Consumer medicine information

Tenofovir ARX

Tenofovir disoproxil fumarate

BRAND INFORMATION

Brand name

Tenofovir ARX

Active ingredient

Tenofovir disoproxil fumarate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Tenofovir ARX.

SUMMARY CMI

TENOFOVIR ARX

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 ARX?

Tenofovir ARX contains the active ingredient Tenofovir disoproxil fumarate. Tenofovir ARX is an antiviral medication used to treat CHB and HIV-1 infection in adults and children aged over 12 years and weighing at least 35 kg.

For more information, see Section 1. Why am I using Tenofovir ARX? in the full CMI.

2. What should I know before I use Tenofovir ARX?

Do not use if you have ever had an allergic reaction to Tenofovir disoproxil fumarate 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 ARX? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Tenofovir ARX 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 ARX?

  • If you are taking this medicine to treat HIV-1 or if you have HIV-1 and HBV co-infection and are taking this medicine, always take this medicine in combination with other anti-HIV-1 medicines. This medicine and other similar medicines may be less likely to work in the future if you are not taking Tenofovir disoproxil fumarate with other anti-HIV-1 medicines because you may develop resistance to those medicines. If you have any questions about what medicines you should or should not be taking, please see your doctor or pharmacist. More instructions can be found in Section 4. How do I use Tenofovir ARX? in the full CMI.

5. What should I know while using Tenofovir ARX?

Things you should do
  • Your doctor will tell you how much of this medicine you should take, depending on your condition and whether you are taking any other medicines.
  • The usual dose is one tablet once a day
Things you should not do
  • Do not breastfeed if you are taking Tenofovir ARX.
  • Do not give this medicine to anyone else, even if they have the same condition as you.
  • Do not take your medicine to treat any other complaint unless your doctor tells you to.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how Tenofovir ARX affects you.
  • Some patients taking this medicine have experienced dizziness.
Drinking alcohol
  • Tell your doctor if you drink alcohol if you are prescribed Tenofovir ARX
Looking after your medicine
  • Keep your medicine in a cool dry place where the temperature will stay below 25°C.
  • Keep your medicine in its pack until it is time to take it. If you take your medicine out of its pack it may not keep well.

For more information, see Section 5. What should I know while using Tenofovir ARX? in the full CMI.

6. Are there any side effects?

Some patients treated with this medicine have had kidney problems. If you have had kidney problems in the past or need to take another drug that can cause kidney problems, your doctor may need to perform additional blood tests.

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 ARX

Active ingredient(s): Tenofovir disoproxil fumarate

Consumer Medicine Information (CMI)

This leaflet provides important information about using Tenofovir ARX. 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 ARX.

Where to find information in this leaflet:

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

1. Why am I using Tenofovir ARX?

Tenofovir ARX contains the active ingredient Tenofovir disoproxil fumarate. Tenofovir ARX belongs to a group of medicines called nucleoside analog reverse transcriptase inhibitors (NRTIs)

Chronic Hepatitis B (CHB): Tenofovir ARX is an antiviral medication used to treat CHB in adults and children aged over 12 years and weighing at least 35 kg. Tenofovir ARX works by interfering with the normal working of enzymes that are essential for HBV to reproduce itself. This may help lower the amount of hepatitis B virus in your body by lowering the ability of the virus to multiply and infect new liver cells. It can improve the inflammation and scar tissue caused by the hepatitis B virus in your liver. Lowering the amount of virus in your body may reduce the chance of developing cirrhosis, liver failure and liver cancer. We do not know how long this medicine may help treat your hepatitis. Sometimes viruses change in your body and medicines no longer work. This is called drug resistance.

Human Immunodeficiency Virus (HIV-1) Infection: Tenofovir ARX is also used to treat HIV-1 infection in adults and children aged over 12 years and weighing at least 35 kg. It is always used in combination with other anti-HIV-1 medicines to treat people with HIV-1 infection. HIV-1 infection destroys CD4 (T) cells, which are important to the immune system. After many T cells are destroyed, acquired immune deficiency syndrome (AIDS) develops. This medicine helps to block HIV-1 reverse transcriptase, an enzyme in your body that is needed for HIV-1 to multiply. It lowers the amount of HIV-1 in the blood (called viral load) and may help to increase the number of T cells. Lowering the amount of HIV-1 in the blood lowers the chance of infections that happen when your immune system is weak (called opportunistic infections). Tenofovir ARX does not cure HIV-1 infection or AIDS. You do not have to have HIV-1 infection to be treated with this medicine for HBV and vice versa. Tenofovir ARX does not reduce the risk of passing HIV-1 or HBV to others through sexual contact or blood contamination. Continue to practice safe sex and do not use or share dirty needles.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed this medicine for another reason. This medicine is available only with a doctor's prescription. This medicine is not addictive. This medicine should not be used in children less than 12 years of age.

2. What should I know before I use Tenofovir ARX?

Warnings

Do not use Tenofovir ARX if:

  • you are allergic to Tenofovir disoproxil fumarate, or any of the ingredients listed at the end of this leaflet.
  • Always check the ingredients to make sure you can use this medicine.

Some of the symptoms of an allergic reaction may include:

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

Do not take this medicine if you are already taking a combination tablet that contains Tenofovir ARX or are taking adefovir.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal. If you are not sure whether you should start taking this medicine, talk to your doctor.

Check with your doctor if you:

  • have any other medical conditions and/or allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

  • kidney problems
  • bone problems
  • liver problems including HBV
  • HIV-1 infection Tell your doctor if you are pregnant or plan to become pregnant.

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

Pregnancy and breastfeeding

The effects of this medicine on pregnant women or their unborn babies are not known.

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

Talk to your doctor if you are breastfeeding or intend to breastfeed. Tenofovir ARX has been found in breast milk at low concentrations and may affect your baby. Do not breastfeed if you have HIV-1 or HBV. If you are a woman who has or will have a baby, talk with your doctor or pharmacist about the best way to feed your baby. If your baby does not already have HIV-1 or HBV, there is a chance that the baby can get HIV-1 or HBV through breastfeeding.

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.

Some medicines may interact with Tenofovir ARX. These include:

  • didanosine
  • atazanavir
  • lopinavir/ritonavir
  • ledipasvir/sofosbuvir
  • sofosbuvir/velpatasvir

If you are taking any of these you may need a different dose or you may need to take different medicines. You may need to be followed more carefully if you are taking these medicines together. Other medicines not listed above may also interact with Tenofovir ARX.

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 ARX.

4. How do I use Tenofovir ARX?

How to use

  • If you are taking this medicine to treat HIV-1 or if you have HIV-1and HBV co-infection and are taking this medicine, always take this medicine in combination with other anti-HIV-1 medicines. This medicine and other similar medicines may be less likely to work in the future if you are not taking Tenofovir disoproxil fumarate with other anti-HIV-1 medicines because you may develop resistance to those medicines. If you have any questions about what medicines you should or should not be taking, please see your doctor or pharmacist.
  • If you have been given this medicine to treat CHB, you are advised to get a HIV-1 test before you start taking this medicine and at any time after that when there is a chance you were exposed to HIV-1.
  • Follow the instructions provided and use Tenofovir ARX until your doctor tells you to stop.

How much to use Tenofovir ARX

Your doctor will tell you how much of this medicine you should take, depending on your condition and whether you are taking any other medicines. The usual dose is one tablet once a day. If you have kidney problems, your doctor may recommend that you take this medicine less frequently.

How to take it

Swallow the tablet whole with water

When to take Tenofovir ARX

Take this medicine at about the same time each day. Taking it at the same time each day will have the best effect. It will also help you remember when to take it. It is best taken with a meal or just afterwards.

How long to take it for

Continue taking your medicine for as long as your doctor tells you. Make sure you always have enough supply of Tenofovir ARX. This is very important because the amount of virus in your blood may increase if the medicine is stopped for even a short time. The virus may develop resistance to Tenofovir ARX and become harder to treat. If you are taking this medicine to treat CHB, stopping treatment may result in very severe hepatitis and serious liver problem.

If you forget to use Tenofovir ARX

It is important that you do not miss any doses.

Tenofovir ARX should be used regularly at the same time.

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

Otherwise, take it as soon as you remember and then go back to taking your medicine as you would normally

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

This may increase the chance of you experiencing side effects.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you use too much Tenofovir ARX

If you think that you have used too much Tenofovir ARX, 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 ARX?

Things you should do

If you are about to be started on any new medicine, tell your doctor and pharmacist that you are taking this medicine.

Tell any other doctors, dentists and pharmacists who are treating you that you take this medicine.

Call your doctor straight away if you:

  • plan to have any vaccinations.
  • become pregnant or plan to breastfeed while taking this medicine, tell your doctor immediately.

Keep all your doctor's appointments so that your progress can be checked. Your doctor may occasionally do tests to make sure the medicine is working and to prevent side effects.

Remind any doctor, dentist or pharmacist you visit that you are using Tenofovir ARX.

Things you should not do

  • Do not breastfeed if you are taking Tenofovir ARX.
  • Do not give this medicine to anyone else, even if they have the same condition as you.
  • Do not take your medicine to treat any other complaint unless your doctor tells you to.
  • Do not stop taking your medicine, or change the dosage, without first checking with your doctor.

