Consumer medicine information

Tenofovir EMT GH

Tenofovir disoproxil phosphate + Emtricitabine

BRAND INFORMATION

Brand name

Tenofovir EMT GH

Active ingredient

Tenofovir disoproxil phosphate + Emtricitabine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Tenofovir EMT GH.

What is in this leaflet

Read all of this leaflet carefully before you start taking this medicine.

This leaflet answers some of the common questions about Tenofovir EMT GH. 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 Tenofovir EMT GH medicine. You may need to read it again.

What Tenofovir EMT GH is used for

Tenofovir EMT GH is used to treat Human Immunodeficiency Virus (HIV) infection in adults. This medicine must be taken in combination with other anti-HIV medicines.

Tenofovir EMT GH contains two active ingredients that belong to a group of antiviral medicines known as nucleoside and nucleotide reverse transcriptase inhibitors (NRTI).

Tenofovir EMT GH is used:

  • to treat Human Immunodeficiency Virus-1 (HIV-1) infection in adults when taken in combination with other anti-HIV medicines.
  • to help reduce the risk of getting HIV infection when used with safer sex practices in:
    - HIV-negative men who have sex with men, who are at high risk of getting infected with HIV-1 through sex; and
    - Male-female sex partners when one partner has HIV-1 infection and the other does not.

When Tenofovir EMT GH is used to treat HIV infection

When used with other HIV-1 medicines to treat HIV-1 infection, Tenofovir EMT GH may help:

  • Reduce the amount of HIV-1 in your blood. This is called “viral load”.
  • Increase the number of CD4+ (T) cells in your blood that help fight off other infections.

Reducing the amount of HIV-1 and increasing the CD4+ (T) cells in your blood may help improve your immune system.

This may reduce your risk of death or infections that can happen when your immune system is weak.

Use in Children and Elderly

Tenofovir EMT GH is for adults.

Do not take Tenofovir EMT GH if you are under the age of 18 years.

Do not take Tenofovir EMT GH if you are over the age of 65 before discussing with your doctor.

Does Tenofovir EMT GH cure HIV or AIDS

Tenofovir EMT GH is not a cure for HIV infection or AIDS. While taking Tenofovir EMT GH you may still develop infections or other illnesses associated with HIV infection.

If you have HIV-1 infection, you must keep taking HIV-1 medicines to control HIV-1 infection and decrease HIV-related illnesses.

Does Tenofovir EMT GH reduce the risk of passing HIV to others

Tenofovir EMT GH does not reduce the risk of passing HIV to others through sexual contact or blood contamination.

It is important to continue to take appropriate precautions to prevent passing HIV to others.

When Tenofovir EMT GH is used to reduce the risk of HIV infection

When used with safer sex practices, Tenofovir EMT GH may help to reduce the risk of getting HIV-1 infection if you are at high risk of getting HIV infection.

Tenofovir EMT GH reduces the risk of getting HIV-1 when you have been taking it before you are exposed to HIV-1.

Before you take Tenofovir EMT GH

When you must not take it

Together with your doctor, you need to decide whether Tenofovir EMT GH is right for you.

Do not take Tenofovir EMT GH if you are allergic to:

  • tenofovir;
  • tenofovir disoproxil phosphate;
  • any of the other ingredients of Tenofovir EMT GH.

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 Tenofovir EMT GH are listed in the 'Product Description' section of this leaflet.

Do not take Tenofovir EMT GH if you are already taking any of the components of Tenofovir EMT GH (tenofovir disoproxil phosphate or emtricitabine).

Do not take Tenofovir EMT GH if you are taking lamivudine.

Do not take Tenofovir EMT GH if you are taking adefovir dipivoxil.

Do not take Tenofovir EMT GH if you are taking tenofovir alafenamide.

Do not take Tenofovir EMT GH 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 Tenofovir EMT GH if the packaging is torn or shows signs of tampering.

If you are not sure whether you should be taking Tenofovir EMT GH, talk to your doctor.

For people using Tenofovir EMT GH to reduce the risk of getting HIV-1 infection
Tenofovir EMT GH can only help reduce your risk of getting HIV-1 before you are infected.

Do not take Tenofovir EMT GH to help reduce your risk of getting HIV-1 if:

  • you already have HIV-1 infection. If you are HIV-positive, you need to take other medicines with Tenofovir EMT GH to treat HIV. Tenofovir EMT GH by itself is not a complete treatment for HIV.
  • you do not know your HIV-1 infection status. You may already be HIV-positive. You need to take other HIV-1 medicines with Tenofovir EMT GH to treat HIV-1.
  • you have had recent flu-like symptoms. Many HIV-1 tests can miss HIV-1 infection in a person who has recently become infected. If you have flu-like symptoms, you could have recently become infected with HIV-1. Tell your healthcare provider if you had a flu-like illness within the last month before starting Tenofovir EMT GH or at any time while taking Tenofovir EMT GH. Symptoms of new HIV-1 infection include: tiredness, fever, joint or muscle aches, headache, sore throat, vomiting or diarrhoea, rash, night sweats or enlarged lymph nodes in the neck or groin.

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, trying to become pregnant or breastfeeding.

The safe use of Tenofovir EMT GH in pregnancy has not been demonstrated. For this reason, it is important that women of child-bearing age receiving treatment with Tenofovir EMT GH use an effective method of contraception to avoid becoming pregnant. If you are a female who is taking Tenofovir EMT GH to reduce the risk of getting HIV-1 infection and you become pregnant while taking Tenofovir EMT GH, talk to your healthcare provider to decide if you should keep taking Tenofovir EMT GH.

The active substances in the innovator medicine, TRUVADA (tenofovir disoproxil fumarate and emtricitabine), have been found in breast milk at low concentrations.

Consequently, it is recommended that nursing mothers do not breast-feed during treatment with Tenofovir EMT GH. 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 liver problems, including hepatitis B, or C virus infection.

Tell your doctor if you are taking medication to treat your hepatitis C virus (HCV) infection (eg. ledipasvir/sofosbuvir, sofosbuvir/velpatasvir).

Tell your doctor if you have kidney problems.

Tell your doctor if you have or have ever had abnormal bones or bone difficulties.

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

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

Avoid doing things that increase your risk of getting HIV-1 or spreading HIV-1 to other people:

  • Do not have any kind of sex without protection. Always practice safe sex. Use latex or non-latex condoms, except lambskin, to reduce contact with semen, vaginal fluids, or blood.
  • Do not share personal items that can have blood or body fluids on them, such as toothbrushes and razor blades.
  • Do not share or re-use needles or other injection equipment.

Ask your healthcare provider if you have any questions about how to prevent getting HIV-1 or spreading HIV-1 to other people.

If you have a long-standing viral infection of your liver (hepatitis B) it may flare up when you stop taking Tenofovir EMT GH. This can cause serious illness particularly if your liver is already not working very well. If you have both HIV and hepatitis B, when you start taking Tenofovir EMT GH and even after you stop, your doctor is likely to arrange tests from time to time to check how well your liver is working.

Taking other medicines

If you have HIV infection, your doctor will generally prescribe Tenofovir EMT GH in combination with other anti-HIV medicines.

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

Tell your doctor if are taking:

  • didanosine (also known as ddI or Videx);
  • ledipasvir/ sofosbuvir (HARVONI);
  • sofosbuvir/velpatasvir (EPCLUSA);
  • sofosbuvir/ velpatasvir/ voxilaprevir (eg. VOSEVI).

Some medicines may affect the way others work. Your doctor or pharmacist will be able to tell you what to do when taking Tenofovir EMT GH tablets with other medicines.

How to take Tenofovir EMT GH

Take Tenofovir EMT GH exactly as prescribed. The usual dose is one (1) Tenofovir EMT GH tablet taken orally once daily. Take Tenofovir EMT GH at the same time each day to keep Tenofovir EMT GH blood levels constant.

Tenofovir EMT GH is best taken with a meal or just afterwards, however taking it without food should not reduce the effectiveness of the medicine.

Tenofovir EMT GH is absorbed rapidly. Do not take another Tenofovir EMT GH dose if vomiting has occurred unless it occurs within one (1) hour after taking Tenofovir EMT GH.

How much to take

Take one Tenofovir EMT GH tablet once daily or as advised by your doctor.

If you are not sure how much Tenofovir EMT GH you should take, check with your doctor or pharmacist. Do not change the amount of Tenofovir EMT GH you take unless told to do so by your doctor.

Your doctor will tell you how much Tenofovir EMT GH to take and how often to take it. You will also find this information on the label of your medicine container.

Because your medicine helps to control your condition, but does not cure it, you will need to take Tenofovir EMT GH every day. If you are taking Tenofovir EMT GH to reduce the risk of HIV-1 infection, take Tenofovir EMT GH every day for the period of time as prescribed by your doctor.

Do not miss any doses of Tenofovir EMT GH. Missing a dose lowers the amount of medicine in your blood.

Do not stop taking Tenofovir EMT GH without first talking to your doctor.

If you forget to take it

It is important to take the prescribed daily dose in order to get the maximum benefit of treatment.

If you forget to take your daily dose of Tenofovir EMT GH, take it as soon as you remember that day, and then go back to taking your medicine as you would normally.

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

Do not take more than one Tenofovir EMT GH tablet in a day.

If you take too much (overdose)

Immediately telephone your doctor or Poisons Information Centre (telephone 13 11 26), or go to the Accident and Emergency department at your nearest hospital if you think you or anyone else may have taken too many Tenofovir EMT GH tablets. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking Tenofovir EMT GH

Things you must do

Tell your doctor or pharmacist that you are taking Tenofovir EMT GH if you are about to be started on any other medicines.

Tell your doctor if you become pregnant or are trying to become pregnant.

Tell your doctor if for any reason you have not taken your medicine exactly as prescribed.

If you are taking Tenofovir EMT GH to reduce your risk of getting HIV

Just taking Tenofovir EMT GH may not keep you from getting HIV.

You must continue using safe sex practices while you are taking Tenofovir EMT GH to reduce your risk of getting HIV.

