HEPSERA 10mg tablets medication leaflet

Hepsera 10 mg tablets

Each tablet contains 10 mg of adefovir dipivoxil.

Each tablet contains 107.4 mg lactose (as monohydrate).

For the full list of excipients, see section 6.1.

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.

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

* compensated liver disease with evidence of active viral replication, persistently elevated serumalanine aminotransferase (ALT) levels and histological evidence of active liver inflammationand fibrosis. Initiation of Hepsera treatment should only be considered when the use of analternative antiviral agent with a higher genetic barrier to resistance is not available orappropriate (see section 5.1).

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

Hepsera.

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

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 andlong-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 asecond agent, without cross-resistance to adefovir, to reduce the risk of resistance and to achieve rapidviral suppression.

Patients should be monitored every six months for hepatitis B biochemical, virological and serologicalmarkers.

Treatment discontinuation may be considered as follows:

- In HBeAg positive patients without cirrhosis, treatment should be administered for at least6-12 months after HBe seroconversion (HBeAg loss and HBV DNA loss withanti-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 aftertreatment 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 morethan 2 years, regular reassessment is recommended to confirm that continuing the selectedtherapy remains appropriate for the patient.

In patients with decompensated liver disease or cirrhosis, treatment cessation is not recommended(see section 4.4).

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

Adefovir is eliminated by renal excretion and adjustments of the dosing interval are required inpatients with a creatinine clearance < 50 ml/min or on dialysis. The recommended dosing frequencyaccording to renal function must not be exceeded (see sections 4.4 and 5.2). The proposed doseinterval 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 thesepatients (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 acreatinine clearance < 30 ml/min or on dialysis. Therefore, use of adefovir dipivoxil is notrecommended in these patients and should only be considered if the potential benefits outweigh thepotential risks. In that case, the limited data available suggest that for patients with creatinineclearance between 10 and 29 ml/min, adefovir dipivoxil (one 10 mg tablet) may be administered every72 hours; for haemodialysis patients, adefovir dipivoxil (one 10 mg tablet) may be administered every7 days following 12 hours continuous dialysis (or 3 dialysis sessions, each of 4 hours duration). Thesepatients should be closely monitored for possible adverse reactions and to ensure efficacy ismaintained (see sections 4.4 and 4.8). No dosing interval recommendations are available for otherdialysis patients (e.g. ambulatory peritoneal dialysis patients) or non-haemodialysed patients withcreatinine clearance less than 10 ml/min.

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 tolamivudine (mutations at rtL180M, rtA181T and/or rtM204I/V) should not be treated with adefovirdipivoxil monotherapy in order to reduce the risk of resistance to adefovir. Adefovir may be used incombination with lamivudine in lamivudine-refractory patients and in patients harbouring HBV withmutations at rtL180M and/or rtM204I/V. However, for patients harbouring HBV that contains thertA181T mutation, consideration should be given to alternative treatment regimens due to the risk ofreduced susceptibility to adefovir (see section 5.1).

In order to reduce the risk of resistance in patients receiving adefovir dipivoxil monotherapy, amodification of treatment should be considered if serum HBV DNA remains above 1,000 copies/ml ator beyond 1 year of treatment.

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 childrenbelow the age of 18 years .

Hepsera tablets should be taken once daily, orally with or without food.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Patients should be advised that therapy with adefovir dipivoxil has not been proven to reduce the riskof transmission of hepatitis B virus to others and therefore appropriate precautions should still betaken.

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 adefovirdipivoxil may increase the risk of renal impairment. While the overall risk of renal impairment inpatients with adequate renal function is low, this is of special importance in patients both at risk of orhaving underlying renal dysfunction, and also in patients receiving medicinal products that may affectrenal function.