It is extremely important that you do not stop taking this medicine without your doctor's advice. If you have a Hepatitis B infection, you may have a ‘flare-up’, where the disease suddenly returns in a worse way than before. This flare-up may lead to liver failure and possibly liver transplantation or death.

After stopping this medicine, tell your doctor immediately about any new, unusual, or worsening symptoms that you notice after stopping treatment. After you stop taking this medicine, your doctor will still need to check your health and take blood tests to check your liver for several months.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Tenofovir ARX affects you.

Some patients taking this medicine have experienced dizziness. Make sure you know how you react to this medicine before you drive a car, operate machinery or do anything else that could be dangerous if you are dizzy.

Drinking alcohol

Tell your doctor if you drink alcohol.

Looking after your medicine

  • Keep your medicine in a cool dry place where the temperature will stay below 25°C.
  • Keep your medicine in its pack until it is time to take it. If you take your medicine out of its pack it 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.

When to discard your medicine (as relevant)

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine left over.

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.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

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

Common side effects

Common side effectsWhat to do
Clinical studies in patients with HIV-1:
  • diarrhoea
  • nausea
  • vomiting
  • dizziness
  • flatulence (intestinal gas)
Clinical studies in patients with CHB:
The only common side effects are:
  • nausea
Marketing experience:
Other side effects reported since this medicine has been marketed include:
  • low blood phosphate and potassium
  • shortness of breath
  • increased liver enzymes, increased amylase
  • inflammation of the liver
  • abdominal pain
  • inflammation of the pancreas
  • rash
  • weakness
Speak to your doctor if you have any of these less serious side effects and they worry you or go straight to the Emergency Department.

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.

Kidney Problems:

Some patients treated with this medicine have had kidney problems. If you have had kidney problems in the past or need to take another drug that can cause kidney problems, your doctor may need to perform additional blood tests. Kidney problems may be associated with muscle problems and softening of the bones.

Effects on Bone:

Laboratory tests show changes in the bones of patients treated with this medicine. It is not known whether long-term use of this medicine will cause damage to your bones. If you have had bone problems in the past, your doctor may need to perform additional tests or may suggest additional medication.

Lactic Acidosis:

Some patients taking antiviral drugs like this medicine have developed a condition called lactic acidosis. This is a build-up in the blood of lactic acid, the same substance that causes your muscles to burn during heavy exercise. Symptoms of lactic acidosis include nausea, vomiting, unusual or unexpected stomach discomfort, and weakness.

If you notice these symptoms or if your medical condition changes suddenly, call your doctor right away.

There have been other side effects in patients taking this medicine. However, these side effects may have been due to other medicines that patients were taking or to the illness itself. Some of these side effects can be serious.

Allergic reactions:

If you think you are having an allergic reaction to Tenofovir disoproxil fumarate, do not take any more of this medicine and tell your doctor immediately or go to the Emergency department at your nearest hospital.

Symptoms of an allergic reaction may include some or all the following:

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

Other side effects not listed above may occur in some patients

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 ARX contains

Active ingredient
(main ingredient)		Each tablet contains 300 mg Tenofovir disoproxil fumarate as the active ingredient.
Other ingredients
(inactive ingredients)
  • lactose
  • crospovidone
  • calcium stearate
  • colloidal anhydrous silica
  • hypromellose
  • macrogol 8000
  • hyprolose
  • titanium dioxide
  • indigo carmine aluminium lake
Potential allergensContains lactose

This medicine does not contain gluten, sucrose, tartrazine or any other azo dyes.Do not take this medicine if you are allergic to any of these ingredients.

What Tenofovir ARX looks like

Tenofovir ARX is 300 mg tablets: light blue, almond shaped, biconvex, coated tablet. Engraved "TEN" over "300" on one side, "APO" on the other side.

Blister and bottle packs of 30 tablets:

Bottle: AUST R 247315*

Blister: AUST R 247314

* Not all pack types may be available.

Who distributes Tenofovir ARX

Arrotex Pharmaceuticals Pty Ltd
15-17 Chapel Street
Cremorne VIC 3121

This leaflet was prepared in September 2024

Published by MIMS November 2024

BRAND INFORMATION

Brand name

Tenofovir ARX

Active ingredient

Tenofovir disoproxil fumarate

Schedule

S4

 

1 Name of Medicine

Tenofovir disoproxil fumarate.

2 Qualitative and Quantitative Composition

Each tablet contains 300 mg tenofovir disoproxil fumarate as the active ingredient.

Excipients with known effect.

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

3 Pharmaceutical Form

Light blue, almond shaped, biconvex, coated tablet. Engraved "TEN" over "300" on one side, "APO" on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Tenofovir disoproxil fumarate in combination with other antiretroviral agents is indicated for the treatment of HIV-infected adults and paediatric patients 12 years of age and older.
Tenofovir disoproxil fumarate is indicated for the treatment of chronic hepatitis B in adults (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
Tenofovir disoproxil fumarate is indicated for the treatment of chronic hepatitis B in paediatric patients 12 years of age and older with compensated liver disease and with evidence of immune active disease, i.e. active viral replication, persistently elevated serum ALT levels or evidence of active inflammation.

4.2 Dose and Method of Administration

Tenofovir ARX tablets are intended for oral administration.

Dosage.

Adults.

The recommended dose is 300 mg (one tablet) once daily taken orally. In order to optimize the absorption of tenofovir, it is recommended that the tablet be taken with food.

Paediatric patients (≥ 12 years of age and ≥ 35 kg).

The recommended dose for paediatric patients (12 years of age and older), who weigh ≥ 35 kg, is 300 mg (one tablet) once daily taken orally. In order to optimize the absorption of tenofovir, it is recommended that the tablet be taken with food.
The safety and efficacy of tenofovir disoproxil fumarate in patients under the age of 12 years have not been established. Tenofovir disoproxil fumarate must not be administered to children under 12, until further data become available.

Elderly.

No data are available on which to make a dose recommendation for patients over the age of 65 years. The safety and efficacy of tenofovir disoproxil fumarate have not been established in patients over the age of 65 years. Caution should be exercised when administering tenofovir disoproxil fumarate to elderly patients until further data become available describing the disposition of tenofovir disoproxil fumarate in these patients (see Section 4.4 Special Warnings and Precautions for Use). The greater frequency of decreased hepatic, renal or cardiac function in these patients, presence of any concomitant illnesses or the need for treatment with other medicinal products concomitantly with tenofovir disoproxil fumarate should be taken into consideration.

Renal impairment.

Tenofovir is eliminated by renal excretion and the exposure to tenofovir increases in patients with renal dysfunction. Dosing interval adjustment is required in all patients with creatinine clearance < 50 mL/min (calculated using the Cockcroft Gault equation), as detailed in Table 1. The proposed dose interval modifications are based on limited data and may not be optimal. The safety and efficacy of these dosing interval adjustment guidelines have not been clinically evaluated. Therefore, clinical response to treatment and renal function should be closely monitored in these patients (see Section 4.4 Special Warnings and Precautions for Use).
The pharmacokinetics of tenofovir have not been evaluated in non-haemodialysis patients with creatinine clearance < 10 mL/min; therefore, no dosing recommendation is available for these patients.
No data are available to make dose recommendations in paediatric patients 12 years of age and older with renal impairment.

Hepatic impairment.

There were no substantial alterations in tenofovir pharmacokinetics in patients with hepatic impairment compared with unimpaired patients. No change in tenofovir disoproxil fumarate dosing is required in patients with hepatic impairment.

Chronic hepatitis B.

Treatment with tenofovir disoproxil fumarate may be discontinued if there is HBsAg loss or HBsAg seroconversion, otherwise the optimal duration of treatment is unknown.

4.3 Contraindications

Known hypersensitivity to tenofovir, tenofovir disoproxil fumarate or to any of the excipients in the film-coated tablets.
Tenofovir disoproxil fumarate must not be administered to children less than 12 years of age until further data become available.
This medicine should not be administered concurrently with fixed dose combination tablets containing tenofovir disoproxil fumarate, tenofovir alafenamide or adefovir dipivoxil.

4.4 Special Warnings and Precautions for Use

General.

Patients receiving tenofovir disoproxil fumarate or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection, and therefore should remain under close clinical observation by physicians experienced in the treatment of patients with HIV associated diseases.
Patients should be advised that antiretroviral therapies, including tenofovir disoproxil fumarate, have not been proven to prevent the risk of transmission of HIV or HBV to others through sexual contact or blood contamination. Appropriate precautions must continue to be used. Patients should also be informed that tenofovir disoproxil fumarate is not a cure for HIV infection.
HIV antibody testing should be offered to all HBV-infected patients before initiating tenofovir disoproxil fumarate therapy (see HIV and HBV co-infection, below).
In the treatment of chronic hepatitis B, limited data are currently available in immuno-suppressed patients or those receiving immuno-suppressive regimens, orthotrophic liver transplant patients and patients co-infected with the hepatitis C or D virus. As clinical studies have not included sufficient numbers of subjects to determine whether these patients respond differently to tenofovir disoproxil fumarate chronic hepatitis B therapy, such patients should be closely monitored.

