Hepsera

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Hepsera 10 mg tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each tablet contains 10 mg adefovir dipivoxil. 
 
Excipient(s) with known effect: 
 
Each tablet contains 113 mg lactose monohydrate. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Tablet. 
 
White to off-white, round, flat-faced, bevelled-edge tablets, 7 mm in diameter, debossed with 
“GILEAD” and “10” on one side and a stylised shape of a liver on the other side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Hepsera is indicated for the treatment of chronic hepatitis B in adults with: 
 
• compensated liver disease with evidence of active viral replication, persistently elevated serum 

alanine aminotransferase (ALT) levels and histological evidence of active liver inflammation 
and fibrosis.  Initiation of Hepsera treatment should only be considered when the use of an 
alternative antiviral agent with a higher genetic barrier to resistance is not available or 
appropriate (see section 5.1). 

 
• decompensated liver disease in combination with a second agent without cross-resistance to 

Hepsera. 
 
4.2 Posology and method of administration 
 
Therapy should be initiated by a physician experienced in the management of chronic hepatitis B. 
 
Posology 
 
Adults: The recommended dose of Hepsera is 10 mg (one tablet) once daily taken orally with or 
without food. 
 
Higher doses must not be administered. 
 
The optimum duration of treatment is unknown.  The relationship between treatment response and 
long-term outcomes such as hepatocellular carcinoma or decompensated cirrhosis is not known. 
 
In patients with decompensated liver disease, adefovir should always be used in combination with a 
second agent, without cross-resistance to adefovir, to reduce the risk of resistance and to achieve rapid 
viral suppression. 
 



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Patients should be monitored every six months for hepatitis B biochemical, virological and serological 
markers. 
 
Treatment discontinuation may be considered as follows: 
 
- In HBeAg positive patients without cirrhosis, treatment should be administered for at least 

6-12 months after HBe seroconversion (HBeAg loss and HBV DNA loss with 
anti-HBe detection) is confirmed or until HBs seroconversion or there is loss of efficacy 
(see section 4.4).  Serum ALT and HBV DNA levels should be followed regularly after 
treatment discontinuation to detect any late virological relapse. 

 
- In HBeAg negative patients without cirrhosis, treatment should be administered at least until 

HBs seroconversion or there is evidence of loss of efficacy.  With prolonged treatment for more 
than 2 years, regular reassessment is recommended to confirm that continuing the selected 
therapy remains appropriate for the patient. 

 
In patients with decompensated liver disease or cirrhosis, treatment cessation is not recommended 
(see section 4.4). 
 
Special populations 
Elderly: No data are available to support a dose recommendation for patients over the age of 65 years 
(see section 4.4). 
 
Renal impairment: Adefovir is eliminated by renal excretion and adjustments of the dosing interval are 
required in patients with a creatinine clearance < 50 ml/min or on dialysis.  The recommended dosing 
frequency according to renal function must not be exceeded (see sections 4.4 and 5.2).  The proposed 
dose interval modification is based on extrapolation of limited data in patients with end stage renal 
disease (ESRD) and may not be optimal. 
 
Patients with creatinine clearance between 30 and 49 ml/min: 
It is recommended to administer adefovir dipivoxil (one 10 mg tablet) every 48 hours in these patients.  
There are only limited data on the safety and efficacy of this dosing interval adjustment guideline.  
Therefore, clinical response to treatment and renal function should be closely monitored in these 
patients (see section 4.4). 
 
Patients with creatinine clearance < 30 ml/min and dialysis patients: 
There are no safety and efficacy data to support the use of adefovir dipivoxil in patients with a 
creatinine clearance < 30 ml/min or on dialysis.  Therefore, use of adefovir dipivoxil is not 
recommended in these patients and should only be considered if the potential benefits outweigh the 
potential risks.  In that case, the limited data available suggest that for patients with creatinine 
clearance between 10 and 29 ml/min, adefovir dipivoxil (one 10 mg tablet) may be administered every 
72 hours; for haemodialysis patients, adefovir dipivoxil (one 10 mg tablet) may be administered every 
7 days following 12 hours continuous dialysis (or 3 dialysis sessions, each of 4 hours duration).  These 
patients should be closely monitored for possible adverse reactions and to ensure efficacy is 
maintained (see sections 4.4 and 4.8).  No dosing interval recommendations are available for other 
dialysis patients (e.g. ambulatory peritoneal dialysis patients) or non-haemodialysed patients with 
creatinine clearance less than 10 ml/min. 
 
Hepatic impairment: No dose adjustment is required in patients with hepatic impairment 
(see section 5.2). 
 
Clinical resistance: Lamivudine-refractory patients and patients harbouring HBV with evidence of 
resistance to lamivudine (mutations at rtL180M, rtA181T and/or rtM204I/V) should not be treated 
with adefovir dipivoxil monotherapy in order to reduce the risk of resistance to adefovir.  Adefovir 
may be used in combination with lamivudine in lamivudine-refractory patients and in patients 
harbouring HBV with mutations at rtL180M and/or rtM204I/V.  However, for patients harbouring 



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HBV that contains the rtA181T mutation, consideration should be given to alternative treatment 
regimens due to the risk of reduced susceptibility to adefovir (see section 5.1). 
 
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 1 year of treatment. 
 
Paediatric population: Hepsera is not recommended for use in children below the age of 18 years due 
to limitations of the available data on safety and efficacy (see section 5.1). 
 
Method of administration 
Hepsera tablets should be taken once daily, orally with or without food. 
 
4.3 Contraindications 
 
• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
4.4 Special warnings and precautions for use 
 
General: Patients should be advised that therapy with adefovir dipivoxil has not been proven to reduce 
the risk of transmission of hepatitis B virus to others and therefore appropriate precautions should still 
be taken. 
 
Renal function: Adefovir is excreted renally, by a combination of glomerular filtration and active 
tubular secretion.  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. 
 
It is recommended that creatinine clearance is calculated in all patients prior to initiating therapy with 
adefovir dipivoxil and that renal function (creatinine clearance and serum phosphate) be monitored 
every four weeks during the first year and then every three months thereafter.  In patients at risk for 
renal impairment, consideration should be given to more frequent monitoring of renal function. 
 
In patients who develop renal insufficiency and have advanced liver disease or cirrhosis, dosing 
interval adjustment of adefovir or switch to an alternative therapy for hepatitis B infection should be 
considered.  Treatment cessation for chronic hepatitis B in these patients is not recommended. 
 
Patients with creatinine clearance between 30 and 49 ml/min: 
The dosing interval of adefovir dipivoxil should be adjusted in these patients (see section 4.2).  In 
addition, renal function should be closely monitored with a frequency tailored to the individual 
patient’s medical condition. 
 
Patients with creatinine clearance < 30 ml/min and dialysis patients: 
Adefovir dipivoxil is not recommended in patients with a creatinine clearance of < 30 ml/min or on 
dialysis.  Administration of adefovir dipivoxil in these patients should only be considered if the 
potential benefits outweigh the potential risks.  If treatment with adefovir dipivoxil is considered 
essential, then the dosing interval should be adjusted (see section 4.2).  These patients should be 
closely monitored for possible adverse reactions and to ensure efficacy is maintained. 
 
Patients receiving medicinal products that may affect renal function: 
Adefovir dipivoxil should not be administered concurrently with tenofovir disoproxil fumarate 
(Viread). 
 