You must stay HIV-negative to keep taking Tenofovir EMT GH to reduce your risk of infection.

Know your HIV status and the HIV status of your partners.

Get tested for HIV at least every three (3) months or when your healthcare provider tells you.

Get tested for other sexually transmitted infections such as syphilis and gonorrhoea. These infections make it easier for HIV to infect you. Tenofovir EMT GH will not stop you from getting these other infections.

If you think you were exposed to HIV, tell your healthcare provider right away. They may want to do more tests to be sure you are still HIV-negative.

Get information and support to help reduce risky sexual behaviour.

Have fewer sex partners.

Do not miss any doses of Tenofovir EMT GH. Missing doses may increase your risk of getting HIV infection.

If you do become HIV-positive, you need more medicine than Tenofovir EMT GH alone to treat HIV. Tenofovir EMT GH by itself is not a complete treatment for HIV.

If you have HIV and take only Tenofovir EMT GH, over time your HIV may become harder to treat.

Things you must not do

Do not stop taking Tenofovir EMT GH or change the dose without first checking with your doctor.

Do not give this medicine to anyone else even if their symptoms seem similar to yours.

Do not use Tenofovir EMT GH to treat any other complaints unless you doctor says to.

Things to be careful of

Be careful driving or operating machinery until you know how Tenofovir EMT GH affects you.

Side effects

Like all medicines, Tenofovir EMT GH 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 Tenofovir EMT GH, even if you do not think the problems are connected with the medicine or are not listed in this leaflet.

The most common side effects in people taking Tenofovir EMT GH to treat HIV-1 infection include:

  • diarrhoea;
  • nausea;
  • tiredness;
  • headache;
  • dizziness;
  • depression;
  • problems sleeping;
  • abnormal dreams;
  • rash.

Common side effects in people who take Tenofovir EMT GH to reduce the risk of getting HIV-1 infection include:

  • stomach-area (abdominal) pain;
  • headache;
  • decreased weight.

Ask your doctor or pharmacist to answer any question you may have about these or other effects.

Allergy

Some people are allergic to medicines.

If you have any of the following symptoms soon after taking your medicine, DO NOT TAKE ANY MORE Tenofovir EMT GH 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. All of these side effects 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 medicines.

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;
  • nausea;
  • stomach-area pains.

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

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. 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 analogue-containing medicines, like Tenofovir EMT GH, for a long time.

Hepatic Flares

Your doctor should test you to see if you have chronic hepatitis B infection before you start taking Tenofovir EMT GH.

If you have chronic hepatitis B infection you should not stop your Tenofovir EMT GH treatment without first discussing this with your doctor, as some patients have had blood tests or symptoms indicating a worsening of their hepatitis (“hepatic flare”) after stopping individual components (tenofovir disoproxil fumarate and emtricitabine) of the innovator product Truvada.

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

Tenofovir EMT GH is not approved for the treatment of hepatitis B, so you must discuss your hepatitis B therapy with your healthcare provider.

Other possible side effects

This list of side effects is not complete. Tenofovir EMT GH may cause other serious side effects. Tell your doctor if you notice anything else that is making you feel unwell, even if it is not on this list.

New and worse kidney problems

If you have had kidney problems in the past or need to take another drug that can cause kidney problems, your healthcare provider may need to perform additional blood tests to check your kidneys.

Bone problems

Bone problems can happen in some people who take Tenofovir EMT GH. Bone problems include bone pain, or softening or thinning of bones, which may lead to fractures. Your healthcare provider may need to do tests to check your bones.

Signs and symptoms of inflammation

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

Some people may get other side effects while taking Tenofovir EMT GH. If you are concerned, talk to your doctor or pharmacist.

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

Do not be alarmed by this list of possible side-effects. Most of them are very rare and you may not experience any of them.

After taking Tenofovir EMT GH

Storage

Keep Tenofovir EMT GH 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 Tenofovir EMT GH tablets in a cool, dry place where it stays below 25°C.

Do not store Tenofovir EMT GH or any other medicine in a bathroom or near a sink.

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

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

Disposal

If your doctor tells you to stop taking Tenofovir EMT GH, or the tablets have passed their expiry date, ask your pharmacist what to do with any tablets left over.

Product description

What it looks like

Tenofovir EMT GH tablets are oval-shaped and blue in colour and are plain on both sides.

Tenofovir EMT GH tablets are supplied in bottles containing 30 and 100 tablets with a child resistant closure.

Not all pack sizes may be marketed.

Ingredients

Active ingredient

Each Tenofovir EMT GH tablet contains the following active ingredients:

  • 291 mg tenofovir disoproxil phosphate (which is equivalent to 245 mg of tenofovir disoproxil);
  • 200 mg emtricitabine.

Note: The innovator product contains 300 mg of tenofovir disoproxil fumarate and 200 mg of emtricitabine. 291 mg of tenofovir disoproxil phosphate is equivalent to 300 mg of tenofovir disoproxil fumarate. Bioequivalence has been established between the two salt forms of tenofovir disoproxil.

Other ingredients

  • croscarmellose sodium;
  • microcrystalline cellulose;
  • mannitol;
  • colloidal anhydrous silica;
  • stearic acid.

The tablet film-coating (OPADRY II complete film coating system 39K505001 Blue [PI 138537]) contains the following ingredients:

  • triacetin;
  • hypromellose;
  • indigo carmine aluminium lake;
  • lactose monohydrate;
  • titanium dioxide.

Australian Registration Numbers

Tenofovir EMT GH: AUST R 269196.

Distributor

Generic Health Pty Ltd
Suite 2, Level 2
19-23 Prospect Street
Box Hill, VIC, 3128
Australia
Email: ghinfo@generichealth.com.au
Telephone: +61 3 9809 7900
Website: www.generichealth.com.au

This leaflet was prepared in February 2021.

Published by MIMS March 2021

BRAND INFORMATION

Brand name

Tenofovir EMT GH

Active ingredient

Tenofovir disoproxil phosphate + Emtricitabine

Schedule

S4

 

Notes

Distributed by Generic Health Pty Ltd

1 Name of Medicine

Tenofovir disoproxil phosphate and emtricitabine.

2 Qualitative and Quantitative Composition

Each Tenofovir EMT GH tablet contains 291 mg tenofovir disoproxil phosphate and 200 mg emtricitabine.

List of excipients with known effects.

Mannitol.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

The tablets are blue, oval-shaped, biconvex, film-coated, plain on both sides.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of HIV-1 infection.

Tenofovir EMT GH is indicated for the treatment of HIV infected adults over the age of 18 years, in combination with other antiretroviral agents.

Pre-exposure prophylaxis.

Tenofovir EMT GH is indicated in combination with safer sex practices for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 in adults at high risk. This indication is based on clinical trials in men who have sex with men (MSM) at high risk for HIV-1 infection and in heterosexual serodiscordant couples (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

4.2 Dose and Method of Administration

Each Tenofovir EMT GH tablet contains 291 mg of tenofovir disoproxil phosphate and 200 mg of emtricitabine. The innovator product contains 300 mg of tenofovir disoproxil fumarate and 200 mg of emtricitabine - 291 mg of tenofovir disoproxil phosphate is equivalent to 300 mg of tenofovir disoproxil fumarate. Bioequivalence has been established between the two salt forms of tenofovir disoproxil.

Recommended dose for treatment of HIV-1 infection.

Adults.

The recommended dose of Tenofovir EMT GH is one tablet (containing 291 mg tenofovir disoproxil phosphate and 200 mg emtricitabine), taken orally, once daily. In order to optimise the absorption of tenofovir, it is recommended that Tenofovir EMT GH tablets should be taken with food.

Recommended dose for pre-exposure prophylaxis.

Adults.

The dose of Tenofovir EMT GH in HIV-1 uninfected adults is one tablet (containing 291 mg tenofovir disoproxil phosphate and 200 mg of emtricitabine), taken orally, once daily. In order to optimise the absorption of tenofovir, it is recommended that Tenofovir EMT GH should be taken with food.

Children.

The safety and efficacy of tenofovir disoproxil and emtricitabine combination tablets have not been established in patients under the age of 18 years. Consequently, Tenofovir EMT GH tablets should not be administered to children or adolescents.

Elderly.

No data are available on which to make a dose recommendation for patients over the age of 65 years.

Dosage adjustment.

Renal insufficiency.

Treatment of HIV-1 infection.

Significantly increased drug exposures occurred when tenofovir disoproxil or emtricitabine were administered to patients with moderate to severe renal impairment (See product information specific to tenofovir disoproxil tablets and product information specific to emtricitabine tablets). Therefore, the dosing interval of Tenofovir EMT GH should be adjusted in patients with baseline creatinine clearance < 60 mL/min using the recommendations in Table 1. The safety and effectiveness of these dosing interval adjustment recommendations have not been clinically evaluated, therefore, clinical response to treatment and renal function should be closely monitored in these patients.

Pre-exposure prophylaxis.

Do not use Tenofovir EMT GH for a PrEP indication in HIV-1 uninfected individuals with estimated creatinine clearance below 60 mL/min (see Section 4.4 Special Warnings and Precautions for Use).
Routine monitoring of estimated creatinine clearance should be performed in all individuals with mild renal impairment. If a decrease in estimated creatinine clearance is observed in uninfected individuals while using Tenofovir EMT GH for PrEP, evaluate potential causes and re-assess potential risks and benefits of continued use (see Section 4.4 Special Warnings and Precautions for Use).

Hepatic impairment.

The pharmacokinetics of tenofovir disoproxil and emtricitabine combination tablets or emtricitabine have not been studied in subjects with hepatic impairment. There were no substantial alterations in tenofovir pharmacokinetics in subjects with hepatic impairment compared with unimpaired subjects. No change in tenofovir disoproxil dosing is required in patients with hepatic impairment. Emtricitabine is not significantly metabolised by liver enzymes, so the impact of hepatic impairment should be limited.