It is recommended that creatinine clearance is calculated in all patients prior to initiating therapy withadefovir dipivoxil and that renal function (creatinine clearance and serum phosphate) be monitoredevery four weeks during the first year and then every three months thereafter. In patients at risk forrenal 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, dosinginterval adjustment of adefovir or switch to an alternative therapy for hepatitis B infection should beconsidered. 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). Inaddition, renal function should be closely monitored with a frequency tailored to the individualpatient’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 ondialysis. Administration of adefovir dipivoxil in these patients should only be considered if thepotential benefits outweigh the potential risks. If treatment with adefovir dipivoxil is consideredessential, then the dosing interval should be adjusted (see section 4.2). These patients should beclosely 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 areexcreted renally (e.g. cyclosporin and tacrolimus, intravenous aminoglycosides, amphotericin B,foscarnet, pentamidine, vancomycin, or medicinal products which are secreted by the same renaltransporter, human Organic Anion Transporter 1 (hOAT1), such as cidofovir). Co-administration of10 mg adefovir dipivoxil with medicinal products in these patients may lead to an increase in serumconcentrations of either adefovir or a co-administered medicinal product. The renal function of thesepatients should be closely monitored with a frequency tailored to the individual patient’s medicalcondition.

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 bytransient increases in serum ALT. After initiating antiviral therapy, serum ALT may increase in somepatients as serum HBV DNA levels decline. In patients with compensated liver disease, theseincreases in serum ALT are generally not accompanied by an increase in serum bilirubinconcentrations or hepatic decompensation (see section 4.8).

Patients with advanced liver disease or cirrhosis may be at a higher risk for hepatic decompensationfollowing hepatitis exacerbation which may be fatal. In these patients, including patients withdecompensated liver disease, treatment cessation is not recommended and these patients should bemonitored 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 afterstopping treatment as exacerbations of hepatitis have occurred after discontinuation of 10 mg adefovirdipivoxil. These exacerbations occurred in the absence of HBeAg seroconversion and presented asserum ALT elevations and increases in serum HBV DNA. Elevations in serum ALT that occurred inpatients with compensated liver function treated with 10 mg adefovir dipivoxil were not accompaniedby clinical and laboratory changes associated with liver decompensation. Patients should be closelymonitored after stopping treatment. Most post-treatment exacerbations of hepatitis were seen within12 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 associatedwith severe hepatomegaly and hepatic steatosis, have been reported with the use of nucleosideanalogues. As adefovir is structurally related to nucleoside analogues, this risk cannot be excluded.

Treatment with nucleoside analogues should be discontinued when rapidly elevating aminotransferaselevels, progressive hepatomegaly or metabolic/lactic acidosis of unknown aetiology occur. Benigndigestive symptoms, such as nausea, vomiting and abdominal pain, might be indicative of lacticacidosis 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 beexercised when prescribing nucleoside analogues to any patient (particularly obese women) withhepatomegaly, hepatitis or other known risk factors for liver disease. These patients should befollowed closely.

To differentiate between elevations in transaminases due to response to treatment and increasespotentially related to lactic acidosis, physicians should ensure that changes in ALT are associated withimprovements 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 orhepatitis D.

Co-infection with HIV

Limited data are available on the safety and efficacy of 10 mg adefovir dipivoxil in patients withchronic hepatitis B, co-infected with HIV. To date there is no evidence that daily dosing with 10 mgadefovir dipivoxil results in emergence of adefovir-associated resistance mutations in the HIV reversetranscriptase. Nonetheless, there is a potential risk of selection of HIV strains resistant to adefovir withpossible cross-resistance to other antiviral medicinal products.

As far as possible, treatment of hepatitis B by adefovir dipivoxil in an HIV co-infected patient shouldbe reserved for patients whose HIV RNA is controlled. Treatment with 10 mg adefovir dipivoxil hasnot been shown to be effective against HIV replication and therefore should not be used to control

HIV infection.

The clinical experience in patients > 65 years of age is very limited. Caution should be exercised whenprescribing adefovir dipivoxil to the elderly, keeping in mind the greater frequency of decreased renalor cardiac function in these patients, and the increase in concomitant diseases or concomitant use ofother medicinal products in the elderly.