Caution is advised in patients receiving other medicinal products that may affect renal function or are 
excreted renally (e.g. cyclosporin and tacrolimus, intravenous aminoglycosides, amphotericin B, 



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foscarnet, pentamidine, vancomycin, or medicinal products which are secreted by the same renal 
transporter, human Organic Anion Transporter 1 (hOAT1), such as cidofovir).  Co-administration of 
10 mg adefovir dipivoxil with medicinal products in these patients may lead to an increase in serum 
concentrations of either adefovir or a co-administered medicinal product.  The renal function of these 
patients should be closely monitored with a frequency tailored to the individual patient’s medical 
condition. 
 
For renal safety in patients pre- and post-transplantation with lamivudine-resistant HBV, 
see section 4.8. 
 
Hepatic function: Spontaneous exacerbations in chronic hepatitis B are relatively common and are 
characterised by transient increases in serum ALT.  After initiating antiviral therapy, serum ALT may 
increase in some patients as serum HBV DNA levels decline.  In patients with compensated liver 
disease, these increases in serum ALT are generally not accompanied by an increase in serum bilirubin 
concentrations or hepatic decompensation (see section 4.8). 
 
Patients with advanced liver disease or cirrhosis may be at a higher risk for hepatic decompensation 
following hepatitis exacerbation which may be fatal.  In these patients, including patients with 
decompensated liver disease, treatment cessation is not recommended and these patients should be 
monitored closely during therapy. 
 
In the event of these patients developing renal insufficiency, see above Renal function. 
 
If treatment cessation is necessary, patients should be closely monitored for several months after 
stopping treatment as exacerbations of hepatitis have occurred after discontinuation of 10 mg adefovir 
dipivoxil.  These exacerbations occurred in the absence of HBeAg seroconversion and presented as 
serum ALT elevations and increases in serum HBV DNA.  Elevations in serum ALT that occurred in 
patients with compensated liver function treated with 10 mg adefovir dipivoxil were not accompanied 
by clinical and laboratory changes associated with liver decompensation.  Patients should be closely 
monitored after stopping treatment.  Most post-treatment exacerbations of hepatitis were seen within 
12 weeks of discontinuation of 10 mg adefovir dipivoxil. 
 
Lactic acidosis and severe hepatomegaly with steatosis: Occurrences of lactic acidosis (in the absence 
of hypoxaemia), sometimes fatal, usually associated with severe hepatomegaly and hepatic steatosis, 
have been reported with the use of nucleoside analogues.  As adefovir is structurally related to 
nucleoside analogues, this risk cannot be excluded.  Treatment with nucleoside analogues should be 
discontinued when rapidly elevating aminotransferase levels, progressive hepatomegaly or 
metabolic/lactic acidosis of unknown aetiology occur.  Benign digestive symptoms, such as nausea, 
vomiting and abdominal pain, might be indicative of lactic acidosis development.  Severe cases, 
sometimes with fatal outcome, were associated with pancreatitis, liver failure/hepatic steatosis, renal 
failure and higher levels of serum lactate.  Caution should be exercised when prescribing nucleoside 
analogues to any patient (particularly obese women) with hepatomegaly, hepatitis or other known risk 
factors for liver disease.  These patients should be followed closely. 
 
To differentiate between elevations in transaminases due to response to treatment and increases 
potentially related to lactic acidosis, physicians should ensure that changes in ALT are associated with 
improvements in other laboratory markers of chronic hepatitis B. 
 
Co-infection with hepatitis C or D: There are no data on the efficacy of adefovir dipivoxil in patients 
co-infected with hepatitis C or hepatitis D. 
 
Co-infection with HIV: Limited data are available on the safety and efficacy of 10 mg adefovir 
dipivoxil in patients with chronic hepatitis B, co-infected with HIV.  To date there is no evidence that 
daily dosing with 10 mg adefovir dipivoxil results in emergence of adefovir-associated resistance 
mutations in the HIV reverse transcriptase.  Nonetheless, there is a potential risk of selection of 
HIV strains resistant to adefovir with possible cross-resistance to other antiviral medicinal products. 
 



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As far as possible, treatment of hepatitis B by adefovir dipivoxil in an HIV co-infected patient should 
be reserved for patients whose HIV RNA is controlled.  Treatment with 10 mg adefovir dipivoxil has 
not been shown to be effective against HIV replication and therefore should not be used to control 
HIV infection. 
 
Elderly: The clinical experience in patients > 65 years of age is very limited.  Caution should be 
exercised when prescribing adefovir dipivoxil to the elderly, keeping in mind the greater frequency of 
decreased renal or cardiac function in these patients, and the increase in concomitant diseases or 
concomitant use of other medicinal products in the elderly. 
 
Resistance: Resistance to adefovir dipivoxil (see section 5.1) 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.  Virological response should be closely monitored in 
patients treated with adefovir dipivoxil, with HBV DNA measured every 3 months.  If viral rebound 
occurs, resistance testing should be performed.  In case of emergence of resistance, treatment should 
be modified. 
 
Hepsera contains lactose monohydrate.  Consequently, patients with rare hereditary problems of 
galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take 
this medicinal product. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Interaction studies have only been performed in adults. 
 
The potential for CYP450 mediated interactions involving adefovir with other medicinal products is 
low, based on the results of in vitro experiments in which adefovir did not influence any of the 
common CYP isoforms known to be involved in human drug metabolism and based on the known 
elimination pathway of adefovir.  A clinical study in liver-transplant patients has shown that no 
pharmacokinetic interaction occurs when adefovir dipivoxil 10 mg once daily is administered 
concomitantly with tacrolimus, an immunosuppressant which is predominantly metabolised via the 
CYP450 system.  A pharmacokinetic interaction between adefovir and the immunosuppressant, 
cyclosporin, is also considered unlikely as cyclosporin shares the same metabolic pathway as 
tacrolimus.  Nevertheless, given that tacrolimus and cyclosporin can affect renal function, close 
monitoring is recommended when either of these agents is coadministered with adefovir dipivoxil 
(see section 4.4). 
 
Concomitant administration of 10 mg adefovir dipivoxil and 100 mg lamivudine did not alter the 
pharmacokinetic profile of either medicinal product. 
 
Adefovir is excreted renally, by a combination of glomerular filtration and active tubular secretion.  
Co-administration of 10 mg adefovir dipivoxil with other medicinal products that are eliminated by 
tubular secretion or alter tubular function may increase serum concentrations of either adefovir or the 
co-administered medicinal product (see section 4.4). 
 
Due to the high pharmacokinetic variability of pegylated interferon, no definitive conclusion can be 
drawn regarding the effect of adefovir and pegylated interferon co-administration on the 
pharmacokinetic profile of either medicinal product.  Even though a pharmacokinetic interaction is 
unlikely given the two products are eliminated via different pathways, caution is recommended if both 
products are co-administered. 
 
4.6 Fertility, pregnancy and lactation 
 
The use of adefovir dipivoxil must be accompanied by the use of effective contraception. 
 
Pregnancy 
There are limited data on the use of adefovir dipivoxil in pregnant women. 



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Studies in animals administered adefovir intravenously have shown reproductive toxicity 
(see section 5.3).  Studies in orally dosed animals do not indicate teratogenic or foetotoxic effects. 
 
