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Drug Details

HEPSERA 10 mg tablets

• Drug Class Description
  Antiviral for systemic use
• Generic Name
  Adefovir Dipivoxil
• Presentation
  Tablet. White to offwhite, round, flatfaced, bevellededge tablets, debossed with “GILEAD” and “10” on one side and a stylised shape of a liver on the other side.
• Description
  Each tablet contains 10 mg adefovir dipivoxil. Excipient(s): Each tablet contains 113 mg lactose monohydrate
• 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.

• Adult Dosage
  

  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 longterm outcomes such as hepatocellular carcinoma or decompensated cirrhosis is not known.

  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, treatment should be administered at least until HBeAg seroconversion (HBeAg and HBV DNA loss with HBeAb detection on 2 consecutive serum samples at least 3 months apart) or until HBsAg seroconversion or in case of evidence of loss of efficacy.

  In HBeAg negative (pre-core mutant) patients, treatment should be administered at least until HBsAg seroconversion or in case of evidence of loss of efficacy.

  In patients with decompensated liver disease or cirrhosis, treatment cessation is not recommended.

  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.

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

  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. 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.

  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. No dosing interval recommendations are available for other dialysis patients (e.g. ambulatory peritoneal dialysis patients) or nonhaemodialysed patients with creatinine clearance less than 10 ml/min.

  Hepatic impairment: No dose adjustment is required in patients with hepatic impairment.

  Clinical resistance: Lamivudinerefractory patients and patients harbouring HBV with evidence of resistance to lamivudine (mutations at rtL180M, rtA181T and/or rtM204I/V) should not be treated with adefovir dipivoxil monotherapy in order to reduce the risk of resistance to adefovir. Adefovir may be used in combination with lamivudine in lamivudinerefractory patients and in patients harbouring HBV with mutations at rtL180M and/or rtM204I/V. However, for patients harbouring HBV that contains the rtA181T mutation, consideration should be given to alternative treatment regimens due to the risk of reduced susceptibility to adefovir.

  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.

• Child Dosage
  The safety and efficacy of Hepsera in patients under the age of 18 years have not been established. Hepsera should not be administered to children or adolescents.
• Elderly Dosage
  No data are available to support a dose recommendation for patients over the age of 65 years (See Special Precautions).
• Contra Indications
  

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

• Special Precautions
  

  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, 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. 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. 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). Coadministration of 10 mg adefovir dipivoxil with medicinal products in these patients may lead to an increase in serum concentrations of either adefovir or a coadministered 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 posttransplantation with lamivudine-resistant HBV.

  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. 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 posttreatment 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.

  Coinfection with hepatitis C or D: There are no data on the efficacy of adefovir dipivoxil in patients coinfected with hepatitis C or hepatitis D.

  Coinfection with HIV: Limited data are available on the safety and efficacy of 10 mg adefovir dipivoxil in patients with chronic hepatitis B, coinfected 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 crossresistance to other antiviral medicinal products.

  As far as possible, treatment of hepatitis B by adefovir dipivoxil in an HIV coinfected 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 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 glucosegalactose malabsorption should not take this medicinal product.

• Interactions
  

  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 livertransplant 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.

  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. Coadministration 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 coadministered medicinal product.

  No data on the concomitant use with other medicinal products (including interferon) are available

• Adverse Drug Reactions
  

  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 placebocontrolled 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 postliver 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. 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).

  Nervous system disorders:

  Common ( 1/100, < 1/10): headache.

  Gastrointestinal disorders:

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

  Frequency not known: pancreatitis.

  Skin and subcutaneous tissue disorders:

  Common ( 1/100, < 1/10): rash, pruritus.

  Musculoskeletal and connective tissue disorders:

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

  Renal and urinary disorders:

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

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

  Frequency not known: Fanconi syndrome, proximal renal tubulopathy.

  General disorders and administration site conditions:

  Very common ( 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. 

  Longterm safety data in patients with compensated disease:

  In a longterm 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 longterm 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:

  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.