Section 4.8 of the SmPC was updated to combine the wording of the two adverse drug reactions “proximal renal tubulopathy” and “Fanconi syndrome” to one adverse drug reaction “Proximal renal tubulopathy (including Fanconi syndrome)” with a change in frequency from ‘unknown’ to ‘uncommon’

Update to sections 4.1 and 4.2 of the SPC to reflect the evolving standard of care for HBV patients.  Namely that Hepsera treatment should only be initiated when the use of an alternative antiviral agent with a higher genetic barrier to resistance (i.e. Viread) is not available or appropriate, and the need for combination therapy in patients with decompensated liver disease.

• Re-wording of the paediatric license in section 4.2 to state 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 
• Update to section 5.1 to include long-term data from GS-US-103-0518
• Date changed for the revision of the text (section 10)

2.       QUALITATIVE AND QUANTITATIVE COMPOSITION

3.       PHARMACEUTICAL form

The following is a summary of the amendments to the SPC:

• Update of sections 4.2 and 5.1 of the SPC to reflect current data regarding the impact of the rtA181T mutation on the clinical response to adefovir dipivoxil
• Update of section 4.4 to emphasise the need to monitor renal function prior to starting treatment with adefovir dipivoxil.

• Update of section 5.1 of the SPC to reflect the paediatric weight and Body Mass Index (BMI) Z score data from Study GS-US-103-518 following up to 96 weeks of treatment with adefovir dipivoxil.

 The following statements have been added.

 In patients at risk of renal impairment (see section 4.8), consideration should be given to more frequent monitoring of renal function.

 Adefovir dipivoxil should not be administered concurrently with tenofovir disoproxil fumarate (Viread).

 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.

 The following statements have been deleted

 The renal function of these patients should be closely monitored with a frequency tailored to the individual patient¡¯s medical condition.

 Co‑administration of 10 mg adefovir dipivoxil with medicinal products that are eliminated by active tubular secretion may lead to an increase in serum concentrations of either adefovir or a co‑administered medicinal product due to competition for this elimination pathway (see section 4.5).

 Apart from ibuprofen, lamivudine, paracetamol, trimethoprim/sulfamethoxazole and tacrolimus, the effect of co‑administration of 10 mg adefovir dipivoxil with medicinal products that are excreted renally or other medicinal products known to affect renal function has not been evaluated

or tenofovir disoproxil fumarate).  In healthy volunteers, a single dose of adefovir dipivoxil given with tenofovir disoproxil fumarate does not result in a relevant drug-drug interaction with regard to pharmacokinetics.  However, the clinical safety, including potential renal effects of the co-administration of adefovir dipivoxil and tenofovir disoproxil fumarate is unknown.  Such co‑administration is only advisable if the patient is closely monitored

 Section 4.5

 The following statements have been deleted:

 Adefovir did not alter the pharmacokinetics of trimethoprim/sulfamethoxazole, paracetamol, ibuprofen, tenofovir disoproxil fumarate and tacrolimus, five medicinal products that also undergo or may affect tubular secretion.

 The pharmacokinetics of adefovir were unaltered when 10 mg adefovir dipivoxil was co‑administered with trimethoprim/sulfamethoxazole, paracetamol or tenofovir disoproxil fumarate (see section 4.4).  Comparisons with historical pharmacokinetic data from healthy subjects and HBV‑infected patients suggest that adefovir pharmacokinetics are also unaffected by tacrolimus co‑administration.

 Concomitant administration of 10 mg adefovir dipivoxil and 800 mg ibuprofen 3 times daily resulted in increases in AUC and C_max of adefovir of 23 % and 33 %, respectively.  These increases are considered to be due to higher bioavailability rather than a reduction in renal clearance and are not considered clinically relevant.

 At doses of adefovir dipivoxil 6‑ to 12‑fold higher than the 10 mg dose recommended for the treatment of chronic hepatitis B, there were no interactions with zidovudine, nelfinavir, nevirapine, indinavir, efavirenz, delavirdine, or lamivudine.  Concomitant administration of 60 mg adefovir dipivoxil with saquinavir soft capsules resulted in an increase in adefovir AUC (20 %) and concomitant administration with didanosine buffered tablets resulted in an increase in didanosine AUC (29 %).  Neither of these increases in systemic exposure were considered clinically significant.

 Section 4.7

The following statement has been added

However, based on the safety profile and mechanism of action, adefovir dipivoxil is expected to have no or negligible influence on these abilities.

 Section 4.8

 The following statement was amended

 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 %).

 The following study information was added:

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).

Frequencies are defined as ¡­..or not known (identified through post-marketing safety surveillance and the frequency cannot be estimated from the available data).

 The following statements have been added or amended.

 Gastrointestinal disorders:

Common (¡Ý 1/100, < 1/10): diarrhoea, vomiting, abdominal pain, dyspepsia, nausea, flatulence.

Frequency not known: pancreatitis.

Renal and urinary disorders:

Very common (¡Ý 1/10): increases in creatinine.

Common (¡Ý 1/100, < 1/10): renal failure, abnormal renal function, hypophosphatemia.

Frequency not known: Fanconi syndrome,

General disorders and administration site conditions:

Very common (¡Ý 1/10): asthenia.

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 ¡Ý 0.3 mg/dl by week 48 were at a statistically significant higher risk of a subsequent confirmed increase in creatinine of ¡Ý 0.5 mg/dl.  Hypophosphatemia and a decrease in carnitine concentrations were reported each in 3 % of patients on extended treatment.

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.

Section 5.1

Resistance mutations updated to include patient numbers and weeks of exposure.

Sections 9 and 10 dates updated