Adefovir dipivoxil is not recommended during pregnancy and in women of childbearing potential not 
using contraception.  Adefovir dipivoxil should be used during pregnancy only if the potential benefit 
justifies the potential risk to the foetus. 
 
There are no data on the effect of adefovir dipivoxil on transmission of HBV from mother to infant.  
Therefore, the standard recommended procedures for immunisation of infants should be followed to 
prevent neonatal acquisition of HBV. 
 
Breast-feeding 
A risk to the newborns/infants cannot be excluded.  It is recommended that mothers being treated with 
adefovir dipivoxil do not breast-feed their infants. 
 
Fertility 
No human data on the effect of adefovir dipivoxil on fertility are available.  Animal studies do not 
indicate harmful effects of adefovir dipivoxil on male and female fertility. 
 
4.7 Effects on ability to drive and use machines 
 
No studies on the effects on the ability to drive and use machines have been performed.  However, 
based on the safety profile and mechanism of action, adefovir dipivoxil is expected to have no or 
negligible influence on these abilities. 
 
4.8 Undesirable effects 
 
a. Summary of the safety profile 
In patients with compensated liver disease, the most frequently reported adverse reactions during 
48 weeks of adefovir dipivoxil therapy were asthenia (13 %), headache (9 %), abdominal pain (9 %) 
and nausea (5 %). 
In patients with decompensated liver disease, the most frequently reported adverse reactions during up 
to 203 weeks of adefovir dipivoxil therapy were increased creatinine (7 %) and asthenia (5 %). 
 
b. Tabulated summary of adverse reactions 
Assessment of adverse reactions is based on experience from post-marketing surveillance and from 
three pivotal clinical studies in patients with chronic hepatitis B: 
 
• two placebo-controlled studies in which 522 patients with chronic hepatitis B and compensated 

liver disease received double-blind treatment with 10 mg adefovir dipivoxil (n=294) or placebo 
(n=228) for 48 weeks. 

• an open-label study in which pre- (n=226) and post-liver transplantation patients (n=241) with 
lamivudine-resistant HBV were treated with 10 mg adefovir dipivoxil once daily, for up to 
203 weeks (median 51 and 99 weeks, respectively). 

 
The adverse reactions considered at least possibly related to treatment are listed below, by body 
system organ class, and frequency (see Table 1).  Within each frequency grouping, undesirable effects 
are presented in order of decreasing seriousness.  Frequencies are defined as very common (≥ 1/10), 
common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100) or not known (identified through post-
marketing safety surveillance and the frequency cannot be estimated from the available data). 
 



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Table 1: Tabulated summary of adverse reactions associated with adefovir dipivoxil based on 
clinical study and post-marketing experience 
 
Frequency Adefovir dipivoxil 
Nervous system disorders: 
Common: Headache 
Gastrointestinal disorders: 
Common: Diarrhoea, vomiting, abdominal pain, dyspepsia, nausea, flatulence 
Not known: Pancreatitis 
Skin and subcutaneous tissue disorders: 
Common: Rash, pruritus 
Musculoskeletal and connective tissue disorders: 

Not known: Osteomalacia (manifested as bone pain and infrequently contributing to fractures) and myopathy, both associated with proximal renal tubulopathy 
Renal and urinary disorders: 
Very common: Increases in creatinine 
Common: Renal failure, abnormal renal function, hypophosphatemia 
Uncommon: Proximal renal tubulopathy (including Fanconi syndrome) 
General disorders and administration site conditions: 
Very common: Asthenia 
 
c. Description of selected adverse reactions 
Exacerbation of hepatitis: 
Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of 
treatment with 10 mg adefovir dipivoxil (see section 4.4). 
 
Long-term safety data in patients with compensated disease: 
In a long-term safety study of 125 HBeAg negative patients with compensated liver disease, the 
adverse event profile was overall unchanged after a median exposure of 226 weeks.  No clinically 
significant changes in renal function were observed.  However, mild to moderate increases in serum 
creatinine concentrations, hypophosphatemia and a decrease in carnitine concentrations were reported 
in 3 %, 4 % and 6 % of patients, respectively, on extended treatment. 
 
In a long-term safety study of 65 HBeAg positive patients with compensated liver disease (after a 
median exposure of 234 weeks), 6 patients (9 %) 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.  Patients with a confirmed increase in creatinine of ≥ 0.3 mg/dl by week 48 
were at a statistically significant higher risk of a subsequent confirmed increase in creatinine of 
≥ 0.5 mg/dl.  Hypophosphatemia and a decrease in carnitine concentrations were reported each in 3 % 
of patients on extended treatment. 
 
Based on post-marketing data, long-term treatment with adefovir dipivoxil may lead to progressive 
alteration of renal function resulting in renal impairment (see section 4.4). 
 
Safety in patients with decompensated disease: 
Renal toxicity is an important feature of the safety profile of adefovir dipivoxil in patients with 
decompensated liver disease.  In clinical studies of wait-listed and post-liver transplantation patients, 
four percent (19/467) of patients discontinued treatment with adefovir dipivoxil due to renal adverse 
events. 
 
d. Paediatric population 
Because of insufficient data on safety and efficacy, Hepsera should not be used in children under the 
age of 18 years (see Sections 4.2 and 5.1). 
 



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Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation 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 via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
Administration of 500 mg adefovir dipivoxil daily for 2 weeks and 250 mg daily for 12 weeks has 
been associated with the gastrointestinal disorders listed above and anorexia. 
 
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; the median haemodialysis clearance of adefovir is 
104 ml/min.  The elimination of adefovir by peritoneal dialysis has not been studied. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Nucleoside and nucleotide reverse transcriptase inhibitors, ATC code: 
J05AF08. 
 
Mechanism of action and pharmacodynamic effects: Adefovir dipivoxil is an oral prodrug of adefovir, 
an acyclic nucleotide phosphonate analogue of adenosine monophosphate, which is actively 
transported into mammalian cells where it is converted by host enzymes to adefovir diphosphate.  
Adefovir diphosphate inhibits viral polymerases by competing for direct binding with the natural 
substrate (deoxyadenosine triphosphate) and, after incorporation into viral DNA, causes DNA chain 
termination.  Adefovir diphosphate selectively inhibits HBV DNA polymerases at concentrations 12-, 
700-, and 10-fold lower than those needed to inhibit human DNA polymerases α, β, and γ, 
respectively.  Adefovir diphosphate has an intracellular half-life of 12 to 36 hours in activated and 
resting lymphocytes. 
 
Adefovir is active against hepadnaviruses in vitro, including all common forms of lamivudine-resistant 
HBV (rtL180M, rtM204I, rtM204V, rtL180M/rtM204V), famciclovir-associated mutations (rtV173L, 
rtP177L, rtL180M, rtT184S or rtV207I) and hepatitis B immunoglobulin escape mutations (rtT128N 
and rtW153Q), and in in vivo animal models of hepadnavirus replication. 
 
Clinical efficacy and safety: 
The demonstration of the benefit of adefovir dipivoxil is based on histological, virological, 
biochemical, and serological responses in adults with: 
 
• HBeAg positive and HBeAg negative chronic hepatitis B with compensated liver disease. 
 
• lamivudine-resistant HBV with either compensated or decompensated liver disease, including 

patients pre- and post-liver transplantation or co-infected with HIV.  In the majority of these 
studies adefovir dipivoxil 10 mg was added to ongoing lamivudine treatment in patients failing 
lamivudine therapy. 

