Consumer medicine information

APO-Adefovir Tablets

Adefovir dipivoxil

BRAND INFORMATION

Brand name

APO-Adefovir

Active ingredient

Adefovir dipivoxil

Schedule

SUMMARY CMI

APO-Adefovir Tablets

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 APO-Adefovir Tablets?

APO-Adefovir Tablets contains the active ingredient adefovir dipivoxil. APO-Adefovir Tablets is used to treat chronic hepatitis B in patients 12 years of age or older.

For more information, see Section 1. Why am I using APO-Adefovir Tablets? in the full CMI.

2. What should I know before I use APO-Adefovir Tablets?

Do not use if you have ever had an allergic reaction to adefovir dipivoxil 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 APO-Adefovir Tablets? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with APO-Adefovir Tablets 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 APO-Adefovir Tablets?

The recommended dose is one 10mg tablet taken once daily. Doses greater than 10mg daily should not be taken.
Swallow tablet with water.

More instructions can be found in Section 4. How do I use APO-Adefovir Tablets? in the full CMI.

5. What should I know while using APO-Adefovir Tablets?

Things you should do	Remind any doctor, dentist or pharmacist you visit that you are using APO-Adefovir Tablets. you are pregnant or are planning to become pregnant you are breastfeeding or are planning to breast-feed you are about to have any blood tests you are going to have surgery or an anesthetic or are going into hospital
Things you should not do	Do not stop using this medicine suddenly without first checking with your doctor. Do not give this medicine to anyone else, even if their symptoms seem similar to yours. Do not take your medicine to treat any other condition unless your doctor tells you to.
Driving or using machines	Be careful when driving or operating machinery until you know how this medicine affects you.
Drinking alcohol	Tell your doctor if you drink alcohol
Looking after your medicine	Keep your medicine in its original packaging until it is time to take it. Keep your medicine in a cool dry place where the temperature will stay below 25°C. Keep this medicine where children cannot reach it.

For more information, see Section 5. What should I know while using APO-Adefovir Tablets? in the full CMI.

6. Are there any side effects?

Tell your doctor as soon as possible if you do not feel well while you are taking adefovir or if you have any questions or concerns. All medicines can have side effects. Sometimes they are serious but most of the time they are not. If you experience any side effects, stop taking your medicine and contact your doctor immediately or go to the Accident and Emergency department at your nearest hospital.

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

APO-Adefovir Tablets

Active ingredient: Adefovir dipivoxil

Consumer Medicine Information (CMI)

This leaflet provides important information about using APO-Adefovir Tablets. 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 APO-Adefovir Tablets.

Where to find information in this leaflet:

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

1. Why am I using APO-Adefovir Tablets?

APO-Adefovir Tablets contains the active ingredient adefovir dipivoxil. APO-Adefovir Tablets belongs to a group of medicines called antiviral medicines.

APO-Adefovir Tablets is used to is used to treat chronic hepatitis B in patients 12 years of age or older.

Hepatitis B is caused by infection with the hepatitis B virus (HBV) which can damage the liver. Adefovir reduces the amount of the virus in your body, by lowering the ability of the virus to multiply and infect new liver cells and 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 adefovir may help treat your hepatitis. Sometimes viruses change in your body and medicines no longer work. This is called drug resistance. There is no evidence that this medicine is addictive.

2. What should I know before I use APO-Adefovir Tablets?

Warnings

Do not use APO-Adefovir Tablets if:

you are hypersensitive to, or have had an allergic reaction to adefovir dipivoxil or any of the ingredients listed at the end of this leaflet.
Always check the ingredients to make sure you can use this medicine.
These medicines should not be administered with adefovir:
- VIREAD (tenofovir disoproxil fumarate)
- TRUVADA (tenofovir disoproxil fumarate/emtricitabine combination tablet),
- ATRIPLA (tenofovir disoproxil fumarate/ emtricitabine/efavirenz combination tablet)
- STRIBILD (tenofovir disoproxil fumarate/emtricitabine/elvitegravir/cobicistat)
- EVIPLERA (tenofovir disoproxil fumarate/emtricitabine/ rilpivirine combination tablet).
- tenofovir alafenamide tablet
If you are taking this, you may need a different dose or you may need to take different medicines.
Other medicines not listed above may also interact with adefovir.

Check with your doctor if you:

have allergies to:
- any other medicines
- any other substances, such as foods, preservatives or dyes.
You have or have had any medical conditions, especially the following:
- kidney problems
If you have reduced function of your kidneys or are at risk of having reduced function then adefovir may damage your kidneys. While taking this medicine you will require regular tests of your kidney function and may require a smaller dose of this medicine than patients with normal kidney function.
- unrecognised or untreated HIV infection.
Adefovir may reduce the effectiveness of some drugs used to treat HIV. There is limited experience in treating individuals with both chronic hepatitis B infection and HIV. Your doctor should offer to test your blood to see if you have HIV infection before you start treatment with this medicine.
If you think you are having an allergic reaction to adefovir, do not take any more of this medicine and tell your doctor immediately or go to the Accident and Emergency department at your nearest hospital.
Symptoms of an allergic reaction may include some or all of the following:
- cough, 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
- fainting
- hay fever-like symptoms.
You are over the age of 65.
You are planning to have surgery or an anaesthetic.
You are currently receiving or are planning to receive dental treatment.
You are taking or are planning to take any other medicines. This includes vitamins and supplements that are available from your pharmacy, supermarket or health food shop.

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

Pregnancy and breastfeeding

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

The safe use of adefovir in human pregnancy has not been demonstrated. For this reason, it is important that women of childbearing age receiving treatment with adefovir use an effective method of contraception to avoid becoming pregnant. Do not take this medicine whilst pregnant until you and your doctor have discussed the risks and benefits involved.

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

It is not known whether adefovir is excreted in human breast milk. Consequently, nursing mothers should stop breastfeeding during treatment with this medicine.

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 interfere with APO-Adefovir Tablets and affect how it works.

These medicines should not be administered with adefovir:

VIREAD (tenofovir disoproxil fumarate)
TRUVADA (tenofovir disoproxil fumarate/emtricitabine combination tablet),
ATRIPLA (tenofovir disoproxil fumarate/ emtricitabine/efavirenz combination tablet)
STRIBILD (tenofovir disoproxil fumarate/emtricitabine/elvitegravir/cobicistat)
EVIPLERA (tenofovir disoproxil fumarate/emtricitabine/ rilpivirine combination tablet).
tenofovir alafenamide tablet

If you are taking this, you may need a different dose or you may need to take different medicines.