4.3 Contraindications

Tenofovir EMT GH is contraindicated in patients with known hypersensitivity to tenofovir, tenofovir disoproxil, tenofovir disoproxil phosphate, emtricitabine or any other components of the tablet.
Tenofovir EMT GH must not be administered to children or adolescents under the age of 18 years.
Tenofovir EMT GH is a fixed dose combination of tenofovir disoproxil phosphate and emtricitabine. Tenofovir EMT GH should not be administered concomitantly with other medicinal products containing any of the same active components: tenofovir disoproxil, or emtricitabine, drugs containing tenofovir alafenamide, lamivudine or adefovir dipivoxil.
Do not use Tenofovir EMT GH for pre-exposure prophylaxis in individuals with unknown or positive HIV-1 status.
Tenofovir EMT GH should be used in HIV-infected patients only in combination with other antiretroviral agents.

4.4 Special Warnings and Precautions for Use

General.

Patients receiving Tenofovir EMT GH and emtricitabine tablets 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 informed that Tenofovir EMT GH is not a cure for HIV infection.

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 alone or in combination, 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 or uninfected individual with known risk factors for liver disease, however, cases have also been reported in HIV-1 infected patients with no known risk factors. Treatment with Tenofovir EMT GH should be suspended in any patient or uninfected individual 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).

Treatment of HIV-1 infection.

Dosing interval adjustment of Tenofovir EMT GH tablet is required in all patients with creatinine clearance < 60 mL/min (calculated using the Cockcroft Gault equation), (see Section 4.2 Dose and Method of Administration). Renal function should be closely monitored in these patients. The safety and efficacy of Tenofovir EMT GH therapy have not been established in patients with creatinine clearance between 30 and 59 mL/min, and so the potential benefit of Tenofovir EMT GH therapy should be assessed against the potential risk of renal toxicity. Tenofovir EMT GH tablets should not be administered to patients with creatinine clearance < 30 mL/min or patients requiring haemodialysis.

Pre-exposure prophylaxis.

Tenofovir EMT GH tablets for a PrEP indication should not be used if estimated creatinine clearance is less than 60 mL/min. If a decrease in estimated creatinine clearance is observed in uninfected individuals while using Tenofovir EMT GH tablets for PrEP, evaluate potential causes and re-assess potential risks and benefits of continued use (see Section 4.2 Dose and Method of Administration).

Drug interactions.

Tenofovir disoproxil.

When tenofovir disoproxil (as fumarate) was administered with didanosine the Cmax and AUC of didanosine administered as either the buffered or enteric-coated formulation at a dose of 400 mg daily increased significantly (see Table 3). The mechanism of this interaction is unknown. Higher didanosine concentrations could potentiate didanosine-associated adverse events, including pancreatitis, lactic acidosis and neuropathy. Suppression of CD4 cell counts has been observed in patients receiving tenofovir disoproxil (as fumarate) 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 co-administered with Tenofovir EMT GH tablets. Data are not available to recommend a dose adjustment of didanosine for patients weighing < 60 kg.
When co-administered, Tenofovir EMT GH tablets and didanosine EC may be taken under fasted conditions or with a light meal (< 400 kcal, 20% fat). Co-administration of didanosine buffered tablet formulation with Tenofovir EMT GH tablets should be under fasted conditions. Co-administration of Tenofovir EMT GH tablets 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.

Ledipasvir/sofosbuvir, sofosbuvir/velpatasvir, and sofosbuvir/velpatasvir/voxilaprevir.

Co-administration of tenofovir disoproxil (as fumarate) and Harvoni (ledipasvir/sofosbuvir), Epclusa (sofosbuvir/velpatasvir) or Vosevi (sofosbuvir/velpatasvir/voxilaprevir) has been shown to increase tenofovir exposure.
Patients receiving a regimen containing tenofovir disoproxil concomitantly with Harvoni, Epclusa or Vosevi should be monitored for adverse reactions associated with tenofovir disoproxil (see Table 2).

Sofosbuvir.

In a drug interaction study of a regimen containing tenofovir disoproxil (as fumarate) given concomitantly with Sovaldi (sofosbuvir), tenofovir Cmax increased by 25%. Tenofovir AUC and Cmin were unaltered by sofosbuvir coadministration. No dose adjustment of Atripla or Tenofovir EMT GH is required (see Table 2).
Tenofovir disoproxil affects the pharmacokinetics of atazanavir (Table 3). Tenofovir EMT GH 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.
Since tenofovir and emtricitabine are primarily eliminated by the kidneys, co-administration of Tenofovir EMT GH tablets with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of tenofovir, emtricitabine, and/or other renally eliminated drugs.

Bone effects.

Bone toxicities including a reduction in bone mineral density have been observed in tenofovir disoproxil studies in three animal species. Clinically relevant bone abnormalities have not been seen in long term clinical studies (> 3 years) of tenofovir disoproxil in HIV-1 infected adults and were also not seen in studies in HIV-1 uninfected individuals but long term data are lacking in this population. However, bone abnormalities (infrequently contributing to fractures) may be associated with proximal renal tubulopathy (see Section 4.8 Adverse Effects (Undesirable Effects), From post marketing surveillance). If bone abnormalities are suspected during therapy then appropriate consultation should be obtained.

Hepatitis B virus (HBV) infection.

Individuals should be tested for the presence of chronic hepatitis B virus (HBV) before initiating Tenofovir EMT GH. Discontinuation of tenofovir disoproxil/emtricitabine combination tablet therapy in patients infected with HBV may be associated with severe acute exacerbations of hepatitis. Patients infected with HBV should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping tenofovir disoproxil/emtricitabine combination treatment. If appropriate, resumption of anti-hepatitis B therapy may be warranted. In patients with advanced liver disease or cirrhosis, treatment discontinuation is not recommended since post-treatment exacerbation of hepatitis may lead to hepatic decompensation.

Early virologic failure.

Clinical studies in HIV-infected patients have demonstrated that certain regimens that only contain three nucleoside reverse transcriptase inhibitors (NRTI) are generally less effective than triple drug regimens containing two NRTIs in combination with either a non-nucleoside reverse transcriptase inhibitor or a HIV-1 protease inhibitor. In particular, early virological failure and high rates of resistance mutations have been reported in clinical studies of combinations of tenofovir, lamivudine and abacavir or tenofovir, lamivudine and didanosine. Triple nucleoside regimens should therefore be used with caution. Patients on a therapy utilising a triple nucleoside-only regimen should be carefully monitored and considered for treatment modification.

Immune reconstitution syndrome.

Immune reconstitution syndrome has been reported in patients treated with combination antiviral therapy, including emtricitabine and tenofovir disoproxil. 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 jiroveci 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.

Comprehensive management for use in pre-exposure prophylaxis (PrEP).

Tenofovir EMT GH should only be used for PrEP as part of a comprehensive prevention strategy including other HIV-1 prevention measures, because tenofovir disoproxil/emtricitabine combination tablet is not always effective in preventing the acquisition of HIV-1. Counsel uninfected individuals about safer sex practices that include consistent and correct use of condoms, knowledge of their HIV-1 status and that of their partner(s), and regular testing for other sexually transmitted infections that can facilitate HIV-1 transmission (such as syphilis and gonorrhoea). Counsel uninfected individuals prior to initiation of PrEP about risk and benefits, precautions and limitation of pre-exposure prophylaxis using Tenofovir EMT GH tablets.
Tenofovir EMT GH should only be used to reduce the risk of acquiring HIV-1 in individuals confirmed to be HIV-negative immediately prior to initiating and routinely reconfirmed while taking Tenofovir EMT GH tablets for PrEP. Drug resistant HIV-1 variants have been identified in individuals with undetected HIV-1 infection who are taking Tenofovir EMT GH for a PrEP indication, because Tenofovir EMT GH alone does not constitute a complete treatment regimen for HIV-1 infection.
When considering Tenofovir EMT GH for pre-exposure prophylaxis, the uninfected individuals should be counselled about the importance of strict adherence to the recommended Tenofovir EMT GH dosing schedule. The effectiveness of Tenofovir EMT GH in reducing the risk of acquiring HIV-1 is strongly correlated with patient adherence and detectable drug blood levels.
Many HIV-1 tests, such as rapid tests, detect anti-HIV antibodies and may not identify HIV-1 during the acute stage of infection. Prior to initiating Tenofovir EMT GH for a PrEP indication, evaluate seronegative individuals for current or recent signs or symptoms consistent with acute viral infections (e.g. fever, fatigue, myalgia, skin rash, etc.) and ask about potential exposure events (e.g. unprotected, or condom broke during sex with an HIV-1 infected partner) that may have occurred within the last month.
If clinical symptoms consistent with acute viral infection are present and recent (< 1 month) exposures are suspected, delay starting PrEP for at least one month and reconfirm negative HIV-1 status.
While using Tenofovir EMT GH for a PrEP indication, HIV-1 screening tests should be repeated at least every 3 months. If symptoms consistent with acute HIV-1 infection develop following a potential exposure event, PrEP should be discontinued until negative HIV-1 infection status is confirmed.
Tenofovir EMT GH does not reduce the risk of other sexually transmitted infections and regular monitoring is recommended. Monitoring of renal function, such as with urine dipstick testing, should be considered for patients at risk for renal disease (see Section 4.4 Special Warnings and Precautions for Use, Use in renal impairment).
When considering Tenofovir EMT GH for pre-exposure prophylaxis the following factors may help to identify individuals at high risk of acquiring HIV-1 infection:
has partner(s) known to be HIV-1 infected; or
engages in high risk sexual behaviour (see Section 5.1 Pharmacodynamic Properties, Clinical trials, iPrEx trial) or sexual activity within a high prevalence area or social network or has partners from high prevalence areas.
When Tenofovir EMT GH is used to reduce the risk of acquiring HIV-1, advise uninfected individuals about the importance of the following:
Confirming that they are HIV-negative before starting to take Tenofovir EMT GH to reduce the risk of acquiring HIV-1.
Hepatitis B vaccination should be offered as appropriate.
Tenofovir EMT GH should only be used as part of a complete prevention strategy including other prevention measures. In clinical trials, tenofovir/emtricitabine combination tablet only protected some subjects from acquiring HIV-1.
Using condoms consistently and correctly to lower the chance of sexual contact with any body fluids such as semen, vaginal secretions, or blood.
Knowing their HIV status and the status of their partner(s).
In the case of use of Tenofovir EMT GH for PrEP in an uninfected partner in a serodiscordant relationship, the importance of effective antiretroviral treatment of the HIV-1 infected partner in accordance with the current treatment guidelines should be fully explained.
Getting tested regularly (at least every 3 months) for HIV-1 and ask their partner(s) to get tested as well.
Counselled about the importance of safety risks including monitoring of kidney function.
HIV-1 resistance substitutions may emerge in individuals with undetected HIV-1 infection who are taking Tenofovir EMT GH, because Tenofovir EMT GH alone does not constitute a complete regimen for HIV-1 treatment (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).
Reporting any symptoms of acute HIV-1 infection (flu-like symptoms) to their healthcare provider immediately.
Signs and symptoms of acute infection include: fever, headache, fatigue, arthralgia, vomiting, myalgia, diarrhea, pharyngitis, rash, night sweats, and adenopathy (cervical and inguinal).
Getting tested for other sexually transmitted infections such as syphilis and gonorrhoea that may facilitate HIV-1 transmission.
Learning about sexual risk behaviour and getting support to help reduce sexual risk behaviour.
Taking Tenofovir EMT GH on a regular dosing schedule and strictly adhere to the recommended dosing schedule to reduce the risk of acquiring HIV-1. Uninfected individuals who miss doses are at greater risk of acquiring HIV-1 than those who do not miss doses (see Section 4.4 Special Warnings and Precautions for Use).
Risks and benefits of Tenofovir EMT GH in women who may be pregnant or intending to become pregnant.