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, including tenofovir disoproxil fumarate, in the treatment of HIV infection. A majority of these cases have been reported in women. The preclinical and clinical data suggest that the risk of occurrence of lactic acidosis, a class effect of nucleoside analogues is low for tenofovir disoproxil fumarate. However, as tenofovir is structurally related to nucleoside analogues, this risk cannot be excluded. Caution should be exercised when administering tenofovir disoproxil fumarate to any patient, and particularly to those with known risk factors for liver disease. Treatment with tenofovir disoproxil fumarate should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity.

HIV and HBV co-infection.

Due to the risk of development of HIV resistance, tenofovir disoproxil fumarate should only be used as part of an appropriate antiretroviral combination regimen in HIV/HBV co-infected patients.

Exacerbation of hepatitis after discontinuation of treatment.

Discontinuation of anti-HBV therapy, including tenofovir disoproxil fumarate may be associated with severe acute exacerbations of hepatitis. Patients infected with HBV who discontinue tenofovir disoproxil fumarate should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, resumption of anti-hepatitis B therapy may be warranted. In patients with advanced liver disease or cirrhosis, discontinuation of anti-hepatitis B therapy is not recommended since post-treatment exacerbation of hepatitis may lead to hepatic decompensation.

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-NRTI 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 utilizing 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 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, generalized 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.

Bone effects.

Bone toxicities including a reduction in bone mineral density (BMD) have been observed in studies in three animal species (see Section 5.3 Preclinical Safety Data, Animal toxicology). Clinically relevant bone abnormalities have not been seen in long term clinical studies in adults (> 3 years).
Bone abnormalities may be associated with proximal renal tubulopathy (see Section 4.8 Adverse Effects (Undesirable Effects), Post-marketing experience). If bone abnormalities are suspected during therapy, then appropriate consultation should be obtained.
There is limited clinical experience with tenofovir disoproxil fumarate in paediatric patients. In a clinical study of HIV-1 infected paediatric patients 12 years of age and older (Study 0321), bone effects were similar to adult patients. Under normal circumstances BMD increases rapidly in this age group. In this study, the mean rate of bone gain was less in the tenofovir disoproxil fumarate treated group compared to the placebo group. Six tenofovir disoproxil fumarate treated patients and one placebo treated patient had significant (> 4%) lumbar spine BMD loss in 48 weeks. Markers of bone turnover in tenofovir disoproxil fumarate treated paediatric patients 12 years of age and older suggest increased bone turnover, consistent with the bone effects observed in adults. The effects of tenofovir disoproxil fumarate associated changes in BMD and biochemical markers on long-term bone health and fracture risk are unknown. In a clinical study (Study 115) conducted in paediatric subjects 12 years of age and older with chronic HBV infection, both the tenofovir disoproxil fumarate and placebo treatment arms experienced an overall increase in mean spine BMD, as expected for an adolescent population. The percent increase from baseline in spine BMD in tenofovir disoproxil fumarate treated subjects was less than the increase observed in placebo-treated subjects. During the study, three subjects in the tenofovir disoproxil fumarate group and two subjects in the placebo group had a decrease of more than 4% in lumbar spine BMD.

Use in renal impairment.

Dosing interval adjustment is required in all patients with creatinine clearance < 50 mL/min (see Section 4.2 Dose and Method of Administration). The proposed dose interval modifications are based on limited data and may not be optimal. The safety and efficacy of these dosing interval adjustment guidelines have not been clinically evaluated, and so the potential benefit of tenofovir disoproxil fumarate therapy should be assessed against the potential risk of renal toxicity. Therefore, clinical response to treatment and renal function should be closely monitored in these patients.
Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphataemia), has been reported in association with the use of tenofovir disoproxil fumarate (see Section 4.8 Adverse Effects (Undesirable Effects), Post-marketing experience).
Tenofovir disoproxil fumarate should be avoided with concurrent or recent use of a nephrotoxic agent.
It is recommended that creatinine clearance is calculated in all patients prior to initiating therapy and, as clinically appropriate, during tenofovir disoproxil fumarate therapy. Patients at risk for, or with a history of, renal dysfunction, including patients who have previously experienced renal events while receiving adefovir dipivoxil, should be routinely monitored for changes in serum creatinine and phosphorus.

Use in the elderly.

Tenofovir disoproxil fumarate has not been studied in patients over the age of 65. 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.

The safety and efficacy of tenofovir disoproxil fumarate in paediatric patients aged 12 to < 18 years is supported by data from two randomized studies in which tenofovir disoproxil fumarate was administered to HIV infected treatment-experienced patients and patients with chronic hepatitis B (see Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 4.8 Adverse Effects (Undesirable Effects)). The safety and efficacy of tenofovir disoproxil fumarate has not been established in children less than 12 years of age.
The clinical relevance of the long term effects of tenofovir disoproxil fumarate treatment on BMD are unknown and, at present, the data on the reversibility of renal toxicity effects is limited. Therefore, a multidisciplinary approach is recommended to consider the benefit/risk balance of treatment.
As hepatitis B is a chronic disease of the liver, ongoing clinical monitoring is recommended.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Based on the results of in vitro experiments and the known elimination pathway of tenofovir, the potential for CYP450 mediated interactions involving tenofovir with other medicinal products is low.
Tenofovir is excreted renally. Co-administration of tenofovir disoproxil fumarate with medicinal products that decrease or compete for renal clearance may increase serum concentrations of tenofovir. Tenofovir disoproxil fumarate has been evaluated in healthy volunteers in combination with abacavir, didanosine, efavirenz, emtricitabine, entecavir, indinavir, lamivudine (3TC), ledipasvir/sofosbuvir, lopinavir/ritonavir, methadone, nelfinavir, oral contraceptives, ribavirin, rifampicin, saquinavir/ritonavir, sofosbuvir and tacrolimus (see Tables 2 and 3).
When administered with tenofovir disoproxil fumarate, 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 4). 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 patients weighing ≥ 60 kg, the didanosine dose should be reduced to 250 mg when it is co-administered with tenofovir disoproxil fumarate. Data are not available to recommend a dose adjustment of didanosine for adult or paediatric patients weighing < 60 kg. When co-administered, tenofovir disoproxil fumarate 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 disoproxil fumarate should be under fasted conditions. Co-administration of tenofovir disoproxil fumarate 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.
Tenofovir disoproxil fumarate affects the pharmacokinetics of atazanavir. Tenofovir disoproxil fumarate 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.
Co-administration of tenofovir disoproxil fumarate and ledipasvir/sofosbuvir, sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevir has been shown to increase tenofovir exposure. Patients receiving a regimen containing tenofovir disoproxil fumarate concomitantly with ledipasvir/sofosbuvir, sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevir should be monitored for adverse reactions associated with tenofovir disoproxil fumarate.
Since tenofovir is primarily eliminated by the kidneys, co-administration of tenofovir disoproxil fumarate with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of tenofovir and/or increase the concentrations of other renally eliminated drugs.

Drug interactions.

At concentrations substantially higher (~ 300-fold) than those observed in vivo, tenofovir did not inhibit in vitro drug metabolism mediated by any of the following human CYP450 isoforms: CYP3A4, CYP2D6, CYP2C9 or CYP2E1. However, a small (6%) but statistically significant reduction in metabolism of CYP1A substrate was observed. Based on the results of in vitro experiments and the known elimination pathway of tenofovir, the potential for CYP450 mediated interactions involving tenofovir with other medicinal products is low (see Metabolism, above).
Tenofovir is primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion. Co-administration of tenofovir disoproxil fumarate with drugs that are eliminated by active tubular secretion may increase serum concentrations of either tenofovir or the co-administered drug, due to competition for this elimination pathway. Drugs that decrease renal function may also increase serum concentrations of tenofovir.
Tenofovir disoproxil fumarate has been evaluated in healthy volunteers in combination with abacavir, didanosine, efavirenz (EFV), emtricitabine, entecavir, indinavir, lamivudine (3TC), ledipasvir/sofosbuvir, lopinavir/ritonavir, methadone, nelfinavir, oral contraceptives, ribavirin, saquinavir/ritonavir, sofosbuvir, sofosbuvir/velpatasvir, sofosbuvir/velpatasvir/voxilaprevir and tacrolimus. Tables 2 and 3 summarize pharmacokinetic effects of co-administered drug on tenofovir pharmacokinetics and effects of tenofovir disoproxil fumarate on the pharmacokinetics of co-administered drug.
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. Table 4 summarizes the drug interaction between tenofovir disoproxil fumarate and didanosine. When administered with multiple doses of tenofovir disoproxil fumarate, the Cmax and AUC of didanosine 400 mg increased significantly. The mechanism of this interaction is unknown. When didanosine 250 mg enteric coated capsules were administered with tenofovir disoproxil fumarate, systemic exposures to didanosine were similar to those seen with the 400 mg enteric-coated capsules alone under fasted conditions (see Section 4.4 Special Warnings and Precautions for Use).
Following multiple dosing to HIV- and HBV-negative subjects receiving either chronic methadone maintenance therapy or oral contraceptives, steady state tenofovir pharmacokinetics were similar to those observed in previous studies, indicating lack of clinically significant drug interactions between these agents and tenofovir disoproxil fumarate. 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.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are limited clinical data with respect to the effect of tenofovir disoproxil on fertility. Animal studies do not indicate harmful effects of tenofovir disoproxil on fertility (see Section 5.3 Preclinical Safety Data).
(Category B3)
Tenofovir disoproxil fumarate (300 mg given once daily to mothers) in combination with standard of care (administration of hepatitis B immunoglobulin and hepatitis B vaccine in infants) was evaluated for the prevention of mother to child transmission (MTCT) of HBV in three controlled, clinical studies in women who were pregnant and chronically infected with HBV. In these studies, tenofovir disoproxil fumarate was administered to a total of 327 HBeAg-positive pregnant women from 28 to 32 weeks gestation through 1 to 2 months postpartum. Patients were followed up to 12 months after delivery; there were no new safety findings in mothers compared with the known safety profile of tenofovir disoproxil fumarate in HBV-infected adults and there were no clinically relevant safety findings in the infants.
Animal studies do not indicate harmful effects of tenofovir disoproxil on pregnancy (see Section 5.3 Preclinical Safety Data).
Because animal reproduction studies are not always predictive of human response, tenofovir disoproxil fumarate should be used during pregnancy only if clearly needed.
 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. It is recommended that HIV and HBV infected women do not breast-feed their infants in order to avoid transmission of HIV and HBV to the infant.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on ability to drive or use machines have been performed. However, patients should be informed that dizziness has been reported during treatment with tenofovir disoproxil fumarate.

