/Efavirenz is recommended.
There are no well controlled clinical studies of Tenofovir/Emtricitabine/Efavirenz in pregnant women. No embryofoetal development studies have been conducted with tenofovir disoproxil, emtricitabine and efavirenz in combination. Tenofovir/Emtricitabine/Efavirenz should not be used during pregnancy unless the potential benefit to the mother clearly outweighs the potential risk to the foetus and there are no other appropriate treatment options.
In post-marketing experience through an antiretroviral pregnancy registry, more than 750 pregnancies with first-trimester exposure to efavirenz as part of a combination antiretroviral regimen have been reported with no specific malformation pattern. Retrospectively in this registry, a small number of neural tube defects, including meningomyelocele have been reported but causality has not been established.

Efavirenz.

Malformations have been observed in 3 of 20 foetuses/infants from efavirenz-treated cynomolgus monkeys (versus 0 of 20 concomitant controls) in a developmental toxicity study. The pregnant monkeys were dosed throughout pregnancy (postcoital days 20 to 150) with efavirenz 60 mg/kg daily, a dose which resulted in plasma drug concentrations similar to those seen in humans given 600 mg/day. Anencephaly and unilateral anophthalmia were observed in one foetus, microophthalmia was observed in another foetus, and cleft palate was observed in a third foetus. Efavirenz crosses the placenta in cynomolgus monkeys and produces foetal blood concentrations similar to maternal blood concentrations. Because teratogenic effects have been seen in primates at efavirenz exposures similar to those seen in the clinic at the recommended dose, pregnancy should be avoided in women receiving efavirenz.
Efavirenz has been shown to cross the placenta in rats and rabbits and produces foetal blood concentrations of efavirenz similar to maternal blood concentrations. An increase in foetal resorptions was observed in rats at efavirenz doses that produced peak plasma concentrations and AUC values in female rats equivalent to or lower than those achieved in humans given efavirenz 600 mg once daily. Efavirenz produced no reproductive toxicities when given to pregnant rabbits at doses that produced peak plasma concentrations similar to, and AUC values approximately half of, those achieved in humans when given efavirenz 600 mg once daily.

Efavirenz.

Studies in rats have demonstrated that efavirenz is secreted into the milk of lactating rats; concentrations of efavirenz were eight times higher than those in maternal plasma. Efavirenz has also been shown to pass into human breast milk.

Tenofovir.

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 are unknown.

Emtricitabine.

Samples of breast milk obtained from five HIV-1 infected mothers show that emtricitabine is secreted in human milk at estimated neonatal concentrations 3 to 12 times higher than the emtricitabine IC₅₀ but 3 to 12 times lower than the C_min (minimal expected trough concentration in adults) achieved from oral administration of emtricitabine. Breastfeeding infants whose mothers are being treated with emtricitabine may be at risk for developing viral resistance to emtricitabine. Other emtricitabine-associated risks in infants breastfed by mothers being treated with emtricitabine are unknown.
Because of the potential for both HIV transmission and for serious adverse events in nursing infants, mothers should be instructed not to breast feed if they are receiving Tenofovir/Emtricitabine/Efavirenz.

4.7 Effects on Ability to Drive and Use Machines

Tenofovir/Emtricitabine/Efavirenz may cause dizziness, impaired concentration and/or drowsiness. Patients should be instructed that if they experience these symptoms they should avoid potentially hazardous tasks such as driving or operating machinery.

4.8 Adverse Effects (Undesirable Effects)

As Tenofovir/Emtricitabine/Efavirenz contains tenofovir disoproxil, emtricitabine and efavirenz, adverse events associated with these individual antiretroviral agents may be expected to occur with the fixed combination tablet.
For additional safety information about Viread (tenofovir disoproxil), Emtriva (emtricitabine) or Stocrin (efavirenz) in combination with other antiretroviral agents, consult the Product Information for these products.
In addition to the adverse events in Study 934 (Table 2) and Study 073, the following adverse events were observed in clinical studies of tenofovir disoproxil, emtricitabine or efavirenz in combination with other antiretroviral agents.

Tenofovir.

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 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 discoloration which was reported with higher frequency in the Emtriva treated group.
Skin discoloration, 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.

Efavirenz.

Efavirenz was generally well tolerated in clinical trials. Efavirenz has been studied in over 9,000 patients. In a subset of 1,008 patients who received efavirenz 600 mg daily in combination with PIs and/or NRTIs in controlled clinical studies, the most frequently reported undesirable effects of at least moderate severity reported in at least 5% of patients were rash (11.6%), dizziness (8.5%), nausea (8.0%), headache (5.7%) and fatigue (5.5%). The most notable undesirable effects associated with efavirenz are nervous system symptoms (see Section 4.4 Special Warnings and Precautions for Use, Nervous system symptoms), psychiatric symptoms (see Section 4.4 Special Warnings and Precautions for Use, Psychiatric symptoms), and rash (see Section 4.4 Special Warnings and Precautions for Use, Skin rash).

Psychiatric symptoms (see Section 4.4 Special Warnings and Precautions for Use).