Use in renal impairment.

Tenofovir EMT GH is principally eliminated by the kidney. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported in association with the use of tenofovir disoproxil (as fumarate) tablets (see Section 4.8 Adverse Effects (Undesirable Effects), From post marketing surveillance).
Tenofovir EMT GH should be avoided with concurrent or recent use of a nephrotoxic agent.
It is recommended that creatinine clearance is calculated in all individual prior to initiating therapy and, as clinically appropriate, during Tenofovir EMT GH therapy. All individuals 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.

Use in the elderly.

Clinical studies of tenofovir and emtricitabine did not contain sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. In general, dose selection for the elderly patient should be cautious, keeping in mind the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy (see Section 4.2 Dose and Method of Administration).

Paediatric use.

Safety and effectiveness in paediatric patients have not been established.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Tenofovir disoproxil/emtricitabine combination tablets.

The drug interactions described are based on studies conducted with tenofovir disoproxil (as fumarate) or emtricitabine as individual agents; no drug interaction studies have been conducted using tenofovir disoproxil/emtricitabine combination tablets.

Tenofovir disoproxil and emtricitabine.

The steady state pharmacokinetics of tenofovir and emtricitabine were unaffected when tenofovir disoproxil and emtricitabine were administered together versus each agent dosed alone.
In vitro and clinical pharmacokinetic drug-drug interaction studies have shown the potential for CYP450 mediated interactions involving tenofovir disoproxil (as fumarate) and emtricitabine with other medicinal products is low.
Tenofovir and emtricitabine are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion. No drug-drug interactions due to competition for renal excretion have been observed; however, co-administration of tenofovir disoproxil/emtricitabine combination tablets with drugs that are eliminated by active tubular secretion may increase serum concentrations of tenofovir, emtricitabine, and/or the co-administered drug. Drugs that decrease renal function may increase serum concentrations of tenofovir and/or emtricitabine.
No clinically significant drug interactions have been observed between tenofovir disoproxil and abacavir, efavirenz, emtricitabine, indinavir, lamivudine, lopinavir/ritonavir, methadone, nelfinavir, saquinavir/ritonavir and oral contraceptives in studies conducted in healthy volunteers. In a study conducted in healthy volunteers dosed with a single 600 mg dose of ribavirin, no clinically significant drug interactions were observed between tenofovir disoproxil and ribavirin. Similarly, no clinically significant drug interactions have been observed between emtricitabine and famciclovir, indinavir, d4T, zidovudine and tenofovir disoproxil.
In drug interaction studies between regimens containing tenofovir disoproxil and Harvoni (ledipasvir/sofosbuvir), Sovaldi (sofosbuvir), Epclusa (sofosbuvir/velpatasvir), and Vosevi (sofosbuvir/velpatasvir/voxilaprevir) increases in tenofovir exposure were observed. Table 2 summarises the changes in pharmacokinetic parameters for tenofovir disoproxil in the presence of sofosbuvir, ledipasvir/sofosbuvir, sofosbuvir/velpatasvir, and sofosbuvir/velpatasvir/voxilaprevir (see Section 4.4 Special Warnings and Precautions for Use, Drug interactions).
When unboosted atazanavir (400 mg) was co-administered with tenofovir disoproxil (as fumarate), atazanavir increased tenofovir Cmax by 14% and AUC by 24%. Similarly, lopinavir (400 mg)/ritonavir (100 mg) increased tenofovir AUC by 32%.
Co-administration of tenofovir disoproxil with didanosine and atazanavir results in changes in the pharmacokinetics of didanosine and atazanavir that may be of clinical significance. Concomitant dosing of tenofovir disoproxil with didanosine buffered tablets or enteric-coated capsules significantly increases the Cmax and AUC of didanosine. When didanosine 250 mg enteric-coated capsules were administered with tenofovir disoproxil, systemic exposures of didanosine were similar to those seen with the 400 mg enteric-coated capsules alone under fasted conditions. The mechanism of this interaction is unknown. Tenofovir decreases atazanavir concentration. Table 3 summarises the effects of tenofovir disoproxil on the pharmacokinetics of didanosine and atazanavir.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No reproductive toxicity studies have been conducted with tenofovir disoproxil and emtricitabine in combination. Male and female rat fertility and mating performance or early embryonic development were unaffected by an oral tenofovir disoproxil fumarate dose (590 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 did not affect fertility in male rats or in female and male mice at respective approximate exposures (AUC) of 130 and 50-80 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).
(Category B3)
No clinical data are available for pregnant women being treated with tenofovir disoproxil or emtricitabine. No embryofoetal development studies have been conducted with tenofovir disoproxil and emtricitabine in combination.
Reproductive toxicity studies performed in rats and rabbits did not reveal any evidence of harm to the foetus due to tenofovir at respective exposures (AUC) of 4-13 and 66-fold the human exposure. Subcutaneous treatment of pregnant rhesus monkeys with a dose of 30 mg/kg/day of the tenofovir base during the last half of pregnancy resulted in reduced foetal serum phosphorus concentrations. No evidence of embryofoetal toxicity or teratogenicity was observed in mice or rabbits at respective emtricitabine exposures (AUC) of 50 and 130 fold the clinical exposure. Impaired weight gain observed in pregnant rabbits at doses resulting in emtricitabine exposures (AUC) at least 33 times the clinical exposure was not associated with any adverse foetal effects. Because animal reproduction studies are not always predictive of human response, Tenofovir EMT GH should be used during pregnancy only if clearly needed. If an uninfected individual becomes pregnant while taking Tenofovir EMT GH for a PrEP indication, careful consideration should be given to whether use of Tenofovir EMT GH should be continued, taking into account the potential increased risk of HIV-1 infection during pregnancy.
 Because of the potential for HIV transmission and for serious adverse reactions in nursing infants, mothers should be instructed not to breast feed if they are receiving Tenofovir EMT GH for treatment or to reduce the risk of acquiring HIV-1.

Tenofovir disoproxil.

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 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 concentrations 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.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects of tenofovir disoproxil/emtricitabine combination tablet on the ability to drive and use machines have been performed. However, patients should be informed that dizziness has been reported during treatment with both tenofovir disoproxil and emtricitabine.

4.8 Adverse Effects (Undesirable Effects)

Adverse effects for clinical trials experience in HIV-1 infected patients.

Four hundred and forty seven HIV-1 infected patients have received combination therapy with emtricitabine capsules and tenofovir disoproxil tablets with either a non-nucleoside reverse transcriptase inhibitor or protease inhibitor for 48 weeks in ongoing clinical studies.

Study 934 - treatment emergent adverse events.

Study 934 was an open-label active-controlled study in which 511 antiretroviral-naive patients received either emtricitabine plus tenofovir disoproxil administered in combination with efavirenz (n=257) or lamivudine/zidovudine combination tablet 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-naive patients (Table 4). Adverse events leading to study drug discontinuation occurred in significantly smaller number of patients in the tenofovir disoproxil/emtricitabine combination tablet group compared to the lamivudine/zidovudine combination tablet 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 tenofovir disoproxil/emtricitabine combination tablet group and 6% of patients in the lamivudine/zidovudine combination tablet group.

Laboratory abnormalities.

Laboratory abnormalities observed in this study were generally consistent with those seen in previous studies (Table 5).

Tenofovir disoproxil tablets.

From clinical studies.

More than 12,000 patients have been treated with tenofovir disoproxil 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 tenofovir disoproxil fumarate 300 mg once daily in Phase I-III clinical trials; over 11,000 patients have received tenofovir disoproxil in expanded access studies.

Treatment-experienced patients.

Treatment-emergent adverse events.

The most common adverse events that occurred in patients receiving tenofovir disoproxil with other antiretroviral agents in clinical trials were mild to moderate gastrointestinal events, such as nausea, diarrhoea, vomiting and flatulence. Less than 1% of patients discontinued participation in the clinical studies due to gastrointestinal adverse events (Study 907).
A summary of treatment-emergent adverse events that occurred during the first 48 weeks of Study 907 is provided in Table 6.

Laboratory abnormalities.

Laboratory abnormalities observed in this study occurred with similar frequency in the tenofovir disoproxil and placebo-treated groups. A summary of Grade 3 and 4 laboratory abnormalities is provided in Table 7.

Treatment-naive patients.

Treatment-emergent adverse events.