Other medicines not listed above may also interact with adefovir.

4. How do I use APO-Adefovir Tablets?

How much to take / use

The recommended dose is one 10mg tablet taken once daily. Doses greater than 10mg daily should not be taken.
Follow the instructions provided and use APO-Adefovir Tablets until your doctor tells you to stop.
If you have reduced function of your kidneys, you may require a lower dose. You may be prescribed another HBV medicine to take with this medicine. Check with your doctor if you have any questions.
This medicine is absorbed rapidly. Do not take another dose of this medicine if vomiting has occurred unless advised to do so by your doctor.

When to take / use APO-Adefovir Tablets

APO-Adefovir Tablets should be used at the same time each day. Taking it at the same time each day will have the best effect and will also help you remember when to take it.
It does not matter if you take it with or without food. Food does not affect how this medicine works.

How long take Apo-Adefovir Tablet

This medicine helps to control your condition, but does not cure it, you will need to take this medicine every day. Continue taking your medicine for as long as your doctor tells you.
It is very important to continue taking this medicine because the amount of virus in your blood may increase if the medicine is stopped for even a short period of time. The virus may develop resistance to adefovir, become harder to treat and may result in very severe hepatitis and serious liver problems.
Make sure you have enough to last over weekends and holidays

If you forget to use APO-Adefovir Tablets

APO-Adefovir Tablets should be used regularly at the same time each day.

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

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

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 to help you remember.

If you use too much APO-Adefovir Tablets

If you think that you have used too much APO-Adefovir Tablets, 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 APO-Adefovir Tablets?

Things you should do

Call your doctor straight away if you:

you are about to be started on any new medicine
you are pregnant or are planning to become pregnant
you are breastfeeding or are planning to breast-feed
you are about to have any blood tests
you are going to have surgery or an anesthetic or are going into hospital

Remind any doctor, dentist or pharmacist you visit that you are using APO-Adefovir Tablets

Things you should not do

Do not stop using this medicine suddenly or change the dose without first checking with your doctor.
Give this medicine to anyone else, even if their symptoms seem similar to yours.
Take your medicine to treat any other condition unless your doctor tells you to.

Things to be careful of

This medicine does not reduce the risk of passing HBV to others through sexual contact or blood contamination. Therefore, it is important to continue to take appropriate precautions to prevent passing HBV to others.
Hepatic flares
It is extremely important that you do not stop taking this medicine without your doctor's advice. Some patients with hepatitis B infection may have a "flare-up" of Hepatitis B if they stop taking this medicine, 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.
Renal impairment
Long-term treatment with adefovir dipivoxil may increase the risk of renal impairment. While the overall risk of renal impairment in patients with adequate renal function is low, this is of special importance in patients both at risk of or having underlying renal dysfunction, and also in patients receiving medicinal products that may affect renal function.
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 APO-Adefovir Tablets affects you.

Drinking alcohol

Tell your doctor if you drink alcohol.

Looking after your medicine

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 windowsills. Heat and dampness can destroy some medicines.
Keep your medicine in its original packaging until it is time to take it.
If you take your medicine out of its original packaging it may not keep well.
Keep your medicine in a cool dry place where the temperature will stay below 25°C.

Keep it where young children cannot reach it.

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

Getting rid of any unwanted medicine

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

Do not use this medicine after the expiry date.

6. Are there any side effects?

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

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

Less serious side effects

Less serious side effects	What to do
Weakness Headache Nausea Flatulence Diarrhoea Problems with digestion Stomach pain	Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effects

What to do

Serious Liver Problems (hepatotoxicity)
- Your skin or the white part of your eyes turns yellow (jaundice)
- Your urine turns dark
- Your bowel movements (stools) turn light in colour
- Nausea
- Stomach pains
These side effects may be due to a condition called hepatotoxicity with liver enlargement and fat deposits in the liver (steatosis) which sometimes occurs in patients taking antiviral medicines.
Lactic Acidosis
- You feel very weak or tired.
- You have unusual (not normal) muscle pain.
- You have trouble breathing.
- You have stomach pain with nausea and vomiting.
- You feel cold, especially in your arms and legs.
- You feel dizzy or lightheaded.
- You have a fast or irregular heartbeat.
These side effects may be due to a condition called lactic acidosis (build-up of an acid in the blood). Lactic acidosis can be a medical emergency and may need to be treated in the hospital.

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

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

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

Reporting side effects

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

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

7. Product details

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

What APO-Adefovir Tablet contains

Active ingredient	adefovir dipivoxil
Other ingredients (inactive ingredients)	Lactose monohydrate pregelatinized maize starch Croscarmellose sodium Magnesium stearate Purified talc
Potential allergens	Lactose

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

This medicine is gluten-free, sucrose-free, tartrazine-free and free of other azo dyes.

What APO-Adefovir Tablets looks like

APO-Adefovir 10mg Tablet

White to off-white, round, flat-faced bevelled edge tablet. Engraved "APO" on one side, "A10" on the other side.

Available in bottles (white, round HDPE bottle with white PP 'Lift N Peel' child-resistant cap and desiccant) of 30 tablets. AUST R 212048.

Who distributes APO-Adefovir Tablets

Arrotex Pharmaceuticals Pty Ltd
15-17 Chapel St,
Cremorne VIC 3121
arrotex.com.au

This leaflet was prepared in November 2024

Published by MIMS January 2025

BRAND INFORMATION

Brand name

APO-Adefovir

Active ingredient

Adefovir dipivoxil

Schedule

1 Name of Medicine

Adefovir dipivoxil.

2 Qualitative and Quantitative Composition

Each tablet contains adefovir dipivoxil 10 mg.

Excipients with known effect.

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

3 Pharmaceutical Form

10 mg tablets.

White to off-white, round, flat-faced bevelled edge tablet. Engraved "APO" on one side, "A10" on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Adefovir dipivoxil is indicated for the treatment of chronic hepatitis B in patients 12 years of age and older with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease.
For adult patients, this indication is based on histological, virological, biochemical, and serological responses in adult patients with HBeAg+ and HBeAg-/HBVDNA+ chronic hepatitis B with compensated liver function, and in adult patients with clinical evidence of lamivudine-resistant hepatitis B virus with either compensated or decompensated liver function.
For adolescent patients (12 to < 18 years of age), the indication is based on virological and biochemical responses in patients with HBeAg+ chronic hepatitis B virus with compensated liver function.