Serious psychiatric adverse reactions have been reported in patients treated with efavirenz. In controlled trials of 1008 adults treated with regimens containing efavirenz for an average of 1.6 years and 635 adults treated with control regimens for an average of 1.3 years, the frequency of specific serious psychiatric events among patients who received efavirenz or control regimens, respectively, were severe depression (1.6%, 0.6%), suicidal ideation (0.6%, 0.3%), nonfatal suicide attempts (0.4%, 0%), aggressive behaviour (0.4%, 0.3%), paranoid reactions (0.4%, 0.3%), and manic reactions (0.1%, 0%).
Patients with a history of psychiatric disorders appear to be at greater risk of these serious psychiatric adverse experiences, with the frequency of each of the above events ranging from 0.3% for manic reactions to 2.0% for both severe depression and suicidal ideation. There have also been occasional postmarketing reports of death by suicide, delusions, psychosis-like behaviour, and catatonia although a causal relationship to the use of efavirenz cannot be determined from these reports.

Nervous system symptoms (see Section 4.4 Special Warnings and Precautions for Use).

Symptoms including, but not limited to, dizziness, insomnia, somnolence, impaired concentration, abnormal dreaming, agitation, euphoria, amnesia, stupor, abnormal thinking, and depersonalization, are frequently reported undesirable effects in patients receiving efavirenz 600 mg daily in clinical studies. In controlled clinical studies where 600 mg efavirenz was administered with other antiretroviral agents, 19.4% of patients experience nervous system symptoms of moderate-to-severe intensity compared to 9.0% of patients receiving control regimens. These symptoms were severe in 2.0% of patients receiving efavirenz 600 mg daily and in 1.3% of patients receiving control regimens.
In clinical studies, 2.1% of patients treated with 600 mg of efavirenz discontinued therapy because of nervous system symptoms.
Nervous system symptoms usually begin during the first 1-2 days of therapy and generally resolve after the first 2-4 weeks. After 4 weeks of therapy, the prevalence of nervous system symptoms of at least moderate severity ranged from 5% to 9% in patients treated with regimens containing efavirenz, and from 3% to 5% in patients treated with a control regimen. In a study of uninfected volunteers, a representative nervous system symptom had a median time to onset of 1 hour post-dose and a median duration of 3 hours. Dosing at bedtime or on an empty stomach may improve the tolerability of these symptoms (see Section 4.2 Dose and Method of Administration). Dose reduction or splitting the daily dose has not been shown to provide benefit and is not recommended.

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

In clinical studies, 26% of patients treated with 600 mg of efavirenz experience skin rash compared with 17% of patients treated in control groups. Skin rash was considered treatment related in 18% of patients treated with efavirenz. Severe rash occurred in less than 1% of patients treated with efavirenz, and 1.7% discontinued therapy because of rash. The incidence of erythema multiforme or Steven-Johnson syndrome was approximately 0.1%.
Rashes are usually mild-to-moderate maculopapular skin eruptions that occur within the first 2 weeks of initiating therapy with efavirenz. In most patients, rash resolves with continuing therapy with efavirenz within 1 month. Tenofovir/Emtricitabine/Efavirenz can be reinitiated in patients who interrupted therapy because of rash. Use of appropriate antihistamines and/or corticosteroids is recommended when Tenofovir/Emtricitabine/Efavirenz is restarted.
Experience with efavirenz in patients who discontinued other antiretroviral agents of the NNRTI class is limited. Nineteen patients who discontinued nevirapine because of rash have been treated with efavirenz. Mild-to-moderate rash developed in nine of these patients while receiving therapy with efavirenz, and two discontinued because of rash.
Other, less frequent, clinically significant treatment related undesirable effects reported in all clinical trials include: allergic reaction, hypersensitivity, abnormal coordination, ataxia, confusion, stupor, vertigo, vomiting, diarrhoea, hepatitis, impaired concentration, insomnia, anxiety, abnormal dreams, somnolence, depression, abnormal thinking, agitation, amnesia, delirium, emotional lability, euphoria, hallucination and psychosis.
A few cases of pancreatitis has been reported, although a causal relationship with efavirenz has not been established.

Tenofovir + emtricitabine + efavirenz.

Study 934.

Study 934 was an open-label active-controlled study in which 511 antiretroviral naïve patients received either tenofovir disoproxil, emtricitabine and efavirenz in combination (n=257) or Combivir (lamivudine/zidovudine) administered in combination with efavirenz (n=254). Adverse events observed in this study were generally consistent with those seen in previous studies in treatment-experienced or treatment-naïve patients (Table 2). Adverse events leading to study drug discontinuation occurred in significantly smaller number of patients in the Truvada group compared to the Combivir group (5% vs 11%, p=0.010). The most frequently occurring adverse event leading to study drug discontinuation was anaemia (including decreased haemoglobin), no patient in the Truvada group and 6% of patients in the Combivir group.

Study 073.

In Study 073, patients with stable, virologic suppression on antiretroviral therapy and no history of virologic failure were randomised to receive Tenofovir/Emtricitabine/Efavirenz or to stay on their baseline regimen. There were higher rates of adverse events leading to study drug discontinuation and adverse events related to the study drug in patients switching to Tenofovir/Emtricitabine/Efavirenz compared to that in patients who stayed on the standard baseline regimen. The majority of patients who discontinued study drug due to adverse events had switched to Tenofovir/Emtricitabine/Efavirenz from a prior protease inhibitor-based regimen and the events that led to discontinuation were expected events consistent with the known safety profile of efavirenz e.g. nervous system symptoms. The adverse reactions observed in Study 073 were generally consistent with those seen in Study 934 and those seen with the individual components of Tenofovir/Emtricitabine/Efavirenz when each was administered in combination with other antiretroviral agents.