Resistance to adefovir dipivoxil (see section 5.1) can result in viral load rebound which may result inexacerbation of hepatitis B and, in the setting of diminished hepatic function, lead to liverdecompensation and possible fatal outcome. Virological response should be closely monitored inpatients treated with adefovir dipivoxil, with HBV DNA measured every 3 months. If viral reboundoccurs, resistance testing should be performed. In case of emergence of resistance, treatment should bemodified.

Hepsera contains lactose monohydrate. Consequently, patients with rare hereditary problems ofgalactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not takethis medicinal product.

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

The potential for CYP450 mediated interactions involving adefovir with other medicinal products islow, based on the results of in vitro experiments in which adefovir did not influence any of thecommon CYP isoforms known to be involved in human drug metabolism and based on the knownelimination pathway of adefovir. A clinical study in liver-transplant patients has shown that nopharmacokinetic interaction occurs when adefovir dipivoxil 10 mg once daily is administeredconcomitantly 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 astacrolimus. Nevertheless, given that tacrolimus and cyclosporin can affect renal function, closemonitoring 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 thepharmacokinetic 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 bytubular secretion or alter tubular function may increase serum concentrations of either adefovir or theco-administered medicinal product (see section 4.4).

Due to the high pharmacokinetic variability of pegylated interferon, no definitive conclusion can bedrawn regarding the effect of adefovir and pegylated interferon co-administration on thepharmacokinetic profile of either medicinal product. Even though a pharmacokinetic interaction isunlikely given the two products are eliminated via different pathways, caution is recommended if bothproducts are co-administered.

Interaction studies have only been performed in adults.

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

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 reproductivetoxicity (see section 5.3). Studies in orally dosed animals do not indicate teratogenic or foetotoxiceffects.

Adefovir dipivoxil is not recommended during pregnancy and in women of childbearing potential notusing contraception. Adefovir dipivoxil should be used during pregnancy only if the potential benefitjustifies 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 toprevent neonatal acquisition of HBV.

It is unknown whether adefovir dipivoxil is excreted in human milk. A risk to the newborns/infantscannot be excluded. It is recommended that mothers being treated with adefovir dipivoxil do notbreast-feed their infants.

No human data on the effect of adefovir dipivoxil on fertility are available. Animal studies do notindicate harmful effects of adefovir dipivoxil on male and female fertility.

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

In patients with compensated liver disease, the most frequently reported adverse reactions during48 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 upto 203 weeks of adefovir dipivoxil therapy were increased creatinine (7 %) and asthenia (5 %).

Assessment of adverse reactions is based on experience from post-marketing surveillance and fromthree pivotal clinical studies in patients with chronic hepatitis B:

* two placebo-controlled studies in which 522 patients with chronic hepatitis B and compensatedliver 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) withlamivudine-resistant HBV were treated with 10 mg adefovir dipivoxil once daily, for up to203 weeks (median 51 and 99 weeks, respectively).

The adverse reactions considered at least possibly related to treatment are listed below, by bodysystem organ class, and frequency (see Table 1). Within each frequency grouping, undesirable effectsare 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 post-marketing safety surveillance and the frequency cannot be estimated from the available data).

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

Frequency Adefovir dipivoxil

Common: Headache

Common: Diarrhoea, vomiting, abdominal pain, dyspepsia, nausea, flatulence

Not known: Pancreatitis

Common: Rash, pruritus

Osteomalacia (manifested as bone pain and infrequently contributing to fractures)

Not known:

and myopathy, both associated with proximal renal tubulopathy

Very common: Increases in creatinine

Common: Renal failure, abnormal renal function, hypophosphatemia

Uncommon: Proximal renal tubulopathy (including Fanconi syndrome)

Very common: Asthenia

Exacerbation of hepatitis

Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation oftreatment 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, theadverse event profile was overall unchanged after a median exposure of 226 weeks. No clinicallysignificant changes in renal function were observed. However, mild to moderate increases in serumcreatinine concentrations, hypophosphatemia and a decrease in carnitine concentrations were reportedin 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 amedian exposure of 234 weeks), 6 patients (9 %) had confirmed increases in serum creatinine of atleast 0.5 mg/dl from baseline with 2 patients discontinuing from the study due to the elevated serumcreatinine concentration. Patients with a confirmed increase in creatinine of ≥ 0.3 mg/dl by week 48were 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 progressivealteration 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 withdecompensated 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 adverseevents.