4.2 Dose and Method of Administration

APO-Adefovir tablets are intended for oral administration.

Dosage.

Adults.

The recommended dose of adefovir dipivoxil is one tablet, once daily taken orally, without regard to food. Doses higher than those recommended must not be administered. The optimum duration of treatment is unknown.

Children and adolescents.

The recommended dose of adefovir dipivoxil in chronic hepatitis B patients ≥ 12 years of age with adequate renal function is one tablet, once daily taken orally, without regard to food. Adefovir dipivoxil is not recommended for use in children below 12 years of age.

Elderly.

No data are available to support a dose recommendation for patients over the age of 65 years. In general, caution should be exercised when prescribing to elderly patients, keeping in mind the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Renal impairment.

Significantly increased drug exposures were seen when adefovir dipivoxil was administered to adults with renal impairment (see Section 5.2 Pharmacokinetic Properties). Therefore, the dosing interval of adefovir dipivoxil should be adjusted in patients with baseline creatinine clearance < 50 mL/min (calculated using the Cockcroft Gault equation) using the following suggested guidelines (see Table 1). The safety and effectiveness of these dosing interval adjustment guidelines have not been clinically evaluated. Additionally, it is important to note that these guidelines are for patients with pre-existing renal impairment at baseline. They may not be appropriate for patients in whom renal insufficiency evolves during treatment with adefovir dipivoxil. Therefore, clinical response to treatment and renal function should be closely monitored in these patients.

The pharmacokinetics of adefovir has not been evaluated in non-haemodialysis patients with creatinine clearance < 10 mL/min, therefore, no dosing recommendation is available for these patients.
No clinical data are available to make dosing recommendations in adolescent patients with renal insufficiency (see Section 4.4 Special Warnings and Precautions for Use).

Hepatic impairment.

Pharmacokinetic properties were similar in patients with moderate and severe hepatic impairment compared to healthy volunteers. No change in dosing is required in patients with hepatic impairment.

Clinical resistance.

In order to reduce the risk of resistance in patients receiving adefovir dipivoxil monotherapy, a modification of treatment should be considered if serum HBV DNA remains above 1000 copies/mL at or beyond 1 year of treatment. In lamivudine-resistant patients, in order to reduce the risk of resistance, adefovir dipivoxil should be used in combination with lamivudine and not as adefovir dipivoxil monotherapy.

4.3 Contraindications

Adefovir dipivoxil is contraindicated in patients with known hypersensitivity to adefovir, adefovir dipivoxil or to any of the excipients in adefovir dipivoxil tablets.

4.4 Special Warnings and Precautions for Use

Adefovir dipivoxil should not be administered concurrently with Viread (tenofovir disoproxil fumarate), Truvada (tenofovir disoproxil fumarate/emtricitabine combination tablet), Atripla (tenofovir disoproxil fumarate/emtricitabine/efavirenz combination tablet), Stribild (tenofovir disoproxil fumarate/emtricitabine/elvitegravir/cobicistat) or Eviplera (tenofovir disoproxil fumarate/emtricitabine/rilpivirine combination tablet).
Adefovir dipivoxil should not be administered concurrently with products containing tenofovir alafenamide.
Patients should be advised that therapy of chronic hepatitis B with adefovir dipivoxil has not been proven to reduce the risk of transmission of hepatitis B virus to others through sexual contact or blood contamination and therefore, appropriate precautions should still be taken.

Post-treatment exacerbations of hepatitis.

Severe acute exacerbation of hepatitis has been reported in patients with discontinuation of anti-hepatitis B therapy, including adefovir dipivoxil. Patients who discontinue the drug should be monitored at repeated intervals over a period of time for hepatic function. If appropriate, resumption of anti-hepatitis B therapy may be warranted.
In clinical trials of adefovir dipivoxil, exacerbations of hepatitis (ALT elevations 10 times the upper limit of normal or greater) occurred in up to 25% of patients after discontinuation of adefovir. Most of these events occurred within 12 weeks of drug discontinuation. These exacerbations generally occurred in the absence of HBeAg seroconversion, and presented as serum ALT elevations in addition to re-emergence of viral replication. In the HBeAg positive and HBeAg negative studies in patients with compensated liver function, the exacerbations were not generally accompanied by hepatic decompensation. However, patients with advanced liver disease or cirrhosis may be at higher risk for hepatic decompensation. Although most events appear to have been self-limited or resolved with reinitiation of treatment, severe hepatitis exacerbations, including fatalities, have been reported.
Therefore, patients should be closely monitored after stopping treatment.

Use in renal impairment.

Adefovir is eliminated by renal excretion, therefore adjustments to the dosing interval of adefovir dipivoxil are recommended in patients with renal insufficiency (see Section 4.2 Dose and Method of Administration).
Treatment with adefovir dipivoxil may result in renal impairment. Long-term treatment with adefovir dipivoxil may increase the risk of renal impairment. While the overall risk of renal impairment in patients with adequate renal function is low, this is of special importance in patients both at risk of or having underlying renal dysfunction, and also in patients receiving medicinal products that may affect renal function.

Nephrotoxicity.

Chronic administration of adefovir dipivoxil (10 mg once daily) may result in nephrotoxicity. Nephrotoxicity characterised by a delayed onset of gradual increases in serum creatinine and decreases in serum phosphorus was historically shown to be the treatment limiting toxicity of adefovir dipivoxil therapy at substantially higher doses in HIV infected patients (60 and 120 mg daily) and in chronic hepatitis B patients (30 mg daily). The overall risk of nephrotoxicity in patients with adequate renal function is low. However, this is of special importance in patients at risk of or having underlying renal dysfunction and patients taking concomitant nephrotoxic agents such as cyclosporine, tacrolimus, aminoglycosides, vancomycin and nonsteroidal anti-inflammatory drugs (see Section 4.8 Adverse Effects (Undesirable Effects)).
It is recommended that creatinine clearance is calculated in all patients prior to initiating therapy with adefovir dipivoxil. It is important to monitor renal function for all patients during treatment with adefovir dipivoxil, particularly for those with pre-existing or other risks for renal impairment. Patients with renal insufficiency at baseline or during treatment may require dose adjustment (see Section 4.2 Dose and Method of Administration). The risks and benefits of adefovir treatment should be carefully evaluated prior to discontinuing adefovir in a patient with treatment emergent nephrotoxicity.
Caution should be exercised when adefovir dipivoxil is administered concomitantly with nephrotoxic agents.
The efficacy and safety of adefovir dipivoxil have not been studied in patients less than 18 years of age with different degrees of renal impairment and no data are available on which to make dosage recommendations in these patients (see Section 4.2 Dose and Method of Administration).
Caution should therefore be exercised when prescribing adefovir dipivoxil to patients with underlying renal dysfunction and renal function in these patients should be closely monitored.

