Consumer medicine information

Atripla

Tenofovir disoproxil fumarate; Emtricitabine; Efavirenz

BRAND INFORMATION

Brand name

Atripla

Active ingredient

Tenofovir disoproxil fumarate; Emtricitabine; Efavirenz

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Atripla.

What is in this leaflet

This leaflet answers some of the common questions about ATRIPLA tablets. It does not contain all of the available information.

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

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

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

What is ATRIPLA

ATRIPLA is used to treat Human Immunodeficiency Virus (HIV-1) infection in adults. This medicine can be taken alone or in combination with other anti-HIV medicines.

ATRIPLA consists of three medicines:

  • VIREAD® (tenofovir disoproxil fumarate, also called tenofovir DF)
  • EMTRIVA® (emtricitabine or FTC)
  • STOCRIN® (efavirenz)

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

VIREAD and EMTRIVA belong to a group of antiviral medicines known as nucleoside and nucleotide reverse transcriptase inhibitors (NRTI).

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

Tenofovir DF and emtricitabine are components of TRUVADA® and ATRIPLA® tablets.

How ATRIPLA 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.

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

Use in Children and Elderly

ATRIPLA is for adults. Do not take ATRIPLA if you are under the age of 18 years. Do not take ATRIPLA if you are over the age of 65 before discussing with your doctor.

Does ATRIPLA cure HIV OR AIDS

ATRIPLA does not cure HIV-1 infection or AIDS.

The long-term effects of ATRIPLA are not known at this time. People taking ATRIPLA 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) infection.

This medicine is only available from a pharmacist after it has been prescribed by a doctor who specialises in the treatment of HIV-1 infection.

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

Does ATRIPLA reduce the risk of passing HIV to others

ATRIPLA 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.

Before you take ATRIPLA

Who must not take it

Together with your doctor, you need to decide whether ATRIPLA is right for you. If you are not sure whether you should be taking ATRIPLA, talk to your doctor.

Do not take ATRIPLA if you are allergic to:

  • tenofovir
  • tenofovir DF
  • emtricitabine,
  • efavirenz or
  • any of the other ingredients of ATRIPLA

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.

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

If you are not sure whether you should be taking ATRIPLA, talk to your doctor.

Before you start to take it

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

Tell your doctor if you are pregnant, or planning to become pregnant during your course of medication. Women taking ATRIPLA should not become pregnant. Serious birth defects have been seen in the babies of animals and women treated with efavirenz (a component of ATRIPLA) during pregnancy. It is not known whether efavirenz caused these defects.

Tell your doctor immediately if you become pregnant while taking ATRIPLA Also, talk to your doctor if you want to become pregnant.

Do not breast-feed if you are taking ATRIPLA. Do not breast-feed if you are taking ATRIPLA. The active substances in this medicine (tenofovir and emtricitabine and efavirenz) have been found in breast milk at low concentrations.

It is recommended that nursing mothers do not breast-feed during treatment with ATRIPLA. In general, women infected with HIV should not breast-feed their infants in order to avoid transmission of HIV to their newborn infant.

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

Tell your doctor if you have bone problems.

Tell your doctor if you have liver problems, including Hepatitis B Virus (HBV) infection. Your doctor may want to do tests to check your liver while you take ATRIPLA.

Tell your doctor if you have ever had mental illness or are using recreational drugs or alcohol.

Tell your doctor if you have ever had seizures or are taking medicine for seizures.

Tell your doctor if you have ever had a serious allergic drug reaction involving the skin (e.g. Stevens-Johnson syndrome).

Taking other medicines

ATRIPLA 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 ATRIPLA.

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

Medicines you should not take with ATRIPLA

The following medicines may cause serious or life-threatening side effects when taken with ATRIPLA.

Do not take Zepatier (elbasvir/grazoprevir) with ATRIPLA. It may lose its effect and reduce your response to Zepatier.