Laboratory abnormalities.

Laboratory abnormalities observed in this study were generally consistent with those seen in previous studies (Table 3).

Laboratory abnormalities observed in Study 073 were generally consistent with those in Study 934.

Postmarketing surveillance.

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

Immune system disorders.

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).
Tenofovir.

Immune system disorders.

Allergic reaction (including angioedema).

Metabolism and nutrition disorders.

Hypokaleamia, 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 disoproxil therapy in the absence of proximal renal tubulopathy.

Exacerbations of hepatitis after discontinuation of treatment.

In HIV infected patients co-infected 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).
Efavirenz.

Psychiatric disorders.

Paranoid reaction, neurosis, completed suicide, psychosis, delusion, catatonia.

Nervous system disorders.

Convulsions, cerebellar coordination and balance disturbances, tremor.

Eye disorders.

Blurred vision.

Ear and labyrinth disorders.

Tinnitus.

Gastrointestinal disorders.

Abdominal pain, pancreatitis.

Hepatobiliary disorders.

Hepatic failure.

Skin and subcutaneous tissue disorders.

Pruritus, photoallergic dermatitis, redistribution/accumulation of body fat in areas such as the back of the neck, breasts, abdomen and retroperitoneum.

Vascular disorders.

Flushing.

Reproductive system and breast disorders.

Gynecomastia.
A few of the post marketing reports of hepatic failure, including cases in patients with no pre-existing hepatic disease or other identifiable risk factors, were characterized by a fulminant course, progressing in some cases to transplantation or death.

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

Treatment of overdose with Tenofovir/Emtricitabine/Efavirenz should consist of general supportive measures, including monitoring of vital signs and observation of the patient's clinical status. Administration of activated charcoal may be used to aid removal of unabsorbed efavirenz. There is no specific antidote for overdose with efavirenz. Haemodialysis can remove both tenofovir disoproxil and emtricitabine (refer to detailed information below). However, since efavirenz is highly protein bound, dialysis is unlikely to remove significant quantities of it from blood.

Tenofovir.

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 disoproxil, was administered daily for 7 days. In the second study, 600 mg of tenofovir disoproxil 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 emtricitabine 1200 mg were administered to 11 patients. No severe adverse reactions were reported. The effects of higher doses are not known.
Haemodialysis treatment removes approximately 30% of the emtricitabine dose over a 3-hour dialysis period starting within 1.5 hours of emtricitabine dosing (blood flow rate of 400 mL/min and a dialysate flow rate of 600 mL/min). It is not known whether emtricitabine can be removed by peritoneal dialysis.

Efavirenz.

Some patients accidentally taking 600 mg twice daily have reported increased nervous system symptoms. One patient experienced involuntary muscle contractions.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

Each Tenofovir Disoproxil/Emtricitabine/Efavirenz Viatris 300/200/600 tablet contains 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of tenofovir disoproxil maleate. The innovator product contains 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate. All clinical data in this product information (including Pharmacokinetic, Pharmacodynamic, and Clinical trial data) relevant to tenofovir are based on tenofovir disoproxil fumarate. Bioequivalence has been established between the two salt forms of tenofovir disoproxil.

5.1 Pharmacodynamic Properties

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

Mechanism of action.

Tenofovir disoproxil. Tenofovir disoproxil maleate is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. Tenofovir disoproxil 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. Emtricitabine is a synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate. Emtricitabine 5'-triphosphate inhibits the activity of the HIV-1 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.
Efavirenz. Efavirenz is a selective non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1 RT with respect to template, primer or nucleoside triphosphates, with a small component of competitive inhibition. Human immunodeficiency virus-type 2 (HIV-2) RT and human cellular DNA polymerases (α, β, γ, and δ) are not inhibited by concentrations of efavirenz well in excess of those achieved clinically.

Cardiac electrophysiology.

The effect of efavirenz on the QTc interval was evaluated in an open-label, positive and placebo-controlled, fixed single sequence 3-period, 3-treatment crossover QT study in 58 healthy subjects enriched for CYP2B6 polymorphisms. The mean C_max of efavirenz in subjects with CYP2B6 *6/*6 genotype following the administration of 600 mg daily dose for 14 days was 2.25-fold the mean C_max observed in subjects with CYP2B6 *1/*1 genotype. A positive relationship between efavirenz concentration and QTc prolongation was observed. Based on the concentration-QTc relationship, the mean QTc prolongation and its upper bound 90% confidence interval are 8.7 msec and 11.3 msec, respectively, in subjects with CYP2B6*6/*6 genotype following the administration of 600 mg daily dose for 14 days (see Section 4.4 Special Warnings and Precautions for Use).

Antiviral activity in vitro.

Tenofovir, emtricitabine and efavirenz.

In combination studies evaluating the in vitro antiviral activity of emtricitabine and efavirenz together, efavirenz and tenofovir together and emtricitabine and tenofovir together, additive to synergistic antiviral effects were observed.

Tenofovir.