Because of insufficient data on safety and efficacy, Hepsera should not be used in children under theage of 18 years (see Sections 4.2 and 5.1).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Administration of 500 mg adefovir dipivoxil daily for 2 weeks and 250 mg daily for 12 weeks hasbeen associated with the gastrointestinal disorders listed above and anorexia.

If overdose occurs, the patient must be monitored for evidence of toxicity, and standard supportivetreatment applied as necessary.

Adefovir can be removed by haemodialysis; the median haemodialysis clearance of adefovir is104 ml/min. The elimination of adefovir by peritoneal dialysis has not been studied.

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

J05AF08.

Adefovir dipivoxil is an oral prodrug of adefovir, an acyclic nucleotide phosphonate analogue ofadenosine monophosphate, which is actively transported into mammalian cells where it is convertedby host enzymes to adefovir diphosphate. Adefovir diphosphate inhibits viral polymerases bycompeting for direct binding with the natural substrate (deoxyadenosine triphosphate) and, afterincorporation into viral DNA, causes DNA chain termination.

Adefovir diphosphate selectively inhibits HBV DNA polymerases at concentrations 12-, 700-, and10-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 restinglymphocytes.

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 (rtT128Nand rtW153Q), and in in vivo animal models of hepadnavirus replication.

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

In these clinical studies patients had active viral replication (HBV DNA ≥ 100,000 copies/ml) andelevated 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 chronichepatitis B patients with compensated liver disease, significantly more patients (p < 0.001) in the10 mg adefovir dipivoxil groups (53 and 64 %, respectively) had histological improvement frombaseline at week 48 than in the placebo groups (25 and 33 %). Improvement was defined as areduction from baseline of two points or more in the Knodell necro-inflammatory score with noconcurrent worsening in the Knodell fibrosis score. Histological improvement was seen regardless ofbaseline demographic and hepatitis B characteristics, including prior interferon-alpha therapy. Highbaseline 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-inflammatoryand fibrosis scores relative to placebo-treated patients.

Assessment of the change in fibrosis after 48 weeks treatment using the Knodell scores confirms thatpatients treated with adefovir dipivoxil 10 mg had more regression and less progression of fibrosisthan patients treated with placebo.

In the two studies mentioned above, treatment with 10 mg adefovir dipivoxil was associated withsignificant reductions in serum HBV DNA (3.52 and 3.91 log10 copies/ml, respectively, versus 0.55and 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 ofquantification (< 400 copies/ml Roche Amplicor Monitor PCR assay) (21 and 51 % versus 0 %) whencompared 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 adefovirdipivoxil 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 andseroconversion.

In the HBeAg negative study patients on adefovir dipivoxil (0-48 weeks) were re-randomised in ablinded-manner to continue on adefovir dipivoxil or receive placebo for an additional 48 weeks. Atweek 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 ofserum HBV DNA was associated with normalisation of ALT levels. In most patients who stoppedtreatment 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 to96 weeks therapy when analysed using the Ishak score (median change: Δ= -1). No differences in themedian 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 adefovirdipivoxil treatment during weeks 49 to 96, were offered the opportunity to receive open-labeltreatment with adefovir dipivoxil from study week 97 through to week 240. Serum HBV DNA levelsremained undetectable and ALT levels normalised in approximately two thirds of patients followingtreatment with adefovir dipivoxil for up to 240 weeks. Clinically and statistically significantimprovement in fibrosis was seen in the changes in Ishak scores from the start of adefovir dipivoxiltreatment to the end of the study (week 240) (median change: Δ= -1).By the end of the study, 7 of12 patients (58 %) with bridging fibrosis or cirrhosis at baseline, had an improved Ishak fibrosis scoreof ≥ 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-livertransplantation (n=186) and post-liver transplantation (n=208)), treatment with 10 mg adefovirdipivoxil 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 of109 (71 %) patients and 64 of 159 (40 %) patients, respectively, achieved undetectable HBV DNAlevels at week 48 (< 1,000 copies/ml Roche Amplicor Monitor PCR assay). Treatment with 10 mgadefovir dipivoxil showed similar 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 48in 51-85 % of the patients.