Do not take St. Johns wort (Hypericum perforatum) or products containing St. Johns wort with ATRIPLA. 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 ATRIPLA levels and lead to increased viral load and possible resistance to ATRIPLA or cross-resistance to other anti-HIV drugs.

Voriconazole (e.g. Vfend) should not be taken with ATRIPLA. It may lose its effect or may increase the chance of having side effects from ATRIPLA.

Do not take ATRIPLA if you are already taking any other medicines that contain the same active ingredients.

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

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

  • efavirenz (e.g. STOCRIN)
  • lamivudine (e.g. Combivir, Zeffix, Kivexa, Trizivir)

Do not take ATRIPLA 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 ATRIPLA.
  • 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 ATRIPLA.
  • Didanosine (also known as ddI or Videx); tenofovir DF (a component of ATRIPLA) 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 ATRIPLA 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 DF (a component of ATRIPLA) in your blood which could result in more side effects. Atazanavir sulphate is not recommended with ATRIPLA. You may need to be monitored more carefully if you are taking ATRIPLA 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 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 ATRIPLA.
  • Hepatitis C antiviral agents such as ledipasvir/sofosbuvir (e.g. HARVONI) or sofosbuvir/velpatasvir (e.g. EPCLUSA), sofosbuvir/velpatasvir/voxilaprevir (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 ATRIPLA. Be sure to tell your healthcare provider about all medicines that you take.

How to take ATRIPLA

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

Never change the dose on your own.

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

How much to take

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

How to take it

Always take ATRIPLA on an empty stomach.

Swallow ATRIPLA with water.

Taking ATRIPLA at bedtime may make some side effects less bothersome.

If you forget to take ATRIPLA

Do not miss a dose of ATRIPLA.

Take the missed dose right away, unless it is almost time for your next dose.

Carry on with your regular dosing schedule.

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

If you take too much (overdose)

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

While you are taking ATRIPLA

Things you must do

Tell your doctor or pharmacist that you are taking ATRIPLA if you are about to be started on any other medicines. Your doses may need adjustment.

When your ATRIPLA 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 ATRIPLA and become harder to treat.

Things you must not do

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

Women taking ATRIPLA should not become pregnant. See “Before you start to take it”.

Women of child-bearing age receiving treatment with ATRIPLA should not rely only on hormone-based birth control, such as pills, injections or implants. ATRIPLA 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.

Taking ATRIPLA with alcohol or other medicines causing similar side effects as ATRIPLA, such as drowsiness, may increase those side effects.

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

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

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

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

Things to be careful of

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

SIDE EFFECTS

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

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

ATRIPLA may cause the following serious side effects:

Lactic Acidosis

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

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

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

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

Serious Liver Problems (hepatotoxicity)

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

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

These side effects may be due to a condition called hepatotoxicity with liver enlargement (hepatomegaly) 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 ATRIPLA, for a long time.

Hepatic Flares

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

You may require medical exams and blood tests for several months after stopping treatment. ATRIPLA 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 ATRIPLA.

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 ATRIPLA.

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

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

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

Pancreatitis

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

  • Severe stomach pain or cramps
  • Nausea
  • Vomiting

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

Common Side Effects:

Patients may have the following during treatment with ATRIPLA:

  • dizziness
  • headache
  • trouble sleeping
  • drowsiness
  • trouble concentrating
  • dizziness
  • unusual dreams

These side effects may be reduced if you take ATRIPLA 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.

Tell your doctor right away if any of these side effects continue or if they bother you.

It is possible that these symptoms may be more severe if ATRIPLA is used with alcohol or mood altering (recreational) drugs.

Other common side effects may include:

  • 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

Other possible side effects:

  • Changes in body fat. 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 ATRIPLA.

Tell your doctor or pharmacist if you notice any side effects while taking ATRIPLA.

Contact your doctor before stopping ATRIPLA because of side effects or for any other reason.