The adverse reactions seen in a double-blind active controlled study in which 600 treatment-naive patients received tenofovir disoproxil tablets (N=299) or d4T (N=301) in combination with lamivudine and efavirenz for 144 weeks (Study 903) were generally consistent, with the addition of dizziness, with those seen in treatment-experienced patients (Table 8).
Mild adverse events (Grade 1) were common with a similar incidence in both arms, and included dizziness, diarrhoea and nausea.

Laboratory abnormalities.

With the exception of triglyceride elevations that were more common in the d4T group (14%) compared with tenofovir disoproxil (3%), laboratory abnormalities observed in this study occurred with similar frequency in the tenofovir disoproxil and d4T treatment arms. A summary of Grade 3 and 4 laboratory abnormalities is provided in Table 9.

Adverse reactions from clinical trial experience in HIV-1 uninfected adult subjects.

No new adverse reactions to tenofovir disoproxil and emtricitabine combination tablets were identified from two randomised placebo-controlled clinical trials (iPrEx, Partners PrEP) in which 2830 HIV-1 uninfected adults received tenofovir disoproxil and emtricitabine combination tablets once daily for pre-exposure prophylaxis. Subjects were followed for a median of 71 weeks and 87 weeks, respectively. These trials enrolled HIV-negative individuals ranging in age from 18 to 67 years. The iPrEx trial enrolled only males or transgender females of Hispanic/Latino (72%), White (18%), Black (9%) and Asian (5%) race. The Partners PrEP trial enrolled both males (61-64% across treatment groups) and females in Kenya and Uganda. Table 10 provides a list of all adverse events that occurred in ≥ 2% of patients in any treatment group in the iPrEx and Partners PrEP trials.

Laboratory abnormalities.

Table 11 provides a list of laboratory abnormalities observed in both trials. Six subjects in the TDF-containing arms of the Partners PrEP trial discontinued participation in the study due to an increase in blood creatinine compared with no discontinuations in the placebo group. One patient in the combination tenofovir disoproxil and emtricitabine tablets arm of the iPrEx trial discontinued from the study due to an increase in blood creatinine and another due to low phosphorous.
In addition to the laboratory abnormalities described above, Grade 1 proteinuria (1+) occurred in 6% of subjects receiving tenofovir disoproxil and emtricitabine combination tablets in the iPrEx trial. Grades 2-3 proteinuria (2-4+) and glycosuria (3+) occurred in less than 1% of subjects treated with tenofovir disoproxil and emtricitabine combination tablets in the iPrEx trial and Partners PrEP trial.

Changes in bone mineral density.

In clinical trials of HIV-1 uninfected individuals, decreases in BMD were observed. In the iPrEx trial, a substudy of 503 subjects found mean changes from baseline in BMD ranging from -0.4% to -1.0% across total hip, spine, femoral neck, and trochanter in the combination tenofovir disoproxil and emtricitabine group compared with the placebo group, which returned toward baseline after discontinuation of treatment. Thirteen percent of subjects receiving tenofovir disoproxil and emtricitabine combination tablets vs. 6% of subjects receiving placebo lost at least 5% of BMD at the spine during treatment. Bone fractures were reported in 1.7% of the combination tenofovir disoproxil and emtricitabine tablets group compared with 1.4% in the placebo group. No correlation between BMD and fractures was noted (see Section 5.1 Pharmacodynamic Properties, Clinical trials). The Partners PrEP trial found similar fracture rates between treatment and placebo groups (0.8% and 0.6%, respectively). No BMD evaluations were conducted during this trial (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Emtricitabine.

More than 2,000 adult patients with HIV infection have been treated with emtricitabine 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 303 and 301A in which 440 treatment experienced (303) and 571 treatment naive (301A) patients received emtricitabine 200 mg (N=580) or comparator drug (N=431) for 48 weeks.
The most common adverse events that occurred in patients receiving emtricitabine 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 because of to these events. All adverse events were reported with similar frequency in emtricitabine and control treatment groups with the exception of skin discolouration which was reported with higher frequency in the emtricitabine treated group.
Skin discolouration manifested by hyperpigmentation on the palms and/or soles was generally mild and asymptomatic. The mechanism and clinical significance are unknown.
In addition to the adverse reactions reported in adults, anaemia has been reported commonly and hyperpigmentation very commonly, in paediatric patients.
A summary of emtricitabine treatment emergent clinical adverse events in studies 303 and 301A is provided in Table 12.

Laboratory abnormalities.

Laboratory abnormalities observed in the emtricitabine studies occurred with similar frequency in the treatment and placebo-treated/comparator groups.
A summary of Grade 3 and 4 laboratory abnormalities is provided in Table 13.

From 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 emtricitabine (FTC) and/or tenofovir disoproxil (as fumarate) tablets.

Immune system disorders.

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

Metabolism and nutrition disorders.

Hypokalaemia, hypophosphataemia, lactic acidosis.

Respiratory, thoracic, and mediastinal disorders.

Dyspnoea.

Gastrointestinal disorders.

Increased amylase, abdominal pain, pancreatitis.

Hepatobiliary disorders.

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

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 disoproxil therapy in the absence of proximal renal tubulopathy.

Adverse reactions attendant to class.

Nephrotoxicity (elevation in serum creatinine and urine protein, and decrease in serum phosphorus) is the dose-limiting toxicity associated with other nucleotide analogues (cidofovir and high doses of adefovir dipivoxil evaluated for HIV disease (60 mg and 120 mg)).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

There is no known antidote for Tenofovir EMT GH. If overdose occurs the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary.

Tenofovir disoproxil.

Clinical experience of doses higher than the therapeutic dose of tenofovir disoproxil is available from two studies. In one study, intravenous tenofovir, equivalent to 16.7 mg/kg/day of tenofovir disoproxil fumarate1, 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 tenofovir disoproxil fumarate, a four-hour haemodialysis session removed approximately 10% of the administered tenofovir dose.
1 Each Tenofovir EMT GH tablet contains 291 mg of tenofovir disoproxil phosphate and 200 mg of emtricitabine. The innovator product contains 300 mg of tenofovir disoproxil fumarate and 200 mg of emtricitabine - 291 mg of tenofovir disoproxil phosphate is equivalent to 300 mg of tenofovir disoproxil fumarate.

Emtricitabine.

Limited clinical experience is available at doses higher than the therapeutic dose of emtricitabine. 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.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Each Tenofovir EMT GH tablet contains 291 mg of tenofovir disoproxil phosphate and 200 mg of emtricitabine. The innovator product contains 300 mg of tenofovir disoproxil fumarate and 200 mg of emtricitabine - 291 mg of tenofovir disoproxil phosphate is equivalent to 300 mg of tenofovir disoproxil fumarate. All clinical data in this product information (including Pharmacokinetic, Pharmacodynamic, and Clinical Trial data) relevant to tenofovir are based on tenofovir disoproxil fumarate. Bioequivalence has been established between the two salt forms of tenofovir disoproxil.
Tenofovir disoproxil and emtricitabine belong to the nucleoside and nucleotide reverse transcriptase inhibitors pharmacotherapeutic group (ATC code: J05AF30).

Mechanism of action.

Tenofovir disoproxil.

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

Emtricitabine.

Emtricitabine, a synthetic nucleoside analogue of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate. Emtricitabine 5'-triphosphate inhibits the activity of the HIV-1 reverse transcriptase 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 polymerase α, β, epsilon and mitochondrial DNA polymerase γ.

Antiviral activity in vitro.

Tenofovir disoproxil plus emtricitabine.

In combination studies evaluating the in vitro antiviral activity of tenofovir and emtricitabine together, synergistic antiviral effects were observed.
Additive to synergistic effects were observed in combination studies with protease inhibitors, integrase strand transfer inhibitors, and with nucleoside and non-nucleoside analogue inhibitors of HIV-1 reverse transcriptase.

Tenofovir disoproxil.

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 0.04-8.5 micromolar. In drug combination studies of tenofovir with nucleoside reverse transcriptase inhibitors (abacavir, didanosine, lamivudine (3TC), stavudine (d4T), zalcitabine, zidovudine (AZT)), non-nucleoside reverse transcriptase inhibitors (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 0.5-2.2 micromolar). In addition, tenofovir has also been shown to be active in vitro against HIV-2, with similar potency as observed against HIV-1.

Emtricitabine.

The in vitro antiviral activity of 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 0.0013-0.64 micromolar (0.0003-0.158 microgram/mL). In drug combination studies of emtricitabine with nucleoside reverse transcriptase inhibitors (abacavir, 3TC, d4T, zalcitabine, AZT), non-nucleoside reverse transcriptase inhibitors (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 0.007-0.075 micromolar) and showed strain specific activity against HIV-2 (IC50 values ranged from 0.007-1.5 micromolar).

Prophylactic activity in a nonhuman primate model of HIV transmission.

Emtricitabine and tenofovir disoproxil.

The prophylactic activity of the combination of daily oral emtricitabine and tenofovir disoproxil was evaluated in a controlled study of macaques inoculated once weekly for 14 weeks with SIV/HIV-1 chimeric virus (SHIV) applied to the rectal surface. Of the 18 control animals, 17 became infected after a median of 2 weeks. In contrast, 4 of the 6 animals treated daily with oral emtricitabine and tenofovir disoproxil remained uninfected and the two infections that did occur were significantly delayed until 9 and 12 weeks and exhibited reduced viremia. An M184I-expressing FTC-resistant variant emerged in 1 of the 2 macaques after 3 weeks of continued drug exposure.

Anti-hepatitis B virus activity in vitro.

Tenofovir disoproxil.

Tenofovir inhibits HBV production in HepG2 2.2.15 with an IC50 value of 1.1 micromolar.

Emtricitabine.

Emtricitabine inhibits HBV production against laboratory strains of HBV with IC50 values in the range of 0.01 to 0.04 micromolar.

Drug resistance.

Tenofovir disoproxil.

