Consumer medicine information

Tenofovir/Emtricitabine Sandoz 301/200

Tenofovir disoproxil succinate; Emtricitabine

BRAND INFORMATION

Brand name

Tenofovir/Emtricitabine Sandoz 301/200

Active ingredient

Tenofovir disoproxil succinate; Emtricitabine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Tenofovir/Emtricitabine Sandoz 301/200.

SUMMARY CMI

Tenofovir/Emtricitabine Sandoz® 301/200

Consumer Medicine Information (CMI) summary

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

1. Why am I using Tenofovir/Emtricitabine Sandoz 301/200?

Tenofovir/Emtricitabine Sandoz 301/200 contains the active ingredients tenofovir disoproxil succinate and emtricitabine. Tenofovir/Emtricitabine Sandoz 301/200 is used to help control Human Immunodeficiency Virus (HIV) infection.

For more information, see Section 1. Why am I using Tenofovir/Emtricitabine Sandoz 301/200? in the full CMI.

2. What should I know before I use Tenofovir/Emtricitabine Sandoz 301/200?

Do not use if you have ever had an allergic reaction to tenofovir disoproxil succinate/emtricitabine or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use Tenofovir/Emtricitabine Sandoz 301/200? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Tenofovir/Emtricitabine Sandoz 301/200 and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Tenofovir/Emtricitabine Sandoz 301/200?

  • Take one Tenofovir/Emtricitabine Sandoz 301/200 tablet once daily or as advised by your doctor at the same time each day.

More instructions can be found in Section 4. How do I use Tenofovir/Emtricitabine Sandoz 301/200? in the full CMI.

5. What should I know while using Tenofovir/Emtricitabine Sandoz 301/200?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using Tenofovir/Emtricitabine Sandoz 301/200.
  • Do not miss any doses of Tenofovir/Emtricitabine Sandoz 301/200.
  • Tell your doctor if you become pregnant while taking this medicine.
  • Tell your doctor if you for any reason have not taken your medicine exactly as prescribed.
  • Tell your doctor if you think you were exposed to HIV.
Things you should not do
  • Do not stop using this medicine or change the dose without checking with your doctor.
  • Do not give this medicine to anyone else even if their symptoms seem similar to yours.
  • Do not use this medicine to treat any other complaints unless your doctor says to.
Driving or using machines
  • Be careful before you drive or use any machines until you know how Tenofovir/Emtricitabine Sandoz 301/200 affects you.
Drinking alcohol
  • Tell your doctor if you drink alcohol.
Looking after your medicine
  • Keep the medicine in a cool dry place where the temperature stays below 25°C.
  • Keep your capsules in the original pack until it is time to take them.

For more information, see Section 5. What should I know while using Tenofovir/Emtricitabine Sandoz 301/200? in the full CMI.

6. Are there any side effects?

You may experience serious side effects when taking Tenofovir/Emtricitabine Sandoz 301/200.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

Tenofovir/Emtricitabine Sandoz® 301/200

Active ingredient(s): tenofovir disoproxil succinate / emtricitabine

Consumer Medicine Information (CMI)

This leaflet provides important information about using Tenofovir/Emtricitabine Sandoz 301/200. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Tenofovir/Emtricitabine Sandoz 301/200.

Where to find information in this leaflet:

1. Why am I using Tenofovir/Emtricitabine Sandoz 301/200?
2. What should I know before I use Tenofovir/Emtricitabine Sandoz 301/200?
3. What if I am taking other medicines?
4. How do I use Tenofovir/Emtricitabine Sandoz 301/200?
5. What should I know while using Tenofovir/Emtricitabine Sandoz 301/200?
6. Are there any side effects?
7. Product details

1. Why am I using Tenofovir/Emtricitabine Sandoz 301/200?

Tenofovir/Emtricitabine Sandoz 301/200 contains the active ingredients tenofovir disoproxil succinate and emtrictaibine. Tenofovir/Emtricitabine Sandoz 301/200 belong to a group of antiviral medicines known as nucleoside and nucleotide reverse transcriptase inhibitors (NRTI).

Tenofovir/Emtricitabine Sandoz 301/200 is used to treat Human Immunideficiency Virus-1 (HIV-1) infection in adults when taken in combination with other anti-HIV medicines and 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.
  • Male-female sex partners when one partner has HIV-1 infection and the other does not.

When Tenofovir/Emtricitabine Sandoz 301/200 is used to treat HIV infection:

When used with other HIV-1 medicines to treat HIV-1 infection, Tenofovir/Emtricitabine Sandoz 301/200 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.

Does Tenofovir/Emtricitabine Sandoz 301/200 cure HIV or AIDS:

Tenofovir/Emtricitabine Sandoz 301/200 is not a cure for HIV infection or AIDS. While taking Tenofovir/Emtricitabine Sandoz 301/200 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/Emtricitabine Sandoz 301/200 reduce the risk of passing HIV to others:

Tenofovir/Emtricitabine Sandoz 301/200 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/Emtricitabine Sandoz 301/200 is used to reduce the risk of HIV infection:

When used with safer sex practices, Tenofovir/Emtricitabine Sandoz 301/200 may help to reduce the risk of getting HIV-1 infection if you are at high risk of getting HIV infection.

Tenofovir/Emtricitabine Sandoz 301/200 reduces the risk of getting HIV-1 when you have been taking it before you are exposed to HIV-1.