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

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

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

After taking ATRIPLA

Storage

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

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

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

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

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

GENERAL ADVICE

Talk to your doctor or pharmacist if you have any questions about this medicine or your condition.

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

Do not use ATRIPLA for a condition for which it was not prescribed.

Do not give ATRIPLA to other people, even if they have the same symptoms that you have. It may harm them.

This leaflet summarises the most important information about ATRIPLA. If you would like more information, ask your doctor or pharmacist. Your doctor or pharmacist can give you information about this medicine that was written for doctors or pharmacists (Product Information/Data Sheet).

PRODUCT DESCRIPTION

What the tablets look like

ATRIPLA tablets are capsule-shaped and pink in colour.

Each tablet is debossed with “123” on one side and plain on the other side.

ATRIPLA tablets are supplied in bottles containing 30 tablets.

Ingredients

Each ATRIPLA tablet contains the following active ingredients:

  • tenofovir disoproxil fumarate
  • emtricitabine
  • efavirenz

Each ATRIPLA tablet also contains the following inactive ingredients:

  • croscarmellose sodium
  • hyprolose
  • magnesium stearate
  • microcrystalline cellulose
  • sodium lauryl sulphate
  • iron oxide black
  • iron oxide red
  • macrogol
  • poly(vinyl alcohol)
  • talc
  • titanium dioxide

SPONSOR

ATRIPLA tablets are supplied in Australia by:

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

In New Zealand:

Gilead Sciences (NZ)
c/- PricewaterhouseCoopers
Level 8 Pricewaterhousecoopers Tower
188 Quay Street
Auckland 1010

Date of preparation: 07 May 2019

AUST R 154491

ATRIPLA is a trademark of Gilead Sciences, LLC. HARVONI, EPCLUSA, EMTRIVA, TRUVADA, VOSEVI and VIREAD are trademarks of Gilead Sciences, Inc. STOCRIN is a trademark of Merck & Co., Inc. Other brands listed are the trademarks of their respective owners and are not trademarks of Gilead Sciences.

Published by MIMS July 2019

BRAND INFORMATION

Brand name

Atripla

Active ingredient

Tenofovir disoproxil fumarate; Emtricitabine; Efavirenz

Schedule

S4

 

1 Name of Medicine

Atripla (tenofovir disoproxil fumarate/ emtricitabine/ efavirenz).

6.7 Physicochemical Properties

Chemical structure.

Tenofovir disoproxil fumarate.

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

Emtricitabine.

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

Efavirenz.

The chemical name of efavirenz is (S)-6-chloro-4-(cyclopropylethynyl)- 1,4-dihydro-4-(trifluoromethyl)- 2H-3,1-benzoxazin-2-one. It has a molecular formula of C14H9ClF3NO2 and a molecular weight of 315.68. It has the following structural formula:

CAS number.

Tenofovir DF CAS registry number: 202138-50-9.
Emtricitabine CAS registry number: 143491-57-0.
Efavirenz CAS registry number: 154598-52-4.
Tenofovir DF has a solubility of 13.4 mg/mL in water at 25°C. The partition coefficient (log p) for tenofovir disoproxil is 1.25 and the pKa is 3.75.
Emtricitabine has a solubility of approximately 112 mg/mL in water at 25°C. The partition coefficient (log p) for emtricitabine is -0.43 and the pKa is 2.65.
Efavirenz is practically insoluble in water (< 10 microgram/mL).

2 Qualitative and Quantitative Composition

Each film-coated tablet contains 300 mg tenofovir disoproxil fumarate (tenofovir DF) which is equivalent to 245 mg of tenofovir disoproxil, 200 mg emtricitabine and 600 mg efavirenz.
Tenofovir DF is a white to off-white crystalline powder.
Emtricitabine is a white to off-white crystalline powder.
Efavirenz is a white to slightly pink crystalline powder.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Atripla is available as film-coated tablets. The tablets are capsule shaped and pink in colour. Each tablet is debossed with '123' on one side and plain on the other side.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

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

Mechanism of action.