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 microM. 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 microM). 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 emtricitabine against laboratory and clinical isolates of HIV was assessed in lymphoblastoid cell lines, the MAGI-CCR5 cell line, and peripheral blood mononuclear cells. The IC₅₀ value for emtricitabine was in the range of 0.0013 to 0.64 microM (0.0003 to 0.158 microgram/mL).
In drug combination studies of emtricitabine with NRTIs (abacavir, 3TC, d4T, zalcitabine, AZT), NNRTIs (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, nelfinavir, ritonavir, saquinavir), additive to synergistic effects were observed. Emtricitabine displayed antiviral activity in vitro against HIV-1 clades A, C, D, E, F, and G (IC₅₀ values ranged from 0.007 to 0.075 microM) and showed strain specific activity against HIV-2 (IC₅₀ values ranged from 0.007 to 1.5 microM).

Efavirenz.

The in vitro antiviral activity of efavirenz was assessed in lymphoblastoid cell lines, peripheral blood mononuclear cells (PBMCs) and macrophage/monocyte cultures enriched from PBMCs. The 90 to 95% inhibitory concentration (IC₉₀ to IC₉₅) of efavirenz for wild-type laboratory adapted strains and clinical isolates ranged from 1.7 to less than or equal to 25 nanoM. Efavirenz demonstrated synergistic activity in cell culture in combination with the NRTIs AZT or didanosine, or the protease inhibitor, indinavir.

Antihepatitis B virus activity in vitro.

In vitro studies evaluating the HBV activity of Tenofovir/Emtricitabine/Efavirenz and efavirenz have not been conducted.

Tenofovir and emtricitabine.

Tenofovir inhibits HBV production in HepG2 2.2.15 with an IC₅₀ value of 1.1 microM. Emtricitabine inhibits HBV production against laboratory strains of HBV with IC₅₀ values in the range of 0.01 to 0.04 microM.

Drug resistance.

Tenofovir, emtricitabine and efavirenz.

HIV isolates with reduced susceptibility to the combination of tenofovir, emtricitabine and efavirenz have been selected in cell culture and in clinical studies. Genotypic analysis of these isolates identified the K103N, M184V/I and/or the K65R amino acid substitutions in the viral RT.

Tenofovir.

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, emtricitabine, lamivudine and tenofovir.
Tenofovir-resistant isolates of HIV-1 have also been recovered from some patients treated with tenofovir disoproxil in combination with other antiretroviral agents. In treatment-naïve patients treated with tenofovir disoproxil + 3TC + efavirenz through 144 weeks, viral isolates from 8/47 (17%) patients with virologic failure showed reduced susceptibility to tenofovir. In treatment-naïve patients treated with tenofovir disoproxil + emtricitabine + efavirenz through 144 weeks, none of the HIV isolates from 19 patients analyzed for resistance showed reduced susceptibility to tenofovir or the presence of the K65R mutation. In treatment-experienced patients, 14/304 (4.6%) of the tenofovir disoproxil-treated patients with virologic failure showed reduced susceptibility to tenofovir. Genotypic analysis of the resistant isolates showed the K65R mutation in the HIV-1 reverse transcriptase gene.

Emtricitabine.

Emtricitabine-resistant isolates of HIV have been selected in vitro. Genotypic analysis of these isolates showed that the reduced susceptibility to emtricitabine was associated with a mutation in the HIV reverse transcriptase gene at codon 184 which resulted in an amino acid substitution of methionine by valine or isoleucine (M184V/I).
Emtricitabine-resistant isolates of HIV have been recovered from some patients treated with emtricitabine alone or in combination with other antiretroviral agents. In a clinical study, viral isolates from 37.5% of treatment-naïve patients with virologic failure showed reduced susceptibility to emtricitabine. Genotypic analysis of these isolates showed that the resistance was due to M184V/I mutations in the HIV reverse transcriptase gene. In a second study in treatment-naïve patients, genotyping of viral isolates from 2/12 (17%) patients showed development of the M184V/I mutation.

Efavirenz.

The potency of efavirenz in cell culture against viral variants with amino acid substitutions at positions 48, 108, 179, 181 or 236 in RT or variants with amino acid substitutions in the protease was similar to that observed against wild type viral strains. The single substitutions which led to the highest resistance to efavirenz in cell culture correspond to a leucine to isoleucine change at position 100 (L100I, 17 to 22-fold resistance) and a lysine to asparagine at position 103 (K103N, 18 to 33-fold resistance). Greater than 100-fold loss of susceptibility was observed against HIV variants expressing K103N in addition to other amino acid substitutions in RT. K103N was the most frequently observed RT substitution in viral isolates from patients who experienced a significant rebound in viral load during clinical studies of efavirenz in combination with indinavir or AZT + 3TC. Substitutions at RT positions 98, 100, 101, 108, 138, 188, 190 or 225 were also observed, but at lower frequencies, and often only in combination with K103N. The pattern of amino acid substitutions in RT associated with resistance to efavirenz was independent of the other antiviral medications used in combination with efavirenz.
In a clinical study of treatment-naïve patients (Study 934, see Section 5.1, Clinical trials) resistance analysis was performed on HIV isolates from all virologic failure patients with confirmed HIV RNA > 400 copies/mL at week 144 while on study drug or after treatment switch. Genotypic resistance to efavirenz, predominantly the K103N substitution, was the most common form of resistance that developed. Resistance to efavirenz occurred in 68% (13/19) analysed patients in the tenofovir/emtricitabine group and in 72% (21/29) analysed patients in the Combivir (zidovudine/lamivudine group).