HIV-1 isolates with reduced susceptibility to tenofovir have been selected in vitro. These viruses expressed a K65R mutation in reverse transcriptase and showed a 2-4 fold reduction in susceptibility to tenofovir. In addition, a K70E substitution in HIV-1 reverse transcriptase has been selected by tenofovir and results in low-level reduced susceptibility to abacavir, emtricitabine, tenofovir and lamivudine.
Tenofovir-resistant isolates of HIV-1 have also been recovered from some patients treated with tenofovir disoproxil in combination with other antiretroviral agents. In treatment-naïve patients treated with tenofovir disoproxil plus lamivudine plus 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 emtricitabine plus tenofovir disoproxil plus efavirenz through 144 weeks, none of the HIV isolates from 19 patients analysed for resistance showed reduced susceptibility to tenofovir or the presence of the K65R mutation. In treatment-experienced patients, 14/304 (4.6%) of the tenofovir disoproxil-treated patients with virologic failure showed reduced susceptibility to tenofovir. Genotypic analysis of the resistant isolates showed the K65R mutation in the HIV-1 reverse transcriptase gene.

Emtricitabine.

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

iPrEx trial.

In a clinical study of HIV-1 seronegative subjects (see Section 5.1 Pharmacodynamic Properties, Clinical trials), no amino acid substitutions associated with resistance to emtricitabine or tenofovir were detected at the time of seroconversion among 48 subjects in the combination tenofovir disoproxil/emtricitabine group and 83 subjects in the placebo group who became infected with HIV-1 during the trial. Ten subjects were observed to be HIV-1 infected at time of enrolment. The M184V/I substitutions associated with resistance to emtricitabine were observed in 3 of the 10 subjects (2 of 2 in the combination tenofovir disoproxil/emtricitabine group and 1 of 8 in the placebo group). One of the two subjects in the tenofovir disoproxil and emtricitabine group harboured wild type virus at enrolment and developed the M184V substitution 4 weeks after enrolment. The other subject had indeterminate resistance at enrolment but was found to have the M184I substitution 4 weeks after enrolment.

Partners PrEP trial.

In a clinical study of HIV-1 seronegative subjects (see Section 5.1 Pharmacodynamic Properties, Clinical trials), no variants expressing amino acid substitutions associated with resistance to emtricitabine or tenofovir were detected at the time of seroconversion among 12 subjects in the combination tenofovir disoproxil/emtricitabine group, 15 subjects in the tenofovir disoproxil group, and 51 subjects in the placebo group. Fourteen subjects were observed to be HIV-1 infected at the time of enrolment (3 in the combination tenofovir disoproxil/emtricitabine group, 5 in the tenofovir disoproxil group, and 6 in the placebo group). One of the three subjects in the tenofovir disoproxil and emtricitabine group who was infected with wild type virus at enrolment selected an M184V expressing virus by week 12. Two of the five subjects in the tenofovir disoproxil group had tenofovir-resistant viruses at the time of seroconversion; one subject infected with wild type virus at enrolment developed a K65R substitution by week 16, while the second subject had virus expressing the combination of D67N and K70R substitutions upon seroconversion at week 60, although baseline virus was not genotyped and it is unclear if the resistance emerged or was transmitted. Following enrolment, 4 subjects (2 in the tenofovir disoproxil group, 1 in the tenofovir disoproxil and emtricitabine group and 1 in the placebo group) had virus expressing K103N or V106A substitutions, which confer high-level resistance to NNRTIs but have not been associated with tenofovir or emtricitabine and may have been present in the infecting virus.

Cross-resistance.

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

Tenofovir disoproxil.

The K65R and K70E substitutions can also be selected by abacavir, or didanosine, and result in reduced susceptibility to these agents plus abacavir, didanosine emtricitabine, tenofovir and lamivudine. Patients with HIV-1 expressing three or more thymidine analogue associated mutations (TAMs) that included either the M41L or L210W reverse transcriptase mutation showed reduced susceptibility to tenofovir disoproxil fumarate. Multinucleoside resistant HIV-1 with a T69S double insertion mutation in the reverse transcriptase showed reduced susceptibility to tenofovir.

Emtricitabine.

Emtricitabine-resistant isolates (M184V/I) were cross-resistant to lamivudine and zalcitabine but retained sensitivity to abacavir, didanosine, d4T, tenofovir, zidovudine, 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 zidovudine (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.

Clinical trials.

Clinical study 934, which demonstrated the safety and efficacy of emtricitabine capsules and tenofovir disoproxil tablets in combination with efavirenz in treatment-naive adults, supports the use of tenofovir disoproxil/emtricitabine combination tablets for the treatment of HIV-1 infection. Additional supportive data are derived from study 903, in which lamivudine (3TC) and tenofovir were used in combination in treatment-naive adults. In clinical study 303 emtricitabine and lamivudine demonstrated comparable efficacy, safety and resistance patterns as part of multidrug regimens. For additional information about these trials, please refer to the Product Information for tenofovir disoproxil fumarate tablets and emtricitabine capsules. The iPrEx study and Partners PrEP study support the use of tenofovir disoproxil/emtricitabine combination tablets to help reduce the risk of acquiring HIV-1.

Tenofovir disoproxil/emtricitabine combination tablets.

Study 934: emtricitabine capsule plus tenofovir disoproxil tablet plus efavirenz compared with lamivudine/zidovudine combination plus efavirenz.

Study 934 is a randomised, open-label, active controlled multicentre study comparing two different dosing regimens in 511 antiretroviral-naive HIV-1 infected patients. Patients were randomised to receive either emtricitabine capsule plus tenofovir disoproxil tablet administered in combination with efavirenz or lamivudine/zidovudine combination tablet administered in combination with efavirenz. For patients randomised to receive emtricitabine plus tenofovir disoproxil the two drugs were administered individually for the first 96 weeks and then switched to tenofovir disoproxil/emtricitabine tablets (fixed dose combination) during weeks 96 to 144, without regard to food.
For inclusion in the study, antiretroviral treatment naive adult patients (≥ 18 years) with plasma HIV RNA greater than 10,000 copies/mL, must have an estimated glomerular filtration rate as measured by Cockcroft-Gault method of ≥ 50 mL/min, adequate haematologic function, hepatic transaminases and alanine aminotransferases ≤ 3 ULN, total bilirubin ≤ 1.5 mg/dL, serum amylase ≤ 1.5 ULN and serum phosphorus ≥ 2.2 mg/dL. Exclusion criteria included: a new AIDS defining condition diagnosed within 30 days (except on the basis of CD4 criteria), ongoing therapy with nephrotoxic drugs or agents that interacted with efavirenz, pregnancy/lactation, a history of clinically significant renal/ bone disease or malignant disease other than Kaposi's sarcoma or basal-cell carcinoma, or a life expectancy of less than one year. If efavirenz-associated central nervous system toxicities occurred, nevirapine could be substituted for efavirenz. Patients who were not receiving their originally assigned treatment regimen after week 48 or 96 and during the 30-day extension study window were not eligible to continue to weeks 96 or 144 respectively.
Patients had a mean age of 38 years (range 18 to 80), 86% were male, 59% were Caucasian and 23% were Black. The mean baseline CD4 cell count was 245 cells/mm3 (range 2 to 1191) and median baseline plasma HIV-1 RNA was 5.01 log10 copies/mL (range 3.56 to 6.54). Patients were stratified by baseline CD4 count (< or ≥ 200 cells/mm3); 41% had CD4 cell counts < 200 cells/mm3 and 51% of patients had baseline viral loads > 100,000 copies/mL. Treatment outcomes at 48 and 144 weeks for those patients who did not have efavirenz resistance at baseline are presented in Table 14.
In this study, emtricitabine capsule plus tenofovir disoproxil tablet in combination with efavirenz was statistically significantly superior to lamivudine/zidovudine combination tablet 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 14). The difference in the proportions of responders between the emtricitabine capsule plus tenofovir disoproxil tablet group and the lamivudine/zidovudine combination tablet 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 emtricitabine capsule plus tenofovir disoproxil tablet and the lamivudine/zidovudine combination tablet arms, respectively, achieved and maintained HIV-1 RNA < 50 copies/mL. The difference in the proportions of responders between the emtricitabine capsule plus tenofovir disoproxil tablet group and the lamivudine/zidovudine combination tablet 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 tenofovir disoproxil/emtricitabine combination tablet group (64%) compared with the lamivudine/zidovudine combination tablet 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 emtricitabine capsule plus tenofovir disoproxil tablet plus efavirenz arm, and 158 cells/mm3 and 271 cells/mm3 for the lamivudine/zidovudine combination tablet plus 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 drug or after treatment switch. Genotypic resistance to efavirenz, predominantly the K103N mutation, was the most common form of resistance that developed in both treatment groups. Resistance to efavirenz occurred in 68% (13/19) analysed patients in the tenofovir disoproxil/emtricitabine combination tablet group and in 72% (21/29) analysed patients in the lamivudine/zidovudine combination tablet group. The M184V mutation, associated with resistance to emtricitabine and lamivudine developed significantly less in the analysed patients in the tenofovir disoproxil/emtricitabine combination tablet group 11% (2/19) compared with the analysed patients in the lamivudine/zidovudine combination tablet group, 34% (10/29). Two patients in the lamivudine/zidovudine combination tablet group developed thymidine analogue mutations, specifically D67N or K70R mutations in the reverse transcriptase gene. No patient in either treatment group developed the K65R mutation, which is associated with reduced susceptibility to tenofovir disoproxil.

iPrEx trial.