Tenofovir disoproxil fumarate.

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

Emtricitabine.

A synthetic nucleoside 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.

Is a selective 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.

Pharmacodynamics.

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 Cmax 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 Cmax 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 disoproxil fumarate, 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 disoproxil fumarate.

The in vitro antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, primary monocyte/ macrophage cells and peripheral blood lymphocytes. The IC50 (50% inhibitory concentration) values for tenofovir were in the range of 0.04 to 8.5 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 Atripla and efavirenz have not been conducted.

Tenofovir disoproxil fumarate 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 disoproxil fumarate, 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 disoproxil fumarate.

HIV-1 isolates with reduced susceptibility to tenofovir have been selected in vitro. These viruses expressed a K65R mutation in RT and showed a 2 to 4-fold reduction in susceptibility to tenofovir. In addition, a K70E substitution in HIV-1 RT 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 DF in combination with other antiretroviral agents. In treatment naïve patients treated with tenofovir DF + 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 DF + 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 DF treated patients with virologic failure showed reduced susceptibility to tenofovir. Genotypic analysis of the resistant isolates showed the K65R mutation in the HIV-1 RT 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 RT 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 RT 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 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 Truvada (tenofovir DF/ emtricitabine) group and in 72% (21/29) analysed patients in the Combivir (zidovudine/ lamivudine group).

Cross resistance.

Cross resistance among certain RT inhibitors has been recognized.

Tenofovir disoproxil fumarate.

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 DF 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 RT mutation showed reduced susceptibility to tenofovir DF. Multinucleoside resistant HIV-1 with a T69S double insertion mutation in the RT 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 Atripla 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 Atripla was used in antiretroviral treatment experienced patients and the demonstration of bioequivalence between Atripla tablets and the three individual agents coadministered under fasting conditions.

Study 934: tenofovir DF + 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 Cockroft 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 DF, 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 DF + 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 DF + 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 DF + 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 DF + 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) analyzed 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 RT gene. No patient in either treatment group developed the K65R or K70E mutation, which is associated with reduced susceptibility to Viread.

Study 073: Atripla 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 Atripla 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 NNRTI. 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 Atripla 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 Atripla (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 Atripla group was to be declared noninferior to the stable baseline regimen (SBR) group if the lower confidence limit of the responder difference (Atripla minus SBR) was greater than -0.15.
Table 5 summarises treatment outcomes through week 48.
The responder difference (HIV-1 RNA < 200 copies/mL), Atripla minus SBR, was 1% (95% CI: -7% to 9%, p = 0.82) at week 48. Atripla was noninferior to SBR in this study.
There were no differences in HIV symptom index, quality of life and adherence between the Atripla and the SBR group. Differences were reported in medication preference; the proportion of patients reporting they preferred Atripla compared to their previous regimen increased from 64% at week 4 to 85% at week 48.

5.2 Pharmacokinetic Properties

One Atripla 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 DF, emtricitabine and efavirenz were used to determine the pharmacokinetics of tenofovir DF, emtricitabine and efavirenz in HIV infected patients.

Tenofovir disoproxil fumarate.

The pharmacokinetic properties of tenofovir DF are summarized in Table 6. Following oral administration of tenofovir DF, maximum tenofovir serum concentrations are achieved in 1.0 ± 0.4 hour. In vitro binding of tenofovir to human plasma proteins is < 0.7% and is independent of concentration over the range of 0.01 to 25 microgram/mL. Approximately 70 to 80% of the intravenous dose of tenofovir is recovered as unchanged drug in the urine. Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion. Following a single oral dose of tenofovir DF, the terminal elimination half-life of tenofovir is approximately 17 hours.

Emtricitabine.