4.8 Adverse Effects (Undesirable Effects)

From clinical studies.

Clinical trials in adult patients with HIV infection. More than 12,000 patients have been treated with tenofovir disoproxil fumarate alone or in combination with other antiretroviral medicinal products for periods of 28 days to 215 weeks in Phase I-III clinical trials and expanded access studies. A total of 1,544 patients have received tenofovir disoproxil fumarate 300 mg once daily in Phase I-III clinical trials; over 11,000 patients have received tenofovir disoproxil fumarate in expanded access studies.
Treatment-experienced adult patients.

Treatment-emergent adverse events.

The most common adverse events that occurred in patients receiving tenofovir disoproxil fumarate 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 5.

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 6.
Treatment-naïve adult patients.

Treatment-emergent adverse events.

In a double-blind active controlled study in which 600 treatment-naïve patients received tenofovir disoproxil fumarate (n = 299) or d4T (n = 301) in combination with lamivudine and efavirenz for 144 weeks (Study 903), the adverse reactions seen were generally consistent, with the addition of dizziness, with those seen in treatment-experienced patients (see Table 7).
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 8.

Study 934 - treatment emergent adverse events.

Study 934 was an open-label active-controlled study in which 511 antiretroviral-naïve patients received either tenofovir disoproxil fumarate + emtricitabine administered in combination with efavirenz (n = 257) or lamivudine/zidovudine administered in combination with efavirenz (n = 254). Adverse events observed in this study were generally consistent with those seen in previous studies in treatment-experienced or treatment-naïve patients (see Table 9). Adverse events leading to study drug discontinuation occurred in significantly smaller number of patients in the tenofovir DF/emtricitabine group compared to the lamivudine/zidovudine 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 DF/emtricitabine group and 6% of patients in the lamivudine/zidovudine group.

Laboratory abnormalities.

Laboratory abnormalities observed in this study were generally consistent with those seen in previous studies (Table 10).
Clinical trials in paediatric patients 12 years of age and older with HIV infection. Assessment of adverse reactions is based on one randomized study (Study 321) in 87 HIV-infected paediatric patients (12 to 18 years of age) who received treatment with tenofovir disoproxil fumarate (n = 45) or placebo (n = 42) in combination with other antiretroviral agents for 48 weeks. The adverse reactions observed in paediatric patients 12 years of age and older who received treatment with tenofovir disoproxil fumarate were consistent with those observed in clinical studies in adults. Bone effects similar to those seen in adults were observed in this study (see Section 4.4 Special Warnings and Precautions for Use).
Clinical trials in adult patients with hepatitis B. Assessment of adverse reactions is based on experience in two double-blind comparative controlled Studies (0102 and 0103) in which 641 patients with chronic hepatitis B and compensated liver disease received treatment with tenofovir disoproxil fumarate 300 mg daily (n = 426) or adefovir dipivoxil 10 mg daily (n = 215) for 48 weeks (see Table 11).
The adverse reactions with suspected (at least possible) relationship to treatment are listed below by body system organ class and frequency.

Gastrointestinal disorders.

Common: nausea.

Laboratory abnormalities.

A summary of Grade 3 and 4 laboratory abnormalities is provided in Table 12.

Treatment beyond 48 weeks.

The adverse reactions observed with continued treatment for 384 weeks were consistent with the safety profile of tenofovir disoproxil fumarate. Grade 3/4 laboratory abnormalities were similar in nature and frequency in patients continuing treatment for up to 288 weeks in these studies.

Nucleos(t)ide-experienced patients.

No new adverse reactions to tenofovir disoproxil fumarate were identified in those patients in Studies 0102, 0103 and 0106 and 0121 who had been previously treated with adefovir dipivoxil, lamivudine or other nucleoside analogues (n = 493).

Patients with decompensated liver disease.

No new adverse reactions to tenofovir disoproxil fumarate were identified from a double-blind active-controlled study (0108) in which patients with decompensated liver disease received treatment with tenofovir disoproxil fumarate (n = 45) for 48 weeks. Among the 45 subjects receiving tenofovir disoproxil fumarate, the most frequently reported treatment-emergent adverse reactions of any severity were abdominal pain (22%), nausea (20%), insomnia (18%), pruritus (16%), vomiting (13%), dizziness (13%), and pyrexia (11%). Two of 45 (4%) subjects died through Week 48 of the study due to progression of liver disease. Three of 45 (7%) subjects discontinued treatment due to an adverse event. Four of 45 (9%) subjects experienced a confirmed increase in serum creatinine of 0.5 mg/dL (1 subject also had a confirmed serum phosphorus < 2 mg/dL through Week 48). Three of these subjects (each of whom had a Child-Pugh score ≥ 10 and MELD score ≥ 14 at entry) developed renal failure. Because both tenofovir disoproxil fumarate and decompensated liver disease may have an impact on renal function, the contribution of tenofovir disoproxil fumarate to renal impairment in this population is difficult to ascertain.
One of 45 subjects experienced an on-treatment hepatic flare during the 48 Week study.
At week 168, in this population of patients with decompensated liver disease, the rate of death was of 13% (6/45) in the tenofovir disoproxil fumarate group, 11% (5/45) in the emtricitabine plus tenofovir disoproxil fumarate group and 14% (3/22) in the entecavir group. The rate of serious hepatocellular carcinoma was 18% (8/45) in the tenofovir disoproxil fumarate group, 7% (3/45) in the emtricitabine plus tenofovir disoproxil fumarate group and 9% (2/22) in the entecavir group. The rate of serious ascites, which was experienced in 7% (3/45) in the tenofovir disoproxil fumarate group, 7% (3/45) in the emtricitabine plus tenofovir disoproxil fumarate group and 5% (1/22) in the entecavir group. The rate of serious hepatic encephalopathy was 7% (3/45) in the tenofovir disoproxil fumarate group, 2% (1/45) in the emtricitabine plus tenofovir disoproxil fumarate group and 9% (2/22) in the entecavir group (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
Clinical trials in paediatric patients 12 years of age and older with HBV infection. Assessment of adverse reactions is based on one randomized study (Study 0115) in 106 paediatric patients (12 to < 18 years of age) infected with chronic hepatitis B receiving treatment with tenofovir disoproxil fumarate (n = 52) or placebo (n = 54) for 72 weeks. The adverse reactions observed in paediatric patients who received treatment with tenofovir disoproxil fumarate were consistent with those observed in clinical studies in adults (see Section 4.8 Adverse Effects (Undesirable Effects)).

Post-marketing experience.

In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of tenofovir disoproxil fumarate. Because these events have been reported voluntarily from a population of unknown size, estimates of frequency cannot be made.

Immune system disorders.

Allergic reaction (including angioedema), autoimmune hepatitis (see Section 4.4 Special Warnings and Precautions for Use).

Immune reconstitution syndrome.

In HIV infected patients with severe immune deficiency at the time of initiation of antiretroviral therapy, an inflammatory reaction to infectious pathogens (active or inactive) may arise (see Section 4.4 Special Warnings and Precautions for Use).

Metabolism and nutrition disorders.

Hypokalaemia, hypophosphataemia, lactic acidosis.

Respiratory, thoracic and mediastinal disorders.

Dyspnoea.

Gastrointestinal disorders.

Increased amylase, abdominal pain, pancreatitis.

Hepatobiliary disorders.

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

Skin and subcutaneous tissue disorders.

Rash.

Musculoskeletal and connective tissue disorders.

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

Renal and urinary disorders.

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

General disorders and administration site conditions.

Asthenia.

Reactions as a consequence of proximal renal tubulopathy.

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

Adverse reactions attendant to class.

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

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems and contact Arrotex Medical Information Enquiries/Adverse Drug Reaction Reporting on 1800 195 055.

4.9 Overdose

Symptoms.

Clinical experience of doses higher than the therapeutic dose of tenofovir disoproxil fumarate 300 mg is available from two studies. In one study, intravenous tenofovir, equivalent to 16.7 mg/kg/day tenofovir disoproxil fumarate, was administered daily for 7 days. In the second study, 600 mg 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.

Treatment.