Cross-resistance.

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

Tenofovir.

The K65R mutation selected by tenofovir is also selected in some HIV-1 infected subjects treated with abacavir, didanosine, or zalcitabine. HIV isolates with this mutation also show reduced susceptibility to emtricitabine and 3TC. Therefore, cross-resistance among these drugs may occur in patients whose virus harbours the K65R mutation. The K70E substitution selected by tenofovir disoproxil results in reduced susceptibility to abacavir, didanosine, emtricitabine, and lamivudine. Patients with HIV-1 expressing three or more thymidine analogue associated mutations (TAMs) that included either the M41L or L210W reverse transcriptase mutation showed reduced susceptibility to tenofovir disoproxil. Multinucleoside resistant HIV-1 with a T69S double insertion mutation in the reverse transcriptase showed reduced susceptibility to tenofovir.

Emtricitabine.

Emtricitabine-resistant isolates (M184V/I) were cross-resistant to 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 emtricitabine. Viruses harbouring mutations conferring reduced susceptibility to d4T and AZT (M41L, D67N, K70R, L210W, T215Y/F, K219Q/E) or didanosine (L74V) remained sensitive to emtricitabine. HIV-1 containing the K103N mutation associated with resistance to NNRTIs was susceptible to emtricitabine.

Efavirenz.

Cross-resistance profiles for efavirenz, nevirapine and delavirdine in cell culture demonstrated that the K103N substitution confers loss of susceptibility to all three NNRTIs. Two of three delavirdine resistant clinical isolates examined were cross resistant to efavirenz and contained the K103N substitution. A third isolate which carried a substitution at position 236 of RT was not cross resistant to efavirenz. Viral isolates recovered from PBMCs of patients enrolled in efavirenz clinical trials who showed evidence of treatment failure (viral load rebound) were assessed for susceptibility to NNRTIs. Thirteen isolates previously characterised as efavirenz resistant were also resistant to nevirapine and delavirdine. Five of these NNRTI resistant isolates were found to have K103N or a valine to isoleucine substitution at position 108 (V108I) in RT. Three of the efavirenz treatment failure isolates tested remained sensitive to efavirenz in cell culture and were also sensitive to nevirapine and delavirdine.
The potential for cross resistance between efavirenz and PIs is low because of the different enzyme targets involved. The potential for cross resistance between efavirenz and NRTIs is low because of the different binding sites on the target and mechanism of action.

Clinical trials.

The data available to support the efficacy of Tenofovir/Emtricitabine/Efavirenz tablets include the available data for each individual agent, the data from clinical study 934 where the three agents were used concurrently, clinical study 073 where Tenofovir/Emtricitabine/Efavirenz was used in antiretroviral treatment experienced patients and the demonstration of bioequivalence between Tenofovir/Emtricitabine/Efavirenz tablets and the three individual agents co-administered under fasting conditions.

Study 934: Tenofovir disoproxil + emtricitabine + efavirenz compared with Combivir (lamivudine/ zidovudine) + efavirenz.

Study 934 is a randomized, open-label, active controlled multicentre study comparing two different dosing regimens in 511 antiretroviral-naïve HIV-1 infected patients. Patients were randomised to receive either Emtriva + Viread administered in combination with efavirenz or Combivir (lamivudine/zidovudine) administered in combination with efavirenz. For patients randomized to receive Emtriva + Viread the two drugs were administered individually for the first 96 weeks and then switched to Truvada (fixed dose combination) during weeks 96 to 144, without regard to food.
For inclusion in the study, antiretroviral treatment naïve adult patients (≥ 18 years) with plasma HIV RNA greater than 10,000 copies/mL, must have an estimated glomerular filtration rate as measured by Cockcroft-Gault method of ≥ 50 mL/min, adequate haematologic function, hepatic transaminases and alanine aminotransferases ≤ 3 ULN, total bilirubin ≤ 1.5 mg/dL, serum amylase ≤ 1.5 ULN and serum phosphorus ≥ 2.2 mg/dL. Exclusion criteria included: a new AIDS defining condition diagnosed within 30 days (except on the basis of CD4 criteria), ongoing therapy with nephrotoxic drugs or agents that interacted with efavirenz, pregnancy/lactation, a history of clinically significant renal/ bone disease or malignant disease other than Kaposi's sarcoma or basal-cell carcinoma, or a life expectancy of less than one year. If efavirenz associated central nervous system toxicities occurred, nevirapine could be substituted for efavirenz. Patients who were not receiving their originally assigned treatment regimen after week 48 or 96 and during the 30-day extension study window were not eligible to continue to weeks 96 or 144 respectively.
Patients had a mean age of 38 years (range 18 to 80), 86% were male, 59% were Caucasian and 23% were Black. The mean baseline CD4 cell count was 245 cells/mm³ (range 2 to 1191) and median baseline plasma HIV-1 RNA was 5.01 log10 copies/mL (range 3.56 to 6.54). Patients were stratified by baseline CD4 count (< or ≥ 200 cells/mm³); 41% had CD4 cell counts < 200 cells/mm³ and 51% of patients had baseline viral loads > 100,000 copies/mL. Treatment outcomes at 48 and 144 weeks for those patients who did not have efavirenz resistance at baseline are presented in Table 4.