 
In these clinical studies patients had active viral replication (HBV DNA ≥ 100,000 copies/ml) and 
elevated ALT levels (≥ 1.2 x Upper Limit of Normal (ULN)). 
 
Experience in patients with compensated liver disease: In two placebo-controlled studies (total n=522) 
in HBeAg positive or in HBeAg negative chronic hepatitis B patients with compensated liver disease, 
significantly more patients (p < 0.001) in the 10 mg adefovir dipivoxil groups (53 and 64 %, 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc
http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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respectively) had histological improvement from baseline at week 48 than in the placebo groups (25 
and 33 %).  Improvement was defined as a reduction from baseline of two points or more in the 
Knodell necro-inflammatory score with no concurrent worsening in the Knodell fibrosis score.  
Histological improvement was seen regardless of baseline demographic and hepatitis B characteristics, 
including prior interferon-alpha therapy.  High baseline ALT levels (≥ 2 x ULN) and Knodell 
Histology Activity Index (HAI) scores (≥ 10) and low HBV DNA (< 7.6 log10 copies/ml) were 
associated with greater histological improvement.  Blinded, ranked assessments of both necro-
inflammatory activity and fibrosis at baseline and week 48, demonstrated that patients treated with 
10 mg adefovir dipivoxil had improved necro-inflammatory and fibrosis scores relative to placebo-
treated patients. 
 
Assessment of the change in fibrosis after 48 weeks treatment using the Knodell scores confirms that 
patients treated with adefovir dipivoxil 10 mg had more regression and less progression of fibrosis 
than patients treated with placebo. 
 
In the two studies mentioned above, treatment with 10 mg adefovir dipivoxil was associated with 
significant reductions in serum HBV DNA (3.52 and 3.91 log10 copies/ml, respectively, versus 0.55 
and 1.35 log10 copies/ml), increased proportion of patients with normalisation of ALT (48 and 72 % 
versus 16 and 29 %) or increased proportion of patients with serum HBV DNA below the limits of 
quantification (< 400 copies/ml Roche Amplicor Monitor PCR assay) (21 and 51 % versus 0 %) when 
compared with placebo.  In the study in HBeAg positive patients, HBeAg seroconversion (12 %) and 
HBeAg loss (24 %) was observed significantly more frequently in patients receiving 10 mg adefovir 
dipivoxil than in patients receiving placebo (6 % and 11 %, respectively) after 48 weeks of treatment. 
 
In the HBeAg positive study, treatment beyond 48 weeks resulted in further reductions in serum 
HBV DNA levels and increases in the proportion of patients with ALT normalisation, HBeAg loss and 
seroconversion. 
 
In the HBeAg negative study patients on adefovir dipivoxil (0-48 weeks) were re-randomised in a 
blinded-manner to continue on adefovir dipivoxil or receive placebo for an additional 48 weeks.  At 
week 96, patients continuing on adefovir dipivoxil 10 mg had sustained suppression of serum 
HBV with maintenance of the reduction seen at week 48.  In over two thirds of patients suppression of 
serum HBV DNA was associated with normalisation of ALT levels.  In most patients who stopped 
treatment with adefovir dipivoxil, serum HBV DNA and ALT levels returned towards baseline. 
 
Treatment with adefovir dipivoxil resulted in improvement in the liver fibrosis from baseline to 
96 weeks therapy when analysed using the Ishak score (median change: Δ= -1).  No differences in the 
median fibrosis score were seen between groups using the Knodell fibrosis score. 
 
Patients who completed the first 96 weeks of the HBeAg negative study and received adefovir 
dipivoxil treatment during weeks 49 to 96, were offered the opportunity to receive open-label 
treatment with adefovir dipivoxil from study week 97 through to week 240.  Serum HBV DNA levels 
remained undetectable and ALT levels normalised in approximately two thirds of patients following 
treatment with adefovir dipivoxil for up to 240 weeks.  Clinically and statistically significant 
improvement in fibrosis was seen in the changes in Ishak scores from the start of adefovir dipivoxil 
treatment to the end of the study (week 240) (median change: Δ= -1).  By the end of the study, 7 of 
12 patients (58 %) with bridging fibrosis or cirrhosis at baseline, had an improved Ishak fibrosis score 
of ≥ 2 points.  Five patients achieved and maintained HBsAg seroconversion 
(HBsAg negative/HBsAb positive). 
 
Experience in patients pre- and post-liver transplantation with lamivudine-resistant HBV: In a clinical 
study in 394 chronic hepatitis B patients with lamivudine-resistant HBV (pre-liver transplantation 
(n=186) and post-liver transplantation (n=208)), treatment with 10 mg adefovir dipivoxil resulted in a 
median reduction in serum HBV DNA of 4.1 and 4.2 log10 copies/ml, respectively, at week 48.  In the 
pre-liver transplantation and post-liver transplantation cohorts 77 of 109 (71 %) patients and 64 of 159 
(40 %) patients, respectively, achieved undetectable HBV DNA levels at week 48 (< 1,000 copies/ml 
Roche Amplicor Monitor PCR assay).  Treatment with 10 mg adefovir dipivoxil showed similar 



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efficacy regardless of the patterns of lamivudine-resistant HBV DNA polymerase mutations at 
baseline.  Improvements or stabilisation were seen in Child-Pugh-Turcotte score.  Normalisation of 
ALT, albumin, bilirubin and prothrombin time was seen at week 48 in 51-85 % of the patients. 
 
In the pre-liver transplantation cohort, 25 of 33 (76 %) patients achieved undetectable HBV DNA 
levels and 84 % of patients had ALT normalisation at 96 weeks.  In the post-liver transplantation 
cohort, 61 of 94 (65 %) and 35 of 45 (78 %) of patients achieved undetectable HBV DNA levels at 
96 and 144 weeks, respectively, and 70 % and 58 % of patients had ALT normalisation at these study 
visits.  The clinical significance of these findings as they relate to histological improvement is not 
known. 
 
Experience in patients with compensated liver disease and lamivudine-resistant HBV: In a 
double-blind comparative study in chronic hepatitis B patients with lamivudine-resistant HBV (n=58), 
there was no median reduction in HBV DNA from baseline after 48 weeks of treatment with 
lamivudine.  Forty-eight weeks of treatment with adefovir dipivoxil 10 mg alone or in combination 
with lamivudine resulted in a similar significant decrease in median serum HBV DNA levels from 
baseline (4.04 log10 copies/ml and 3.59 log10 copies/ml, respectively).  The clinical significance of 
these observed changes in HBV DNA has not been established. 
 
Experience in patients with decompensated liver disease and lamivudine-resistant HBV: In 40 HBeAg 
positive or HBeAg negative patients with lamivudine-resistant HBV and decompensated liver disease 
receiving treatment with 100 mg lamivudine, addition of 10 mg adefovir dipivoxil treatment for 
52 weeks resulted in a median reduction in HBV DNA of 4.6 log10 copies/ml.  Improvement in liver 
function was also seen after one year of therapy. 
 
Experience in patients with HIV co-infection and lamivudine-resistant HBV: In an open-label 
investigator study in 35 chronic hepatitis B patients with lamivudine-resistant HBV and co-infected 
with HIV, continued treatment with 10 mg adefovir dipivoxil resulted in progressive reductions in 
serum HBV DNA levels and ALT levels throughout the course of treatment up to 144 weeks. 
 