If overdose occurs the patient must be monitored for evidence of toxicity (see Section 4.8 Adverse Effects (Undesirable Effects); Section 4.4 Special Warnings and Precautions for Use), and standard supportive treatment applied as necessary.
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.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Tenofovir disoproxil fumarate is a salt of an oral prodrug of tenofovir, a nucleoside monophosphate (nucleotide) analogue and obligate chain terminator with activity against HIV reverse transcriptase and HBV polymerase.
Tenofovir is converted to the active metabolite, tenofovir diphosphate, by constitutively expressed cellular enzymes through two phosphorylation reactions. This conversion occurs in both resting and activated T cells. Tenofovir diphosphate has an intracellular half-life of 10 hours in activated and 50 hours in resting peripheral blood mononuclear cells (PBMCs). Tenofovir diphosphate inhibits viral polymerases by direct binding competition with the natural deoxyribonucleotide substrate 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. At concentrations of up to 300 microM, tenofovir shows no effect on the synthesis of mitochondrial DNA (human liver, skeletal muscle and renal proximal tubular epithelial cells) or lactic acid production (human liver and skeletal muscle cells) in vitro.

Pharmacodynamic effects.

Tenofovir has in vitro antiviral activity against retroviruses and hepadnaviruses.

Anti-HIV-1 activity in vitro.

The in vitro antiviral activity of tenofovir against laboratory and clinical isolates of HIV was assessed in lymphoblastoid cell lines, primary monocyte/macrophage cells and peripheral blood lymphocytes. The IC50 (50% inhibitory concentration) for tenofovir was in the range 0.04-8.5 microM. In drug combination studies of tenofovir with nucleoside and non-nucleoside analogue inhibitors of HIV reverse transcriptase, and protease inhibitors, additive to synergistic effects were observed. In addition, tenofovir has also been shown to be active in vitro against HIV-2, with similar potency as observed against HIV-1.
Tenofovir shows activity within three fold of wild-type IC50 against recombinant HIV-1 expressing didanosine resistance (L74V), zalcitabine resistance (T69D) or multinucleoside drug resistance (Q151M complex) mutations in reverse transcriptase. Tenofovir shows slightly increased activity against HIV-1 expressing the abacavir/lamivudine resistance mutation M184V. The activity of tenofovir against HIV-1 strains with thymidine analogue-associated mutations (thymidine-associated mutations) appears to depend on the type and number of these resistance mutations. In the presence of mutation T215Y, a twofold increase of the IC50 was observed. In 10 samples which had multiple thymidine-associated mutations (mean 3.4), a mean 3.7-fold increase of the IC50 was observed (range 0.8-8.4). There are insufficient data at this time to correlate specific thymidine-associated mutation patterns with reduced susceptibility to tenofovir.
Multinucleoside resistant HIV-1 with T69S double insertions have reduced susceptibility to tenofovir (IC50 > 10-fold compared with wild type). Tenofovir shows activity against nonnucleoside reverse transcriptase inhibitor resistant HIV-1 with K103N or Y181C mutations. Cross-resistance to protease inhibitor resistance mutations is not expected due to the different viral enzymes targeted.
Strains of HIV-1 with reduced susceptibility to tenofovir have been selected in vitro. The selected viruses express a K65R mutation in RT and showed 3 to 4-fold reduced susceptibility to tenofovir. The K65R mutation in RT also results in reduced susceptibility to zalcitabine, didanosine, stavudine (d4T), abacavir and lamivudine (3TC) (14-, 4-, 2-, 3- and 25-fold, respectively). In addition, a K70E substitution in HIV-1 reverse transcriptase has been selected by tenofovir and results in low-level reduced susceptibility tenofovir. This substitution is also associated with reduced susceptibility to abacavir, didanosine, emtricitabine and lamivudine.

Anti-hepatitis B virus activity in vitro.

The in vitro antiviral activity of tenofovir against laboratory strains and clinical isolates of HBV was assessed in HepG2 cells. The EC50 values for tenofovir were in the range 0.06-1.5 microM. Tenofovir diphosphate inhibits recombinant HBV polymerase with a Ki (inhibition constant) of 0.18 microM. In in vitro drug combination studies of tenofovir with nucleoside anti-HBV reverse transcriptase inhibitors lamivudine, telbivudine and entecavir, additive anti-HBV activity was observed. Additive to slight synergistic effects were observed with the combination of tenofovir and emtricitabine.

Clinical trials.

Clinical efficacy in HIV infection.

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-naïve adults and in treatment-experienced adults.
Treatment-experienced adult patients.

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

Study 907 was a 24-week, double-blind, placebo-controlled multicentre study of tenofovir disoproxil fumarate added to a stable background regimen of antiretroviral agents in 550 treatment-experienced patients. After 24 weeks of blinded study treatment, all patients continuing on study were offered open-label tenofovir disoproxil fumarate for an additional 24 weeks. Patients had a mean baseline CD4 cell count of 427 cells/mm3 (range 23-1385), median baseline plasma HIV-1 RNA of 2340 (range 50-75,000) copies/mL and mean duration of prior HIV-1 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-1 RNA < 400 copies/mL and outcomes of patients through 48 weeks are summarized in Table 13.
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-1 RNA < 50 copies/mL (19% and 1%, respectively). Mean change in absolute CD4 counts by Week 24 was +11 cells/mm3 for the tenofovir disoproxil fumarate 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-experienced paediatric patients 12 years of age and older. In study GS-US-104-0321 (study 321), 87 treatment-experienced patients 12 to < 18 years of age were treated with tenofovir disoproxil fumarate (n = 45) or placebo (n = 42) in combination with an optimized background regimen (OBR) for 48 weeks. The mean baseline CD4 cell count was 374 cells/mm3 and the mean baseline plasma HIV-1 RNA was 4.6 log10 copies/mL. The median DAVG24 and DAVG48 in plasma HIV-1 RNA were -1.58 and -1.42 log10 copies/mL, respectively, for the tenofovir disoproxil fumarate treatment group compared with -1.55 and -1.35 log10 copies/mL, respectively, for the placebo group at weeks 24 and 48. Overall, the trial failed to show a difference in virologic response between the two treatment groups. Subgroup analyses suggest the lack of difference in virological response may be attributable to imbalances between treatment arms in baseline viral susceptibility to tenofovir disoproxil fumarate and OBR. In patients with partially active or non-active OBR (genotypic sensitivity score ≤ 1), the addition of tenofovir disoproxil fumarate or placebo resulted in a median DAVG24 in plasma HIV RNA of -1.66 and -1.14 log10 copies/mL, respectively. Although changes in HIV-1 RNA in these highly treatment-experienced patients were less than anticipated, the comparability of the pharmacokinetic and safety data to that observed in adults supports the use of tenofovir disoproxil fumarate in paediatric patients ≥ 12 years of age who weigh ≥ 35 kg whose HIV-1 isolate is expected to be sensitive to tenofovir disoproxil fumarate.
HIV-1 isolates from 43 patients who had plasma HIV-1 RNA ≥ 400 copies/mL were evaluated for tenofovir resistance-associated substitutions. One patient developed the K65R substitution by Week 48.
Treatment-naïve adult patients.

Study 903: tenofovir DF + 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 (300 mg once daily) administered in combination with lamivudine and efavirenz versus d4T, lamivudine and efavirenz in 600 antiretroviral-naïve 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 14.
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 percentage 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. One patient in the tenofovir disoproxil fumarate arm developed the K70E substitution in the virus. From both genotypic and phenotypic analyses there was no evidence for other pathways of resistance to tenofovir disoproxil fumarate.

Study 934: tenofovir DF + emtricitabine + efavirenz compared with lamivudine/zidovudine + efavirenz.