The pharmacokinetic properties of 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 postdose. 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 Cmax, mean Cmin 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 Cmax was 12.9 microM, steady-state Cmin 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 AUC0-∞ of efavirenz and 79% increase in mean Cmax 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 nonprotein 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.

Atripla 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 Cmax of efavirenz by 28% and 79%, respectively, compared to administration in the fasted state. Compared to fasted administration, dosing of tenofovir DF and emtricitabine in combination with either a high fat meal or a light meal increased the AUC and Cmax of tenofovir by approximately 40% and 14%, respectively, without affecting emtricitabine exposures.

Age and gender.

Children and geriatric patients.

Pharmacokinetic studies with Atripla 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 DF, emtricitabine and efavirenz are similar in male and female patients.
The pharmacokinetics of tenofovir DF have not been specifically studied in different ethnic groups.

Patients with impaired renal function.

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

Patients with hepatic impairment.

Atripla 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 Atripla. Atripla should be administered with caution to these patients (see Section 4.4 Special Warnings and Precautions for Use).

Tenofovir disoproxil fumarate and emtricitabine.

The pharmacokinetics of tenofovir following a 300 mg dose of tenofovir DF have been studied in non-HIV infected patients with moderate to severe hepatic impairment. There were no substantial alterations in tenofovir pharmacokinetics in patients with hepatic impairment compared with unimpaired patients. The pharmacokinetics of 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 disoproxil fumarate.

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

Carcinogenicity and mutagenicity.

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

Tenofovir disoproxil fumarate.

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

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

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.
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).

4 Clinical Particulars

4.1 Therapeutic Indications

Atripla 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.

4.3 Contraindications

Atripla is contraindicated in patients with known hypersensitivity to any of the active substances or any other component of the tablets.
Atripla 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).
Atripla 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.

Atripla 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

Atripla is a fixed dose combination of tenofovir DF, emtricitabine and efavirenz and should not be administered concomitantly with other medicinal products containing any of the same active components, tenofovir DF, 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, or tenofovir alafenamide or with adefovir dipivoxil.

General.

Patients receiving Atripla 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 Atripla, 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 Atripla 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 Atripla 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).

Lactic acidosis/ severe hepatomegaly with steatosis.

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases have been reported with the use of antiretroviral nucleoside analogues including the tenofovir DF component of Atripla, 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 Atripla 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).

Renal impairment.

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

Bone effects.

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

Liver disease.

Atripla 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 Atripla 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 Atripla needs to be weighed against the unknown risks of significant liver toxicity (see Section 4.8 Adverse Effects (Undesirable Effects)).

HIV and hepatitis B virus (HBV) coinfection.

Discontinuation of Atripla therapy in patients coinfected with HIV and HBV may be associated with severe acute exacerbations of hepatitis due to the emtricitabine and tenofovir DF components of Atripla. Patients coinfected with HIV and HBV should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping Atripla treatment. If appropriate, initiation of antihepatitis B therapy may be warranted. In patients with advanced liver disease or cirrhosis, discontinuation of antihepatitis B therapy is not recommended since post-treatment exacerbation of hepatitis may lead to hepatic decompensation.

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 Atripla when coadministered with a drug with a known risk of torsades de pointes or when administered to patients at higher risk of torsades 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, 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 Atripla, 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 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. Atripla can be reinitiated in patients interrupting therapy because of rash. Use of appropriate antihistamines and/or corticosteroids is recommended when Atripla 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 NRTIs 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 DF, 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 Atripla 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 Atripla be taken on an empty stomach, preferably at bedtime.

Paediatric use.

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

Use in the elderly.

Clinical studies of tenofovir DF, 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 Atripla to the elderly, keeping in mind the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

4.5 Interactions with Other Medicines and Other Forms of Interactions

General.

As Atripla contains tenofovir DF, emtricitabine and efavirenz, any interactions that have been identified with these agents individually may occur with Atripla.

Tenofovir disoproxil fumarate 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, coadministration of tenofovir DF and emtricitabine with drugs that are eliminated by active tubular secretion may increase serum concentrations of tenofovir, emtricitabine and/or the coadministered 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 DF 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) 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 DF and ribavirin. Similarly, no clinically significant drug interactions have been observed between emtricitabine and famciclovir, indinavir, stavudine, zidovudine and tenofovir DF.

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.
Atripla should not be administered concurrently with voriconazole (see Section 4.3 Contraindications). Caution should be exercised when administering Atripla 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, Cmax and Cmin 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 Atripla with respect to safety and efficacy have not been established. An additional 100 mg/day (300 mg total) of ritonavir, is recommended when Atripla is administered with fosamprenavir/ ritonavir once daily. No change in the ritonavir dose is required when Atripla 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 Atripla. Therefore coadministration of atazanavir/ ritonavir and Atripla 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 DF affects the pharmacokinetics of atazanavir (see Table 4). 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 DF, atazanavir increased tenofovir Cmax by 14% and AUC by 24%.

Indinavir.

Insufficient data are available to make a dosing recommendation with Atripla. 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 Atripla. When tenofovir DF 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, Cmax, and Cmin 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 Atripla 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 Cmax were decreased by 62% and 45 to 50%, respectively. Saquinavir should not be used as sole protease inhibitor (PI) in combination with Atripla. No data are available on the potential interactions of efavirenz with the combination of saquinavir and ritonavir.

Didanosine.

Concomitant dosing of tenofovir DF with didanosine buffered tablets or enteric coated capsules significantly increase the Cmax and AUC of didanosine. When didanosine 250 mg enteric coated capsules were administered with tenofovir DF, systemic exposures of didanosine were similar to those seen with the 400 mg enteric coated capsules alone under fasted conditions. The mechanism of this interaction is unknown. Table 1 summarises the effects of tenofovir DF on the pharmacokinetics of didanosine.
As a result of this increased exposure, patients receiving Atripla 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 DF with didanosine at a dose of 400 mg daily. In adults weighing ≥ 60 kg, the didanosine dose should be reduced to 250 mg daily when it is coadministered with Atripla. Data are not available to recommend a dose adjustment of didanosine for patients weighing < 60 kg. When coadministered, Atripla 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 Atripla should be under fasted conditions.
Coadministration of Atripla 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 Cmax 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 Cmin 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, Cmax, and Cmin of telaprevir were decreased by 18%, 14%, and 25% relative to telaprevir 750 mg every 8 hours administered alone and the AUC, Cmax, and Cmin 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 Atripla is not recommended. Refer to the prescribing information for simeprevir for more information.

Ledipasvir/ sofosbuvir.

Concomitant administration of Harvoni (ledipasvir/ sofosbuvir) with Atripla resulted in increases in tenofovir AUC, Cmax and Cmin of approximately 98%, 79% and 163%, respectively, compared with Atripla alone. No dose adjustment of Atripla or Harvoni is required. Patients receiving Atripla with Harvoni 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 Epclusa (sofosbuvir/velpatasvir) with Atripla increased tenofovir AUC, Cmax, and Cmin by 81%, 77%, and 121%, respectively, compared with Atripla alone, and decreased velpatasvir AUC, Cmax, and Cmin by 53%, 47%, and 57%, respectively, compared with Epclusa alone. Similarly, tenofovir exposure is expected to increase and velpatasvir and voxilaprevir are expected to decrease upon coadministration of Vosevi (sofosbuvir/velpatasvir/voxilaprevir) and Atripla. Coadministration of Atripla with Epclusa or Vosevi is not recommended.

Sofosbuvir.

Concomitant administration of Sovaldi (sofosbuvir) with Atripla resulted in increases in tenofovir Cmax by 25%, compared with Atripla alone. Tenofovir AUC and Cmin were unaltered by sofosbuvir coadministration. No dose adjustment of Atripla or Sovaldi is required.