In a second open-label, one-arm study, 10 mg adefovir dipivoxil and pegylated interferon alpha-2a 
were added to ongoing lamivudine therapy in 18 HIV/HBV co-infected patients with 
lamivudine-resistant HBV.  Patients were all HBeAg positive and had median CD4 cell count of 
441 cells/mm3 (no patient had CD4 count < 200 cells/mm3).  During therapy, serum HBV DNA levels 
were significantly lower compared to baseline for up to 48 weeks of treatment while ALT levels 
declined progressively from week 12.  However, on-treatment HBV DNA response was not 
maintained off-therapy since all the patients had a rebound in HBV DNA after adefovir dipivoxil and 
pegylated interferon alpha-2a discontinuation.  No patients became HBsAg- or HBeAg-negative 
during the study.  Due to the small sample size and the study design, in particular the lack of treatment 
arms with pegylated interferon alpha-2a monotherapy and with adefovir monotherapy, it is not 
possible to draw formal conclusions on the best therapeutic management of HIV co-infected patients 
with lamivudine-resistant HBV. 
 
Clinical resistance in patients receiving adefovir dipivoxil as monotherapy and in combination with 
lamivudine: In several clinical studies (HBeAg positive, HBeAg negative, pre- and post-liver 
transplantation with lamivudine-resistant HBV and lamivudine-resistant HBV co-infected with HIV 
patients), genotypic analyses were conducted on HBV isolates from 379 of a total of 629 patients, 
treated with adefovir dipivoxil for 48 weeks.  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.  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. 
 



12 

Clinical resistance in monotherapy studies in nucleoside naïve patients: In patients receiving 
adefovir dipivoxil monotherapy (HBeAg negative study) the cumulative probability of developing 
adefovir-associated resistance mutations was 0 %, 3 %, 11 %, 18 % and 29 % at 48, 96, 144, 192 and 
240 weeks respectively.  In addition, the long-term (4 to 5 years) development of resistance to 
adefovir dipivoxil was significantly lower in patients who had serum HBV DNA below the limit of 
quantification (< 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 % (2/65), 17 % (11/65) and 20 % (13/65) after a median duration 
exposure of 135, 189 and 235 weeks respectively. 
 
Clinical resistance in studies where adefovir dipivoxil was added to ongoing lamivudine in patients 
with lamivudine-resistance: In an open-label study of pre- and post-liver transplantation patients 
with clinical evidence of lamivudine-resistant HBV, no adefovir-associated resistance mutations 
were observed at week 48.  With up to 3 years of exposure, no patients receiving both adefovir 
dipivoxil and lamivudine developed resistance to adefovir dipivoxil.  However, 4 patients who 
discontinued lamivudine treatment developed the rtN236T mutation while receiving adefovir 
dipivoxil monotherapy and all experienced serum HBV rebound. 
 
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 clinical data 
suggest the adefovir-associated resistance mutation rtA181V may confer a reduced susceptibility to 
lamivudine, and the lamivudine-associated mutation rtA181T may confer a reduced susceptibility to 
adefovir dipivoxil. 
 
Paediatric population: 
The efficacy and safety of a daily dose of 0.25 mg/kg to 10 mg adefovir dipivoxil in children (aged 
from 2 to < 18 years) were examined in a double-blind, randomised, placebo-controlled study in 173 
paediatric patients (115 on adefovir dipivoxil, 58 on placebo) who had HBeAg positive chronic 
hepatitis B, serum ALT levels ≥ 1.5 x upper limit of normal (ULN) and compensated liver disease.  At 
week 48, in children aged 2 to 11 years old, no statistically significant difference was observed in the 
proportions of patients that achieved the primary endpoint of serum HBV DNA < 1,000 copies/ml and 
normal ALT levels between the placebo arm and the adefovir dipivoxil arm.  In the adolescent 
population (n=83) (aged from 12 to < 18 years), significantly more patients treated with adefovir 
dipivoxil achieved the primary efficacy endpoint and obtained significant reductions in serum 
HBV DNA (23 %) compared to placebo-treated patients (0 %).  However, the proportions of subjects 
who achieved HBeAg seroconversion at week 48 were similar (11 %) between the placebo arm and 
the adefovir dipivoxil 10 mg arm in adolescent patients. 
 
Overall, the safety profile of adefovir dipivoxil in children was consistent with the known safety 
profile in adult patients.  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.  At week 48 and 96, mean 
changes from baseline in weight and BMI Z scores tended to decrease in adefovir dipivoxil-treated 
patients.   At week 48, all placebo-treated subjects who did not exhibit HBeAg or HBsAg 
seroconversion, plus all adefovir dipivoxil-treated subjects, were offered the opportunity to receive 
open-label adefovir dipivoxil from study week 49 through to week 240.  A high rate (30%) of hepatic 
flares was reported following discontinuation of adefovir dipivoxil during the 3 years open-label phase 
of the study.  Furthermore, for the few patients who remained on drug at week 240 (n=12) 
BMI Z score was lower than typical for their age and gender.  Very few patients developed adefovir-
associated mutations up to 5 years; however, the number of patients who remained on drugs above 
week 96 was limited.  Due to their limitations, the clinical data available do not allow to draw 
definitive conclusions on the benefit/risk ratio of the adefovir treatment in children with chronic 
hepatitis B (see section 4.2). 
 



13 

5.2 Pharmacokinetic properties 
 
Adefovir dipivoxil is a dipivaloyloxymethyl ester prodrug of the active substance adefovir, an acyclic 
nucleotide analogue which is actively transported into cells where it is converted by host enzymes to 
adefovir diphosphate. 
 
Absorption: The oral bioavailability of adefovir from 10 mg adefovir dipivoxil is 59 %.  Following 
oral administration of a single dose of 10 mg adefovir dipivoxil to chronic hepatitis B patients, the 
median (range) peak serum concentration (Cmax) was achieved after 1.75 h (0.58-4.0 h).  Median Cmax 
and AUC0-∞ values were 16.70 (9.66-30.56) ng/ml and 204.40 (109.75-356.05) ng·h/ml, respectively.  
Systemic exposure to adefovir was not affected when 10 mg adefovir dipivoxil was taken with a high 
fat meal.  The tmax was delayed by two hours. 
 
Distribution: Preclinical studies show that after oral administration of adefovir dipivoxil, adefovir is 
distributed to most tissues with the highest concentrations occurring in kidney, liver and intestinal 
tissues.  In vitro binding of adefovir to human plasma or human serum proteins is ≤ 4 %, over the 
adefovir concentration range of 0.1 to 25 μg/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. 
 
Biotransformation: Following oral administration, adefovir dipivoxil is rapidly converted to adefovir.  
At concentrations substantially higher (> 4,000-fold) than those observed in vivo, adefovir did not 
inhibit any of the following human CYP450 isoforms, CYP1A2, CYP2D6, CYP2C9, CYP2C19, 
CYP3A4.  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. 
 
Elimination: Adefovir is excreted renally by a combination of glomerular filtration and active tubular 
secretion.  The median (min-max) renal clearance of adefovir in subjects with normal renal function 
(Clcr > 80 ml/min) is 211 ml/min (172-316 ml/min), approximately twice calculated creatinine 
clearance (Cockroft-Gault method).  After repeated administration of 10 mg adefovir dipivoxil, 45 % 
of the dose is recovered as adefovir in the urine over 24 hours.  Plasma adefovir concentrations 
declined in a biexponential manner with a median terminal elimination half-life of 7.22 h 
(4.72-10.70 h). 
 