The iPrEx trial was a randomised double-blind placebo-controlled multinational study evaluating tenofovir disoproxil/emtricitabine combination tablets in 2,499 HIV-seronegative men or transgender women who have sex with men and with evidence of high risk behaviour for HIV-1 infection. Evidence of high risk behaviour included any one of the following reported to have occurred up to six months prior to study screening: no condom use during anal intercourse with an HIV-1 positive partner or a partner of unknown HIV status; anal intercourse with more than 3 sex partners; exchange of money, gifts, shelter or drugs for anal sex; sex with male partner and diagnosis of sexually transmitted infection; no consistent use of condoms with sex partner known to be HIV-1 positive.
All subjects received monthly HIV-1 testing, risk-reduction counselling, condoms and management of sexually transmitted infections. Of the 2499 enrolled, 1251 received tenofovir disoproxil/emtricitabine combination tablets and 1248 received placebo. The mean age of subjects was 27 years, 5% were Asian, 9% Black, 18% White, and 72% Hispanic/Latino.
Subjects were followed for 4237 person-years. The primary outcome measure for the study was the incidence of documented HIV seroconversion. At the end of treatment, emergent HIV-1 seroconversion was observed in 131 subjects, of which 48 occurred in the tenofovir disoproxil/emtricitabine combination tablet group and 83 occurred in the placebo group, indicating a 42% (95% CI: 18% to 60%) reduction in risk.
In a post-hoc case control study of plasma and intracellular drug levels in about 10% of study subjects, risk reduction appeared to be the greatest in subjects with detectable intracellular tenofovir. Efficacy was therefore strongly correlated with adherence.

Partners PrEP trial.

The Partners PrEP trial was a randomised, double-blind, placebo-controlled 3 arm trial conducted in 4758 serodiscordant heterosexual couples in Kenya and Uganda to evaluate the efficacy and safety of TDF (N=1589) and FTC/TDF (N=1583) versus (parallel comparison) placebo (N=1586), in preventing HIV-1 acquisition by the uninfected partner.
All subjects received monthly HIV-1 testing, evaluation of adherence, assessment of sexual behaviour, and safety evaluations. Women were also tested monthly for pregnancy. Women who became pregnant during the trial had study drug interrupted for the duration of the pregnancy and while breastfeeding. The uninfected partner subjects were predominantly male (61-64% across study drug groups), and had a mean age of 33-34 years.
Following 7827 person-years of follow up, 82 emergent HIV-1 seroconversions were reported, with an overall observed seroincidence rate of 1.05 per 100 person-years. Of the 82 seroconversions, 13 and 52 occurred in partner subjects randomised to tenofovir disoproxil/emtricitabine combination tablets and placebo, respectively. Two of the 13 seroconversions in the tenofovir disoproxil/emtricitabine combination tablets arm and 3 of the 52 seroconversions in the placebo arm occurred in women during treatment interruptions for pregnancy. The risk reduction for tenofovir disoproxil/emtricitabine combination tablets relative to placebo was 75% (95% CI: 55% to 87%). In a post-hoc case control study of plasma drug levels in about 10% of study subjects, risk reduction appeared to be the greatest in subjects with detectable plasma tenofovir. Efficacy was therefore strongly correlated with adherence.

Tenofovir disoproxil (tenofovir).

The demonstration of benefit of tenofovir disoproxil is based on analyses of plasma HIV-1 RNA levels and CD4 cell counts in controlled studies of tenofovir disoproxil in treatment-naive adults and in treatment-experienced adults.

Treatment-experienced patients.

Study 907: tenofovir plus standard background therapy (SBT) compared with placebo plus SBT.

Study 907 was a 24 week, double-blind placebo-controlled multicentre study of tenofovir disoproxil (as fumarate) added to a stable background regimen of antiretroviral agents in 550 treatment-experienced patients. After 24 weeks of blinded study treatment, all patients continuing on study were offered open-label tenofovir disoproxil for an additional 24 weeks. Patients had a mean baseline CD4 cell count of 427 cells/mm3 (range 23-1385), median baseline plasma HIV RNA of 2340 (range 50-75,000) copies/mL, and mean duration of prior HIV treatment was 5.4 years. Mean age of the patients was 42 years, 85% were male and 69% were Caucasian, 17% Black and 12% Hispanic.
Changes from baseline in log10 copies/mL plasma HIV-1 RNA levels over time up to week 48 are presented in Figure 1.
The percent of patients with HIV RNA < 400 copies/mL and outcomes of patients through 48 weeks are summarised in Table 15.
At 24 weeks of therapy, there was a higher proportion of patients in the tenofovir disoproxil arm compared to the placebo arm with HIV RNA < 50 copies/mL (19% and 1%, respectively). Mean change in absolute CD4 counts by week 24 was +12 cells/mm3 for the tenofovir group and -5 cells/mm3 for the placebo group. Mean change in absolute CD4 counts by week 48 was +4 cells/mm3 for the tenofovir disoproxil group.

Treatment-naive patients.

Study 903: tenofovir disoproxil plus lamivudine plus efavirenz compared to stavudine plus lamivudine plus efavirenz.

Data through 144 weeks are reported for Study 903, a double-blind, active-controlled multicentre study comparing tenofovir disoproxil fumarate (300 mg once daily) administered in combination with lamivudine and efavirenz versus d4T, lamivudine, and efavirenz in 600 antiretroviral-naive patients. Patients had a mean age of 36 years (range 18-64), 74% were male, 64% were Caucasian and 20% were Black. The mean baseline CD4 cell count was 279 cells/mm3 (range 3-956) and median baseline plasma HIV-1 RNA was 77,600 copies/mL (range 417-5,130,000). Patients were stratified by baseline HIV-1 RNA and CD4 count. Forty-three percent of patients had baseline viral loads > 100,000 copies/mL and 39% had CD4 cell counts < 200 cells/mm3. Treatment outcomes through 144 weeks are presented in Table 16.
Achievement of plasma HIV-1 RNA concentrations of less than 400 copies/mL at week 144 was similar between the two treatment groups for the population stratified at baseline on the basis of HIV-1 RNA concentration (≤ or > 100,000 copies/mL) and CD4 cell count (< or ≥ 200 cells/mm3). Through 144 weeks of therapy, 62% and 58% of patients in the tenofovir disoproxil and d4T arms, respectively achieved and maintained confirmed HIV-1 RNA < 50 copies/mL. The mean increase from baseline in CD4 cell count was 263 cells/mm3 for the tenofovir disoproxil arm and 283 cells/mm3 for the d4T arm.
The proportion of patients who achieved and maintained confirmed HIV RNA < 400 using intent-to-treat analysis through 144 weeks of treatment in study 903 is presented in Figure 2.
Genotypic analyses of patients with virologic failure showed development of efavirenz-associated and lamivudine-associated mutations to occur most frequently and with no difference between the treatment arms. The K65R mutation occurred in 8 patients on the tenofovir disoproxil arm and in 2 patients on the d4T arm. Of the 8 patients who developed K65R in the tenofovir disoproxil arm through 144 weeks, 7 of these occurred in the first 48 weeks of treatment and the last one at week 96. Among these patients, 5/8 patients subsequently gained full virologic control (< 50 copies/mL) upon switching to new regimens that included a protease inhibitor in combination with nucleoside reverse transcriptase inhibitors through a median of 155 weeks of follow-up. From both genotypic and phenotypic analyses there was no evidence for other pathways of resistance to tenofovir disoproxil.

Genotypic analyses of tenofovir disoproxil in patients with previous antiretroviral therapy (study 902 and 907).

The virologic response to tenofovir disoproxil therapy has been evaluated with respect to baseline viral genotype (N=222) in treatment experienced patients participating in trials 902 and 907. In both of these studies, 94% of the participants evaluated had baseline HIV isolates expressing at least one NRTI mutation. These included resistance mutations associated with zidovudine (M41L, D67N, K70R, L210W, T215Y/F or K219Q/E/N), the lamivudine/abacavir-associated mutation (M184V), and others. In addition the majority of participants evaluated had mutations associated with either PI or NNRTI use. Virologic responses for patients in the genotype substudy were similar to the overall results in studies 902 and 907.
Several exploratory analyses were conducted to evaluate the effect of specific mutations and mutational patterns on virologic outcome. Descriptions of numerical differences in HIV RNA response are displayed in Table 17. Because of the large number of potential comparisons, statistical testing was not conducted.
Varying degrees of cross-resistance to tenofovir disoproxil from pre-existing zidovudine-associated mutations were observed and appeared to depend on the number and type of mutations. Tenofovir disoproxil-treated patients whose HIV expressed 3 or more zidovudine-associated mutations that included either the M41L or L210W reverse transcriptase mutation showed reduced responses to tenofovir disoproxil therapy; however, these responses were still improved compared with placebo. The presence of the D67N, K70R, T215Y/F or K219Q/E/N mutation did not appear to affect responses to tenofovir disoproxil therapy. The HIV RNA responses by number and type of baseline zidovudine-associated mutations are shown in Table 17.
In the protocol defined analyses, virologic response to tenofovir disoproxil was not reduced in patients with HIV that expressed the lamivudine/ abacavir-associated M184V mutation. In the absence of zidovudine-associated mutations, patients with the M184V mutation receiving tenofovir disoproxil showed a -0.84 log10 copies/mL decrease in their HIV RNA relative to placebo. In the presence of zidovudine-associated mutations, the M184V mutation did not affect the mean HIV RNA responses to tenofovir disoproxil treatment. HIV-1 RNA responses among these patients were durable through week 48.
There were limited data on patients expressing some primary nucleoside reverse transcriptase inhibitor mutations and multi-drug resistant mutations at baseline. However, patients expressing mutations at K65R (N=6), or L74V without zidovudine-associated mutations (N=6) appeared to have reduced virologic responses to tenofovir disoproxil.
The presence of at least one HIV protease inhibitor or non-nucleoside reverse transcriptase inhibitor mutation at baseline did not appear to affect the virologic response to tenofovir disoproxil. Cross-resistance between tenofovir disoproxil and HIV protease inhibitors is unlikely because of the different enzyme targets involved.

Phenotypic analyses of tenofovir disoproxil in patients with previous antiretroviral therapy (study 902 and 907).

The virologic response to tenofovir disoproxil therapy has been evaluated with respect to baseline phenotype (N=100) in treatment experienced patients participating in trials 902 and 907. Phenotypic analysis of baseline HIV from patients in Studies 902 and 907 demonstrated a correlation between baseline susceptibility to tenofovir disoproxil and response to tenofovir disoproxil therapy.
Table 18 summarises the HIV RNA response by baseline tenofovir disoproxil susceptibility.