Elbasvir/grazoprevir.

Coadministration of efavirenz with elbasvir/grazoprevir reduced elbasvir AUC and Cmax by 54% and 45%, respectively, and reduced grazoprevir AUC and Cmax by 83% and 87%, respectively, compared to elbasvir/grazoprevir alone. Concomitant administration of Atripla 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 Atripla 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 Cmax of clarithromycin decreased 39 and 26%, respectively, while the AUC and Cmax 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 Cmax and 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 Atripla. 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 Cmax by 20% in uninfected volunteers. An additional 200 mg/day (total 800 mg/day) of efavirenz is recommended when rifampicin is coadministered with Atripla 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, Cmax and Cmin of itraconazole. Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered.

Voriconazole.

Voriconazole increased efavirenz AUC and Cmax by 44% and 38%, respectively while efavirenz decreased voriconazole AUC and Cmax by 77% and 61% respectively in uninfected volunteers. Coadministration of Atripla 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 Cmax of posaconazole by 50% and 45%, respectively, compared to posaconazole administered alone. Concomitant use of posaconazole and Atripla 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 Atripla 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, bodyweight and height, CYP2C19 genotype) in the multiple variable linear regression analysis, geometric mean atovaquone AUC and Cmax 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 Atripla 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, Cmax, and Cmin of carbamazepine decreased by 27%, 20% and 35%, respectively, while the steady-state AUC, Cmax, and Cmin of efavirenz decreased by 36%, 21%, and 47%, respectively. The steady-state AUC, Cmax, and Cmin 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, 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 Cmax 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 Cmax 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 Cmax 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 Cmax 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, Cmax and Cmin 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).

Antidepressants.

Sertraline.

The Cmax, 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 Cmax of bupropion by 55% and 34%, respectively, compared to bupropion alone. Hydroxybupropion AUC was unchanged and hydroxybupropion Cmax 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 Atripla. Immunosuppressants metabolized by CYP3A4 are not anticipated to affect exposure of efavirenz. There were no clinically significant pharmacokinetic interactions when tenofovir DF/ 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, Cmax, and Cmin, respectively, and 83%, 80%, and 86% decrease in levonorgestrel AUC, Cmax and Cmin, 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 Atripla when coadministered with a drug with a known risk of torsades 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 of fertility.

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

Tenofovir disoproxil fumarate.

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

Emtricitabine.

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 a pregnant women. Pregnancy should be avoided in women receiving Atripla. 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 Atripla. If a woman takes Atripla during the first trimester of pregnancy, or becomes pregnant whilst taking Atripla, 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 Atripla is recommended.
There are no well controlled clinical studies of Atripla in pregnant women. No embryofoetal development studies have been conducted with tenofovir DF, emtricitabine and efavirenz in combination. Atripla 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 postmarketing 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, micro-ophthalmia 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 disoproxil fumarate.

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

4.8 Adverse Effects (Undesirable Effects)

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.
As Atripla contains tenofovir DF, 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 DF), 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 (see Table 4) and study 073, the following adverse events were observed in clinical studies of tenofovir DF, emtricitabine or efavirenz in combination with other antiretroviral agents.

Tenofovir disoproxil fumarate.

More than 12,000 patients have been treated with Viread alone or in combination with other antiretroviral medicinal products for periods of 28 days to 215 weeks in phase I-III clinical trials and expanded access studies. A total of 1,544 patients have received Viread 300 mg once daily in phase I-III clinical trials; over 11,000 patients have received Viread in expanded access studies.
The most common adverse events that occurred in patients receiving Viread with other antiretroviral agents in clinical trials were mild to moderate gastrointestinal events, such as nausea, diarrhoea, vomiting and flatulence.

Emtricitabine.

More than 2000 adult patients with HIV 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, Nervous system symptoms), psychiatric symptoms (see Section 4.4, Psychiatric symptoms) and rash (see Section 4.4, Skin rash).