Linearity/non-linearity: The pharmacokinetics of adefovir are proportional to dose when given as 
adefovir dipivoxil over the dose range of 10 to 60 mg.  Repeated dosing of adefovir dipivoxil 10 mg 
daily did not influence the pharmacokinetics of adefovir. 
 
Gender, age and ethnicity: The pharmacokinetics of adefovir were similar in male and female patients.  
Pharmacokinetic studies have not been conducted in the elderly.  Pharmacokinetic studies were 
principally conducted in Caucasian patients.  The available data do not appear to indicate any 
difference in pharmacokinetics with regard to race. 
 
Renal impairment: The mean (± SD) pharmacokinetic parameters of adefovir following administration 
of a single dose of 10 mg adefovir dipivoxil to patients with varying degrees of renal impairment are 
described in the table below: 
 

 
Renal Function Group 

Unimpaired Mild Moderate Severe 

Baseline Creatinine 
Clearance (ml/min) 

> 80 
(n=7) 

50-80 
(n=8) 

30-49 
(n=7) 

10-29 
(n=10) 

Cmax (ng/ml) 17.8±3.2 22.4±4.0 28.5±8.6 51.6±10.3 
AUC0-∞ (ng·h/ml) 201±40.8 266±55.7 455±176 1240±629 
CL/F (ml/min) 469±99.0 356±85.6 237±118 91.7±51.3 
CLrenal (ml/min) 231±48.9 148±39.3 83.9±27.5 37.0±18.4 



14 

 
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. 
 
It is recommended that the dosing interval of 10 mg adefovir dipivoxil is modified in patients with 
creatinine clearance between 30 and 49 ml/min.  Adefovir dipivoxil is not recommended in patients 
with creatinine clearance of < 30 ml/min or in patients on dialysis (see section 4.2 and 4.4). 
 
Hepatic impairment: Pharmacokinetic properties were similar in patients with moderate and severe 
hepatic impairment compared to healthy volunteers (see section 4.2). 
 
Paediatric population: The pharmacokinetics of adefovir dipivoxil were studied in an efficacy and 
safety study of a daily dose of 0.25 mg/kg to 10 mg adefovir dipivoxil in children (aged 2 to 
< 18 years).  Pharmacokinetic analysis revealed that adefovir exposure was comparable among 3 age 
groups, 2 to 6 years (0.3 mg/kg), 7 to 11 years (0.25 mg/kg) and 12 to 17 years (10 mg) and all age 
groups achieved adefovir exposure in the target range (for efficacy results see section 5.1), which was 
based on adefovir plasma concentrations in adult patients with chronic hepatitis B with established 
safety and efficacy profiles. 
 
5.3 Preclinical safety data 
 
The primary dose-limiting toxic effect associated with administration of adefovir dipivoxil in animals 
(mice, rats and monkeys) was renal tubular nephropathy characterised by histological alterations 
and/or increases in blood urea nitrogen and serum creatinine.  Nephrotoxicity was observed in animals 
at systemic exposures at least 3-10 times higher than those achieved in humans at the recommended 
therapeutic dose of 10 mg/day. 
 
No effects on male or female fertility, or reproductive performance, occurred in rats and there was no 
embryotoxicity or teratogenicity in rats or rabbits administered adefovir dipivoxil orally. 
 
When adefovir was administered intravenously to pregnant rats at doses associated with notable 
maternal toxicity (systemic exposure 38 times that achieved in humans at the therapeutic dose) 
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 at 
systemic exposures approximately 12 times that achieved in humans at the therapeutic dose. 
 
Adefovir dipivoxil was mutagenic in the in vitro mouse lymphoma cell assay (with or without 
metabolic activation), but was not clastogenic in the in vivo mouse micronucleus assay. 
 
Adefovir was not mutagenic in microbial mutagenicity assays involving Salmonella typhimurium 
(Ames) and Escherichia coli in the presence and absence of metabolic activation.  Adefovir induced 
chromosomal aberrations in the in vitro human peripheral blood lymphocyte assay without metabolic 
activation. 
 
In long-term carcinogenicity studies in rats and mice with adefovir dipivoxil, no treatment-related 
increase in tumour incidence was found in mice or rats (systemic exposures approximately 10 and 
4 times those achieved in humans at the therapeutic dose of 10 mg/day, respectively). 
 
 



15 

6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Pregelatinised starch 
Croscarmellose sodium 
Lactose monohydrate 
Talc 
Magnesium stearate 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years. 
 
6.4 Special precautions for storage 
 
Do not store above 30ºC.  Store in the original package in order to protect from moisture.  Keep the 
bottle tightly closed. 
 
6.5 Nature and contents of container 
 
Hepsera is supplied in high-density polyethylene (HDPE) bottles with a child-resistant closure.  Each 
bottle contains 30 tablets, silica gel desiccant and fibre packing material. 
 
The following pack sizes are available: outer cartons containing 1 bottle of 30 tablets and outer cartons 
containing 90 (3 bottles of 30) tablets.  Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Gilead Sciences Ireland UC 
Carrigtohill 
County Cork, T45 DP77 
Ireland 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/03/251/001 
EU/1/03/251/002 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 06 March 2003 
Date of latest renewal: 06 March 2008 
 
 



16 

10. DATE OF REVISION OF THE TEXT 
 
{MM/YYYY} 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu 
 
 
  



17 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 
A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
 



18 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer(s) responsible for batch release 

Gilead Sciences Ireland UC 
IDA Business & Technology Park 
Carrigtohill Co. Cork 
Ireland 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING
AUTHORISATION

• Periodic Safety Update Reports

The marketing authorisation holder shall submit periodic safety update reports for this product 
in accordance with the requirements set out in the list of Union reference dates (EURD list) 
provided for under Article 107c(7) of Directive 2001/83/EC and published on the European 
medicines web-portal. 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT

• Risk Management Plan (RMP)

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 
updates of the RMP. 

An updated RMP should be submitted: 
• At the request of the European Medicines Agency;
• Whenever the risk management system is modified, especially as the result of new information

being received that may lead to a significant change to the benefit/risk profile or as the result of
an important (pharmacovigilance or risk minimisation) milestone being reached.

If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the 
same time. 

• Obligation to conduct post-authorisation measures

The MAH shall complete, within the stated timeframe, the following measures: 

Description Due date 
The MAH commits to ensure continuous assessment of cross-resistance of adefovir 
to established and new nucleos(t)ide analogues, and provide reviews of these 
assessments as new data becomes available. The role of adefovir and add-on 
lamivudine+adefovir in HBV therapy strategy should be regularly discussed in the 
light of emerging data. 

As data 
becomes 
available 



19 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



20 

A. LABELLING



21 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 
 
CARTON AND BOTTLE LABELLING 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Hepsera 10 mg tablets 
Adefovir dipivoxil 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 10 mg adefovir dipivoxil. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose monohydrate, see package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
30 tablets. 
90 (3 bottles of 30) tablets. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30ºC.  Store in the original package in order to protect from moisture.  Keep the 
bottle tightly closed. 
 
