Special Warning : אזהרת שימוש

4.4 Special warnings and precautions for use
General
Patients should be advised that therapy with adefovir dipivoxil has not been proven to reduce the risk of transmission of hepatitis B virus to others and therefore appropriate precautions should still be taken.

Renal function
Adefovir is excreted renally, by a combination of glomerular filtration and active tubular secretion.
Treatment with adefovir dipivoxil may result in renal impairment. Long-term treatment with adefovir dipivoxil may increase the risk of renal impairment. While the overall risk of renal impairment in patients with adequate renal function is low, this is of special importance in patients both at risk of or having underlying renal dysfunction, and also in patients receiving medicinal products that may affect renal function.

It is recommended that creatinine clearance is calculated in all patients prior to initiating therapy with adefovir dipivoxil and that renal function (creatinine clearance and serum phosphate) be monitored every four weeks during the first year and then every three months thereafter. In patients at risk for renal impairment, consideration should be given to more frequent monitoring of renal function.

In patients who develop renal insufficiency and have advanced liver disease or cirrhosis, dosing interval adjustment of adefovir or switch to an alternative therapy for hepatitis B infection should be considered.
Treatment cessation for chronic hepatitis B in these patients is not recommended.

Patients with creatinine clearance between 30 and 49 ml/min
The dosing interval of adefovir dipivoxil should be adjusted in these patients (see section 4.2). In addition, renal function should be closely monitored with a frequency tailored to the individual patient’s medical condition.

Patients with creatinine clearance < 30 ml/min and dialysis patients
Adefovir dipivoxil is not recommended in patients with a creatinine clearance of < 30 ml/min or on dialysis. Administration of adefovir dipivoxil in these patients should only be considered if the potential benefits outweigh the potential risks. If treatment with adefovir dipivoxil is considered essential, then the dosing interval should be adjusted (see section 4.2). These patients should be closely monitored for possible adverse reactions and to ensure efficacy is maintained.



Patients receiving medicinal products that may affect renal function Adefovir dipivoxil should not be administered concurrently with tenofovir disoproxil fumarate (Viread).

Caution is advised in patients receiving other medicinal products that may affect renal function or are excreted renally (e.g. cyclosporin and tacrolimus, intravenous aminoglycosides, amphotericin B, foscarnet, pentamidine, vancomycin, or medicinal products which are secreted by the same renal transporter, human Organic Anion Transporter 1 (hOAT1), such as cidofovir). Co-administration of 10 mg adefovir dipivoxil with medicinal products in these patients may lead to an increase in serum concentrations of either adefovir or a co-administered medicinal product. The renal function of these patients should be closely monitored with a frequency tailored to the individual patient’s medical condition.

For renal safety in patients pre- and post-transplantation with lamivudine-resistant HBV, see section 4.8.

Hepatic function
Spontaneous exacerbations in chronic hepatitis B are relatively common and are characterised by transient increases in serum ALT. After initiating antiviral therapy, serum ALT may increase in some patients as serum HBV DNA levels decline. In patients with compensated liver disease, these increases in serum ALT are generally not accompanied by an increase in serum bilirubin concentrations or hepatic decompensation (see section 4.8).

Patients with advanced liver disease or cirrhosis may be at a higher risk for hepatic decompensation following hepatitis exacerbation which may be fatal. In these patients, including patients with decompensated liver disease, treatment cessation is not recommended and these patients should be monitored closely during therapy.

In the event of these patients developing renal insufficiency, see above Renal function.

If treatment cessation is necessary, patients should be closely monitored for several months after stopping treatment as exacerbations of hepatitis have occurred after discontinuation of 10 mg adefovir dipivoxil.
These exacerbations occurred in the absence of HBeAg seroconversion and presented as serum ALT elevations and increases in serum HBV DNA. Elevations in serum ALT that occurred in patients with compensated liver function treated with 10 mg adefovir dipivoxil were not accompanied by clinical and laboratory changes associated with liver decompensation. Patients should be closely monitored after stopping treatment. Most post-treatment exacerbations of hepatitis were seen within 12 weeks of discontinuation of 10 mg adefovir dipivoxil.

Lactic acidosis and severe hepatomegaly with steatosis
Occurrences of lactic acidosis (in the absence of hypoxaemia), sometimes fatal, usually associated with severe hepatomegaly and hepatic steatosis, have been reported with the use of nucleoside analogues. As adefovir is structurally related to nucleoside analogues, this risk cannot be excluded. Treatment with nucleoside analogues should be discontinued when rapidly elevating aminotransferase levels, progressive hepatomegaly or metabolic/lactic acidosis of unknown aetiology occur. Benign digestive symptoms, such as nausea, vomiting and abdominal pain, might be indicative of lactic acidosis development. Severe cases, sometimes with fatal outcome, were associated with pancreatitis, liver failure/hepatic steatosis, renal failure and higher levels of serum lactate. Caution should be exercised when prescribing nucleoside analogues to any patient (particularly obese women) with hepatomegaly, hepatitis or other known risk factors for liver disease. These patients should be followed closely.

To differentiate between elevations in transaminases due to response to treatment and increases potentially related to lactic acidosis, physicians should ensure that changes in ALT are associated with improvements in other laboratory markers of chronic hepatitis B.

Co-infection with hepatitis C or D

There are no data on the efficacy of adefovir dipivoxil in patients co-infected with hepatitis C or hepatitis D.

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

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

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

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

Hepsera contains lactose monohydrate. Consequently, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.
Excipients
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium- free’.

Effects on Driving

4.7 Effects on ability to drive and use machines

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