2. What should I know before I use Tenofovir/Emtricitabine Sandoz 301/200?

Warnings

Do not use Tenofovir/Emtricitabine Sandoz 301/200 if:

  • you are allergic to tenofovir, tenofovir disoproxil succinate or any of the ingredients listed at the end of this leaflet.
  • Always check the ingredients to make sure you can use this medicine.
  • you are already taking any of the components of Tenofovir/Emtricitabine Sandoz 301/200 (tenofovir disoproxil succinate or emtricitabine).
  • you are taking lamivudine.
  • you are taking adefovir dipivoxil.
  • you are taking tenofovir alafenamide.
  • Do not take 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 if the packaging is torn or shows signs of tampering.

Do not use Tenofovir/Emtricitabine Sandoz 301/200 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/Emtricitabine Sandoz 301/200 to treat HIV. Tenofovir/Emtricitabine Sandoz 301/200 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/Emtricitabine Sandoz 301/200 to treat HIV-1.
  • 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/Emtricitabine Sandoz 301/200 or at any time while taking Tenofovir/Emtricitabine Sandoz 301/200. 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.

Check with your doctor if you:

  • are allergic to foods, dyes, preservatives or any other medicines.
  • have liver problems, including hepatitis B, or C virus infection.
  • are taking medication to treat your hepatitis C virus (HCV) infection (e.g. ledipasvir/sofosbuvir, sofosbuvir/velpatasvir).
  • have kidney problems.
  • have or have ever had abnormal bones or bone difficulties.

If you have a long standing viral infection of your liver (hepatitis B) it may flare up when you stop taking Tenofovir/Emtricitabine Sandoz 301/200.

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/Emtricitabine Sandoz 301/200 and even after you stop, your doctor is likely to arrange tests from time to time to check how well your liver is working.

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

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 safer 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.

Pregnancy and breastfeeding

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

The safe use of Tenofovir/Emtricitabine Sandoz 301/200 in pregnancy has not been demonstrated. For this reason, it is important that women of child-bearing age receiving treatment with Tenofovir/Emtricitabine Sandoz 301/200 use an effective method of contraception to avoid becoming pregnant.

If you are a female who is taking Tenofovir/Emtricitabine Sandoz 301/200 to reduce the risk of getting HIV-1 infection and you become pregnant while taking Tenofovir/Emtricitabine Sandoz 301/200, talk to your healthcare provider to decide if you should keep taking Tenofovir/Emtricitabine Sandoz 301/200.

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

The active substances in this medicine (tenofovir disoproxil succinate 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/Emtricitabine Sandoz 301/200. In general, women infected with HIV should not breast-feed their infants in order to avoid transmission of HIV to their newborn infant.

Use in children and elderly

Tenofovir/Emtricitabine Sandoz 301/200 is for adults.

Do not take Tenofovir/Emtricitabine Sandoz 301/200 if you are under the age of 18 years.

Do not take Tenofovir/Emtricitabine Sandoz 301/200 if you are over the age of 65 years before discussing with your doctor.

3. What if I am taking other medicines?

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

If you have HIV infection your doctor will generally prescribe Tenofovir/Emtricitabine Sandoz 301/200 in combination with other anti-HIV medicines.

Some medicines may interfere with Tenofovir/Emtricitabine Sandoz 301/200 and affect how it works. Your doctor or pharmacist will be able to tell you what to do when taking Tenofovir/Emtricitabine Sandoz 301/200 tablets with other medicines.

Tell your doctor if you are taking:

  • didanosine (also known as ddI or Videx).
  • ledipasvir/sofosbuvir (HARVONI®)
  • sofosbuvir/velpatasvir (EPCLUSA®)
  • sofosbuvir/velpatasvir/voxilaprevir (e.g. VOSEVI®)

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Tenofovir/Emtricitabine Sandoz 301/200.

4. How do I use Tenofovir/Emtricitabine Sandoz 301/200?

How much to take

  • Take one Tenofovir/Emtricitabine Sandoz 301/200 tablet once daily or as advised by your doctor. Your doctor will tell you how much to take and how often to take it.
  • Tenofovir/Emtricitabine Sandoz 301/200 is best taken with a meal or just afterwards, however taking it without food should not reduce the effectiveness of the medicine.
  • Follow the instructions provided and use Tenofovir/Emtricitabine Sandoz 301/200 until your doctor tells you to stop. Do not stop or change you the amount of Tenofovir/Emtricitabine Sandoz 301/200 you take unless advised by your doctor.

Tenofovir/Emtricitabine Sandoz 301/200 is absorbed rapidly. Do not take another Tenofovir/Emtricitabine Sandoz 301/200 dose if vomiting has occurred unless it occurs within 1 hour after taking Tenofovir/Emtricitabine Sandoz 301/200.

Because your medicine helps to control your condition, but does not cure it, you will need to take Tenofovir/Emtricitabine Sandoz 301/200 every day. If you are taking Tenofovir/Emtricitabine Sandoz 301/200 to reduce the risk of HIV-1 infection, take Tenofovir/Emtricitabine Sandoz 301/200 every day for the period of time as prescribed by your doctor.

When to take Tenofovir/Emtricitabine Sandoz 301/200

  • Take Tenofovir/Emtricitabine Sandoz 301/200 at the same time each day to keep Tenofovir/Emtricitabine Sandoz 301/200 blood levels constant.

If you forget to use Tenofovir/Emtricitabine Sandoz 301/200

Tenofovir/Emtricitabine Sandoz 301/200 should be used regularly at the same time each day.