Study 934 is a randomized, open-label, active controlled multicentre study comparing two different dosing regimens in 511 antiretroviral-naïve HIV-1 infected patients. Patients were randomized to receive either emtricitabine + tenofovir disoproxil fumarate administered in combination with efavirenz or lamivudine/zidovudine administered in combination with efavirenz. For patients randomized to receive emtricitabine + tenofovir disoproxil fumarate the two drugs were administered individually for the first 96 weeks and then switched to tenofovir disoproxil fumarate/emtricitabine (fixed dose combination of tenofovir DF 300 mg/emtricitabine 200 mg) during Weeks 96 to 144, without regard to food.
For inclusion in the study, antiretroviral treatment-naïve adult patients (≥ 18 years) with plasma HIV RNA greater than 10,000 copies/mL, must have an estimated glomerular filtration rate as measured by Cockcroft-Gault method of ≥ 50 mL/min, adequate haematologic function, hepatic transaminases and alanine aminotransferases ≤ 3 ULN, total bilirubin ≤ 1.5 mg/dL, serum amylase ≤ 1.5 ULN and serum phosphorus ≥ 2.2 mg/dL. Exclusion criteria included: a new AIDS defining condition diagnosed within 30 days (except on the basis of CD4 criteria), ongoing therapy with nephrotoxic drugs or agents that interacted with efavirenz, pregnancy/lactation, a history of clinically significant renal/bone disease or malignant disease other than Kaposi's sarcoma or basal-cell carcinoma, or a life expectancy of less than one year. If efavirenz associated central nervous system toxicities occurred, nevirapine could be substituted for efavirenz. Patients who were not receiving their originally assigned treatment regimen after Week 48 or 96 and during the 30-day extension study window were not eligible to continue to weeks 96 or 144 respectively.
Patients had a mean age of 38 years (range 18-80), 86% were male, 59% were Caucasian and 23% were Black. The mean baseline CD4 cell count was 245 cells/mm3 (range 2-1191) and median baseline plasma HIV-1 RNA was 5.01 log10 copies/mL (range 3.56-6.54). 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 15.
In this study, tenofovir disoproxil fumarate + emtricitabine in combination with efavirenz was statistically significantly superior to lamivudine/zidovudine in combination with efavirenz with regard to the primary and secondary endpoints: achieving and maintaining HIV-1 RNA < 400 copies/mL through 48 and 144 weeks (Table 15). The difference in the proportions of responders between the tenofovir disoproxil fumarate + emtricitabine group and the lamivudine/zidovudine group was 11.4%, and the 95% CI was 4.3-18.6% (p = 0.002) at Week 48 and a difference of 12.9% (95% CI was 4.2-21.6%, p = 0.004) at Week 144.
Through 48 weeks of therapy, 80% and 70% of patients in the tenofovir disoproxil fumarate + emtricitabine and the lamivudine/zidovudine arms, respectively, achieved and maintained HIV-1 RNA < 50 copies/mL. The difference in the proportions of responders between the tenofovir DF + emtricitabine group and the lamivudine/zidovudine group was 9.1%, and the 95% CI was 1.6-16.6% (p = 0.021) at Week 48. The proportion of patients responding at 144 weeks of therapy was higher in the tenofovir DF/emtricitabine group (64%) compared with the lamivudine/zidovudine group (56%); p = 0.082, a difference of 8.1% and the 95% CI was -0.8-17.0%.
The mean increase from baseline in CD4 cell count was 190 cells/mm3 and 312 cells/mm3 for the tenofovir disoproxil fumarate + emtricitabine + efavirenz arm, and 158 cells/mm3 and 271 cells/mm3 for the lamivudine/zidovudine + 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 DF/emtricitabine group and in 72% (21/29) analysed patients in the lamivudine/zidovudine group. The M184V mutation, associated with resistance to emtricitabine and lamivudine, developed significantly less in the analysed patients in the tenofovir DF/emtricitabine group 11% (2/19) compared with the analysed patients in the lamivudine/zidovudine group, 34% (10/29). Two patients in the lamivudine/zidovudine group developed thymidine analogue mutations, specifically D67N or K70R mutations in the reverse transcriptase gene. No patient in either treatment group developed the K65R or K70E mutation, which is associated with reduced susceptibility to tenofovir disoproxil fumarate.
Genotypic analyses of tenofovir DF in patients with previous antiretroviral therapy (studies 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 Studies 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 sub-study 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 16. 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 DF-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 16.
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 DF in patients with previous antiretroviral therapy (studies 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 Studies 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 17 summarizes the HIV RNA response by baseline tenofovir disoproxil fumarate susceptibility.

Clinical efficacy in chronic hepatitis B.

The demonstration of benefit of tenofovir disoproxil fumarate is based on histological, virological, biochemical and serological responses in adults with HBeAg positive and HBeAg negative chronic hepatitis B with compensated and decompensated liver function; clinical evidence of prior treatment failure; and patients co-infected with HIV-1 and HBV. In these clinical studies patients had active viral replication at baseline. Tenofovir disoproxil fumarate has demonstrated anti-HBV activity in patients with HBV containing lamivudine- or adefovir-resistance-associated mutations.
Study 0102 and 0103: tenofovir DF compared with adefovir dipivoxil. Results through 48 weeks from two randomized, phase III double-blind studies comparing tenofovir disoproxil fumarate to adefovir dipivoxil (ADV) in patients with compensated liver disease are presented in Table 18. Study GS-US-174-0103 (0103) was conducted in 266 (randomized and treated) HBeAg positive patients while study GS-US-174-0102 (0102) was conducted in 375 (randomized and treated) patients negative for HBeAg and positive for HBeAb.
In both of these studies, tenofovir disoproxil fumarate was statistically significantly superior to adefovir dipivoxil for the primary efficacy endpoint of complete response, (defined as HBV DNA levels < 400 copies/mL and Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell fibrosis score). Treatment with tenofovir disoproxil fumarate 300 mg was also associated with significantly greater proportions of patients with HBV DNA < 400 copies/mL, when compared to adefovir dipivoxil 10 mg treatment. Both treatments produced similar results with regard to histological response (defined as Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell fibrosis score) at Week 48 (see Table 18).
In Study 0103, a significantly greater proportion of patients in the tenofovir disoproxil fumarate group than in the adefovir group had normalized ALT and achieved HBsAg loss at Week 48 (see Table 18).
Tenofovir disoproxil fumarate was associated with statistically significantly greater proportions of patients with undetectable HBV DNA (< 169 copies/mL [< 29 IU/mL]; the limit of quantification of the Roche COBAS TaqMan HBV assay), when compared with adefovir dipivoxil (Study 0102; 91% and 56%, respectively and Study 0103; 69% and 9%, respectively).
Response to treatment with tenofovir disoproxil fumarate was comparable in nucleoside-experienced (n = 51) and nucleoside-naïve (n = 375) patients and in patients with normal ALT (n = 21) and abnormal ALT (n = 405) at baseline when Studies 0102 and 0103 were combined. Forty-nine of the 51 nucleoside-experienced patients were previously treated with lamivudine. Seventy-three percent of nucleoside-experienced and 69% of nucleoside-naïve patients achieved complete response to treatment; 90% of nucleoside-experienced and 88% of nucleoside-naïve patients achieved HBV DNA suppression < 400 copies/mL. All patients with normal ALT at baseline and 88% of patients with abnormal ALT at baseline achieved HBV DNA suppression < 400 copies/mL.
Treatment beyond 48 weeks (studies 0102 and 0103). In Studies 0102 (n = 347) and 0103 (n = 238), after receiving double-blind treatment for 48 weeks (either tenofovir disoproxil fumarate or adefovir dipivoxil), patients rolled over with no treatment interruption, to open-label tenofovir disoproxil fumarate.
In Study 0102, 266 of 347 patients (77%) continued through Week 384, while in Study 0103, 146 of 238 (61%) continued through Week 384. At Weeks 96, 144, 192, 240, 288 and 384 viral suppression, biochemical and serological responses were maintained with continued tenofovir disoproxil fumarate treatment (see Tables 19 and 20).
Paired baseline and Week 240 liver biopsy data were available for 331/489 patients who remained in Studies 0102 and 0103 (see Table 21). Ninety-five percent (225/237) of patients without cirrhosis at baseline and 99% (93/94) of patients with cirrhosis at baseline had either no change or an improvement in fibrosis (Ishak fibrosis score). Of the 94 patients with cirrhosis at baseline (Ishak fibrosis score 5-6), 26% (24) experienced no change in Ishak fibrosis score and 72% (68) experienced reversal of cirrhosis by Week 240 with a reduction in Ishak fibrosis score of at least 2 points except for one patient with an initial Ishak score of five.
When the data were evaluated including only patients that completed 384 weeks of therapy (observed (missing data is excluded) and data after the addition of emtricitabine included; on therapy analysis), in the group of patients who received 48 weeks of double-blind treatment with tenofovir disoproxil fumarate followed by open-label treatment with tenofovir disoproxil fumarate; 99% (173/174) and 100% (88/88) of patients had HBV DNA < 400 copies/mL and 88% (141/160) and 81% (70/86) of patients had ALT normalization at Week 384, in Studies 0102 and 0103 respectively. In Study 0103, HBeAg loss was reported for 44% (31/70) of patients and 28% (19/68) of patients experienced HBeAg seroconversion. 14% of patients experienced HBsAg loss and 12% of patients experienced HBsAg seroconversion by Week 384. In study 102, HBsAg loss and seroconversion were 1% in both treatment groups.
Similarly (using the on-therapy analysis), in the group of patients who received 48 weeks of double-blind treatment with adefovir dipivoxil followed by open-label treatment with tenofovir disoproxil fumarate; 100% (90/90) and 95% (55/58) of patients had HBV DNA < 400 copies/mL and 88% (74/84) and 88% (50/57) of patients had ALT normalization, at Week 384, in Studies 0102 and 0103 respectively. In Study 0103, HBeAg loss was reported for 50% (24/48) of patients and 36% (17/47) of patients experienced seroconversion. HBsAg loss was experienced in 13% and 11% of patients experienced HBsAg seroconversion, while on tenofovir disoproxil fumarate.
The proportion of patients in Studies 0102 and 0103 with HBV DNA < 400 copies/mL are shown in Figures 3 and 4.
Nucleos(t)ide experienced patients.

Experience with patients with lamivudine resistance (study GS-US-174-0121).