Psychiatric symptoms (see Section 4.4).

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).

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 to 2 days of therapy and generally resolve after the first 2 to 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 postdose 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).

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 Stevens-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. Atripla can be reinitiated in patients who interrupted therapy because of rash. Use of appropriate antihistamines and/or corticosteroids is recommended when Atripla 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 disoproxil fumarate + emtricitabine + efavirenz.

Study 934.

Study 934 was an open label active controlled study in which 511 antiretroviral naïve patients received either tenofovir DF, 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 Atripla 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 Atripla 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 Atripla 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 Atripla 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.

Post marketing 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 disoproxil fumarate (tenofovir DF). Because these events have been reported voluntarily from a population of unknown size, estimates of frequency cannot be made.

Efavirenz-, emtricitabine- and/or tenofovir DF-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 DF.

Immune system disorders.

Allergic reaction (including angioedema).

Metabolism and nutrition disorders.

Hypokalaemia, hypophosphataemia, lactic acidosis.

Respiratory, thoracic and mediastinal disorders.

Dyspnoea.

Gastrointestinal disorders.

Increased amylase, abdominal pain, pancreatitis.

Hepatobiliary disorders.

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

Skin and subcutaneous tissue disorders.

Rash.

Musculoskeletal and connective tissue disorders.

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

Renal and urinary disorders.

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

General disorders and administration site conditions.

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

Exacerbations of hepatitis after discontinuation of treatment.

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

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.

Gynaecomastia.
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.

Paediatric use.

Atripla 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.

4.2 Dose and Method of Administration

Dosage.

Adults.

The recommended dose of Atripla 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.

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

Elderly.

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

Dosage adjustment.

Renal impairment.

Atripla is not recommended for patients with moderate or severe renal impairment (creatinine clearance (ClCr) < 50 mL/min). Patients with moderate or severe renal impairment require dose interval adjustments of tenofovir DF 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 DF with emtricitabine in patients with mild renal impairment (ClCr 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 Atripla in patients with mild renal impairment.

Hepatic impairment.

Atripla 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 Atripla, however caution should be exercised in administering Atripla to these patients. (See Section 4.4 Special Warnings and Precautions for Use).
Where discontinuation of Atripla is necessary due to one of the components, or where dose modification is necessary, separate preparations of tenofovir DF, 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 Atripla on an empty stomach as compared to the individual component tenofovir DF when taken with food. Administration of Atripla on an empty stomach may decrease tenofovir exposure and may lead to a decrease in the efficacy of Atripla. Patients should therefore be monitored carefully to detect any sign of virological failure and/or emergence of resistance to tenofovir DF.

4.7 Effects on Ability to Drive and Use Machines

Atripla 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.

4.9 Overdose

Treatment of overdose with Atripla 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 DF 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 disoproxil fumarate.

Clinical experience of doses higher than the therapeutic dose of Viread 300 mg is available from two studies. In one study, intravenous tenofovir, equivalent to 16.7 mg/kg/day of tenofovir disoproxil fumarate, was administered daily for 7 days. In the second study, 600 mg of tenofovir disoproxil fumarate 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 Poison Information Centre on 131126 (Australia) and 0800 764 766 (New Zealand).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Atripla tablets contain the following ingredients as excipients:

Tablet core.

Croscarmellose sodium, hyprolose, magnesium stearate, microcrystalline cellulose and sodium lauryl sulfate.

Film-coating.

Iron oxide black, iron oxide red, macrogol, poly(vinyl alcohol), talc and titanium dioxide.

6.2 Incompatibilities

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

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Atripla should be stored below 30°C.

6.5 Nature and Contents of Container

Atripla is supplied in high density polyethylene (HDPE) bottles containing 30 tablets and a desiccant (silica gel canister or sachet) and is closed with a screw cap closure.

6.6 Special Precautions for Disposal

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

Summary Table of Changes