Hepsera 10 mg tablets

Contraindications

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

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. 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-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.

Interaction with other medicinal products and other forms of interaction

Interaction studies have only been performed in adults.

The potential for CYP450 mediated interactions involving adefovir with other medicinal products is low, based on the results of in vitro experiments in which adefovir did not influence any of the common CYP isoforms known to be involved in human drug metabolism and based on the known elimination pathway of adefovir. A clinical study in liver-transplant patients has shown that no pharmacokinetic interaction occurs when adefovir dipivoxil 10 mg once daily is administered concomitantly with tacrolimus, an immunosuppressant which is predominantly metabolised via the CYP450 system. A pharmacokinetic interaction between adefovir and the immunosuppressant, cyclosporin, is also considered unlikely as cyclosporin shares the same metabolic pathway as tacrolimus. Nevertheless, given that tacrolimus and cyclosporin can affect renal function, close monitoring is recommended when either of these agents is coadministered with adefovir dipivoxil (see section 4.4).

Concomitant administration of 10 mg adefovir dipivoxil and 100 mg lamivudine did not alter the pharmacokinetic profile of either medicinal product.

Adefovir is excreted renally, by a combination of glomerular filtration and active tubular secretion. Co-administration of 10 mg adefovir dipivoxil with other medicinal products that are eliminated by tubular secretion or alter tubular function may increase serum concentrations of either adefovir or the co-administered medicinal product (see section 4.4).

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

Pregnancy and lactation

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

Pregnancy

There are limited data on the use of adefovir dipivoxil in pregnant women.

Studies in animals administered adefovir intravenously have shown reproductive toxicity (see section 5.3). Studies in orally dosed animals do not indicate teratogenic or foetotoxic effects.

Adefovir dipivoxil is not recommended during pregnancy and in women of childbearing potential not using contraception. Adefovir dipivoxil should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

There are no data on the effect of adefovir dipivoxil on transmission of HBV from mother to infant. Therefore, the standard recommended procedures for immunisation of infants should be followed to prevent neonatal acquisition of HBV.

Breast-feeding

A risk to the newborns/infants cannot be excluded. It is recommended that mothers being treated with adefovir dipivoxil do not breast-feed their infants.

Fertility

No human data on the effect of adefovir dipivoxil on fertility are available. Animal studies do not indicate harmful effects of adefovir dipivoxil on male and female fertility.

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.

Undesirable effects

a. Summary of the safety profile

In patients with compensated liver disease, the most frequently reported adverse reactions during 48 weeks of adefovir dipivoxil therapy were asthenia (13 %), headache (9 %), abdominal pain (9 %) and nausea (5 %).

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

b. Tabulated summary of adverse reactions

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

• two placebo-controlled studies in which 522 patients with chronic hepatitis B and compensated liver disease received double-blind treatment with 10 mg adefovir dipivoxil (n=294) or placebo (n=228) for 48 weeks.

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

The adverse reactions considered at least possibly related to treatment are listed below, by body system organ class, and frequency (see Table 1). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as very common (≥ 1/10), common (≥ 1/100, < 1/10) 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 on clinical study and post-marketing experience:

Nervous system disorders

Common: Headache

Gastrointestinal disorders

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

Not known: Pancreatitis

Skin and subcutaneous tissue disorders

Common: Rash, pruritus

Musculoskeletal and connective tissue disorders

Not known: Osteomalacia (manifested as bone pain and infrequently contributing to fractures) and myopathy, both associated with proximal renal tubulopathy

Renal and urinary disorders

Very common: Increases in creatinine

Common: Renal failure, abnormal renal function, hypophosphatemia

Not known: Fanconi syndrome, proximal renal tubulopathy

General disorders and administration site conditions

Very common: Asthenia

c. Description of selected adverse reactions

Exacerbation of hepatitis: Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of treatment with 10 mg adefovir dipivoxil (see section 4.4).

Long-term safety data in patients with compensated disease: In a long-term safety study of 125 HBeAg negative patients with compensated liver disease, the adverse event profile was overall unchanged after a median exposure of 226 weeks. No clinically significant changes in renal function were observed. However, mild to moderate increases in serum creatinine concentrations, hypophosphatemia and a decrease in carnitine concentrations were reported in 3 %, 4 % and 6 % of patients, respectively, on extended treatment.

In a long-term safety study of 65 HBeAg positive patients with compensated liver disease (after a median exposure of 234 weeks), 6 patients (9 %) had confirmed increases in serum creatinine of at least 0.5 mg/dl from baseline with 2 patients discontinuing from the study due to the elevated serum creatinine concentration. Patients with a confirmed increase in creatinine of ≥ 0.3 mg/dl by week 48 were at a statistically significant higher risk of a subsequent confirmed increase in creatinine of ≥ 0.5 mg/dl. Hypophosphatemia and a decrease in carnitine concentrations were reported each in 3 % of patients on extended treatment.

Safety in patients with decompensated disease: Renal toxicity is an important feature of the safety profile of adefovir dipivoxil in patients with decompensated liver disease. In clinical studies of wait-listed and post-liver transplantation patients, four percent (19/467) of patients discontinued treatment with adefovir dipivoxil due to renal adverse events.

d. Paediatric population

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

Incompatibilities

Not applicable.