 



22 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Gilead Sciences Ireland UC 
Carrigtohill 
County Cork, T45 DP77 
Ireland 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/03/251/001 30 tablets 
EU/1/03/251/002 90 (3 bottles of 30) tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Hepsera 
[outer packaging only] 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: {number}  
SN: {number} 
NN: {number} 
  



23 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 



24 

Package leaflet: Information for the user 
 

Hepsera 10 mg tablets 
Adefovir dipivoxil 

 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
- Keep this leaflet.  You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only.  Do not pass it on to others.  It may harm them, 

even if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor or pharmacist.  This includes any possible side 

effects not listed in this leaflet.  See section 4. 
 
 
What is in this leaflet 
1. What Hepsera is and what it is used for 
2. What you need to know before you take Hepsera 
3. How to take Hepsera 
4. Possible side effects 
5. How to store Hepsera 
6. Contents of the pack and other information 
 
 
1. What Hepsera is and what it is used for 
 
What Hepsera is 
Hepsera belongs to a group of medicines called antiviral medicines. 
 
What it is used for 
Hepsera is used to treat chronic hepatitis B, an infection with hepatitis B virus (HBV), in adults. 
Infection with the hepatitis B virus leads to damage to the liver.  Hepsera reduces the amount of the 
virus in your body, and has been shown to reduce liver damage. 
 
 
2. What you need to know before you take Hepsera 
 
Do not take Hepsera 
 
• If you are allergic to adefovir, adefovir dipivoxil or any of the other ingredients of this 

medicine (listed in section 6). 
 
• Tell your doctor at once if you could be allergic to adefovir, adefovir dipivoxil or any of the 

other ingredients of Hepsera. 
 
Warnings and precautions 
Talk to your doctor before using Hepsera. 
 
• Tell your doctor if you have had kidney disease, or if tests have shown problems with your 

kidneys.  Hepsera can affect the way your kidneys work.  The risk of this occurring is increased 
with long-term use of Hepsera.  Your doctor should run tests to check your kidneys and liver are 
working properly, before and during your treatment.  Depending on the results, your doctor may 
change how often you take Hepsera. 

 
• If you are over 65 years of age your doctor may monitor your health more closely. 
 
• Don’t stop taking Hepsera without your doctor’s advice. 



25 

 
• After stopping Hepsera tell your doctor immediately about any new, unusual or worsening 

symptoms that you notice after stopping treatment.  Some patients have had symptoms or blood 
tests indicating that their hepatitis has worsened after stopping treatment with Hepsera.  It’s best 
for your doctor to monitor your health after stopping treatment with Hepsera.  You may need 
blood tests for several months after treatment. 

 
• Once you start taking Hepsera: 
 

• look out for possible signs of lactic acidosis – see section 4, Possible side effects. 
• your doctor should order blood tests every three months to check your medicine is 

keeping your chronic hepatitis B infection under control. 
 
• Take care not to infect other people.  Hepsera does not reduce the risk of passing on HBV to 

others through sexual contact or blood contamination.  You must continue to take precautions to 
avoid this.  A vaccine is available to protect those at risk from becoming infected with HBV. 

 
• If you are HIV positive this medicine will not control your HIV infection. 
 
Children and adolescents 
 
• Do not use Hepsera in children or adolescents under 18 years of age. 
 
Other medicines and Hepsera 
 
• Do not take Hepsera if you are taking any medicines containing tenofovir. 
 
• Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 

medicines, including medicines and herbal products obtained without a prescription. 
 
• It is especially important to tell your doctor if you are taking or have recently taken any of 

the following medicines which may damage your kidneys, or interact with Hepsera: 
 

• vancomycin and aminoglycosides, used for bacterial infections 
• amphotericin B, for fungal infections 
• foscarnet, cidofovir or tenofovir disoproxil fumarate, for viral infections 
• pentamidine, for other types of infection. 

 
Hepsera with food and drink 
 
Hepsera can be taken with or without food. 
 
Pregnancy and breast-feeding 
 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicine. 
 
• Tell your doctor immediately if you are pregnant or planning to become pregnant.  It is not 

known whether Hepsera is safe to use during human pregnancy. 
 
• Use an effective method of contraception to avoid becoming pregnant if you are a woman of 

child-bearing age taking Hepsera. 
 
• Do not breast-feed while taking Hepsera.  It is not known whether the active substance in this 

medicine passes into breast milk. 
 



26 

Hepsera contains lactose 
If you are lactose-intolerant, or if you have been told that you have an intolerance to some sugars, talk 
to your doctor before taking Hepsera. 
 
 
3. How to take Hepsera 
 
Always take this medicine exactly as your doctor has told you.  This is to make sure that your 
medicine is fully effective and to reduce the development of resistance to the treatment.  Check with 
your doctor or pharmacist if you are not sure. 
 
• The recommended dose is one 10 mg tablet each day, taken with or without food. 
 
• A different dose may be given to patients with kidney problems. 
 
If you take more Hepsera than you should 
 
If you accidentally take too many Hepsera tablets, contact your doctor or nearest hospital immediately. 
 
If you forget to take Hepsera or you vomit 
 
It is important not to miss a dose. 
 
• If you do miss a dose of Hepsera, take it as soon as you can, and then take your next scheduled 

dose at its regular time. 
 
• If it is nearly time for your next dose, skip the missed dose.  Wait and take the next dose at the 

regular time.  Do not take a double dose (two doses close together). 
 
• If you are sick (vomit) less than 1 hour after taking Hepsera take another tablet.  You do not 

need to take another tablet if you are sick more than 1 hour after taking Hepsera. 
 
If you stop taking Hepsera 
 
• Tell your doctor immediately about any new, unusual or worsening symptoms that you notice 

after stopping treatment.  See section 2 for more details. 
 
• Don’t stop taking Hepsera without your doctor’s advice. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Very rare side effects 
(may affect up to 1 in 10,000 people) 
 
• Lactic acidosis is a serious but very rare side effect of taking Hepsera.  It can cause too 

much lactic acid in the blood and enlargement of the liver.  Lactic acidosis occurs more often in 
women, particularly if they are very overweight.  People with liver disease may also be at risk. 

 
Some of the signs of lactic acidosis are: 
 
• Feeling sick (nausea) and sickness (vomiting) 
 



27 

• Stomach pain 
 

Contact your doctor at once if you get any of these symptoms.  They are the same as some 
of the common side effects of Hepsera.  If you do get any of them, it is unlikely to be serious, 
but you need to check.  Your doctor will monitor you regularly while you take Hepsera. 
 

Uncommon side effects 
(may affect up to 1 in 100 people) 
 
• Damage to kidney tubule cells 
 
Common side effects 
(may affect up to 1 in 10 people) 
 
• Headache 
 
• Feeling sick (nausea) 
 
• Diarrhoea 
 
• Digestive problems including wind or discomfort after eating meals 
 
• Stomach pain 
 
• Kidney problems, as shown by blood tests 
 

Tell a doctor or pharmacist if you are worried about any of these. 
 
Very common side effects 
(may affect more than 1 in 10 people) 
 
• Weakness 
 

Tell a doctor or pharmacist if you are worried about this. 
 
Side effects before or after having a liver transplant 
 
Some patients have experienced: 
• Rash and itching – common 
 
• Feeling sick (nausea) or being sick (vomiting) – common 
 
• Kidney failure – common 
 
• Kidney problems – very common 
 

Tell a doctor or pharmacist if you are worried about any of these. 
 
• Also tests may show decreases in phosphate (common) or increases in creatinine (very 

common) in the blood. 
 