In the pre-liver transplantation cohort, 25 of 33 (76 %) patients achieved undetectable HBV DNAlevels and 84 % of patients had ALT normalisation at 96 weeks. In the post-liver transplantationcohort, 61 of 94 (65 %) and 35 of 45 (78 %) of patients achieved undetectable HBV DNA levels at96 and 144 weeks, respectively, and 70 % and 58 % of patients had ALT normalisation at these studyvisits. The clinical significance of these findings as they relate to histological improvement is notknown.

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 withlamivudine. Forty-eight weeks of treatment with adefovir dipivoxil 10 mg alone or in combinationwith lamivudine resulted in a similar significant decrease in median serum HBV DNA levels frombaseline (4.04 log10 copies/ml and 3.59 log10 copies/ml, respectively). The clinical significance ofthese 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 decompensatedliver disease receiving treatment with 100 mg lamivudine, addition of 10 mg adefovir dipivoxiltreatment 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 HBVand co-infected with HIV, continued treatment with 10 mg adefovir dipivoxil resulted in progressivereductions in serum HBV DNA levels and ALT levels throughout the course of treatment up to144 weeks.

In a second open-label, one-arm study, 10 mg adefovir dipivoxil and pegylated interferon alpha-2awere added to ongoing lamivudine therapy in 18 HIV/HBV co-infected patients withlamivudine-resistant HBV. Patients were all HBeAg positive and had median CD4 cell count of441 cells/mm3 (no patient had CD4 count < 200 cells/mm3). During therapy, serum HBV DNA levelswere significantly lower compared to baseline for up to 48 weeks of treatment while ALT levelsdeclined progressively from week 12. However, on-treatment HBV DNA response was notmaintained off-therapy since all the patients had a rebound in HBV DNA after adefovir dipivoxil andpegylated interferon alpha-2a discontinuation. No patients became HBsAg- or HBeAg-negativeduring the study. Due to the small sample size and the study design, in particular the lack of treatmentarms with pegylated interferon alpha-2a monotherapy and with adefovir monotherapy, it is notpossible to draw formal conclusions on the best therapeutic management of HIV co-infected patientswith lamivudine-resistant HBV.

Clinical resistance in patients receiving adefovir dipivoxil as monotherapy and in combination withlamivudine

In several clinical studies (HBeAg positive, HBeAg negative, pre- and post-liver transplantation withlamivudine-resistant HBV and lamivudine-resistant HBV co-infected with HIV patients), genotypicanalyses were conducted on HBV isolates from 379 of a total of 629 patients, treated with adefovirdipivoxil for 48 weeks. No HBV DNA polymerase mutations associated with resistance to adefovirwere identified when patients were genotyped at baseline and at week 48. After 96, 144, 192 and240 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 HBVpolymerase gene (rtN236T and rtA181V), which conferred clinical resistance to adefovir dipivoxil.

The cumulative probabilities of developing these adefovir-associated resistance mutations in allpatients treated with adefovir dipivoxil were 0 % at 48 weeks and approximately 2 %, 7 %, 14 % and25 % after 96, 144, 192 and 240 weeks, respectively.

Clinical resistance in monotherapy studies in nucleoside naïve patients

In patients receiving adefovir dipivoxil monotherapy (HBeAg negative study) the cumulativeprobability of developing adefovir-associated resistance mutations was 0 %, 3 %, 11 %, 18 % and29 % 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 patientswith serum HBV DNA above 1,000 copies/ml at week 48. In HBeAg positive patients, theincidence 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 patientswith lamivudine-resistance

In an open-label study of pre- and post-liver transplantation patients with clinical evidence oflamivudine-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 lamivudinedeveloped resistance to adefovir dipivoxil. However, 4 patients who discontinued lamivudinetreatment developed the rtN236T mutation while receiving adefovir dipivoxil monotherapy and allexperienced 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 datasuggest the adefovir-associated resistance mutation rtA181V may confer a reduced susceptibility tolamivudine, and the lamivudine-associated mutation rtA181T may confer a reduced susceptibility toadefovir dipivoxil.

The efficacy and safety of a daily dose of 0.25 mg/kg to 10 mg adefovir dipivoxil in children (agedfrom 2 to < 18 years) were examined in a double-blind, randomised, placebo-controlled study in 173paediatric patients (115 on adefovir dipivoxil, 58 on placebo) who had HBeAg positive chronichepatitis B, serum ALT levels ≥ 1.5 x upper limit of normal (ULN) and compensated liver disease. Atweek 48, in children aged 2 to 11 years old, no statistically significant difference was observed in theproportions of patients that achieved the primary endpoint of serum HBV DNA < 1,000 copies/ml andnormal ALT levels between the placebo arm and the adefovir dipivoxil arm. In the adolescentpopulation (n=83) (aged from 12 to < 18 years), significantly more patients treated with adefovirdipivoxil achieved the primary efficacy endpoint and obtained significant reductions in serum

HBV DNA (23 %) compared to placebo-treated patients (0 %). However, the proportions of subjectswho achieved HBeAg seroconversion at week 48 were similar (11 %) between the placebo arm andthe adefovir dipivoxil 10 mg arm in adolescent patients.

Overall, the safety profile of adefovir dipivoxil in children was consistent with the known safetyprofile in adult patients. However, a signal towards a higher rate of decreased appetite and/or foodintake was observed in the adefovir arm as compared to the placebo arm. At week 48 and 96, meanchanges from baseline in weight and BMI Z scores tended to decrease in adefovir dipivoxil-treatedpatients. At week 48, all placebo-treated subjects who did not exhibit HBeAg or HBsAgseroconversion, plus all adefovir dipivoxil-treated subjects, were offered the opportunity to receiveopen-label adefovir dipivoxil from study week 49 through to week 240. A high rate (30%) of hepaticflares was reported following discontinuation of adefovir dipivoxil during the 3 years open-label phaseof the study. Furthermore, for the few patients who remained on drug at week 240 (n=12) BMI Z scorewas lower than typical for their age and gender. Very few patients developed adefovir-associatedmutations up to 5 years; however, the number of patients who remained on drugs above week 96 waslimited. Due to their limitations, the clinical data available do not allow to draw definitive conclusionson the benefit/risk ratio of the adefovir treatment in children with chronic hepatitis B (see section 4.2).

Adefovir dipivoxil is a dipivaloyloxymethyl ester prodrug of the active substance adefovir, an acyclicnucleotide analogue which is actively transported into cells where it is converted by host enzymes toadefovir diphosphate.

The oral bioavailability of adefovir from 10 mg adefovir dipivoxil is 59 %. Following oraladministration 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 highfat meal. The tmax was delayed by two hours.

Preclinical studies show that after oral administration of adefovir dipivoxil, adefovir is distributed tomost tissues with the highest concentrations occurring in kidney, liver and intestinal tissues. In vitrobinding of adefovir to human plasma or human serum proteins is ≤ 4 %, over the adefovirconcentration range of 0.1 to 25 μg/ml. The volume of distribution at steady-state followingintravenous administration of 1.0 or 3.0 mg/kg/day is 392±75 and 352±9 ml/kg, respectively.

Following oral administration, adefovir dipivoxil is rapidly converted to adefovir. At concentrationssubstantially higher (> 4,000-fold) than those observed in vivo, adefovir did not inhibit any of thefollowing human CYP450 isoforms, CYP1A2, CYP2D6, CYP2C9, CYP2C19, CYP3A4. Based on theresults 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.

Adefovir is excreted renally by a combination of glomerular filtration and active tubular secretion. Themedian (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 creatinineclearance (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 concentrationsdeclined in a biexponential manner with a median terminal elimination half-life of 7.22 h(4.72-10.70 h).

The pharmacokinetics of adefovir are proportional to dose when given as adefovir dipivoxil over thedose range of 10 to 60 mg. Repeated dosing of adefovir dipivoxil 10 mg daily did not influence thepharmacokinetics of adefovir.

Gender, age and ethnicity

The pharmacokinetics of adefovir were similar in male and female patients. Pharmacokinetic studieshave 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 pharmacokineticswith regard to race.

The mean (± SD) pharmacokinetic parameters of adefovir following administration of a single dose of10 mg adefovir dipivoxil to patients with varying degrees of renal impairment are described in thetable below:

Renal Function Group Unimpaired Mild Moderate Severe

Baseline Creatinine > 80 50-80 30-49 10-29

Clearance (ml/min) (n=7) (n=8) (n=7) (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 ofperitoneal dialysis on adefovir removal has not been evaluated.

It is recommended that the dosing interval of 10 mg adefovir dipivoxil is modified in patients withcreatinine clearance between 30 and 49 ml/min. Adefovir dipivoxil is not recommended in patientswith creatinine clearance of < 30 ml/min or in patients on dialysis (see section 4.2 and 4.4).

Pharmacokinetic properties were similar in patients with moderate and severe hepatic impairmentcompared to healthy volunteers (see section 4.2).

The pharmacokinetics of adefovir dipivoxil were studied in an efficacy and safety study of a dailydose of 0.25 mg/kg to 10 mg adefovir dipivoxil in children (aged 2 to < 18 years). Pharmacokineticanalysis 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 achievedadefovir exposure in the target range (for efficacy results see section 5.1), which was based onadefovir plasma concentrations in adult patients with chronic hepatitis B with established safety andefficacy profiles.

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 alterationsand/or increases in blood urea nitrogen and serum creatinine. Nephrotoxicity was observed in animalsat systemic exposures at least 3-10 times higher than those achieved in humans at the recommendedtherapeutic dose of 10 mg/day.

No effects on male or female fertility, or reproductive performance, occurred in rats and there was noembryotoxicity or teratogenicity in rats or rabbits administered adefovir dipivoxil orally.

When adefovir was administered intravenously to pregnant rats at doses associated with notablematernal 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 atsystemic 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 withoutmetabolic 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 inducedchromosomal aberrations in the in vitro human peripheral blood lymphocyte assay without metabolicactivation.

In long-term carcinogenicity studies in rats and mice with adefovir dipivoxil, no treatment-relatedincrease in tumour incidence was found in mice or rats (systemic exposures approximately 10 and4 times those achieved in humans at the therapeutic dose of 10 mg/day, respectively).

Pregelatinised starch

Croscarmellose sodium

Lactose monohydrate

Talc

Magnesium stearate

Not applicable.

3 years.

Do not store above 30ºC. Store in the original package in order to protect from moisture. Keep thebottle tightly closed.

Hepsera is supplied in high-density polyethylene (HDPE) bottles with a child-resistant closure. Eachbottle 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 cartonscontaining 90 (3 bottles of 30) tablets. Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Gilead Sciences Ireland UC

Carrigtohill

County Cork, T45 DP77

Ireland

EU/1/03/251/001

EU/1/03/251/002

Date of first authorisation: 06 March 2003

Date of latest renewal: 06 March 2008

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Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu