Hepsera - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Hepsera 10 mg tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 10 mg of adefovir dipivoxil.

Excipient(s) with known effect

Each tablet contains 107.4 mg lactose (as monohydrate).

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Tablets.

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 PARTICULARS4.1 Therapeutic indications

Hepsera is indicated in adults for the treatment of chronic hepatitis B 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.

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).

Elderly population

No data are available to support a dose recommendation for patients over the age of 65 years (see section 4.4).

Patients with 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.

Patients with hepatic impairment

No dose adjustment is required in patients with hepatic impairment (see section 5.2).

Patients with 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 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

The safety and efficacy of Hepsera in children below the age of 18 years have not been established. Currently available data are described in section 5.1. Hepsera is not recommended for use in children below the age of 18 years.

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, 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.

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.

Excipients

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

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.

Paediatric population

Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

The use of adefovir dipivoxil must be accompanied by the use of effective contraception.

Pregnancy

There are no or limited data on the use of adefovir dipivoxil in pregnant women.

Studies in animals administered adefovir intravenously at toxic doses 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

It is unknown whether adefovir dipivoxil is excreted in human milk. 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

Hepsera is expected to have no or negligible influence on the ability to drive and use machines. No studies on the effects on the ability to drive and use machines have been performed.

4.8 Undesirable effects

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 %).

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 to < 1/10), uncommon (> 1/1000 to < 1/100) or not known (identified through postmarketing safety surveillance and the frequency cannot be estimated from the available data).

Table 1: Tabulated summary of adverse reactions associated with adefovir dipivoxil based on clinical study and post-marketing experience

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.

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).

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

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 PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Nucleoside and nucleotide reverse transcriptase inhibitors, ATC code: J05AF08.

Mechanism of action

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.

Pharmacodynamic effects

Adefovir diphosphate selectively inhibits HBV DNA polymerases at concentrations 12-, 700-, and 10-fold lower than those needed to inhibit human DNA polymerases a, P, and y, 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

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 AUCo-v 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 ^g/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.

Pharmacokinetic/phar­macodynamic relationship(s)

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:

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).

6. PHARMACEUTICAL PARTICULARS6.1 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 30°C. 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