The efficacy and safety of tenofovir disoproxil fumarate or 200 mg emtricitabine plus 300 mg tenofovir disoproxil fumarate were evaluated in a randomized, double-blind study, in HBeAg-positive and HBeAg-negative patients with viremia (HBV DNA ≥ 1,000 IU/mL) and genotypic evidence of lamivudine resistance (rtM204I/V +/- rtL180M). One hundred and forty-one adult subjects were randomized to the tenofovir disoproxil fumarate treatment arm. The mean age of subjects randomized to tenofovir disoproxil fumarate was 47 years (range 18-73), 74% were male, 59% were Caucasian, and 37% were Asian. At baseline, 54% of subjects were HBeAg-negative, 46% were HBeAg-positive, and 56% had abnormal ALT. Subjects had a mean HBV DNA of 6.4 log10 copies/mL and mean serum ALT of 71 U/L at baseline.
After 96 weeks of treatment, 126 of 141 subjects (89%) randomized to tenofovir disoproxil fumarate had HBV DNA < 400 copies/mL, and 49 of 79 subjects (62%) had ALT normalization. Among the HBeAg-positive subjects randomized to tenofovir disoproxil fumarate, 10 of 65 subjects (15%) experienced HBeAg loss, and 7 of 65 subjects (11%) experienced anti-HBe seroconversion through Week 96.

Experience with patients co-infected with HIV and HBV (study ACTG 5127).

In a randomized, 48-week double-blind, non-inferiority trial, tenofovir disoproxil fumarate 300 mg daily was compared with adefovir dipivoxil 10 mg daily in the treatment of chronic hepatitis B patients who were co-infected with HIV and were stable on antiretroviral therapy. Mean baseline serum HBV DNA were 9.45 log10 copies/mL and 8.85 log10 copies/mL in subjects randomized to tenofovir disoproxil fumarate (n = 27) and ADV (n = 25), respectively. In subjects for whom there was Week 48 data (n = 35), the mean change from baseline in serum HBV DNA was -5.74 log10 copies/mL for the tenofovir disoproxil fumarate group (n = 18) and -4.03 log10 copies/mL for the adefovir dipivoxil group (n = 17), respectively. A total of 61% of subjects (36% in the tenofovir disoproxil fumarate group and 25% in the adefovir dipivoxil group) had normalized serum ALT at Week 48, but the differences were not statistically significant. The study showed that over 48 weeks, treatment with either adefovir dipivoxil or tenofovir disoproxil fumarate resulted in clinically important suppression of serum HBV DNA and tenofovir disoproxil fumarate was not inferior to adefovir dipivoxil in HBV viral suppression.

Experience in patients who had incomplete viral response to adefovir dipivoxil (study 0106).

The efficacy and safety of tenofovir disoproxil fumarate 300 mg or tenofovir DF/emtricitabine is being evaluated in a randomized, double-blind study (Study GS-US-174-0106, 0106), in HBeAg positive and HBeAg negative patients who had persistent viraemia (HBV DNA ≥ 1000 copies/mL) while receiving adefovir dipivoxil 10 mg for more than 24 weeks. Overall at Week 48, treatment with tenofovir disoproxil fumarate resulted in 66% (35/53) of patients with HBV DNA < 400 copies/mL and 64% (34/53) of patients with undetectable HBV DNA (below 169 copies/mL the limit of quantification of the Roche COBAS TaqMan HBV assay); patients that discontinued prior to 48 weeks, including those who received intensification therapy tenofovir DF/emtricitabine were excluded. In addition, at Week 48, the percentage of patients who had ALT normalization was 33% (9/27).
In Study 0106, patients were also analysed based upon lamivudine- or adefovir-resistant HBV results at baseline; patients that discontinued prior to 48 weeks were considered as failures. Table 22 summarizes Week 48 results of patients treated with tenofovir disoproxil fumarate.
At Week 48, no patient with lamivudine- or adefovir-resistant mutations at baseline, had HBeAg/HBsAg loss and/or seroconversion.

Experience in patients with decompensated liver disease at 48 weeks (study 0108).

Study GS-US-174-0108 (0108) is a randomized, double-blind, active controlled study evaluating the safety and efficacy of tenofovir disoproxil fumarate (n = 45) for 48 weeks in patients with decompensated liver disease. In the tenofovir disoproxil fumarate treatment arm, patients had a mean Child-Pugh-Turcotte (CPT) score of 7.2, mean HBV DNA of 5.8 log10 copies/mL and mean serum ALT of 61 U/L at baseline. Forty-two percent (19/45) of patients had at least 6 months of prior lamivudine experience and 9 of 45 patients (20%) had lamivudine and/or adefovir resistance substitutions at baseline. The co-primary safety endpoints were discontinuation due to an adverse event and confirmed increase in serum creatinine ≥ 0.5 mg/dL or confirmed decrease in serum phosphorus of < 2 mg/dL.
In the tenofovir disoproxil fumarate treatment arm, 3 of 45 patients (7%) discontinued treatment due to an adverse event; 4 of 45 (9%) experienced a confirmed increase in serum creatinine of ≥ 0.5 mg/dL or confirmed decrease in serum phosphorus of < 2 mg/mL through Week 48; these results were similar to those in the non-tenofovir disoproxil fumarate containing treatment arm. HBV DNA < 400 copies/mL and normal ALT were observed in 31 of 44 patients (70%) and 25 of 44 patients (57%), respectively, in the tenofovir disoproxil fumarate treatment arm. The mean change from baseline in CPT score was -0.8; the mean absolute CPT score was 6 at Week 48.
After 168 weeks, 16% (7/45) of the tenofovir disoproxil fumarate group, 4% (2/45) of the emtricitabine plus tenofovir disoproxil fumarate group, and 14% (3/22) of the entecavir group experienced tolerability failure. Thirteen percent (6/45) of the tenofovir disoproxil fumarate group, 13% (6/45) of the emtricitabine plus tenofovir disoproxil fumarate group and 9% (2/22) of the entecavir group had a confirmed increase in serum creatinine ≥ 0.5 mg/dL or confirmed serum phosphate of < 2 mg/dL.

Experience in paediatric patients 12 years of age and older (study 0115).

In Study GS-US-174-0115 (0115), 106 HBeAg negative and positive patients aged 12 to < 18 years with chronic HBV infection [HBV DNA ≥ 105 copies/mL, elevated serum ALT (≥ 2 x ULN) or a history of elevated serum ALT levels in the past 24 months] were treated with tenofovir disoproxil fumarate (n = 52) or placebo (n = 54) for 72 weeks. At Week 72, 88% (46/52) of patients in the tenofovir disoproxil fumarate treatment group and 0% (0/54) of patients in the placebo group had HBV DNA < 400 copies/mL. Seventy-four percent (26/35) of patients in the tenofovir disoproxil fumarate group had normalized ALT at Week 72 compared to 31% (13/42) in the placebo group. Response to treatment with tenofovir disoproxil fumarate was comparable in nucleos(t)ide-naïve patients (n = 20) and nucleos(t)ide-experienced (n = 32) patients. Ninety-five percent of nucleos(t)ide-naïve patients and 84% nucleos(t)ide-experienced patients achieved HBV DNA < 400 copies/mL at Week 72. At Week 72, 96% (27/28) of immune-active patients (HBV DNA ≥ 105 copies/mL, serum ALT > 1.5x ULN) in the tenofovir disoproxil fumarate treatment group and 0% (0/32) of patients in the placebo group had HBV DNA < 400 copies/mL. Seventy-five percent (21/28) of immune-active patients in the tenofovir disoproxil fumarate group had normal ALT at Week 72 compared to 34% (11/32) in the placebo group.
Clinical resistance. Of 279 HBeAg negative and HBeAg positive patients who received treatment with tenofovir disoproxil fumarate for up to 384 weeks in Studies 0102 and 0103, genotypic analysis was performed on HBV isolates for all patients with HBV DNA > 400 copies/mL (n = 2). No amino acid substitutions occurred in these subjects' isolates which were associated with tenofovir resistance.
In Studies 0102 and 0103, 152 patients treated with adefovir dipivoxil for 48 weeks, rolled over to treatment with tenofovir disoproxil fumarate for up to 366 weeks; two patients with HBV DNA remaining > 400 copies/mL were evaluated for resistance. No amino acid substitutions occurred in these subjects' isolates which were associated with tenofovir resistance.
Among the 53 treatment-experienced patients in Study 0106 treated with tenofovir disoproxil fumarate, 17 had HBV DNA > 400 copies/mL following up to 48 weeks of treatment with tenofovir disoproxil fumarate. Among these patients, no amino acid substitutions were observed in association with tenofovir resistance.
In Study 0108, 45 patients (including 9 patients with lamivudine and/or adefovir resistance substitutions at baseline) received tenofovir disoproxil fumarate for up to 168 weeks. Genotypic data from paired baseline and on treatment HBV isolates were available for 8 of 9 patients with HBV DNA > 400 copies/mL. No amino acid substitutions associated with tenofovir resistance were identified in these isolates.
In Studies 0102, 0103 and 0106, 12 patients randomized to tenofovir disoproxil fumarate had HBV containing lamivudine-resistance associated substitutions at baseline. Following up to 48 weeks (0106; n = 7) or 240 weeks (0102 and 0103; n = 4) of treatment with tenofovir disoproxil fumarate, two patients in Study 0106 had HBV DNA > 400 copies/mL; no amino acid substitutions were observed in association with tenofovir resistance.
In Studies 0102, 0103 and 0106, 13 patients treated with tenofovir disoproxil fumarate had adefovir-resistance associated substitutions at baseline. Following up to 48 weeks (0106; n = 8) or 240 weeks (0102 and 0103; n = 5) of treatment with tenofovir disoproxil fumarate, one patient in Study 0103 and two patients in Study 0106 had HBV DNA > 400 copies/mL; no amino acid substitutions were observed in association with tenofovir resistance.
In a paediatric study (GS-US-174-0115), HBV isolates from 5 patients who had plasma HBV DNA > 400 copies/mL were evaluated for tenofovir resistance-associated substitutions. No amino acid substitutions associated with resistance to tenofovir disoproxil fumarate were identified in these isolates by Week 72.
In Study 0121, 141 patients with lamivudine resistance substitutions at baseline received tenofovir disoproxil fumarate for up to 96 weeks. Genotypic data from paired baseline and on treatment HBV isolates were available for 6/9 patients with HBV DNA > 400 copies/mL at their last time point on tenofovir disoproxil fumarate. No amino acid substitutions associated with resistance to tenofovir disoproxil fumarate were identified in these isolates.
Cross resistance. Cross-resistance has been observed among HBV reverse transcriptase inhibitors. In cell based assays, HBV strains expressing the rtV173L, rtL180M and rtM204I/V mutations associated with resistance to lamivudine, telbivudine and reduced susceptibility to entecavir showed a susceptibility to tenofovir ranging from 0.7 to 3.4-fold that of wild type virus. HBV strains expressing the rtL180M, rtT184G, rtS202G/I, rtM204V and rtM250V mutations associated with resistance to entecavir showed a susceptibility to tenofovir ranging from 0.6 to 6.9-fold that of wild type virus. HBV strains expressing the adefovir-associated resistance mutations rtA181V and rtN236T showed a susceptibility to tenofovir ranging from 2.9 to 10-fold that of wild type virus. Viruses containing the rtA181T mutation remained susceptible to tenofovir with EC50 values 1.5-fold that of wild type virus.