In this study, tenofovir disoproxil, emtricitabine and efavirenz in combination was statistically significantly superior to lamivudine/zidovudine in combination with efavirenz with regards to the primary and secondary endpoints: achieving and maintaining HIV-1 RNA < 400 copies/mL through 48 and 144 weeks (Table 4). The difference in the proportions of responders between the tenofovir disoproxil + emtricitabine group and the Combivir group was 11.4%, and the 95% CI was 4.3% to 18.6% (p=0.002) at week 48 and a difference of 12.9% (95% CI was 4.2% to 21.6%, p=0.004) at week 144.
Through 48 weeks of therapy, 80% and 70% of patients in the tenofovir disoproxil + emtricitabine and the lamivudine/zidovudine arms, respectively, achieved and maintained HIV-1 RNA < 50 copies/mL.
The difference in the proportions of responders between the tenofovir disoproxil + emtricitabine group and the Combivir group was 9.1%, and the 95% CI was 1.6% to 16.6% (p=0.021) at week 48. The proportion of patients responding at 144 weeks of therapy was higher in the Truvada group (64%) compared with the Combivir group (56%); p=0.082, a difference of 8.1% and the 95% CI was -0.8% to 17.0%.
The mean increase from baseline in CD4 cell count was 190 cells/mm³ and 312 cells/mm³ for the tenofovir disoproxil + emtricitabine + efavirenz arm, and 158 cells/mm³ and 271 cells/mm³ for the Combivir + efavirenz arm (p=0.002 and p= 0.088) at weeks 48 and 144 respectively.
Resistance analysis was performed on HIV isolates from all patients with > 400 copies/mL of HIV-1 RNA at week 144 while on study or after treatment switch. Genotypic resistance to efavirenz, predominantly the K103N mutation, was the most common form of resistance that developed in both treatment groups. Resistance to efavirenz occurred in 68% (13/19) analysed patients in the Truvada group and in 72% (21/29) analyzed patients in the Combivir group. The M184V mutation, associated with resistance to emtricitabine and 3TC developed significantly less in the analysed patients in the Truvada group 11% (2/19) compared with the analysed patients in the Combivir group, 34% (10/29). Two patients in the Combivir group developed thymidine analog mutations, specifically D67N or K70R mutations in the reverse transcriptase gene. No patient in either treatment group developed the K65R or K70E mutation, which is associated with reduced susceptibility to Viread.

Study 073: Tenofovir/emtricitabine/efavirenz compared to stable baseline regimen (combination therapy).

Study 073 was a 48 week open-label, randomised clinical study in patients with stable, virologic suppression on combination antiretroviral therapy. The study compared the efficacy of Tenofovir/Emtricitabine/Efavirenz to antiretroviral therapy consisting of at least two nucleoside reverse transcriptase inhibitors (NRTIs) administered in combination with a protease inhibitor (with or without ritonavir) or a non-nucleoside reverse transcriptase inhibitor. At baseline, patients had been virologically suppressed (HIV-1 RNA < 200 copies/mL) on their current antiretroviral therapy for at least 12 weeks prior to study entry, and had no known HIV-1 substitutions conferring resistance to the components of Tenofovir/Emtricitabine/Efavirenz or history of virologic failure. Assessments were also included to evaluate change in HIV symptom index, quality of life, medication preference, and adherence.
Patients were randomised to switch to Tenofovir/Emtricitabine/Efavirenz (N=203) or stay on their baseline regimen (SBR) (N=97). Patients had a mean age of 43 years (range 22 to 73 years), 88% were male, 68% were white, 29% were black, and 3% were of other races. At baseline, median CD4 cell count was 516 cells/mm³ and all but 11 patients (3.7%) had HIV-1 RNA < 50 copies/mL. The median time since onset of antiretroviral therapy was three years.
The primary efficacy endpoint was the maintenance of confirmed HIV-1 RNA < 200 copies/mL, defined as the proportion of patients with HIV-1 RNA < 200 copies/mL on their original assigned regimen at Week 48 based on Time to Loss of Virological Response (TLOVR) analysis. The Tenofovir/Emtricitabine/Efavirenz group was to be declared non-inferior to the stable baseline regimen (SBR) group if the lower confidence limit of the responder difference (Tenofovir/Emtricitabine/Efavirenz minus SBR) was greater than -0.15. See Table 5.

The responder difference (HIV-1 RNA < 200 copies/mL), Tenofovir/Emtricitabine/Efavirenz minus SBR, was 1% (95% CI: -7% to 9%, p=0.82) at week 48. Tenofovir/Emtricitabine/Efavirenz was non-inferior to SBR in this study.
There were no differences in HIV symptom index, quality of life and adherence between the Tenofovir/Emtricitabine/Efavirenz and the SBR group. Differences were reported in medication preference; the proportion of patients reporting they preferred Tenofovir/Emtricitabine/Efavirenz compared to their previous regimen increased from 64% at week 4 to 85% at week 48.

5.2 Pharmacokinetic Properties

One Tenofovir/Emtricitabine/Efavirenz tablet is bioequivalent to one Viread tablet (300 mg) plus one Emtriva capsule (200 mg) plus one Stocrin tablet (600 mg) following single-dose administration in fasting healthy subjects (N=45).
The separate pharmaceutical forms of tenofovir, emtricitabine and efavirenz were used to determine the pharmacokinetics of tenofovir, emtricitabine and efavirenz in HIV infected patients.