HIV resistance.

Prior to initiating adefovir therapy, HIV antibody testing should be offered to all patients. Treatment with anti-hepatitis B therapies such as adefovir dipivoxil, that have activity against HIV in a chronic hepatitis B patient with unrecognised or untreated HIV infection may result in emergence of HIV resistance. Adefovir dipivoxil has not been shown to suppress HIV RNA in patients; however, there are limited data on the use of adefovir dipivoxil to treat patients with chronic hepatitis B coinfected with HIV.

Clinical resistance.

Resistance to adefovir dipivoxil can result in viral load rebound which may result in exacerbation of hepatitis B and, in the setting of diminished hepatic function, lead to liver decompensation and possible fatal outcome.
In order to reduce the risk of resistance in patients receiving adefovir dipivoxil monotherapy, a modification of treatment should be considered if serum HBV DNA remains above 1000 copies/mL at or beyond 1 year of treatment. In lamivudine-resistant patients, in order to reduce the risk of resistance, adefovir dipivoxil should be used in combination with lamivudine and not as adefovir dipivoxil monotherapy.

Lactic acidosis/severe hepatomegaly with steatosis.

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with antiretrovirals.
A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with adefovir dipivoxil should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

Use in the elderly.

Clinical studies of adefovir dipivoxil did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised when prescribing to elderly patients, keeping in mind the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Paediatric use.

The safety, efficacy and pharmacokinetics of adefovir dipivoxil in adolescent patients (aged 12 to < 18 years) were evaluated in a double-blind randomized, placebo-controlled study (518) in 83 adolescent patients with chronic hepatitis B and compensated liver disease. The proportion of patients treated with adefovir dipivoxil who achieved the primary efficacy endpoint of serum HBV DNA < 1000 copies/mL and normal ALT levels at the end of 48 weeks blinded treatment was significantly greater (23%) when compared to placebo-treated patients (0%) (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
Paediatric patients aged 2 to < 12 years were also evaluated in study 518 (n = 90). The efficacy of adefovir dipivoxil was not significantly different from placebo in patients less than 12 years of age. The clinical data available are insufficient to draw definitive conclusions on the benefit/risk ratio of adefovir dipivoxil treatment in children below 12 years of age with chronic hepatitis B.
Adefovir dipivoxil is not recommended for use in children below 12 years of age.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Drug interactions.

Since adefovir is eliminated by the kidney, coadministration of adefovir dipivoxil with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of either adefovir and/or these coadministered drugs.
Adefovir should not be administered concurrently with products containing tenofovir disoproxil fumarate or tenofovir alafenamide (see Section 4.4 Special Warnings and Precautions for Use).
Apart from lamivudine, trimethoprim/sulfamethoxazole, paracetamol, ibuprofen, and tacrolimus the effects of coadministration of adefovir dipivoxil with drugs that are excreted renally, or other drugs known to affect renal function have not been evaluated (see Section 5.2 Pharmacokinetic Properties).
Patients should be monitored closely for adverse events when adefovir dipivoxil is coadministered with drugs that are excreted renally or with other drugs known to affect renal function. Ibuprofen 800 mg three times daily increased adefovir exposure by approximately 23%. The clinical significance of this increase in adefovir exposure is unknown and no dose adjustment is recommended (see Section 5.2 Pharmacokinetic Properties).
While adefovir does not inhibit common CYP450 enzymes, the potential for adefovir to induce CYP450 enzymes is not known.
The effect of adefovir on cyclosporine concentrations is not known.

Duration of treatment.

The optimal duration of treatment and the relationship between treatment response and long-term outcomes such as hepatocellular carcinoma or decompensated cirrhosis are not known.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

In reproductive toxicology studies, no evidence of impaired fertility was seen in male or female rats at oral doses up to 30 mg/kg/day (systemic exposure (AUC) approximately 19 times that achieved in humans at the therapeutic dose).
For patients who are on adefovir and subsequently become pregnant, consideration should be given to the possibility of a recurrence of hepatitis on discontinuation of adefovir dipivoxil.
(Category B3)
Reproduction studies conducted with adefovir dipivoxil administered orally have shown no embryotoxicity or teratogenicity in rats at doses up to 35 mg/kg/day (systemic exposure (AUC) at least 23 times that achieved in humans at the therapeutic dose of 10 mg/day), or in rabbits at 20 mg/kg/day (systemic exposure (AUC) 40 times humans).
When adefovir was administered intravenously to pregnant rats at doses associated with notable maternal toxicity (20 mg/kg/day, systemic exposure (AUC) at least 38 times human), embryotoxicity and an increased incidence of foetal malformations (anasarca, depressed eye bulge, umbilical hernia and kinked tail) were observed. No adverse effects on development were seen with adefovir administrated intravenously to pregnant rats at 2.5 mg/kg/day (systemic exposure (AUC) 12 times human).
There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, adefovir dipivoxil should be used during pregnancy only if clearly needed and after careful consideration of the risks and benefits.
There are no studies in pregnant women and no data on the effect of adefovir dipivoxil on transmission of HBV from mother to infant. Therefore appropriate infant immunisations should be used to prevent neonatal acquisition of hepatitis B virus.
It is not known whether adefovir is excreted in human or animal milk. Mothers should be instructed not to breastfeed if they are taking adefovir dipivoxil.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

Adults with compensated liver disease.

Assessment of adverse reactions is based on two placebo-controlled studies (437 and 438) in which 522 patients with chronic hepatitis B and compensated liver disease received double-blind treatment with adefovir dipivoxil (n = 294) or placebo (n = 228) for 48 weeks. Adverse reactions considered at least possibly related to treatment in the first 48 weeks of treatment are listed below, by body system organ class and frequency. Frequencies are defined as very common (≥ 1/10) or common (≥ 1/100, < 1/10).

Nervous system disorders.

Common: headache.

Gastrointestinal disorders.

Common: nausea, flatulence, diarrhoea, dyspepsia, abdominal pain.

General disorders and administration site conditions.

Very common: asthenia.
A summary of adverse events reported in the first 48 weeks is provided in Table 2. Adverse events in the adefovir dipivoxil and placebo groups occurred with similar frequency.

Patients who received adefovir dipivoxil beyond week 48 in study 438 reported adverse reactions similar in nature and severity to those reported in the first 48 weeks of treatment. With increased adefovir exposure, the incidence of adverse events related to treatment increased only slightly.
In addition, the following selected adverse events were reported in less than 3% of patients treated with adefovir:

Body as a whole.

Back pain, chest pain.

Digestive.

Anorexia.

Hematologic and lymphatic.

Anemia, thrombocytopenia.

Metabolic and nutritional.

Weight loss.

Respiratory.

Pharyngitis.

Skin and appendages.

Rash.

Laboratory abnormalities.

In patients with adequate renal function, no patients developed a serum creatinine increase ≥ 0.5 mg/dL from baseline by week 48. A summary of grade 3 and 4 laboratory abnormalities during the first 48 weeks is provided in Table 3.

With extended treatment in 125 HBeAg negative patients (up to 240 weeks duration), 4 patients had confirmed increases in serum creatinine of at least 0.5 mg/dL from baseline with 1 patient discontinuing from the study due to the elevated serum creatinine concentration. No patients had confirmed serum phosphorus levels of ≤ 2.0 mg/dL.
With extended treatment in 65 HBeAg positive patients (up to 234 weeks duration), 6 patients had confirmed increases in serum creatinine of at least 0.5 mg/dL from baseline with 2 patients discontinuing from the study due to the elevated serum creatinine concentration.
Confirmed serum phosphorus levels of ≤ 2.0 mg/dL were observed in two patients, neither of whom discontinued from the study (see Special risk patients below for changes in serum creatinine in patients with underlying renal insufficiency at baseline).

Special risk patients.

Pre- and post-transplantation lamivudine-resistant liver disease. Pre- (n = 226) and post- (n = 241) liver transplantation patients with chronic hepatitis B and lamivudine-resistant HBV were treated in an open-label study with 10 mg adefovir dipivoxil once daily for up to 203 weeks (study 435) with a median time on treatment of 51 and 99 weeks, respectively.
Adverse events considered possibly related to treatment were:

Metabolism and nutrition disorders.

Common: hypophosphatemia, ALT increase, AST increase, hyperkalemia, liver function tests abnormal.

Nervous system disorders.

Common: headache.

Gastrointestinal disorders.

Common: nausea, vomiting, diarrhoea, abdominal pain, jaundice, musculoskeletal, myalgia.

Skin and subcutaneous tissue disorders.

Common: rash, pruritus.

Renal and urinary disorders.

Very common: increased creatinine.
Common: abnormal renal function, renal failure.

General disorders and administration site conditions.

Common: asthenia.
Changes in renal function occurred in waitlisted and post-liver transplantation patients with risk factors for renal dysfunction, including concomitant use of cyclosporine and tacrolimus, renal insufficiency at baseline, hypertension, diabetes, and on-study transplantation. Increases in serum creatinine ≥ 0.5 mg/dL from baseline were observed in 18%, 35%, and 35% of pre-liver transplantation patients by weeks 48, 96, and 144, respectively, by Kaplan-Meier estimates. Increases in serum creatinine ≥ 0.5 mg/dL from baseline were observed in 12%, 28%, and 30% of post-liver transplantation patients by weeks 48, 96, and 144, respectively, by Kaplan-Meier estimates. Elevations in serum creatinine ≥ 0.5 mg/dL from baseline resolved (≤ 0.3 mg/dL increase from baseline) in 8 of 39 (21%) patients in the pre-liver transplantation cohort and in 14 of 43 (33%) patients in the post-liver transplantation cohort by the last study visit. Serum phosphorus values < 2.0 mg/dL were observed in 3/226 (1.3%) of pre-liver transplantation patients and in 6/241 (2.5%) of post-liver transplantation patients by last study visit. Four percent (19 of 467) of pre- and post-liver transplantation patients discontinued adefovir due to renal events.
Due to the presence of multiple concomitant risk factors for renal dysfunction in these patients, the contributory role of adefovir to these changes in serum creatinine and serum phosphorus is difficult to assess.

Paediatric (2 to < 12 years) and adolescent (12 to < 18 years) patients.

Assessment of adverse reactions is based on a placebo-controlled study (study 518) in which 173 paediatric patients (aged 2 to < 12 years) or adolescent patients (aged 12 to < 18 years) with chronic hepatitis B and compensated liver disease received double-blind treatment with adefovir dipivoxil (n = 115), or placebo (n = 58) for 48 weeks (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
The safety profile of adefovir in adolescent patients 12 to < 18 years of age (n = 56) was similar to that observed in adults. No paediatric patients treated with adefovir developed a confirmed serum creatinine increase ≥ 0.5 mg/dL or confirmed phosphorus decrease to < 2 mg/dL from baseline at week 48.
However, a signal towards a higher rate of decreased appetite and/or food intake was observed in the adefovir arm as compared to the placebo arm. Ongoing evaluation and monitoring of safety and long-term resistance data over a longer period of therapy in children and adolescent patients is required.

Postmarketing experience.

In addition to adverse reaction reports from clinical trials the following possible adverse reactions have also been identified during post approval use of adefovir dipivoxil. Because these events have been reported voluntarily from a population of unknown size, estimates of frequency cannot be made.

Hepatobiliary disorders.

Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of treatment with adefovir.

Metabolism and nutrition disorders.

Hypophosphataemia.

Gastrointestinal disorders.

Pancreatitis.

Musculoskeletal and connective tissue disorders.

Osteomalacia (manifested as bone pain and infrequently contributing to fractures) and myopathy, both associated with proximal renal tubulopathy.

Renal and urinary disorders.

Renal failure, proximal renal tubulopathy, Fanconi syndrome.

Reporting suspected adverse effects.

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

4.9 Overdose

Symptoms.

Daily doses of adefovir dipivoxil 500 mg for 2 weeks and 250 mg for 12 weeks have been associated with gastrointestinal side effects.

Treatment.

If overdose occurs the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary.
Adefovir can be removed by haemodialysis (see Section 5.2 Pharmacokinetic Properties, Renal impairment).
The elimination of adefovir by peritoneal dialysis has not been studied.
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.

Adefovir is phosphorylated to the active metabolite, adefovir diphosphate, by cellular kinases. Adefovir diphosphate inhibits HBV DNA polymerase (reverse transcriptase) by competing with the natural substrate deoxyadenosine triphosphate and by causing DNA chain termination after its incorporation into viral DNA. The inhibition constant (K_i) for adefovir diphosphate for HBV DNA polymerase was 0.1 microM.
Adefovir diphosphate has an intracellular half-life of 12 to 36 hours in activated and resting lymphocytes. Adefovir diphosphate is a weak inhibitor of human DNA polymerases α and γ with K_i values of 1.18 microM and 0.97 microM, respectively.

Clinical trials.

Adefovir dipivoxil was compared to placebo in two large controlled trials enrolling patients with chronic hepatitis B and compensated liver function. One study was conducted in patients with HBeAg positive and one study in patients with HBeAg negative disease.
Adefovir dipivoxil was also studied in an open-label trial enrolling chronic hepatitis B patients pre- and post-liver transplantation with lamivudine-resistant HBV and in an active-controlled, double-blind study of patients with lamivudine resistance HBV and compensated liver function.
Study 437: HBeAg positive chronic hepatitis B adults patients treated with adefovir dipivoxil (10 mg or 30 mg) or placebo. Study 437 was a randomised, double-blind, placebo-controlled, three-arm study in patients with HBeAg positive chronic hepatitis B. Patients were serum HBsAg positive for a minimum of 6 months and HBeAg positive at screening. At baseline the median age of patients was 33 years, 74% were male, 59% were Asian and 36% were Caucasian, and 24% had prior interferon-α therapy. Patients had a median total Knodell histology activity index (HAI) score of 10 and a median serum HBV DNA level of 8.36 log₁₀ copies/mL and a median ALT level of 2.3 times the upper limit of normal.
Study 438: Presumed precore mutant (HBeAg negative/anti-HBe positive/HBV DNA positive) chronic hepatitis B adults patients treated with adefovir dipivoxil (10 mg) or placebo. Study 438 was a randomised (2:1), double-blind, placebo-controlled, two-arm study in patients who were HBeAg negative and anti-HBe positive at screening. At baseline the median age of patients was 46 years, 83% were male, 66% were Caucasian and 30% were Asian and 41% had prior interferon-α therapy. At baseline patients had a median total Knodell HAI score of 10, median baseline serum HBV DNA level of 7.08 log₁₀ copies/mL and a median ALT level 2.3 times the upper limit of normal.
The primary efficacy parameter in both studies was histological response. Assessable, paired biopsies at baseline and week 48 were available for 88% and 91% of patients in studies 437 and 438 respectively. Other measures of response included change in serum HBV DNA, change in ALT, HBeAg loss and HBeAg seroconversion (437 only). The results are shown in Tables 4-5.

Histological improvement was observed more frequently in patients treated with adefovir dipivoxil than in those treated with placebo after 48 weeks of treatment.
There was an increased proportion of patients treated with adefovir dipivoxil whose fibrosis regressed and a decreased proportion of patients treated with adefovir dipivoxil whose fibrosis progressed when compared to patients receiving placebo (see Table 5).

Blinded, ranked assessments of both necroinflammatory activity and fibrosis at baseline and at week 48 demonstrated that patients treated with adefovir dipivoxil had improved necroinflammation and fibrosis compared to patients treated with placebo.
Serum HBV DNA levels were reduced at week 48 in the group receiving adefovir dipivoxil compared to placebo (see Table 6).
In study 437, HBeAg seroconversion (12%) and HBeAg loss (24%) were observed more frequently in patients receiving adefovir dipivoxil than in patients receiving placebo (6% and 11%, respectively) after 48 weeks of treatment.

Treatment beyond 48 weeks. In study 437 with continued treatment beyond 48 weeks, maintenance of reductions in serum HBV DNA, and increases in ALT normalization, HBeAg loss and HBeAg seroconversion were observed.
In study 438, patients who received adefovir dipivoxil during the first 48 weeks were rerandomised (2:1) in a blinded manner to continue on adefovir dipivoxil or receive placebo for an additional 48 weeks, whereas patients previously in the placebo arm commenced on adefovir dipivoxil. Measures of response included change in serum HBV DNA and change in ALT. Histology was only reported on a subset of patients at week 96 as biopsy at this time point was optional. Of the 179 patients enrolled in the second 48 weeks of the study, 96% had assessable biopsies at baseline and week 48 and 27% had assessable biopsies at baseline, week 48 and week 96. The results to week 96 are presented in Tables 7 and 8.

At week 96, 50/70 (71%) of patients receiving continued treatment with adefovir dipivoxil achieved a reduction in viral load to nondetectable levels (< 1000 copies/mL), and 47/64 (73%) of patients had normalisation of ALT levels. In most patients who stopped treatment with adefovir dipivoxil, HBV DNA and ALT levels returned towards baseline and there was a reversion of histological improvement.

Long-term safety and efficacy study (LTSES) component of study 438.

Patients who received placebo during the first 48 weeks and adefovir dipivoxil during the second 48 weeks and patients who received adefovir dipivoxil during the first and second 48 weeks continued on adefovir dipivoxil for up to 144 additional weeks for a total of up to 192 weeks of treatment (192-week cohort) or up to 240 weeks of treatment (240-week cohort), respectively. Those patients receiving placebo during weeks 49 to 96 were not eligible to enter the long-term safety and efficacy study (LTSES). 125 patients entered and were analysed as part of the LTSES, covering a total duration of exposure to adefovir of up to 240 weeks.
HBV DNA levels were undetectable in 53 of 69 (77%), 51 of 65 (78%) and 37 of 55 (67%) of patients following treatment with adefovir dipivoxil for 144, 192, and 240 weeks, respectively. ALT normalization was attained in 43 of 64 (67%), 44 of 59 (75%), and 38 of 55 (69%) of patients following treatment with adefovir dipivoxil for 144, 192, and 240 weeks respectively. Similar percentages of undetectable DNA and ALT normalization were observed at weeks 144 and 192 for patients who received adefovir dipivoxil in the 192-week cohort. The results are based on remaining patients at each time point rather than all participating patients, as such these results should be interpreted with caution due to implicit survival bias.
Twelve of 22 (55%) patients treated with adefovir dipivoxil in the 192-week cohort and 17 of 24 (71%) patients treated in the 240-week cohort had an improved Ishak fibrosis score. In the combined 192 week and 240-week cohorts, 7 of 12 patients (58%) with bridging fibrosis or cirrhosis at baseline had an improved Ishak fibrosis score of ≥ 2 points after 192 weeks of treatment or 240 weeks of treatment with adefovir dipivoxil. The results are based on remaining patients at each time point rather than all participating patients, as such these results should be interpreted with caution due to implicit survival bias.
In both cohorts, 6 of 125 patients (5%) who received adefovir dipivoxil experienced HBsAg loss. Five of these 6 patients also achieved and maintained HBsAg seroconversion (HBsAg-/HBsAb+).
A 29% cumulative probability of developing a resistance mutation by week 240 was identified, with a 13% incidence between 193 and 240 weeks of adefovir dipivoxil treatment (see Section 5.2 Pharmacokinetic Properties, Microbiology). Eleven patients who developed genotypic resistance were then treated with lamivudine, all 10 of the patients with HBV DNA subsequently measured demonstrated a response (≥ 1 log₁₀ c/mL drop) to the lamivudine. The decreases in serum HBV DNA in patients harbouring the rtN236T or the rtA181V variants from the start of lamivudine treatment to the last available data ranged from 2.0 to 6.2 log₁₀ copies per mL.
Pre- and post-liver transplantation patients. Adefovir dipivoxil was also evaluated in an open-label, uncontrolled study in 467 chronic hepatitis B patients, aged 16 to 75 years old, pre- (n = 226) and post- (n = 241) liver transplantation with clinical evidence of lamivudine-resistant HBV (study 435). At baseline, 60% of pre-liver transplantation patients were classified as Child-Pugh-Turcotte score of class B or C which is indicative of moderate to severe decompensated liver disease. Median baseline HBV DNA was 7.4 and 8.2 log₁₀ copies/mL, and median baseline ALT values were 77 (1.8 x ULN) and 82 (2.0 x ULN) IU/L in pre- and post-liver transplantation patients, respectively. Treatment with adefovir dipivoxil resulted in a reduction in serum HBV DNA from baseline at week 48.
Improvements were seen in Child-Pugh-Turcotte score, with normalisation of ALT, albumin, bilirubin and prothrombin time at week 48, as shown in Table 9. Adefovir dipivoxil showed similar efficacy regardless of the patterns of lamivudine-resistant HBV DNA polymerase mutations at baseline. The mean improvement in CPT scores in post-transplantation cohort at 48 weeks was 0.2 ± 0.6 in class A patients at baseline, compared to 2.3 ± 1.6 in patients who were class B or C at baseline.
In the pre-transplantation cohort, 61/226 (27%) underwent on study liver transplant.

Treatment beyond 48 weeks.

In the pre-liver transplantation cohort, 33 of the 177 patients that had detectable HBV DNA levels (≥ 1000 copies/mL) at baseline were still on study at the 96 week time point; 25 of these patients had achieved undetectable HBV DNA levels (< 1000 copies/mL) at 96 weeks. Also in the pre-liver transplant cohort, 19 of the 149 patients that had ALT > ULN at baseline were still on study at the 96 week time point; 16 of those patients had ALT normalization at 96 weeks.
In the post-liver transplantation cohort, of the 202 patients that had detectable HBV DNA levels (≥ 1000 copies/mL) at baseline, 94 patients were still on study at the 96 week time point and 45 patients at the 144 week time point; 61 of these patients at 96 weeks and 35 patients at 144 weeks achieved undetectable HBV DNA levels (< 1000 copies/mL) at those time points. Also in the post-liver transplant cohort, of the 156 patients that had ALT > ULN at baseline, 66 patients were still on study at the 96 week time point and 26 patients at the 144 week time point; 46 of these patients at 96 weeks and 15 patients at 144 weeks had ALT normalization at those time points.
The estimated probability of survival in the pre-liver transplant population was 84% by week 48 and 77% by week 96. In the post-liver transplant population the estimated probabilities were 91% by week 48, 88% by week 96 and 87% by week 144. Sixty-seven patients (14.3%) died during treatment or within 30 days of last study dose: 27 (11%) of 241 patients in the post-transplant cohort, 40 (18%) of 226 of patients in the pre-transplant cohort. Forty-seven (70%) of the deaths occurred in the first 24 weeks of the study. Immediate causes of death were related to complications of endstage liver disease or transplantation surgery in the majority of patients and were judged to be unrelated to adefovir dipivoxil treatment.

Efficacy in lamivudine resistant virus. In study 461, a double-blind, active-controlled study in 59 chronic hepatitis B adult patients with clinical evidence of lamivudine-resistant (YMDD mutant) hepatitis B virus, patients were randomised to receive either adefovir monotherapy, adefovir dipivoxil in combination with lamivudine 100 mg, or lamivudine 100 mg alone. At week 48, the mean ± SD decrease in serum HBV DNA was 4.00 ± 1.41 log₁₀ copies/mL for patients treated with adefovir and 3.46 ± 1.10 log₁₀ copies/mL for patients treated with adefovir in combination with lamivudine. These were significant reductions when compared to the mean decrease in serum HBV DNA of 0.31 ± 0.93 log₁₀ copies/mL in patients receiving lamivudine alone (p < 0.001). ALT normalised in 47% of patients treated with adefovir, in 53% of patients treated with adefovir in combination with lamivudine, and 5% of patients treated with lamivudine alone. The mean changes in serum HBV DNA over time are summarised in Figure 1.

Monotherapy with adefovir resulted in a progressive loss of YMDD mutations through 48 weeks; 7 patients (37%) in this treatment group had reverted to wild type HBV at week 48. Continuation of lamivudine therapy, either as monotherapy or in combination with adefovir resulted in the maintenance of YMDD mutations with only one patient in the combination treatment arm reverting to HBV without YMDD mutations through 48 weeks of treatment. Loss of YMDD mutations in the adefovir-treated patients was not associated with serum HBV DNA increases or ALT flares. There was no evidence of the development of adefovir-associated resistance mutations in the HBV polymerase during 48 weeks of treatment with adefovir either alone or in combination with lamivudine.
Study 493 was a double-blind, active-controlled study in patients with chronic hepatitis B who had developed a YMDD variant hepatitis B virus with evidence of reduced response to lamivudine. Stratum A [HBeAg positive, compensated patients (n = 78)] were randomised 1:1 to receive either adefovir dipivoxil once daily or placebo in addition to once daily 100 mg lamivudine. Stratum B [HBeAg positive or negative, decompensated, (n = 38)] was open label with patients receiving adefovir in addition to once daily 100 mg lamivudine. The study had an initial treatment period of 52 weeks but was extended to 104 weeks as a follow on study with blinding and randomised treatments unchanged. Disease progression was defined in the protocol as increase in Child-Pugh-Turcotte of 2 or more points at consecutive visits (4 weeks apart), spontaneous bacterial peritonitis, bleeding gastric/esophageal varices or hepatocellular carcinoma. The proportion of patients with hepatitis B disease progression during the study was greater for the stratum A placebo + lamivudine treatment group (18%) than for the adefovir + lamivudine treatment group (3%). For stratum B, 11% of patients had disease progression.
After 104 weeks of treatment, the stratum A adefovir + lamivudine active arm showed a lower incidence (52% (17/33)) of detectable YMDD variant HBV compared to lamivudine + placebo (92% (22/24)). Seven of 31 (23%) stratum B patients with viral genome assessment had detectable YMDD variant HBV at week 104.
At weeks 100 and 104 of treatment, 76% of subjects receiving adefovir in addition to lamivudine versus 13% receiving lamivudine and placebo in stratum A had serum HBV DNA concentrations ≤ 10⁵ copies/mL or a ≥ 2 log₁₀ reduction from baseline. Eighty-seven percent (87%) of stratum B patients had an HBV DNA response at weeks 100 and 104. Forty-nine percent of adefovir + lamivudine patients versus 10% had an ALT response; 64% of stratum B patients had an ALT response. At week 104, HBeAg loss and seroconversion were observed in similar proportions of stratum A subjects in the adefovir + lamivudine treatment groups (18% and 12%, respectively) compared to the placebo + lamivudine treatment group (12% and 9%, respectively). At week 104, 38% of stratum B subjects exhibited HBeAg loss and 15% seroconverted.
There is no clinical data in patients coinfected with hepatitis C or delta virus.
Efficacy in paediatric (2 to < 12 years) and adolescent (12 to < 18 years) patients. Study 518 was a phase 3, double-blind, randomized, placebo-controlled study in which 170 HBeAg+ and 3 HBeAg- paediatric patients (aged 2 to < 12) or adolescent patients (aged 12 to < 18) with chronic hepatitis B and elevated ALT were randomised 2:1 (115 receiving adefovir and 58 receiving placebo) for a period of 48 weeks. Randomisation was stratified by prior treatment and age 2 to < 7 years old (cohort 1, n = 35), 7 to < 12 years old (cohort 2, n = 55) and 12 to < 18 years old (cohort 3, n = 83). All patients in cohort 3 received 10 mg tablet formulation; all patients in cohorts 1 and 2 received an investigational suspension formulation (0.3 mg/kg/day cohort 1, 0.25 mg/kg/day cohort 2) once daily. This study has a subsequent open-label period (week 49 to 240) which is currently ongoing.
The primary efficacy endpoint was HBV DNA < 1000 copies/mL plus normalization of ALT at the end of week 48. In cohort 3 (n = 83), significantly more patients treated with adefovir achieved the primary efficacy endpoint at the end of 48 weeks of blinded treatment (23%) when compared to the placebo-treated patients (0%), see Table 10. The proportion of patients from cohorts 1 and 2 who responded to treatment with adefovir was not statistically significant when compared to the placebo arm, although the adefovir plasma concentrations in these patients were comparable to those observed in older patients. Overall, 22 of 115 (19%) of paediatric (aged 2 to < 12 years) or adolescent patients (aged 12 to < 18 years) who received adefovir vs 1 of 58 (2%) of placebo-treated patients responded to treatment by week 48.

5.2 Pharmacokinetic Properties

The pharmacokinetics of adefovir have been evaluated in healthy adult volunteers and adult patients with chronic hepatitis B. Adefovir pharmacokinetics are similar between these populations. The pharmacokinetics of adefovir has also been investigated in adult patients with hepatic and renal impairment. The pharmacokinetics of adefovir have been shown to be comparable in Caucasians and Asians. Pharmacokinetic data are not available for other racial groups.

Absorption.

Adefovir dipivoxil is a dipivaloyloxymethyl ester prodrug of the active ingredient adefovir. Based on a cross study comparison, the oral bioavailability of adefovir dipivoxil is approximately 59%.
Following oral administration of a 10 mg single dose of adefovir dipivoxil to chronic hepatitis B patients, (n = 14), the peak adefovir plasma concentration (C_max) was 18.4 ± 6.26 nanogram/mL (mean ± SD) and occurred between 0.58 and 4.00 hours (median = 1.75 hours) postdose. The adefovir area under the plasma concentration time curve (AUC_0-∞) was 220 ± 70.0 nanogram.h/mL. Plasma adefovir concentrations declined in a biexponential manner with a terminal elimination half-life of 7.48 ± 1.65 hours.
The T_max of adefovir was delayed by approximately 2 hours, but adefovir exposure (C_max and AUC) was unaffected when a 10 mg single dose of adefovir dipivoxil was administered with food (an approximately 1000 kcal high fat meal). Adefovir dipivoxil may be taken without regard to food.

Distribution.

In vitro binding of adefovir to human plasma or human serum proteins is ≤ 4% over the adefovir concentration range of 0.1 to 25 microgram/mL. The volume of distribution at steady state following intravenous administration of 1.0 or 3.0 mg/kg/day is 392 ± 75 and 352 ± 9 mL/kg, respectively.

Excretion.

Following oral administration, adefovir dipivoxil is rapidly converted to adefovir. Forty-five percent of the dose is recovered as adefovir in the urine over 24 hours after multiple doses of adefovir dipivoxil. Adefovir is renally excreted by a combination of glomerular filtration and active tubular secretion. The pharmacokinetics of adefovir dipivoxil have been evaluated with a number of drugs that also undergo tubular secretion (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Coadministration of adefovir dipivoxil with other drugs that are eliminated by, or alter tubular secretion may increase serum concentrations of either adefovir or the administered drug.

Linearity/non-linearity.

The pharmacokinetics of adefovir are dose proportional over an adefovir dipivoxil dose range of 10 to 60 mg and are not affected by repeat dosing.

Gender.

Pharmacokinetics of adefovir were similar in male and female patients.

Adolescent patients.

The pharmacokinetics of adefovir were assessed from drug plasma concentrations in 53 HBeAg+ hepatitis B patients with compensated liver disease. The exposure of adefovir following a 48 week daily treatment with adefovir dipivoxil in adolescent patients aged 12 to < 18 years (C_max = 21.96 nanogram/mL and AUC_0-24 = 248.8 nanogram.h/mL) was comparable to that observed in adult patients.