5.2 Pharmacokinetic Properties

Tenofovir disoproxil fumarate is a water soluble ester prodrug of the active ingredient tenofovir. Tenofovir is converted intracellularly to tenofovir monophosphate and tenofovir diphosphate. The pharmacokinetics of tenofovir disoproxil fumarate have been evaluated in healthy volunteers and HIV-1 infected individuals. Tenofovir pharmacokinetics are similar between these populations.

Absorption.

Following oral administration, tenofovir disoproxil fumarate is rapidly absorbed and converted to tenofovir. The oral bioavailability of tenofovir in fasted patients was approximately 25%. Following oral administration of a single dose of tenofovir 300 mg to HIV-1 infected patients in the fasted state, maximum serum concentrations (Cmax) are achieved in 1.0 ± 0.4 hrs. Cmax and AUC values are 296 ± 90 nanogram/mL and 2287 ± 685 nanogram.h/mL, respectively.
Administration of tenofovir disoproxil fumarate following a high-fat meal (~700 to 1000 kcal containing 40-50% fat) increases the oral bioavailability, with an increase in tenofovir AUC0-∞ of approximately 40% and an increase in Cmax of approximately 14%. Food delays the time to tenofovir Cmax by approximately 1 hour. Cmax and AUC of tenofovir are 326 ± 119 nanogram/mL and 3324 ± 1370 nanogram.h/mL following multiple doses of tenofovir disoproxil fumarate 300 mg once daily in the fed state, when meal content was not controlled.

Distribution.

After oral administration of tenofovir disoproxil fumarate, tenofovir is distributed to most tissues with the highest concentrations occurring in the kidney, liver and the intestinal contents (preclinical studies). In vitro protein binding of tenofovir to human plasma or serum protein was less than 0.7% and 7.2%, respectively, over the tenofovir concentration range 0.01-25 microgram/mL. The volume of distribution at steady-state is 1.3 ± 0.6 L/kg and 1.2 ± 0.4 L/kg, following intravenous administration of tenofovir 1.0 mg/kg and 3.0 mg/kg.

Metabolism.

In vitro studies have determined that neither tenofovir disoproxil fumarate nor tenofovir are substrates for the CYP450 enzymes. Moreover, at concentrations substantially higher (~ 300-fold) than those observed in vivo, tenofovir did not inhibit in vitro drug metabolism mediated by any of the major human CYP450 isoforms involved in drug biotransformation (CYP3A4, CYP2D6, CYP2C9, CYP2E1 or CYP1A1/2). Tenofovir disoproxil fumarate at a concentration of 100 microM had no effect on any of the CYP450 isoforms, except CYP1A1/2, where a small (6%) but statistically significant reduction in metabolism of CYP1A1/2 substrate was observed. Based on these data, it is unlikely that clinically significant drug-drug interactions involving tenofovir disoproxil fumarate and medicinal products metabolized by CYP450 would occur.

Excretion.

Tenofovir is primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion. There may be competition for elimination with other compounds that are also renally eliminated.

Linearity/non-linearity.

The pharmacokinetics of tenofovir were independent of tenofovir disoproxil fumarate dose over the dose range 75-600 mg and were not affected by repeated dosing at any dose level.

Special populations.

Gender.

Pharmacokinetics of tenofovir in patients are similar with regard to gender.

Paediatric patients 12 years of age and older.

Steady-state pharmacokinetics of tenofovir were evaluated in eight HIV-1 infected paediatric patients (12 to < 18 years). Mean (± SD) Cmax and AUCtau were 0.38 ± 0.13 microgram/mL and 3.39 ± 1.22 microgram.hr/mL, respectively. Tenofovir exposure achieved in paediatric patients aged 12 years of age and older receiving oral daily doses of tenofovir disoproxil fumarate 300 mg were similar to exposures achieved in adults receiving once-daily doses of tenofovir disoproxil fumarate 300 mg.
Tenofovir exposure in HBV infected paediatric patients (12 to < 18 years of age) receiving oral daily dose of tenofovir disoproxil fumarate 300 mg tablet was similar to exposures achieved in adults receiving once daily doses of tenofovir disoproxil fumarate 300 mg.
Pharmacokinetic studies have not been performed with in paediatric subjects < 12 years of age.

Elderly patients.

Pharmacokinetic studies have not been performed in the elderly (> 65 years).

Ethnicity.

Pharmacokinetics have not been specifically studied in different ethnic groups.

Renal impairment.

The pharmacokinetics of tenofovir are altered in subjects with renal impairment (see Section 4.4 Special Warnings and Precautions for Use). In non-HIV and non-HBV infected subjects with creatinine clearance < 50 mL/min or with end-stage renal disease (ESRD) requiring dialysis, Cmax and AUC0-∞ of tenofovir were increased (see Table 23). It is required that the dosing interval for tenofovir disoproxil fumarate be modified in patients with creatinine clearance < 50 mL/min or in patients with ESRD who require dialysis (see Section 4.2 Dose and Method of Administration).
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.

Hepatic impairment.

The pharmacokinetics of tenofovir following a 300 mg single dose of tenofovir disoproxil fumarate have been studied in non-HIV and non-HBV infected subjects with moderate to severe hepatic impairment. There were no substantial alterations in tenofovir pharmacokinetics in patients with hepatic impairment compared with unimpaired patients. No change in tenofovir disoproxil fumarate dosing is required in patients with hepatic impairment.

Pharmacokinetic/pharmacodynamic relationship.

Tenofovir disoproxil fumarate has demonstrated a dose related significant and sustained anti-HIV effect at doses ranging from 75 mg to 300 mg.

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

Carcinogenicity.

In a long-term carcinogenicity study conducted in mice with tenofovir disoproxil fumarate there was a low incidence of duodenal tumours with the highest dose of 600 mg/kg/day. These were associated with a high incidence of duodenal mucosal hyperplasia, which was also observed with a dose of 300 mg/kg/day. These findings may be related to high local drug concentrations in the 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).
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. Tenofovir base was not active in in vitro bacterial assays for gene mutation, and an equivocal response was seen in the in vitro mouse L5178Y lymphoma assay at a high concentration.

Animal toxicology.

Tenofovir and tenofovir disoproxil fumarate administered in toxicology studies to rats, dogs and monkeys at exposures (based on AUCs) between 6- and 12-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.

Fertility, pregnancy and lactation.

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 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.
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.
In animal studies tenofovir was excreted in milk after oral administration of tenofovir disoproxil fumarate (rats) and after subcutaneous administration of tenofovir base (non-human primates).

6 Pharmaceutical Particulars

6.1 List of Excipients

Lactose, crospovidone, calcium stearate, colloidal anhydrous silica, hypromellose, Macrogol 8000, hyprolose, titanium dioxide, indigo carmine aluminium lake.

6.2 Incompatibilities

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

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

Tenofovir ARX tablets.

Bottle (white, round HDPE bottle with white or blue PP child-resistant cap and desiccant) of 30 tablets. AUST R 247315.
Blister Pack (aluminium/aluminium silver foil) of 30 tablets. AUST R 247314.
Not all pack types may be available.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Tenofovir disoproxil fumarate is a white to off-white crystalline powder with a solubility of 13.4 mg/mL in water at 25°C. The partition coefficient (log P) for tenofovir disoproxil is 1.25 and the pKa is 3.75. The active pharmaceutical product is a single enantiomer that does not undergo racemisation either in vitro or in vivo.

Chemical structure.


Chemical name: 9-[(R)-2[[bis[[(isopropoxycarbonyl) oxy]methoxy]-phosphinyl]- methoxy] propyl]adenine fumarate (1:1).
Molecular formula: C23H34O14N5P.
Molecular weight: 635.52.

CAS number.

202138-50-9.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes