Consumer medicine information

Hepsera Tablets

Adefovir dipivoxil

BRAND INFORMATION

Brand name

Hepsera Tablets

Active ingredient

Adefovir dipivoxil

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Hepsera Tablets.

What is in this leaflet

This leaflet answers some of the common questions about HEPSERA.

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

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

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

What HEPSERA tablets are used for

HEPSERA 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.

How HEPSERA works

HEPSERA belongs to a group of medicines called antiviral medicines.

HEPSERA 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 HEPSERA may help treat your hepatitis. Sometimes viruses change in your body and medicines no longer work. This is called drug resistance.

Use in children

HEPSERA is not recommended for use in children under 12 years of age as its safety and effectiveness in that age group have not been established.

Before you take HEPSERA

Who must not take it

Do not take HEPSERA if you are allergic to:

  • adefovir dipivoxil or
  • any of the other ingredients of HEPSERA.

Some of the symptoms of an allergic reaction may include:

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

The ingredient of HEPSERA is listed in the product description section of this leaflet.

Do not take HEPSERA, if you are already taking any other medicines that contain similar antiretroviral ingredients such as:

  • VIREAD
  • TRUVADA
  • ATRIPLA
  • STRIBILD
  • EVIPLERA
  • GENVOYA

Do not take HEPSERA if you are over the age of 65 before discussing this with your doctor. HEPSERA is not recommended for use in children less than 12 years of age.

Do not take HEPSERA 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 HEPSERA, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you are pregnant, trying to become pregnant or breast-feeding.

The safe use of HEPSERA in human pregnancy has not been demonstrated. For this reason, it is important that women of childbearing age receiving treatment with HEPSERA use an effective method of contraception to avoid becoming pregnant. It is not known whether the active substance (adefovir dipivoxil) in this medicine is excreted in human breast milk. Consequently, nursing mothers should stop breast-feeding during treatment with HEPSERA.

Tell your doctor if you have or have ever had kidney problems. If you have reduced function of your kidneys or are at risk of having reduced function then HEPSERA may damage your kidneys. While taking HEPSERA you will require regular tests of your kidney function and may require a smaller dose of HEPSERA than patients with normal kidney function.

HEPSERA should not be taken if you have unrecognised or untreated HIV infection because HEPSERA 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 HEPSERA.

This medicine is only available from a pharmacist after it has been prescribed by a doctor who specialises in the treatment of chronic hepatitis B infection. If you wish to continue receiving treatment with HEPSERA it is important you remain under the care of a hospital or doctor who specialises in the treatment of chronic hepatitis B infection.

HEPSERA 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.

Your doctor can discuss with you the benefits and risks of taking HEPSERA.

Taking other medicines

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

Tell your doctor or pharmacist if you are already taking VIREAD (tenofovir disoproxil fumarate).

These medicines may be affected by HEPSERA or may affect how well it works. You may need different amounts of the medicine, or you may need to take different medicines. Your doctor or pharmacist will advise you.

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

How to take HEPSERA

Stay under a doctor’s care when taking HEPSERA. Do not change your treatment or stop treatment without first talking with your doctor.

Take HEPSERA exactly as your doctor prescribed it. Follow the directions from your doctor or pharmacist, exactly as written on the label. Set up a dosing schedule and follow it carefully.

Take one HEPSERA 10 mg tablet once daily with or without food. Food does not affect how HEPSERA works. If you have reduced function of your kidneys you may require a lower dose.

Always take the dose recommended by your doctor to ensure that your medicine is fully effective and to reduce the development of drug resistance.

You may be prescribed another HBV medicine to take with HEPSERA. Check with your doctor or pharmacist if you have any questions.

HEPSERA is absorbed rapidly. Do not take another HEPSERA dose if vomiting has occurred unless it occurs within 1 hour after taking HEPSERA.

When your HEPSERA supply starts to run low, get more from your doctor or pharmacist. 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 HEPSERA, become harder to treat and may result in very severe hepatitis and serious liver problems (see SIDE EFFECTS).

How much to take

Take one HEPSERA 10 mg tablet once daily or as advised by your doctor.

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

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

How long to take it

Because your medicine helps to control your condition, but does not cure it, you will need to take HEPSERA every day. Do not stop taking HEPSERA without first talking to your doctor.

If you forget to take it

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

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

Otherwise, take it as soon as you remember, then go back to taking it as you would normally.

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

This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

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

If you take too much (overdose)

Immediately telephone your doctor, pharmacist or Poisons Information Centre 13 11 26 (Australia) and 0800 764 766 (New Zealand) or go to Accident and Emergency at your nearest hospital if you think that you or anyone else may have taken too much HEPSERA. Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

While you are taking HEPSERA

Things you must do

Tell all doctors and pharmacists who are treating you that you are taking HEPSERA.

If you feel that HEPSERA is not helping your condition, tell your doctor or pharmacist.

Tell your doctor if, for any reason, you have not used HEPSERA exactly as prescribed.

Otherwise, your doctor may think that it was not effective and change your treatment unnecessarily.

Tell your doctor as soon as possible if there is any worsening of your condition.

Things you must not do

Do not give HEPSERA to anyone else, even if they have the same condition as you.

Do not stop taking HEPSERA or change the dose without checking with your doctor.

It is important not to suddenly stop taking your HEPSERA tablets, unless advised to do so by your doctor, since your condition may worsen.

Things to be careful of

Be careful driving or operating machinery until you know how HEPSERA medicine affects you.

Side effects

Like all medicines, HEPSERA can have side effects. Some may be serious and need medical attention.

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

Tell your doctor or pharmacist if you notice any of the following:

  • Weakness
  • Headache
  • Nausea
  • Flatulence
  • Diarrhoea
  • Problems with digestion
  • Stomach pain

Hepatic Flares
It is extremely important that you do not stop taking HEPSERA without your doctor’s advice. Some patient’s with hepatitis B infection may have a “flare-up” of Hepatitis B if they stop taking HEPSERA, 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 HEPSERA, tell your doctor IMMEDIATELY about any new, unusual, or worsening symptoms that you notice after stopping treatment. After you stop taking HEPSERA, your doctor will still need to check your health and take blood tests to check your liver for several months.

Serious Liver Problems (hepatotoxicity)
If you have any of the following symptoms after taking your medication, tell your doctor IMMEDIATELY or go to the accident and emergency department at your nearest hospital.

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

  • You feel very weak or tired.
  • You have unusual (not normal) muscle pain.
  • You have trouble breathing.
  • You have stomach pain with nausea and vomiting.
  • You feel cold, especially in your arm 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.

Other side effects
This list of side effects is not complete. There have been other side effects in patients taking HEPSERA. In addition to the side effects listed above, some patients who are waiting for liver transplantation or who have undergone liver transplantation have also experienced an adverse effect on their kidneys, including a change in the amount of creatinine in their blood and failure of the kidneys. Tell your doctor if you notice anything else that is making you feel unwell, even if it is not on this list.

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

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

After taking HEPSERA

Storage

Keep your HEPSERA tablets in the bottle with the cap tightly closed until you take them.

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

Do not store HEPSERA or any other medicine in a bathroom or near a sink. Do not leave it in the car or on a windowsill – heat and dampness can destroy some medicines.

Keep your HEPSERA where young children cannot reach it.

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

Disposal

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 that is left over.

Product description

What it looks like

HEPSERA tablets are white, with “10” and “GILEAD” on one side and a picture of a liver on the other side. Each bottle contains 30 tablets.

Ingredients

Each HEPSERA tablet contains 10 mg of adefovir dipivoxil.

Each HEPSERA tablet also contains the following ingredients:

  • Croscarmellose sodium
  • Lactose monohydrate
  • Magnesium stearate
  • Pregelatinized maize starch
  • Talc

Sponsor

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

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

Date of preparation: 5 July 2016

AUST R 96916

EVIPLERA, EMTRIVA, TRUVADA, HEPSERA, STRIBILD, GENVOYA and VIREAD are registered trademarks of Gilead Sciences, Inc. ATRIPLA is a trademark of Bristol-Myers Squibb & Gilead Sciences, LLC. All other trademarks referenced herein are the property of their respective owners.

BRAND INFORMATION

Brand name

Hepsera Tablets

Active ingredient

Adefovir dipivoxil

Schedule

S4

 

Name of the medicine

Adefovir dipivoxil.

Excipients

Croscarmellose sodium, lactose monohydrate, magnesium stearate, pregelatinised maize starch and talc.

Description

Chemical name: 9-[2 [[bis[(pivaloyloxy)- methoxy]phosphinyl] methoxy]ethyl] adenine. Molecular formula: C20H32N5O8P. MW: 501.48. CAS: 142340-99-6. Adefovir dipivoxil is a white to off white crystalline powder with an intrinsic aqueous solubility of 19 mg/mL at pH 2 and 0.4 mg/mL at pH 7.2. It has an octanol/ aqueous phosphate buffer (pH 7) partition coefficient (log p) of 1.91.
Adefovir dipivoxil is a diester prodrug of adefovir, an acyclic nucleotide analogue of adenosine monophosphate with activity against human hepatitis B virus (HBV).

Pharmacology

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 (Ki) for adefovir diphosphate for HBV DNA polymerase was 0.1 micromolar.
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 Ki values of 1.18 and 0.97 micromolar, respectively.

Pharmacokinetics.

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.

Hepsera is a dipivaloyloxymethyl ester prodrug of the active ingredient adefovir. Based on a cross study comparison, the oral bioavailability of adefovir from Hepsera is approximately 59%.
Following oral administration of a 10 mg single dose of Hepsera to chronic hepatitis B patients (n = 14), the peak adefovir plasma concentration (Cmax) 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 (AUC0 to ∞) was 220 ± 70.0 nanogram.hour/mL. Plasma adefovir concentrations declined in a biexponential manner with a terminal elimination half-life of 7.48 ± 1.65 hours.
The Tmax of adefovir was delayed by approximately two hours, but adefovir exposure (Cmax and AUC) was unaffected when a single dose of Hepsera 10 mg was administered with food (an approximately 1,000 kcal high fat meal). Hepsera 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, Hepsera is rapidly converted to adefovir. 45% of the dose is recovered as adefovir in the urine over 24 hours after multiple doses of Hepsera. Adefovir is renally excreted by a combination of glomerular filtration and active tubular secretion. The pharmacokinetics of Hepsera have been evaluated with a number of drugs that also undergo tubular secretion (see Interactions with Other Medicines). Coadministration of Hepsera with other drugs that are eliminated by or alter tubular secretion may increase serum concentrations of either adefovir or the administered drug.

Linearity/ nonlinearity.

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 Hepsera in adolescent patients aged 12 to < 18 years (Cmax = 21.96 nanogram/mL and AUC0-24 = 248.8 nanogram.h/mL) was comparable to that observed in adult patients.

Elderly patients.

There are no detailed pharmacokinetic data in the elderly.

Renal impairment.

In adults with moderately or severely impaired renal function or with endstage renal disease (ESRD) requiring haemodialysis, Cmax, AUC and half-life (t1/2) were increased. It is recommended that the dosing interval of Hepsera is modified in these patients. (See Dosage and Administration.) In Table 1, the pharmacokinetics of adefovir in patients with varying degrees of renal impairment, following a single dose of Hepsera 10 mg are described.
A four hour period of haemodialysis removed approximately 35% of the adefovir dose. The effect of peritoneal dialysis on adefovir removal has not been evaluated.
The pharmacokinetics of adefovir have not been studied in adolescent patients with renal dysfunction.

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.

Drug interactions.

At concentrations substantially higher (> 4,000-fold) than those observed in vivo, adefovir did not inhibit any of the following human CYP450 isoforms, CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. Adefovir is not a substrate for these enzymes. However, the potential for adefovir to induce CYP450 enzymes is unknown. Based on the results of these in vitro experiments and the known elimination pathway of adefovir, the potential for CYP450 mediated interactions involving adefovir with other medicinal products is low.
The pharmacokinetics of adefovir have been evaluated in healthy volunteers following multiple dose administration of Hepsera (10 mg once daily) in combination with lamivudine (100 mg once daily) (n = 18), trimethoprim/ sulfamethoxazole (160/800 mg twice daily) (n = 18), paracetamol (1,000 mg four times daily) (n = 20) and ibuprofen (800 mg three times daily) (n = 18). The pharmacokinetics of adefovir have also been evaluated in healthy volunteers following single dose Hepsera in combination with multiple dose tenofovir disoproxil fumarate (300 mg daily) (n = 22) and single dose pegylated interferon α-2a (PEG-IFN) (180 microgram) (n = 15). In addition the pharmacokinetics of adefovir have also been evaluated in post-liver transplantation patients following multiple dose administration of Hepsera (10 mg once daily) in combination with tacrolimus (n = 16).
Adefovir did not alter the pharmacokinetics of lamivudine, trimethoprim/ sulfamethoxazole, paracetamol, tenofovir disoproxil fumarate and ibuprofen. The evaluation of the effect of adefovir on the pharmacokinetics of pegylated interferon α-2a was inconclusive.
The pharmacokinetics of adefovir were unchanged when Hepsera was coadministered with lamivudine, trimethoprim/ sulfamethoxazole, and paracetamol, tenofovir disoproxil fumarate, tacrolimus and pegylated interferon α-2a. When Hepsera was coadministered with ibuprofen (800 mg three times daily) increases in adefovir Cmax (33%), AUC (23%) and urinary recovery were observed. This increase appears to be due to higher oral bioavailability, not a reduction in renal clearance of adefovir.
There has been no clinical evaluation of the coadministration of adefovir dipivoxil and tenofovir disoproxil fumarate in HIV/HBV coinfected patients (see also statement on nephrotoxicity under Precautions).

Pharmacokinetic/ pharmacodynamic relationship.

Adefovir dipivoxil has demonstrated a dose related significant and sustained anti-HBV effect at doses ranging from 5 to 125 mg in phase I to II studies of 4 to 12 weeks duration.

Intracellular pharmacokinetics.

Adefovir diphosphate has an intracellular half-life of 12 to 36 hours in activated and resting lymphocytes.

Microbiology.

Resistance to adefovir dipivoxil can result in loss of efficacy and exacerbation of hepatitis B.
Adefovir is active against hepadnaviruses in vitro, including wild type and recombinant HBV variants containing lamivudine resistance associated mutations (rtL180M, rtM204I, rtM204V, rtL180M + rtM204V, rtL180M + rtM204V + rtV173L) in the HBV DNA polymerase gene. Adefovir dipivoxil has also demonstrated anti-HBV activity (median reduction in serum HBV DNA of 4.1 log10 copies/mL at week 48) in patients with HBV containing lamivudine resistance associated mutations (study 435). HBV variants with DNA polymerase mutations rtT128N and rtR153Q or W153Q associated with resistance to hepatitis B immunoglobulin were susceptible to adefovir in vitro. The in vitro IC50 (concentration of drug which inhibits viral replication by 50%) of adefovir against wild type HBV is 0.2 to 2.5 microM in human hepatic cell lines. (See Table 2.)
In several clinical studies (HBeAg positive, HBeAg negative, pre-liver transplantation and post-liver transplantation with lamivudine resistant HBV and lamivudine resistant HBV/ human immunodeficiency virus (HIV) coinfected patients), genotypic analyses were conducted on HBV isolates from 379 of a total of 629 adefovir dipivoxil patients with detectable levels of HBV DNA at week 48. No HBV DNA polymerase mutations associated with resistance to adefovir were identified when patients were genotyped at baseline and at week 48. After 96, 144, 192 and 240 weeks of treatment with adefovir dipivoxil, resistance surveillance was performed for 293, 221, 116 and 64 patients, respectively. Two novel conserved site mutations were identified in the HBV polymerase gene (rtN236T and rtA181V), which conferred clinical resistance to adefovir dipivoxil. Resistance to adefovir dipivoxil is delayed and infrequent. The cumulative probabilities of developing these adefovir associated resistance mutations in all patients treated with adefovir dipivoxil were 0% at 48 weeks and approximately 2, 7, 14 and 25% after 96, 144, 192 and 240 weeks, respectively. These cumulative probabilities combine results in patients receiving adefovir dipivoxil as monotherapy and in combination with lamivudine.
In HBeAg negative patients receiving adefovir dipivoxil monotherapy, the cumulative probabilities (life table analysis) of developing these adefovir associated resistance mutations were approximately 0, 3, 11, 18 and 29% after 48, 96, 144, 192 and 240 weeks, respectively.
In addition, the long-term (four to five years) development of resistance to adefovir dipivoxil was significantly lower in patients who had serum HBV DNA below the limit of quantification (less than 1,000 copies/mL) at week 48 as compared to patients with serum HBV DNA above 1,000 copies/mL at week 48.
In HBeAg positive patients, the incidence of adefovir associated resistance mutations was 3, 17 and 20% after a median duration on adefovir dipivoxil of 135, 189 and 235 weeks, respectively.

Studies where adefovir dipivoxil was added to ongoing lamivudine in patients with lamivudine resistance.

In an open label study of pre-liver and post-liver transplantation patients with clinical evidence of lamivudine resistant HBV (study 435), the incidence of adefovir associated resistance (rtN236T or rtA181V) mutations was 0% at 48 weeks. With up to three years of exposure, no patients receiving both adefovir dipivoxil and lamivudine developed resistance to adefovir dipivoxil. However, four patients who discontinued lamivudine treatment developed the rtN236T mutation while receiving adefovir dipivoxil monotherapy and all experienced serum HBV DNA rebound. All four patients who developed the rtN236T mutation in their HBV lost the lamivudine associated mutations present at baseline.
In a study of 35 HIV/HBV coinfected patients with lamivudine resistant HBV (study 460i) who added adefovir dipivoxil to lamivudine, no adefovir associated mutations were observed in HBV isolates from any of the 15 patients tested after 144 weeks of therapy.
The currently available data both in vitro and in patients suggest that HBV expressing the adefovir associated resistance mutation rtN236T is susceptible to lamivudine. Preliminary data both in vitro and in patients suggest the adefovir associated resistance mutation rtA181V may confer a reduced susceptibility to lamivudine.
No adefovir associated HIV reverse transcriptase mutations (K65R or K70E) were detected through 48 and 144 weeks of Hepsera 10 mg therapy in 35 and 15 HIV/HBV coinfected patients, respectively. Further genotypic analysis from seven patients after 144 weeks of Hepsera treatment also did not identify the K65R or K70E mutations in these patients.

Clinical resistance in adolescent patients.

In a phase 3 study GS-US-103-0518 (study 518), HBV isolates from 49 of 56 adolescent patients (aged 12 to < 18 years) had serum HBV DNA > 169 copies/mL and were evaluated for adefovir resistance associated substitutions. rtN236T and/or rtA181V adefovir resistance associated substitutions were not observed at 48 weeks. However, the rtA181T substitution was present in baseline and week 48 isolates from two lamivudine experienced adolescent patients treated with Hepsera. Assessment for the development of potential drug resistance for those patients that experience virologic failure will continue through the end of the study (maximum treatment duration 240 weeks).

Clinical Trials

Hepsera 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.
Hepsera was also studied in an open label trial enrolling chronic hepatitis B patients pre-liver transplantation 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 adult patients treated with adefovir dipivoxil (10 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 six 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. 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 adult 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 3, 4 and 5.
Histological improvement was observed more frequently in patients treated with Hepsera than in those treated with placebo after 48 weeks of treatment.
There was an increased proportion of patients treated with Hepsera whose fibrosis regressed and a decreased proportion of patients treated with Hepsera whose fibrosis progressed when compared to patients receiving placebo (see Table 4).
Blinded, ranked assessments of both necroinflammatory activity and fibrosis at baseline and at week 48 demonstrated that patients treated with Hepsera had improved necroinflammation and fibrosis compared to patients treated with placebo.
Serum HBV DNA levels were reduced at week 48 in the group receiving Hepsera compared to placebo (see Table 5).
In study 437, HBeAg seroconversion (12%) and HBeAg loss (24%) were observed more frequently in patients receiving Hepsera 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 normalisation, HBeAg loss and HBeAg seroconversion were observed.
In study 438, patients who received Hepsera during the first 48 weeks were rerandomised (2:1) in a blinded manner to continue on Hepsera or receive placebo for an additional 48 weeks, whereas patients previously in the placebo arm commenced on Hepsera. 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 6 and 7.
At week 96, 50/70 (71%) of patients receiving continued treatment with Hepsera achieved a reduction in viral load to nondetectable levels (< 1,000 copies/mL) and 47/64 (73%) of patients had normalisation of ALT levels. In most patients who stopped treatment with Hepsera, HBV DNA and ALT levels returned towards baseline and there was a reversion of histological improvement.

Long-term safety and efficacy study component of study 438.

Patients who received placebo during the first 48 weeks and Hepsera during the second 48 weeks and patients who received Hepsera during the first and second 48 weeks continued on Hepsera 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 Hepsera 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 Hepsera for 144, 192 and 240 weeks, respectively. ALT normalisation was attained in 43 of 64 (67%), 44 of 59 (75%) and 38 of 55 (69%) of patients following treatment with Hepsera for 144, 192 and 240 weeks, respectively. Similar percentages of undetectable DNA and ALT normalisation were observed at weeks 144 and 192 for patients who received Hepsera 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.
12 of 22 (55%) patients treated with Hepsera 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 Hepsera. 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 Hepsera experienced HBsAg loss. Five of these six 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 Hepsera treatment (see Microbiology). Eleven patients who developed genotypic resistance were then treated with lamivudine, all ten of the patients with HBV DNA subsequently measured demonstrated a response (≥ 1 log10 copies/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/mL.

Pre-liver transplantation and post-liver transplantation patients.

Hepsera was also evaluated in an open label, uncontrolled study in 467 chronic hepatitis B patients, aged 16 to 75 years old, pre-liver transplantation (n = 226) and post-liver transplantation (n = 241) 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, median baseline ALT values were 77 (1.8 x ULN) and 82 (2.0 x ULN) IU/L in pre-liver transplantation and post-liver transplantation patients, respectively. Treatment with Hepsera 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 8. Hepsera 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 (≥ 1,000 copies/mL) at baseline were still on study at the 96 week time point; 25 of these patients had achieved undetectable HBV DNA levels (< 1,000 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 normalisation at 96 weeks.
In the post-liver transplantation cohort, of the 202 patients that had detectable HBV DNA levels (≥ 1,000 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 (< 1,000 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 normalisation 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. 67 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. 47 (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 Hepsera treatment.

Efficacy in lamivudine resistant virus.

In study 461, a double blind, active controlled study in 59 chronic hepatitis B patients with clinical evidence of lamivudine resistant (YMDD mutant) hepatitis B virus, patients were randomised to receive either Hepsera monotherapy, Hepsera 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 Hepsera and 3.46 ± 1.10 log10 copies/mL for patients treated with Hepsera 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 Hepsera, in 53% of patients treated with Hepsera 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 Hepsera 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 Hepsera 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 Hepsera 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 Hepsera 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 HBV with evidence of reduced response to lamivudine. Stratum A (HBeAg positive, compensated patients (n = 78)) were randomised 1:1 to receive either Hepsera once daily or placebo in addition to once daily lamivudine 100 mg. Stratum B (HBeAg positive or negative, decompensated, (n = 38)) was open label with patients receiving Hepsera in addition to once daily lamivudine 100 mg. 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 two or more points at consecutive visits (four weeks apart), spontaneous bacterial peritonitis, bleeding gastric/ oesophageal 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 Hepsera + lamivudine treatment group (3%). For stratum B, 11% of patients had disease progression.
After 104 weeks of treatment, the stratum A Hepsera + lamivudine active arm showed a lower incidence (52% (17/33)) of detectable YMDD variant HBV compared to lamivudine + placebo (92% (22/24)). 7 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 Hepsera 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. 87% of stratum B patients had a HBV DNA response at weeks 100 and 104. 49% of Hepsera + 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 Hepsera + 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 are 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 Hepsera 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 Hepsera 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 9). The proportion of patients from cohorts 1 and 2 who responded to treatment with Hepsera 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 Hepsera vs 1 of 58 (2%) of placebo treated patients responded to treatment by week 48.

Indications

Hepsera 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-/ HBV DNA+ 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.

Contraindications

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

Precautions

Hepsera should not be administered concurrently with products containing tenofovir disoproxil fumarate or tenofovir alafenamide.

Post-treatment exacerbations of hepatitis.

Severe acute exacerbation of hepatitis has been reported in patients with discontinuation of antihepatitis B therapy, including Hepsera. Patients who discontinue the drug should be monitored at repeated intervals over a period of time for hepatic function. If appropriate, resumption of antihepatitis B therapy may be warranted.
In clinical trials of Hepsera, exacerbations of hepatitis (ALT elevations ten times the upper limit of normal or greater) occurred in up to 25% of patients after discontinuation of Hepsera. 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 re-initiation of treatment, severe hepatitis exacerbations, including fatalities, have been reported. Therefore, patients should be closely monitored after stopping treatment.

Changes in renal function.

Adefovir is eliminated by renal excretion, therefore, adjustments to the dosing interval of Hepsera are recommended in patients with renal insufficiency (see Dosage and Administration).

Nephrotoxicity.

Chronic administration of Hepsera (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 cyclosporin, tacrolimus, aminoglycosides, vancomycin and nonsteroidal anti-inflammatory drugs (NSAIDs) (see Adverse Effects).
It is recommended that creatinine clearance is calculated in all patients prior to initiating therapy with Hepsera. It is important to monitor renal function for all patients during treatment with Hepsera, 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 Dosage and Administration). The risks and benefits of Hepsera treatment should be carefully evaluated prior to discontinuing Hepsera in a patient with treatment emergent nephrotoxicity.
Caution should be exercised when Hepsera is administered concomitantly with nephrotoxic agents.
The efficacy and safety of Hepsera 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 Dosage and Administration).
Caution should therefore be exercised when prescribing Hepsera to patients with underlying renal dysfunction and renal function in these patients should be closely monitored.

HIV resistance.

Prior to initiating Hepsera therapy, HIV antibody testing should be offered to all patients. Treatment with antihepatitis B therapies such as Hepsera that have activity against HIV in a chronic hepatitis B patient with unrecognised or untreated HIV infection may result in emergence of HIV resistance. Hepsera has not been shown to suppress HIV RNA in patients; however, there are limited data on the use of Hepsera 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 1,000 copies/mL at or beyond one 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 analogues 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 analogues to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with Hepsera 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 children

The safety, efficacy and pharmacokinetics of Hepsera 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 Hepsera who achieved the primary efficacy endpoint of serum HBV DNA < 1,000 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 Clinical Trials.)
Paediatric patients aged 2 to < 12 years were also evaluated in study 518 (n=90). The efficacy of Hepsera 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 Hepsera treatment in children below 12 years of age with chronic hepatitis B.
Hepsera is not recommended for use in children below 12 years of age.

Use in the elderly.

Clinical studies of Hepsera did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently to 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.

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.

Carcinogenesis, mutagenesis, impairment of fertility.

Carcinogenicity studies in mice and rats receiving adefovir have been conducted. In mice, at oral dose levels of 1, 3 or 10 mg/kg/day, no treatment related increases in tumour incidence were found at 10 mg/kg/day (systemic exposure (AUC) was approximately ten times that achieved in humans at a therapeutic dose of 10 mg/day). In rats dosed at oral levels of 0.5, 1.5 or 5 mg/kg/day, no drug related increase in tumour incidence was observed (systemic exposure (AUC) at the high dose was approximately four times that at the human therapeutic dose). Adefovir dipivoxil was mutagenic in the in vitro mouse lymphoma cell assay (with or without metabolic activation). Adefovir induced chromosomal aberrations in the in vitro human peripheral blood lymphocyte assay without metabolic activation. Adefovir was not clastogenic in the in vivo mouse micronucleus assay at oral doses up to 2,000 mg/kg and it was not mutagenic in the Ames bacterial reverse mutation assay using S. typhimurium and E. coli strains in the presence or absence of metabolic activation. 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).

Use in pregnancy.

(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 human).
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 fetal 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, Hepsera 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 Hepsera on transmission of HBV from mother to infant. Therefore appropriate infant immunisations should be used to prevent neonatal acquisition of hepatitis B virus.

Use in lactation.

It is not known whether adefovir is excreted in human or animal milk. Mothers should be instructed not to breastfeed if they are taking Hepsera.

Effects on ability to drive and use machines.

No studies on the effects on ability to drive or use machines have been performed.

Interactions

Since adefovir is eliminated by the kidney, coadministration of Hepsera with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of either adefovir and/or these coadministered drugs.
Apart from lamivudine, trimethoprim/ sulfamethoxazole, paracetamol, ibuprofen and tacrolimus the effects of coadministration of Hepsera with drugs that are excreted renally, or other drugs known to affect renal function have not been evaluated (see Pharmacokinetics).
Patients should be monitored closely for adverse events when Hepsera 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 Pharmacokinetics).
While adefovir does not inhibit common CYP450 enzymes, the potential for adefovir to induce CYP450 enzymes is not known.
The effect of adefovir on cyclosporin concentrations is not known.

Adverse 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 Hepsera (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 10. Adverse events in the Hepsera and placebo groups occurred with similar frequency.
Patients who received Hepsera 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 Hepsera exposure, the incidence of adverse events related to treatment increased only slightly.

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 11.
With extended treatment in 125 HBeAg negative patients (up to 240 weeks duration), four patients had confirmed increases in serum creatinine of at least 0.5 mg/dL from baseline with one 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), six patients had confirmed increases in serum creatinine of at least 0.5 mg/dL from baseline with two 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 Adverse Effects, 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 adefovir dipivoxil 10 mg 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: hypophosphataemia.

Nervous system disorders.

Common: headache.

Gastrointestinal disorders.

Common: nausea, vomiting, diarrhoea, abdominal pain.

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 wait listed and post-liver transplantation patients with risk factors for renal dysfunction, including concomitant use of cyclosporin 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. 4% (19 of 467) of pre-liver and post-liver transplantation patients discontinued Hepsera due to renal events.
Due to the presence of multiple concomitant risk factors for renal dysfunction in these patients, the contributory role of Hepsera 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 Hepsera (n = 115), or placebo (n = 58) for 48 weeks (see Clinical Trials).
The safety profile of Hepsera in adolescent patients 12 to < 18 years of age (n = 56) was similar to that observed in adults. No paediatric patients treated with Hepsera 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 Hepsera 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 postapproval 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 Hepsera.

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.

Dosage and Administration

Adults.

The recommended dose of Hepsera is 1 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 Hepsera in chronic hepatitis B patients ≥ 12 years of age with adequate renal function is one tablet, once daily taken orally, without regard to food. Hepsera 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 insufficiency.

Significantly increased drug exposures were seen when Hepsera was administered to adults with renal impairment (see Pharmacokinetics). Therefore, the dosing interval of Hepsera should be adjusted in patients with baseline creatinine clearance < 50 mL/minute (calculated using the Cockcroft Gault equation) using the following suggested guidelines (see Table 12). 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 Hepsera. Therefore, clinical response to treatment and renal function should be closely monitored in these patients.
The pharmacokinetics of adefovir has not been evaluated in nonhaemodialysis patients with creatinine clearance < 10 mL/minute, 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 Precautions).

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 1,000 copies/mL at or beyond one 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.

Overdosage

Daily doses of adefovir dipivoxil 500 mg for two weeks and 250 mg for 12 weeks have been associated with gastrointestinal side effects.
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 Pharmacokinetics, Renal impairment). The elimination of adefovir by peritoneal dialysis has not been studied.

Presentation

Tablets, 10 mg (white, flat faced, marked 10 and GILEAD, stylised figure of a liver on reverse): 30's (high density polyethylene (HDPE) bottle with silica gel desiccant).

Storage

Store below 25°C.
Store in original container.

Poison Schedule

S4.