Tenofovir.

The pharmacokinetic properties of tenofovir disoproxil are summarized in Table 6. Following oral administration of tenofovir disoproxil, 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 disoproxil, the terminal elimination half-life of tenofovir is approximately 17 hours.

Emtricitabine.

The pharmacokinetic properties of emtricitabine are summarized in Table 6. Following oral administration of emtricitabine 200 mg capsules, emtricitabine is rapidly absorbed with peak plasma concentrations occurring at 1 to 2 hours post-dose. In vitro binding of emtricitabine to human plasma proteins is < 4% and is independent of concentration over the range of 0.02 to 200 microgram/mL. Following administration of radiolabelled emtricitabine approximately 86% is recovered in the urine and 13% is recovered as metabolites. The metabolites of emtricitabine include 3'-sulfoxide diastereomers and their glucuronic acid conjugate. Emtricitabine is eliminated by a combination of glomerular filtration and active tubular secretion. Following a single oral dose of emtricitabine 200 mg capsules, the plasma emtricitabine half-life is approximately 10 hours.

Efavirenz.

Peak efavirenz plasma concentrations of 1.6 to 9.1 microM were attained by 5 hours following single oral doses of 100 to 1600 mg administered to uninfected volunteers. The steady state mean C_max, mean C_min and mean AUC were linear with 200 mg, 400 mg and 600 mg daily doses. In 35 patients receiving efavirenz 600 mg once daily, steady state C_max was 12.9 microM, steady state C_min was 5.6 microM and AUC was 184 microM.h.
Administration of a single 600 mg efavirenz tablet with a high fat/high caloric meal (approximately 1000 kcal, 500 to 600 kcal from fat) was associated with a 28% increase in mean AUC_0-∞ of efavirenz and 79% increase in mean C_max of efavirenz relative to the exposures achieved when given under fasted conditions.
Efavirenz is highly bound (approximately 99.5 to 99.75%) to human plasma proteins, predominantly albumin. In HIV-1 infected patients (n=9) who received efavirenz 200 to 600 mg once daily for at least one month, cerebrospinal fluid concentrations ranged from 0.26 to 1.19% (mean 0.69%) of the corresponding plasma concentration. This proportion is approximately 3-fold higher than the non-protein-bound (free) fraction of efavirenz in plasma.
Studies in humans and in vitro studies using human liver microsomes have demonstrated that efavirenz is principally metabolised by the cytochrome P450 system to hydroxylated metabolites with subsequent glucuronidation of these hydroxylated metabolites. These metabolites are essentially inactive against HIV-1.
The in vitro studies suggest that CYP3A4 and CYP2B6 are the major isozymes responsible for efavirenz metabolism. In vitro studies have shown that efavirenz inhibited P450 isozymes 2C9, 2C19 and 3A4 with Ki values (8.5 to 17 microM) in the range of observed efavirenz plasma concentrations. In in vitro studies, efavirenz did not inhibit CYP2E1 and inhibited CYP2D6 and CYP1A2 (Ki values 82 to 160 microM) only at concentrations well above those achieved clinically.
Efavirenz plasma exposure may be increased in patients with the homozygous G516T genetic variant of the CYP2B6 isoenzyme. The clinical implications of such an association are unknown; however, the potential for an increased frequency and severity of efavirenz-associated adverse events cannot be excluded.
Efavirenz has been shown to induce P450 enzymes resulting in the induction of its own metabolism. Efavirenz has a relatively long terminal half-life of 52 to 76 hours after single doses and 40 to 55 hours after multiple doses. Approximately 14 to 34% of a radiolabelled dose of efavirenz was recovered in the urine and less than 1% of the dose was excreted in urine as unchanged efavirenz.

Effect of food.

Tenofovir/Emtricitabine/Efavirenz has not been evaluated in the presence of food. Administration of a single 600 mg efavirenz tablet with a high fat/high caloric meal increased the mean AUC and C_max of efavirenz by 28% and 79%, respectively, compared to administration in the fasted state. Compared to fasted administration, dosing of tenofovir disoproxil and emtricitabine in combination with either a high fat meal or a light meal increased the AUC and C_max of tenofovir by approximately 40% and 14%, respectively, without affecting emtricitabine exposures.

Age and gender.

Children and geriatric patients.

Pharmacokinetic studies with Tenofovir/Emtricitabine/Efavirenz 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).

Gender.

The pharmacokinetics of tenofovir disoproxil, emtricitabine and efavirenz are similar in male and female patients. The pharmacokinetics of tenofovir disoproxil have not been specifically studied in different ethnic groups.

Patients with impaired renal function.

Tenofovir/Emtricitabine/Efavirenz is not recommended for patients with moderate or severe renal impairment (creatinine clearance (CrCl) < 50 mL/min)). Patients with moderate or severe renal impairment require dose interval adjustment of emtricitabine and tenofovir disoproxil that cannot be achieved with the combination tablet (see Section 4.4 Special Warnings and Precautions for Use).

Patients with hepatic impairment.