Emtricitabine.

Treatment-experienced patients.

Study 303: emtricitabine once daily plus stable background therapy (SBT) compared to lamivudine twice daily plus SBT.

Study 303 was a 48 week, open-label, active-controlled multicentre study comparing emtricitabine (200 mg once daily) to lamivudine, in combination with d4T or zidovudine and a protease inhibitor or NNRTI in 440 patients who were on a lamivudine-containing triple-antiretroviral drug regimen for at least 12 weeks prior to study entry and had HIV RNA ≤ 400 copies/mL.
Patients were randomised 1:2 to continue therapy with lamivudine (150 mg twice daily) or to switch to emtricitabine (200 mg once daily). All patients were maintained on their stable background regimen. Patients had a mean age of 42 years (range 22-80), 86% were male, 64% Caucasian, 21% African-American and 13% Hispanic. Patients had a mean baseline CD4 cell count of 527 cells/mm3 (range 37-1909), and a median baseline plasma HIV RNA of 1.7 log10 copies/mL (range 1.7-4.0). The median duration of prior antiretroviral therapy was 27.6 months. Treatment outcomes through 48 weeks are presented in Table 19.
The mean increase from baseline in CD4 cell count was 29 cells/mm3 for the emtricitabine arm and 61 cells/mm3 for the lamivudine arm.

Treatment-naive patients.

Study 301A: emtricitabine once daily plus didanosine once daily plus efavirenz once daily compared to stavudine twice daily plus didanosine once daily plus efavirenz once daily.

Study 301A was a 48 week double-blind, active-controlled multicentre study comparing emtricitabine (200 mg once daily) administered in combination with didanosine and efavirenz versus d4T, didanosine and efavirenz in 571 antiretroviral naive patients. Patients had a mean age of 36 years (range 18-69), 85% were male, 52% Caucasian, 16% African-American and 26% Hispanic. Patients had a mean baseline CD4 cell count of 318 cells/mm3 (range 5-1317) and a median baseline plasma HIV RNA of 4.9 log10 copies/mL (range 2.6-7.0). Thirty-eight percent of patients had baseline viral loads > 100,000 copies/mL and 31% had CD4 cell counts < 200 cells/mL. Treatment outcomes through 48 weeks are presented in Table 20.
The mean increase from baseline in CD4 cell count was 168 cells/mm3 for the emtricitabine arm and 134 cells/mm3 for the d4T arm.

5.2 Pharmacokinetic Properties

Each Tenofovir EMT GH tablet contains 291 mg of tenofovir disoproxil phosphate and 200 mg of emtricitabine. The innovator product contains 300 mg of tenofovir disoproxil fumarate and 200 mg of emtricitabine - 291 mg of tenofovir disoproxil phosphate is equivalent to 300 mg of tenofovir disoproxil fumarate. All clinical data in this product information (including Pharmacokinetic, Pharmacodynamic, and Clinical Trial data) relevant to tenofovir are based on tenofovir disoproxil fumarate. Bioequivalence has been established between the two salt forms of tenofovir disoproxil.

Pharmacokinetics in adults.

Tenofovir disoproxil/emtricitabine combination tablets.

One tenofovir disoproxil fumarate 300 mg plus emtricitabine 200 mg fixed dose combination tablet was bioequivalent to one tenofovir disoproxil fumarate tablet (300 mg) plus one emtricitabine capsule (200 mg) following single-dose administration to fasting healthy subjects (N=39).

Tenofovir disoproxil.

The pharmacokinetic properties of tenofovir disoproxil (as fumarate) are summarised in Table 21. Following oral administration of tenofovir disoproxil (as fumarate), 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 0.01-25 microgram/mL. Approximately 70-80% of the intravenous dose of tenofovir is recovered as unchanged drug in the urine. Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion. Following a single oral dose of tenofovir disoproxil (as fumarate), the terminal elimination half-life of tenofovir is approximately 17 hours.

Emtricitabine.

The pharmacokinetic properties of emtricitabine are summarised in Table 21. Following oral administration of emtricitabine capsules, emtricitabine is rapidly absorbed with peak plasma concentrations occurring at 1-2 hours post-dose. In vitro binding of emtricitabine to human plasma proteins is < 4% and is independent of concentration over the range of 0.02-200 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 capsule, the plasma emtricitabine half-life is approximately 10 hours.

Effects of food on oral absorption.

Administration of tenofovir disoproxil (as fumarate)/emtricitabine combination tablet following a high fat meal (~700-1000 kcal containing 40-60% fat) delayed the time of tenofovir Cmax by approximately 0.75 hour. An increase in tenofovir AUC of approximately 40% and an increase in Cmax of approximately 14% were observed. Similar findings were observed when tenofovir disoproxil (as fumarate)/emtricitabine combination tablet was administered with a light meal. Emtricitabine systemic exposures (AUC and Cmax) were unaffected when tenofovir disoproxil (as fumarate)/emtricitabine combination tablet was administered with either a high fat or a light meal (see Section 4.2 Dose and Method of Administration).

Age and gender.

Children and geriatric patients.

Pharmacokinetics of tenofovir and emtricitabine have not been fully evaluated in children (< 18 years) or in the elderly (> 65 years) (see Section 4.4 Special Warnings and Precautions for Use, Paediatric Use, Use in the elderly).

Gender.

Tenofovir and emtricitabine pharmacokinetics are similar in male and female patients.

Patients with impaired renal function.

The pharmacokinetics of tenofovir and emtricitabine are altered in subjects with renal impairment (see Section 4.4 Special Warnings and Precautions for Use, Use in renal impairment). In subjects with creatinine clearance < 50 mL/min, or with end-stage renal disease (ESRD) requiring dialysis, Cmax, and AUC0-∞ of tenofovir and emtricitabine were increased. It is required that the dosing interval for Tenofovir EMT GH be modified in patients with creatinine clearance < 60 mL/min (see Section 4.2 Dose and Method of Administration). Tenofovir EMT GH should not be used in patients with creatinine clearance < 30 mL/min and in patients with end-stage renal disease requiring dialysis (see Section 4.4 Special Warnings and Precautions for Use, Use in renal impairment).
Tenofovir EMT GH for PrEP indication should not be used in HIV-1 uninfected individuals with estimated creatinine clearance below 60 mL/min. If a decrease in estimated creatinine clearance is observed in uninfected individuals while using Tenofovir EMT GH for PrEP, evaluate potential causes and re-assess potential risks and benefits of continued use (see Section 4.2 Dose and Method of Administration).

Patients with hepatic impairment.

Tenofovir disoproxil/emtricitabine combination tablets.

The pharmacokinetics of tenofovir following a 300 mg dose of tenofovir disoproxil fumarate 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 tenofovir disoproxil/emtricitabine combination tablets or emtricitabine have not been studied in patients with hepatic impairment; however, emtricitabine is not significantly metabolised by liver enzymes, so the impact of liver impairment should be limited.

5.3 Preclinical Safety Data

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

Mutagenicity.

Tenofovir disoproxil was mutagenic in an in vitro mouse L5178Y lymphoma cell assay (tk locus) and in an ex vivo assay for unscheduled DNA synthesis in rat hepatocytes, but it was negative in in vitro bacterial assays for gene mutation and an in vivo mouse micronucleus test for chromosomal damage. Emtricitabine was not mutagenic in bacteria or mouse lymphoma cell assays in vitro nor clastogenic in the mouse micronucleus test in vivo.

Carcinogenicity.

No carcinogenicity studies have been conducted with tenofovir disoproxil and emtricitabine in combination. In a long-term carcinogenicity study conducted in mice with tenofovir disoproxil fumarate 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 tumorigenic 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).
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).

6 Pharmaceutical Particulars

6.1 List of Excipients

Tenofovir EMT GH tablets contain the following ingredients as excipients:
Core: croscarmellose sodium, microcrystalline cellulose, mannitol, colloidal anhydrous silica and stearic acid.
Coating: Opadry II complete film coating system 39K505001 Blue (PI 138537).

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

Store below 25°C.

6.5 Nature and Contents of Container

Tenofovir EMT GH is available as tablets. The tablets are supplied in bottles of 30 tablets or 100 tablets with a child resistant closure.
Tenofovir EMT GH tablets are supplied in high density polyethylene (HDPE) bottles containing either 30 tablets with 1 molecular sieve sachet or 100 tablets with 3 molecular sieve sachets and is closed with a child resistant closure.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Tenofovir disoproxil phosphate.

Tenofovir disoproxil phosphate is a phosphoric acid salt of the bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir.
Tenofovir disoproxil phosphate is a white to off-white powder with a solubility of 82.05 mg/mL in water at 37°C. The partition coefficient (log P) for tenofovir disoproxil is 0.81 and the pKa is the range of 3.5 - 4.5.

Emtricitabine.

Emtricitabine is the (-) enantiomer of a thio analogue of cytidine, which differs from other cytidine analogues in that it has a fluorine in the 5-position.
Emtricitabine is a white to off-white powder with a solubility of approximately 70.53 mg/mL in water at 37°C. The partition coefficient (log P) for emtricitabine is -0.43 and the pKa is 2.32.

Chemical structure.

Tenofovir disoproxil phosphate.


Chemical Name: (R)-5-[[2-(6-amino-9H-purin-9-yl)-1-methyl ethoxy] methyl]-2, 4, 6, 8-tetraoxa-5-phosphanonanedioic acid, bis (1-methylethyl) ester, 5-oxide, phosphate (1:1).
Molecular Formula: C19H33N5O14P2.
Molecular Weight: 617.44.

Emtricitabine.


Chemical Name: 5-fluoro-1-(2R, 5S)-[2-(hydroxymethyl)-1, 3-oxathiolan-5-yl] cytosine.
Molecular Formula: C8H10FN3O3S.
Molecular Weight: 247.25.

CAS number.

Tenofovir disoproxil phosphate.

1453166-76-1.

Emtricitabine.

143491-57-0.

7 Medicine Schedule (Poisons Standard)

(S4) Prescription Only Medicine.

Summary Table of Changes