If you miss your dose at the usual time, take it as soon as you remember that day, and then go back to taking your medicine as you would normally.

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

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

Do not take more than one Tenofovir/Emtricitabine Sandoz 301/200 tablet in a day.

If you use too much Tenofovir/Emtricitabine Sandoz 301/200

If you think that you have used too much Tenofovir/Emtricitabine Sandoz 301/200, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

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

5. What should I know while using Tenofovir/Emtricitabine Sandoz 301/200?

Things you should do

Call your doctor straight away if you:

  • Become pregnant or are trying to become pregnant.
  • For any reason have not taken your medicine exactly as prescribed.
  • Think you were exposed to HIV. They may want to do more tests to be sure you are still HIV-negative.

Remind any doctor, dentist or pharmacist you visit that you are using Tenofovir/Emtricitabine Sandoz 301/200.

Do not miss any doses of Tenofovir/Emtricitabine Sandoz 301/200. Missing doses may increase your risk of getting HIV infection.

If you become HIV-positive, you need more medicine than Tenofovir/Emtricitabine Sandoz 301/200 alone to treat HIV. Tenofovir/Emtricitabine Sandoz 301/200 by itself is not a complete treatment for HIV.

If you have HIV and take only Tenofovir/Emtricitabine Sandoz 301/200, over time your HIV may become harder to treat.

Get information and support to help reduce risky sexual behaviour. Have fewer sex partners.

If you are taking Tenofovir/Emtricitabine Sandoz 301/200 to reduce your risk of getting HIV:

  • Just taking Tenofovir/Emtricitabine Sandoz 301/200 may not keep you from getting HIV.
  • You must continue using safer sex practices while you are taking Tenofovir/Emtricitabine Sandoz 301/200 to reduce your risk of getting HIV.
  • You must stay HIV-negative to keep taking Tenofovir/Emtricitabine Sandoz 301/200 to reduce your risk of infection
  • Know you HIV status and the HIV status of your partners.
  • Get tested for HIV at least every 3 months or when your healthcare provider tells you.
  • Get tested for other sexually transmitted infections such as syphilis and gonorrhea. These infections make it easier for HIV to infect you. Tenofovir/Emtricitabine Sandoz 301/200 will not stop you from getting these other infections.

Things you should not do

  • Do not stop using this medicine 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 this medicine to treat any other complaints unless your doctor says to.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Tenofovir/Emtricitabine Sandoz 301/200 affects you.

Drinking alcohol

Tell your doctor if you drink alcohol.

Looking after your medicine

  • Keep tablets in a cool, dry place where it stays below 25°C.
  • Keep your tablets in the bottle with the cap tightly closed until you taken them. If you take Tenofovir/Emtricitabine Sandoz 301/200 tablets out of their pack, they may not keep well.

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

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

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

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

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

Do not use this medicine after the expiry date.

6. Are there any side effects?

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

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

Less serious side effects

Less serious side effectsWhat to do
Taking Tenofovir/Emtricitabine Sandoz 301/200 to treat HIV-1 infection:
  • diarrhoea
  • nausea
  • tiredness
  • headache
  • dizziness
  • depression
  • problems sleeping
  • abnormal dreams
  • rash
Taking Tenofovir/Emtricitabine Sandoz 301/200 to reduce the risk of getting HIV-1 infection:
  • stomach-area (abdomen) pain
  • headache
  • decreased weight
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Allergy:
  • 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
Pancreatitis:
  • Severe stomach pain or cramps
  • Nausea
  • Vomiting
Serious Liver Problems (hepatotoxicity):
  • Your skin or the white part of your eyes turns yellow (jaundice)
  • Your urine turns dark
  • Your bowel movements (stools) turn light in colour
  • You don't feel like eating food for several days or longer
  • Nausea
  • Stomach-area pains
Lactic Acidosis (build up of acid in the blood):
  • You feel very weak or tired
  • You have unusual (not normal) muscle pain
  • You have trouble breathing
  • You have stomach pain with nausea and vomiting
  • You feel cold, especially in your arms and legs
  • You feel dizzy or light headed
  • You have a fast or irregular heartbeat
Hepatic Flares:
  • Your doctor should test you to see if you have chronic hepatitis B infection before you start taking Tenofovir/Emtricitabine Sandoz 301/200.
    If you have chronic hepatitis B infection you should not stop your Tenofovir/Emtricitabine Sandoz 301/200 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 Tenofovir/Emtricitabine Sandoz 301/200.
    You may require medical exams and blood tests for several months after stopping treatment.
    Tenofovir/Emtricitabine Sandoz 301/200 is not approved for the treatment of hepatitis B, so you must discuss your hepatitis B therapy with your healthcare provider.
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/Emtricitabine Sandoz 301/200. 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.
Do not take any more Tenofovir/ Emtricitabine Sandoz 301/200 and call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

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

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

Reporting side effects

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

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

7. Product details

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

What Tenofovir/Emtricitabine Sandoz 301/200 contains

Active ingredient
(main ingredient)
  • Tenofovir disproxil succinate 300.6 mg
  • Emtricitabine 200 mg
Other ingredients
(inactive ingredients)
  • croscarmellose sodium
  • lactose monohydrate
  • magnesium stearate
  • microcrystalline cellulose
  • pregelatinised maize starch

Film coating:

  • polyvinyl alcohol
  • macrogol 3350
  • purified talc
  • indigo carmine aluminium lake (E132)
  • titanium dioxide (E171)
Potential allergensLactose monohydrate

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

What Tenofovir/Emtricitabine Sandoz 301/200 looks like

Tenofovir/Emtricitabine Sandoz 301/200 tablets are blue, capsule-shaped, film-coated and plain on both sides. Tenofovir/Emtricitabine Sandoz 301/200 are supplied in bottles containing 30 tablets (AUST R 326237).

Who distributes Tenofovir/Emtricitabine Sandoz 301/200

Tenofovir/Emtricitabine Sandoz 301/200 is supplied in Australia by:

Sandoz Pty Ltd
100 Pacific Highway
North Sydney, NSW 2060
Australia

Tel: 1800 726 369

This leaflet was prepared in January 2025.

® Registered Trade Mark. The trade marks mentioned in this material are the property of their respective owners.

Published by MIMS March 2025

BRAND INFORMATION

Brand name

Tenofovir/Emtricitabine Sandoz 301/200

Active ingredient

Tenofovir disoproxil succinate; Emtricitabine

Schedule

S4

 

1 Name of Medicine

Tenofovir disoproxil succinate/ emtricitabine.

2 Qualitative and Quantitative Composition

Each film-coated tablet contains 300.6 mg tenofovir disoproxil succinate which is equivalent to 245 mg of tenofovir disoproxil and 200 mg emtricitabine.
Tenofovir disoproxil succinate is a white to off-white crystalline powder. Emtricitabine is a white to off-white crystalline powder.

Excipients with known effect.

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

3 Pharmaceutical Form

The tablets are blue, capsule-shaped, film-coated and plain on both sides.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of HIV-1 infection.

Tenofovir/Emtricitabine Sandoz 301/200 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/Emtricitabine Sandoz 301/200 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

Recommended dose for treatment of HIV-1 infection.

Adults.

The recommended dose of Tenofovir/Emtricitabine Sandoz 301/200 is one tablet (containing 300.6 mg tenofovir disoproxil succinate and 200 mg emtricitabine), taken orally, once daily. In order to optimise the absorption of tenofovir, it is recommended that Tenofovir/Emtricitabine Sandoz 301/200 should be taken with food.

Recommended dose for pre-exposure prophylaxis.

Adults.

The dose of Tenofovir/Emtricitabine Sandoz 301/200 in HIV-1 uninfected adults is one tablet (containing 300.6 mg tenofovir disoproxil succinate and 200 mg of emtricitabine), taken orally, once daily. In order to optimise the absorption of tenofovir, it is recommended that Tenofovir/Emtricitabine Sandoz 301/200 should be taken with food.

Children.

The safety and efficacy of tenofovir disoproxil fumarate and emtricitabine tablets has not been established in patients under the age of 18 years. Consequently, Tenofovir/Emtricitabine Sandoz 301/200 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 fumarate tablets or emtricitabine tablets were administered to patients with moderate to severe renal impairment (see Viread and Emtriva Product Information). Therefore, the dosing interval of Tenofovir/Emtricitabine Sandoz 301/200 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/Emtricitabine Sandoz 301/200 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/Emtricitabine Sandoz 301/200 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 fumarate and emtricitabine 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/Emtricitabine Sandoz 301/200 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/Emtricitabine Sandoz 301/200 is contraindicated in patients with known hypersensitivity to tenofovir, tenofovir disoproxil fumarate, tenofovir disoproxil succinate, tenofovir disoproxil maleate, emtricitabine or any other components of the tablet.
Tenofovir/Emtricitabine Sandoz 301/200 must not be administered to children or adolescents under the age of 18 years.
Tenofovir/Emtricitabine Sandoz 301/200 is a fixed-dose combination of tenofovir disoproxil succinate and emtricitabine. Tenofovir/Emtricitabine Sandoz 301/200 should not be administered concomitantly with other medicinal products containing any of the same active components: tenofovir disoproxil succinate, or emtricitabine; drugs containing tenofovir disoproxil fumerate, tenofovir disoproxil maleate, tenofovir alafenamide, lamivudine, or adefovir dipivoxil.
Do not use Tenofovir/Emtricitabine Sandoz 301/200 for pre-exposure prophylaxis in individuals with unknown or positive HIV-1 status.
Tenofovir/Emtricitabine Sandoz 301/200 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/Emtricitabine Sandoz 301/200 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/Emtricitabine Sandoz 301/200 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/Emtricitabine Sandoz 301/200 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).

Use in renal impairment.

Tenofovir and emtricitabine are 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) (see Section 4.8 Adverse Effects (Undesirable Effects), From postmarketing surveillance).
Tenofovir/Emtricitabine Sandoz 301/200 should be avoided with concurrent or recent use of a nephrotoxic agent.
It is recommended that creatinine clearance is calculated in all individuals prior to initiating therapy and, as clinically appropriate, during tenofovir disoproxil fumarate/emtricitabine combination 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.

Treatment of HIV-1 infection.

Dosing interval adjustment of Tenofovir/Emtricitabine Sandoz 301/200 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 disoproxil fumarate/emtricitabine combination therapy have not been established in patients with creatinine clearance between 30 and 59 mL/min, and so the potential benefit of tenofovir disoproxil fumarate/emtricitabine combination therapy should be assessed against the potential risk of renal toxicity. Tenofovir/Emtricitabine Sandoz 301/200 should not be administered to patients with creatinine clearance < 30 mL/min or patients requiring haemodialysis.

Pre-exposure prophylaxis.

Tenofovir/Emtricitabine Sandoz 301/200 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/Emtricitabine Sandoz 301/200 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 fumarate.

When tenofovir disoproxil 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 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/Emtricitabine Sandoz 301/200. Data are not available to recommend a dose adjustment of didanosine for patients weighing < 60 kg.
When co-administered, Tenofovir/Emtricitabine Sandoz 301/200 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/Emtricitabine Sandoz 301/200 should be under fasted conditions. Co-administration of Tenofovir/Emtricitabine Sandoz 301/200 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.

Coadministration of tenofovir disoproxil 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 fumarate concomitantly with Harvoni, Epclusa or Vosevi should be monitored for adverse reactions associated with tenofovir disoproxil fumarate (see Table 2).

Sofosbuvir.

In a drug interaction study of a regimen containing tenofovir disoproxil 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/Emtricitabine Sandoz 301/200 is required (see Table 2).
Tenofovir disoproxil fumarate affects the pharmacokinetics of atazanavir (see Table 3). Tenofovir/Emtricitabine Sandoz 301/200 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/Emtricitabine Sandoz 301/200 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 fumarate studies in three animal species. Clinically relevant bone abnormalities have not been seen in long-term clinical studies (> 3 years) of tenofovir disoproxil fumarate tablets 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 postmarketing surveillance). If bone abnormalities are suspected during therapy then appropriate consultation should be obtained.

Hepatitis B virus (HBV).

Individuals should be tested for the presence of chronic hepatitis B virus (HBV) before initiating combination tenofovir disoproxil fumarate/emtricitabine therapy. Discontinuation of combination tenofovir disoproxil fumarate/emtricitabine 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 combination tenofovir disoproxil fumarate/emtricitabine 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 fumarate. 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/Emtricitabine Sandoz 301/200 should only be used for PrEP as part of a comprehensive prevention strategy including other HIV-1 prevention measures, because combination tenofovir disoproxil fumarate/emtricitabine 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 gonorrhea). Counsel uninfected individuals prior to initiation of PrEP about risk and benefits, precautions and limitation of pre-exposure prophylaxis using Tenofovir/Emtricitabine Sandoz 301/200.
Tenofovir/Emtricitabine Sandoz 301/200 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/Emtricitabine Sandoz 301/200 for PrEP. Drug resistant HIV-1 variants have been identified in individuals with undetected HIV-1 infection who are taking Tenofovir/Emtricitabine Sandoz 301/200 for a PrEP indication, because Tenofovir/Emtricitabine Sandoz 301/200 alone does not constitute a complete treatment regimen for HIV-1 infection.
When considering Tenofovir/Emtricitabine Sandoz 301/200 for pre-exposure prophylaxis, the uninfected individuals should be counselled about the importance of strict adherence to the recommended Tenofovir/Emtricitabine Sandoz 301/200 dosing schedule. The effectiveness of Tenofovir/Emtricitabine Sandoz 301/200 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/Emtricitabine Sandoz 301/200 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/Emtricitabine Sandoz 301/200 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/Emtricitabine Sandoz 301/200 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/Emtricitabine Sandoz 301/200 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 behavior (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/Emtricitabine Sandoz 301/200 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/Emtricitabine Sandoz 301/200 to reduce the risk of acquiring HIV-1.
Hepatitis B vaccination should be offered as appropriate.
Tenofovir/Emtricitabine Sandoz 301/200 should only be used as part of a complete prevention strategy including other prevention measures. In clinical trials, combination tenofovir disoproxil fumarate/emtricitabine therapy 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/Emtricitabine Sandoz 301/200 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/Emtricitabine Sandoz 301/200, because Tenofovir/Emtricitabine Sandoz 301/200 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, diarrhoea, 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/Emtricitabine Sandoz 301/200 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/Emtricitabine Sandoz 301/200 in women who may be pregnant or intending to become pregnant.

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 of laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Tenofovir disoproxil fumarate and emtricitabine tablets.

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

Tenofovir disoproxil fumarate and emtricitabine.

The steady-state pharmacokinetics of tenofovir and emtricitabine were unaffected when tenofovir disoproxil fumarate 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 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 fumarate and emtricitabine 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 fumarate 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 fumarate and ribavirin. Similarly, no clinically significant drug interactions have been observed between emtricitabine and famciclovir, indinavir, d4T, zidovudine and tenofovir disoproxil fumarate.
In drug interaction studies between regimens containing tenofovir disoproxil fumarate 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 fumarate 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 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 fumarate 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 as fumarate 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 fumarate, 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 fumarate 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 fumarate 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 (600 mg/kg/day) that achieved systemic drug exposures that were in excess of the expected value in humans receiving the therapeutic dose (5-fold based on plasma AUC). There was, however, an alteration of the oestrous cycle in female rats.
Emtricitabine 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 fumarate or emtricitabine. No embryofoetal development studies have been conducted with tenofovir disoproxil fumarate 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/Emtricitabine Sandoz 301/200 should be used during pregnancy only if clearly needed. If an uninfected individual becomes pregnant while taking Tenofovir/Emtricitabine Sandoz 301/200 for a PrEP indication, careful consideration should be given to whether use of Tenofovir/Emtricitabine Sandoz 301/200 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/Emtricitabine Sandoz 301/200 for treatment or to reduce the risk of acquiring HIV-1.

Tenofovir disoproxil fumarate.

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

Emtricitabine.

Samples of breast milk obtained from five HIV-1 infected mothers show that emtricitabine is secreted in human milk at estimated neonatal concentrations 3 to 12 times higher than the emtricitabine IC50 but 3 to 12 times lower than the Cmin (minimal expected trough 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 combination tenofovir disoproxil fumarate/emtricitabine 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 fumarate and emtricitabine.

4.8 Adverse Effects (Undesirable Effects)

Reporting suspected adverse effects.

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

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 tablets and tenofovir disoproxil fumarate 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 tablet + tenofovir disoproxil fumarate tablet administered in combination with efavirenz (n=257) or Combivir (lamivudine/zidovudine) administered in combination with efavirenz (n=254). Adverse events observed in this study were generally consistent with those seen in previous studies in treatment-experienced or treatment-naive patients (see Table 4). Adverse events leading to study drug discontinuation occurred in significantly smaller number of patients in the tenofovir disoproxil fumarate and emtricitabine tablets group compared to the Combivir group (5% vs 11%, p=0.010). The most frequently occurring adverse event leading to study drug discontinuation was anaemia (including decreased haemoglobin), no patient in the tenofovir disoproxil fumarate and emtricitabine tablets group and 6% of patients in the Combivir group.

Laboratory abnormalities.

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

Tenofovir.

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

Treatment-emergent adverse events.

The most common adverse events that occurred in patients receiving tenofovir disoproxil fumarate tablets 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 fumarate 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 fumarate 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 (see 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 fumarate (3%), laboratory abnormalities observed in this study occurred with similar frequency in the tenofovir disoproxil fumarate 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 fumarate and emtricitabine tablet were identified from two randomised placebo controlled clinical trials (iPrEx, Partners PrEP) in which 2830 HIV-1 uninfected adults received tenofovir disoproxil fumarate and emtricitabine tablet 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 tenofovir disoproxil fumarate and emtricitabine 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 fumarate and emtricitabine tablet in the iPrEx trial. Grades 2-3 proteinuria (2-4+) and glycosuria (3+) occurred in less than 1% of subjects treated with tenofovir disoproxil fumarate and emtricitabine 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 tenofovir disoproxil fumarate and emtricitabine treatment group compared with the placebo group, which returned toward baseline after discontinuation of treatment. Thirteen percent of subjects receiving tenofovir disoproxil fumarate and emtricitabine treatment 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 tenofovir disoproxil fumarate and emtricitabine 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 2000 adult patients with HIV infection have been treated with emtricitabine tablets 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 tablet 200 mg (N=580) or comparator drug (N=431) for 48 weeks.
The most common adverse events that occurred in patients receiving emtricitabine tablets 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 postmarketing surveillance.

In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of tenofovir disoproxil 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.

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

4.9 Overdose

There is no known antidote for tenofovir disoproxil fumarate and emtricitabine. If overdose occurs the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary.

Tenofovir disoproxil fumarate.

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

Emtricitabine.

Limited clinical experience is available at doses higher than the therapeutic dose of emtricitabine. In once 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 131126 (Australia) and 0800 764 766 (New Zealand).

5 Pharmacological Properties

Tenofovir/Emtricitabine Sandoz 301/200 tablet contains 200 mg of emtricitabine with 300.6 mg of tenofovir disoproxil succinate salt as compared to the innovator product which contained 300 mg tenofovir disoproxil fumarate salt. All clinical data in this product information (including Pharmacokinetic, Pharmacodynamic, and Clinical Trial data) relevant to tenofovir are based on tenofovir disoproxil fumarate.

5.1 Pharmacodynamic Properties

Tenofovir disoproxil fumarate and emtricitabine belong to the nucleoside and nucleotide reverse transcriptase inhibitors pharmacotherapeutic group (ATC code: J05AF30).

Mechanism of action.

Tenofovir disoproxil.

Tenofovir disoproxil succinate is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. Tenofovir disoproxil succinate 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 analog 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 fumarate 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 fumarate.

The in vitro antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, primary monocyte/macrophage cells and peripheral blood lymphocytes. The IC50 (50% inhibitory concentration) values for tenofovir were in the range of 0.04-8.5 microM. 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 microM). In addition, tenofovir has also been shown to be active in vitro against HIV-2, with similar potency as observed against HIV-1.

Emtricitabine.

The in vitro antiviral activity of emtricitabine against laboratory and clinical isolates of HIV was assessed in lymphoblastoid cell lines, the MAGI-CCR5 cell line, and peripheral blood mononuclear cells. The IC50 value for emtricitabine was in the range of 0.0013-0.64 microM (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 microM) and showed strain specific activity against HIV-2 (IC50 values ranged from 0.007-1.5 microM).
Prophylactic activity in a nonhuman primate model of HIV transmission.

Emtricitabine and tenofovir disoproxil fumarate.

The prophylactic activity of the combination of daily oral emtricitabine and tenofovir disoproxil fumarate 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 fumarate 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 fumarate.

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

Emtricitabine.

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

Tenofovir disoproxil fumarate.