Tenofovir/Emtricitabine/Efavirenz is not recommended for patients with moderate or severe hepatic impairment because of insufficient data to determine whether dose adjustment of efavirenz is necessary. Patients with mild hepatic impairment may be treated with Tenofovir/Emtricitabine/Efavirenz. Tenofovir/Emtricitabine/Efavirenz should be administered with caution to these patients (see Section 4.4 Special Warnings and Precautions for Use).

Tenofovir and emtricitabine.

The pharmacokinetics of tenofovir following a 300 mg dose of tenofovir disoproxil 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 emtricitabine have not been studied in patients with moderate to severe hepatic impairment; however, emtricitabine is not significantly metabolized by liver enzymes, so the impact of liver impairment should be limited.

Efavirenz.

Because of the extensive cytochrome P450 mediated metabolism of efavirenz and limited clinical experience in patients with chronic liver disease, caution should be exercised in administering efavirenz to patients with liver disease.

5.3 Preclinical Safety Data

Genotoxicity.

Tenofovir.

Tenofovir disoproxil 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.

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

Efavirenz.

Efavirenz was not genotoxic in assays for gene mutations (S. typhimurium, E. coli and Chinese hamster ovary cells) and chromosomal damage (human peripheral blood lymphocytes, Chinese hamster ovary cells, and a mouse micronucleus assay).

Carcinogenicity.

No carcinogenicity studies have been conducted with tenofovir disoproxil, emtricitabine and efavirenz in combination.

Tenofovir.

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

Emtricitabine.

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

Efavirenz.

Long-term carcinogenicity studies in mice and rats were carried out with efavirenz. Mice were dosed with 0, 25, 75,150 or 300 mg/kg/day for 2 years. Incidences of hepatocellular adenomas and carcinomas and pulmonary alveolar/bronchiolar adenomas were increased above background in females. No increases in tumour incidence above background were seen in males. There was no NOAEL in females established for this study because tumour findings occurred at all doses. AUC at the NOAEL (150 mg/kg) in the males was approximately 0.9 times that in humans at the recommended clinical dose. In the rat study no increases in tumour incidence were observed at doses up to 100 mg/kg/day, for which AUCs were 0.1 (males) or 0.2 (females) times those in humans at the recommended clinical dose.

6 Pharmaceutical Particulars

6.1 List of Excipients

Tablet core.

Microcrystalline cellulose, hyprolose, iron oxide red, croscarmellose sodium, magnesium stearate, lactose monohydrate, colloidal anhydrous silica and sodium metabisulfite.

Film coating.

Opadry II complete film coating system 85F540043 pink (ARTG no. 109120).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

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

Tenofovir Disoproxil/Emtricitabine/Efavirenz Viatris 300/200/600 should be stored below 25°C.
This medicinal product does not require any special storage conditions.

6.5 Nature and Contents of Container

Tenofovir Disoproxil/Emtricitabine/Efavirenz Viatris 300/200/600 is supplied in high density polyethylene (HDPE) bottles with polypropylene (PP) child resistant closure containing 30 tablets.

Australian Register of Therapeutic Goods (ARTG).

AUST R 280721 - Tenofovir Disoproxil/Emtricitabine/Efavirenz Viatris 300/200/600 tenofovir disoproxil maleate 300 mg/emtricitabine 200 mg/efavirenz 600 mg tablet bottle.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Chemical structure.

Active ingredient: tenofovir disoproxil maleate.

The chemical name for tenofovir disoproxil maleate is: bis(hydroxymethyl) [[(R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl] phosphonate, bis(isopropyl carbonate) (ester), (2Z)-but-2-enedioate (1:1). The molecular formula is C₁₉H₃₀N₅O₁₀P.C₄H₄O₄ and molecular weight is 635.51.

Active ingredient: emtricitabine.

The chemical name for emtricitabine is: 5-fluoro-1-(2R,5S)-[2-(hydroxymethyl)- 1,3-oxathiolan-5- yl]cytosine. The molecular formula is C₈H₁₀FN₃O₃S and molecular weight is 247.24.

Active ingredient: efavirenz.

The chemical name for efavirenz is: (4S)-6-Chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3 ,1- benzoxazin-2-one. The molecular formula is C₁₄H₉ClF₃NO₂ and molecular weight is 315.68.

CAS number.

Tenofovir disoproxil maleate registry no.: 1276030-80-8.
Emtricitabine registry no.: 143491-57-0.
Efavirenz registry no.: 154598-52-4.
Tenofovir disoproxil maleate is a white to off-white crystalline powder with a solubility of 128 mg/mL in water at 25°C. The partition coefficient (log p) for tenofovir is 0.67 and the pKa is 3.5.
Emtricitabine is a white to off-white crystalline powder with a solubility of approximately 170 mg/mL in water at 25°C. The partition coefficient (log p) for emtricitabine is -0.43 and the pKa is 4.90.
Efavirenz is a white to slightly pink crystalline powder. It is practically insoluble in water (< 10 microgram/mL). The partition coefficient (log p) for efavirenz is 5.4 and the pKa is 10.2.

7 Medicine Schedule (Poisons Standard)

S4 (Prescription Only Medicine).

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Tenofovir Disoproxil/Emtricitabine/Efavirenz Viatris 300/200/600

Tenofovir disoproxil maleate; Emtricitabine; Efavirenz

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Tenofovir Disoproxil/Emtricitabine/Efavirenz Viatris 300 mg/200 mg/600 mg Tablets