Hepsera 10 mg tablets

1. Name Of The Medicinal Product

Hepsera 10 mg tablets

2. Qualitative And Quantitative Composition

Each tablet contains 10 mg adefovir dipivoxil.

Excipient(s):

Each tablet contains 113 mg lactose monohydrate.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Tablet.

White to off

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

• decompensated liver disease.

4.2 Posology And Method Of Administration

Therapy should be initiated by a physician experienced in the management of chronic hepatitis B.

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

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

- 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).

Children and adolescents: Hepsera is not recommended for use in children below the age of 18 years due to insufficient data on safety and efficacy (see section 5.1).

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

Renal insufficiency: 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

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

Clinical resistance: Lamivudine

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.

4.3 Contraindications

• Hypersensitivity to the active substance or to any of the excipients.

4.4 Special Warnings And Precautions For Use

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. While the overall risk of renal impairment in patients with adequate renal function is low, this is of special importance in patients at risk of, or having underlying renal dysfunction and 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.

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 normal renal function:

Patients with normal renal function should be monitored for changes in serum creatinine every 3 months and creatinine clearance calculated. In patients at risk of renal impairment (see section 4.8), consideration should be given to more frequent monitoring of renal function.

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

For renal safety in patients pre

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

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 There are no data on the efficacy of adefovir dipivoxil in patients co

Co Limited data are available on the safety and efficacy of 10 mg adefovir dipivoxil in patients with chronic hepatitis B, co

As far as possible, treatment of hepatitis B by adefovir dipivoxil in an HIV co

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.

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.

Hepsera contains lactose monohydrate. Consequently, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose

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

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

Due to the high pharmacokinetic variability of pegylated interferon, no definitive conclusion can be drawn regarding the effect of adefovir and pegylated interferon co

4.6 Pregnancy And Lactation

Pregnancy: There are no adequate data on the use of adefovir dipivoxil in pregnant women.

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 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.

Given that the potential risks to developing human foetuses are unknown, it is recommended that women of child

Lactation: It is not known whether adefovir is excreted in human milk. Mothers should be instructed not to breast

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

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 %).

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

• an open-label study in which pre

The adverse reactions considered at least possibly related to treatment are listed below, by body system organ class, and frequency. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as very common (

Nervous system disorders:

Common (

Gastrointestinal disorders:

Common (

Frequency not known: pancreatitis.

Skin and subcutaneous tissue disorders:

Common (

Musculoskeletal and connective tissue disorders:

Frequency not known: myopathy, osteomalacia (both associated with proximal renal tubulopathy).

Renal and urinary disorders:

Very common (

Common (

Frequency not known: Fanconi syndrome, proximal renal tubulopathy.

General disorders and administration site conditions:

Very common (

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

In a long

In a long

Safety in patients with decompensated disease:

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 %). 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.

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.

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

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 experience: 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

In these clinical studies patients had active viral replication (HBV DNA

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 %, 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 interferon₁₀ 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

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=

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=

Experience in patients pre In a clinical study in 394 chronic hepatitis B patients with lamivudine-resistant HBV (pre₁₀ copies/ml, respectively, at week 48. In the pre

In the pre

Experience in patients with compensated liver disease and lamivudine In a double₁₀ 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 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 In an open-label investigator study in 35 chronic hepatitis B patients with lamivudine-resistant HBV and co

In a second open³ (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

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) was examined in a double

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

The clinical data available are insufficient to draw definitive conclusions on the benefit/risk ratio of the adefovir treatment in children with chronic hepatitis B (see section 4.2).

Clinical resistance in patients receiving adefovir dipivoxil as monotherapy and in combination with lamivudine: In several clinical studies (HBeAg positive, HBeAg negative, pre

Clinical resistance in monotherapy studies in nucleoside naïve patients: In patients receiving adefovir dipivoxil monotherapy (HBeAg negative study) the cumulative probability of developing adefovir

Clinical resistance in studies where adefovir dipivoxil was added to ongoing lamivudine in patients with lamivudine-resistance: In an open-label study of pre

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

5.2 Pharmacokinetic Properties

Absorption: Adefovir dipivoxil is a dipivaloyloxymethyl ester prodrug of the active substance adefovir. 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 (C_max) was achieved after 1.75 h (0.58_max and AUC₀ values were 16.70 (9.66·h/ml, respectively. Systemic exposure to adefovir was not affected when 10 mg adefovir dipivoxil was taken with a high fat meal. The t_max 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

Biotransformation: Following oral administration, adefovir dipivoxil is rapidly converted to adefovir. At concentrations substantially higher (> 4,000in 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_cr> 80 ml/min) is 211 ml/min (172

Linearity/non 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 children or 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.

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.

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 (n=8)	30 (n=7)	10 (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

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).

5.3 Preclinical Safety Data

The primary dose

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

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

2 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

The following pack sizes are available: outer cartons containing 1 x 30 tablet and 3 x 30 tablet bottles. Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

Any unused product or waste material should be disposed of in accordance with local requirements.

7. Marketing Authorisation Holder

Gilead Sciences International Limited

Cambridge

CB21 6GT

United Kingdom

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 last renewal: 06 March 2008

10. Date Of Revision Of The Text

06/2009

Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/.