Other possible side effects 
 
The frequency of the following side effects is not known (frequency cannot be estimated from the 
available data):  
• Kidney failure 



28 

 
• Kidney problems may lead to softening of the bones (which causes bone pain and sometimes 

leads to fractures) and muscle pain or weakness. 
 
• Inflammation of the pancreas (pancreatitis) 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist.  This includes any possible side effects 
not listed in this leaflet.  You can also report side effects directly via the national reporting system 
listed in Appendix V.  By reporting side effects you can help provide more information on the safety 
of this medicine. 
 
 
5. How to store Hepsera 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the bottle and carton after {EXP}.  
The expiry date refers to the last day of that month. 
 
Do not store above 30ºC (86ºF).  Store in the original package in order to protect from moisture.  Keep 
the bottle tightly closed. 
 
Return any left over tablets to your pharmacist.  Only keep them if your doctor tells you to.  Do not 
throw away any medicines via wastewater or household waste.  Ask your pharmacist how to throw 
away medicines you no longer use.  These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Hepsera contains 
 
• The active substance in Hepsera is adefovir dipivoxil.  Each tablet contains 10 mg adefovir 

dipivoxil. 
 
• The other ingredients are: pregelatinised starch, croscarmellose sodium, lactose monohydrate, 

talc and magnesium stearate. 
 
What Hepsera looks like and contents of the pack 
 
Hepsera 10 mg tablets are round, white to off-white tablets.  The tablets are marked with “GILEAD” 
and “10” on one side and a stylised shape of a liver on the other side.  Hepsera 10 mg tablets are 
supplied in bottles of 30 tablets with silica gel desiccant.  The silica gel desiccant is contained in either 
a separate sachet or a small canister and should not be swallowed. 
 
The following pack sizes are available: outer cartons containing 1 bottle of 30 tablets and outer cartons 
containing 90 (3 bottles of 30) tablets.  Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder and Manufacturer 
 
Marketing Authorisation Holder: 
 
Gilead Sciences Ireland UC 
Carrigtohill 
County Cork, T45 DP77 
Ireland 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc
http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


29 

Manufacturer: 
 
Gilead Sciences Ireland UC 
IDA Business & Technology Park 
Carrigtohill 
County Cork 
Ireland 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Gilead Sciences Belgium SPRL-BVBA 
Tél/Tel: + 32 (0) 24 01 35 50 
 

Lietuva 
Gilead Sciences Poland Sp. z o.o. 
Tel: + 48 22 262 8702 
 

България 
Gilead Sciences Ireland UC 
Тел.: + 353 (0) 1 686 1888 
 

Luxembourg/Luxemburg 
Gilead Sciences Belgium SPRL-BVBA 
Tél/Tel: + 32 (0) 24 01 35 50 
 

Česká republika 
Gilead Sciences s.r.o. 
Tel: + 420 (0) 910 871 986 
 

Magyarország 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 
 

Danmark 
Gilead Sciences Sweden AB 
Tlf: + 46 (0) 8 5057 1849 
 

Malta 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 
 

Deutschland 
Gilead Sciences GmbH 
Tel: + 49 (0) 89 899890-0 
 

Nederland 
Gilead Sciences Netherlands B.V. 
Tel: + 31 (0) 20 718 36 98 
 

Eesti 
Gilead Sciences Poland Sp. z o.o. 
Tel: + 48 22 262 8702 
 

Norge 
Gilead Sciences Sweden AB 
Tlf: + 46 (0) 8 5057 1849 
 

Ελλάδα 
Gilead Sciences Ελλάς Μ.ΕΠΕ. 
Τηλ: + 30 210 8930 100 
 

Österreich 
Gilead Sciences GesmbH 
Tel: + 43 1 260 830 
 

España 
Gilead Sciences, S.L. 
Tel: + 34 91 378 98 30 
 

Polska 
Gilead Sciences Poland Sp. z o.o. 
Tel: + 48 22 262 8702 
 

France 
Gilead Sciences 
Tél: + 33 (0) 1 46 09 41 00 
 

Portugal 
Gilead Sciences, Lda. 
Tel: + 351 21 7928790 
 

Hrvatska 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 
 

România 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 

Ireland 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 214 825 999 
 

Slovenija 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 
 



30 

Ísland 
Gilead Sciences Sweden AB 
Sími: + 46 (0) 8 5057 1849 
 

Slovenská republika 
Gilead Sciences Slovakia s.r.o. 
Tel: + 421 (0) 232 121 210 
 

Italia 
Gilead Sciences S.r.l. 
Tel: + 39 02 439201 
 

Suomi/Finland 
Gilead Sciences Sweden AB 
Puh/Tel: + 46 (0) 8 5057 1849 
 

Κύπρος 
Gilead Sciences Ελλάς Μ.ΕΠΕ. 
Τηλ: + 30 210 8930 100 
 

Sverige 
Gilead Sciences Sweden AB 
Tel: + 46 (0) 8 5057 1849 
 

Latvija 
Gilead Sciences Poland Sp. z o.o. 
Tel: + 48 22 262 8702 
 

United Kingdom 
Gilead Sciences Ltd 
Tel: + 44 (0) 8000 113 700 
 

 
This leaflet was last revised in {MM/YYYY}. 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu 
 
This leaflet is available in all EU/EEA languages on the European Medicines Agency website. 

  



31 

ANNEX IV 

SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS 
OF THE MARKETING AUTHORISATION(S) 



32 

Scientific conclusions 
 
Taking into account the PRAC Assessment Report on the PSUR(s) for adefovir, the scientific 
conclusions of the CHMP are as follows: 
 
Based on a PRAC request, the MAH has reconsidered the frequency categories of Fanconi syndrome 
and proximal renal tubulopathy in the SmPC for Hepsera. The safety data derived from 5 pivotal 
randomized controlled studies, including a total of 1,174 patients, were reviewed. On the basis of an 
algorithm defining possible proximal renal tubulopathy and/or Fanconi syndrome as confirmed 
abnormalities, 28 cases of proximal renal tubulopathy (including possible Fanconi syndrome) were 
retrieved in the clinical safety dataset. After reviewing the description of the cases, 5 cases of possible 
proximal renal tubulopathy and/or Fanconi syndrome were sufficiently well documented with no 
alternative aetiology and/or having a temporal association with Hepsera treatment. On the basis of 
these data, the frequency of these adverse drug reactions is calculated to be 0.4% corresponding to the 
frequency category uncommon. As a result, the frequency category of proximal renal tubulopathy and 
Fanconi syndrome is revised from unknown to uncommon in section 4.8 of Hepsera SmPC and in the 
corresponding section of the package leaflet. Moreover, to emphasize that the frequency is more 
driven by the more common event proximal renal tubulopathy, the terms are combined as follows 
“Proximal renal tubulopathy (including Fanconi syndrome)” rather the two terms separated. 
 
The CHMP agrees with the scientific conclusions made by the PRAC. 
 
Grounds for the variation to the terms of the marketing authorisation(s) 
 
On the basis of the scientific conclusions for adefovir the CHMP is of the opinion that the benefit-risk 
balance of the medicinal product(s) containing adefovir is unchanged subject to the proposed changes 
to the product information. 
 
The CHMP recommends that the terms of the marketing authorisation(s) should be varied. 
 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET
	SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS OF THE MARKETING AUTHORISATION(S)