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 fumarate in combination with other antiretroviral agents. In treatment-naive patients treated with tenofovir disoproxil fumarate + lamivudine + efavirenz through 144 weeks, viral isolates from 8/47 (17%) patients with virologic failure showed reduced susceptibility to tenofovir. In treatment-naive patients treated with emtricitabine + tenofovir disoproxil fumarate + 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 fumarate-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 tenofovir disoproxil fumarate and 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 enrollment. The M184V/I substitutions associated with resistance to emtricitabine were observed in 3 of the 10 subjects (2 of 2 in the tenofovir disoproxil fumarate and emtricitabine group and 1 of 8 in the placebo group). One of the two subjects in the tenofovir disoproxil fumarate and emtricitabine group harbored wild type virus at enrollment and developed the M184V substitution 4 weeks after enrollment. The other subject had indeterminate resistance at enrollment but was found to have the M184I substitution 4 weeks after enrollment.

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 tenofovir disoproxil fumarate and emtricitabine group, 15 subjects in the tenofovir disoproxil fumarate group, and 51 subjects in the placebo group. Fourteen subjects were observed to be HIV-1 infected at the time of enrollment (3 in the tenofovir disoproxil fumarate and emtricitabine group, 5 in the tenofovir disoproxil fumarate group, and 6 in the placebo group). One of the three subjects in the tenofovir disoproxil fumarate and emtricitabine group who was infected with wild type virus at enrollment selected an M184V expressing virus by week 12. Two of the five subjects in the tenofovir disoproxil fumarate group had tenofovir-resistant viruses at the time of seroconversion; one subject infected with wild type virus at enrollment 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 enrollment, 4 subjects (2 in the tenofovir disoproxil fumarate group, 1 in the tenofovir disoproxil fumarate 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 fumarate.

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 and tenofovir disoproxil fumarate in combination with efavirenz in treatment-naive adults, supports the use of tenofovir disoproxil fumarate and emtricitabine 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 Viread and Emtriva. The iPrEx study and Partners PrEP study support the use of tenofovir disoproxil fumarate and emtricitabine tablets to help reduce the risk of acquiring HIV-1.

Tenofovir disoproxil fumarate and emtricitabine tablets study 934: emtricitabine + tenofovir disoproxil fumarate + efavirenz compared with Combivir (lamivudine/zidovudine) + 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 tablet + tenofovir disoproxil fumarate tablet administered in combination with efavirenz or Combivir (lamivudine/zidovudine) administered in combination with efavirenz. For patients randomised to receive emtricitabine + tenofovir disoproxil fumarate the two drugs were administered individually for the first 96 weeks and then switched to tenofovir disoproxil fumarate and emtricitabine tablet 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 tablet + tenofovir disoproxil fumarate tablet in combination with efavirenz was statistically significantly superior to lamivudine/zidovudine in combination with efavirenz with regards to the primary and secondary endpoints: achieving and maintaining HIV-1 RNA < 400 copies/mL through 48 and 144 weeks (see Table 14). The difference in the proportions of responders between the emtricitabine tablet + tenofovir disoproxil fumarate tablet group and the Combivir group was 11.4%, and the 95% CI was 4.3% to 18.6% (p=0.002) at week 48 and a difference of 12.9% (95% CI was 4.2% to 21.6%, p=0.004) at week 144.
Through 48 weeks of therapy, 80% and 70% of patients in the emtricitabine tablet + tenofovir disoproxil fumarate tablet and the lamivudine/zidovudine arms, respectively, achieved and maintained HIV-1 RNA < 50 copies/mL. The difference in the proportions of responders between the emtricitabine tablet + tenofovir disoproxil fumarate tablet group and the Combivir group was 9.1%, and the 95% CI was 1.6% to 16.6% (p=0.021) at week 48. The proportion of patients responding at 144 weeks of therapy was higher in the tenofovir disoproxil fumarate and emtricitabine tablet group (64%) compared with the Combivir group (56%); p=0.082, a difference of 8.1% and the 95% CI was -0.8% to 17.0%.
The mean increase from baseline in CD4 cell count was 190 cells/mm3 and 312 cells/mm3 for the emtricitabine tablet + tenofovir disoproxil fumarate tablet + efavirenz arm, and 158 cells/mm3 and 271 cells/mm3 for the Combivir + efavirenz arm (p=0.002 and p = 0.088) at weeks 48 and 144, respectively.
Resistance analysis was performed on HIV isolates from all patients with > 400 copies/mL of HIV-1 RNA at week 144 while on study 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 fumarate and emtricitabine tablet group and in 72% (21/29) analysed patients in the Combivir group.
The M184V mutation, associated with resistance to emtricitabine and lamivudine developed significantly less in the analysed patients in the tenofovir disoproxil fumarate and emtricitabine tablet group 11% (2/19) compared with the analysed patients in the Combivir group, 34% (10/29). Two patients in the Combivir group developed thymidine analog mutations, specifically D67N or K70R mutations in the reverse transcriptase gene. No patient in either treatment group developed the K65R mutation, which is associated with reduced susceptibility to tenofovir disoproxil fumarate.

iPrEx trial.

The iPrEx trial was a randomised double-blind placebo-controlled multinational study evaluating tenofovir disoproxil fumarate and emtricitabine tablet in 2499 HIV-seronegative men or transgender women who have sex with men and with evidence of high risk behavior for HIV-1 infection. Evidence of high risk behavior 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 counseling, condoms and management of sexually transmitted infections. Of the 2499 enrolled, 1251 received tenofovir disoproxil fumarate and emtricitabine tablet 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 fumarate and emtricitabine 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 fumarate and emtricitabine tablet and placebo, respectively. Two of the 13 seroconversions in the tenofovir disoproxil fumarate and emtricitabine tablet 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 fumarate and emtricitabine tablet 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 fumarate.

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

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

Study 907 was a 24 week, double-blind placebo-controlled multicentre study of tenofovir disoproxil fumarate tablet 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 fumarate tablet 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 fumarate 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 fumarate group.
Treatment-naive patients.

Study 903: tenofovir disoproxil fumarate + lamivudine + efavirenz compared to stavudine + lamivudine + efavirenz.

Data through 144 weeks are reported for Study 903, a double-blind, active-controlled multicentre study comparing tenofovir disoproxil fumarate tablet (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 fumarate 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 fumarate 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 fumarate arm and in 2 patients on the d4T arm. Of the 8 patients who developed K65R in the tenofovir disoproxil fumarate 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 fumarate.
Genotypic analyses of tenofovir disoproxil fumarate in patients with previous antiretroviral therapy (study 902 and 907). The virologic response to tenofovir disoproxil fumarate 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 fumarate from pre-existing zidovudine-associated mutations were observed and appeared to depend on the number and type of mutations. Tenofovir disoproxil fumarate-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 fumarate 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 fumarate 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 fumarate 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 fumarate 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 fumarate 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 fumarate.
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 fumarate. Cross-resistance between tenofovir disoproxil fumarate and HIV protease inhibitors is unlikely because of the different enzyme targets involved.
Phenotypic analyses of tenofovir disoproxil fumarate in patients with previous antiretroviral therapy (study 902 and 907). The virologic response to tenofovir disoproxil fumarate 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 fumarate and response to tenofovir disoproxil fumarate therapy. Table 18 summarises the HIV RNA response by baseline tenofovir disoproxil fumarate susceptibility.

Emtricitabine.

Treatment-experienced patients.

Study 303: emtricitabine once daily + stable background therapy (SBT) compared to lamivudine twice daily + 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 + didanosine once daily + efavirenz once daily compared to stavudine twice daily + didanosine once daily + 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

Pharmacokinetics in adults.

One tenofovir disoproxil fumarate and emtricitabine 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 fumarate.

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

Effects of food on oral absorption.

Administration of tenofovir disoproxil fumarate and emtricitabine 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 fumarate and emtricitabine tablet was administered with a light meal. Emtricitabine systemic exposures (AUC and Cmax) were unaffected when tenofovir disoproxil fumarate and emtricitabine 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).

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/Emtricitabine Sandoz 301/200 be modified in HIV-1 infected patients with creatinine clearance < 60 mL/min (see Section 4.2 Dose and Method of Administration). Tenofovir/Emtricitabine Sandoz 301/200 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/Emtricitabine Sandoz 301/200 for a 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/Emtricitabine Sandoz 301/200 for PrEP, evaluate potential causes and reassess potential risks and benefits of continued use (see Section 4.2 Dose and Method of Administration).

Patients with hepatic impairment.

Tenofovir disoproxil fumarate and emtricitabine tablet.

The pharmacokinetics of tenofovir following a 300 mg dose of tenofovir disoproxil fumarate tablet has 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 fumarate and emtricitabine tablet 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 fumarate 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.

Carcinogenicity.

No carcinogenicity studies have been conducted with tenofovir disoproxil fumarate and emtricitabine in combination. In a long-term carcinogenicity study conducted in mice with tenofovir disoproxil (as 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 gastro-intestinal tract, likely to result in much higher exposure margins than that based on the AUC. At therapeutic doses the risk of these duodenal effects occurring in humans is likely to be low. The systemic drug exposure (AUC) with the 600 mg/kg/day dose was approximately 15 times the human exposure at the therapeutic dose of 300 mg/day. No tumourigenic response was observed in rats treated with doses of up to 300 mg/kg/day (5 times the human systemic exposure at the therapeutic dose based on AUC).
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).

Genotoxicity.

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

6 Pharmaceutical Particulars

6.1 List of Excipients

Tenofovir/Emtricitabine Sandoz 301/200 tablets contain the following ingredients as excipients:

Tablet core.

Croscarmellose sodium, lactose monohydrate, magnesium stearate (E470b), microcrystalline cellulose (E460) and pregelatinised maize starch.

Film-coating.

Polyvinyl alcohol, macrogol 3350, purified talc, indigo carmine aluminium lake (E132), titanium dioxide (E171).

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/Emtricitabine Sandoz 301/200 is supplied in high density polyethylene (HDPE) bottles containing 30 tablets and a desiccant (silica gel canister or sachet) and is closed with a plastic (PP) child-resistant cap.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Chemical structure.

Tenofovir disoproxil succinate.

The chemical name of tenofovir disoproxil succinate is (R)-(((1-(6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) phosphoryl) bis(oxy)bis(methylene) isopropyl dicarbonate succinate. It has a molecular formula of C19H30N5O10P.C4H6O4 and a molecular weight of 637.53. It has the following structural formula:

Emtricitabine.

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

CAS number.

Tenofovir disoproxil succinate CAS registry number: 1637632-97-3.
Emtricitabine CAS registry number: 143491-57-0.
The partition coefficient (log p) for tenofovir disoproxil is 1.25 and the pKa is 3.75.
Emtricitabine has a solubility of approximately 112 mg/mL in water at 25°C. The partition coefficient (log p) for emtricitabine is -0.43 and the pKa is 2.65.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription only medicine.

Summary Table of Changes