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Medicine information : HEPSERA 10 mg tablets
| Drug class description : | Antiviral for systemic use |
| Generic Name : | Adefovir Dipivoxil |
| Drug description : | Tablet. White to off-white, round, flat-faced, bevelled-edge tablets, debossed with “GILEAD” and “10” on one side and a stylised shape of a liver on the other side. |
| Presentation : | Each tablet contains 10 mg adefovir dipivoxil equivalent to 5.45 mg adefovir. |
| 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 : | Posology and method of administration 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 long-term 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 (See Special Precautions). 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 (See Special Precautions). In patients with decompensated liver disease or cirrhosis, treatment cessation is not recommended (See Special Precautions). Renal insufficiency: Adefovir is eliminated by renal excretion, therefore adjustments of the dosing interval are required in patients with a creatinine clearance < 50 ml/min, as detailed below. The recommended dosing frequency according to renal function must not be exceeded (See Special Precautions). 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. The safety and effectiveness of these dosing interval adjustment guidelines have not been clinically evaluated. Therefore, clinical response to treatment and renal function should be closely monitored in these patients (See Special Precautions). Recommended Dosing Interval: Creatinine Clearance (ml/min)*: 20-49 - Every 48 hours. 10-19 - Every 72 hours. Haemodialysis Patients: Every 7 days following dialysis** * Calculated using ideal body weight ** After 12 hours cumulative dialysis or three dialysis sessions, each of four hours duration No dosing recommendations are available for non-haemodialysed patients with creatinine clearance < 10 ml/min. Hepatic impairment: No dose adjustment is required in patients with hepatic impairment. |
| 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: 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. Adefovir is excreted renally, by a combination of glomerular filtration and active tubular secretion, therefore adjustments to the dosing interval of 10 mg adefovir dipivoxil are recommended in patients with creatinine clearance < 50 ml/min (See Adult Dosage). Apart from ibuprofen, lamivudine, paracetamol and trimethoprim/sulfamethoxazole, 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 (e.g. 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 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 coadministration of adefovir dipivoxil and tenofovir disoproxil fumarate is unknown. Such co-administration is only advisable if the patient is closely monitored. 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 Interactions). Patients with normal renal function should be monitored for changes in serum creatinine every 3 months and creatinine clearance calculated. Caution is advised in patients with creatinine clearance < 50 ml/min and in patients receiving medicinal products that may effect renal function. The renal function of these patients should be closely monitored with a frequency tailored to the individual patient’s medical condition. Patients with creatinine clearance below 10 ml/min have not been studied (See Adult Dosage). These patients should be closely monitored for possible adverse reactions and to ensure efficacy is maintained. Patients with ESRD managed with other forms of dialysis such as ambulatory peritoneal dialysis have not been studied. 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 Adverse Reactions). Patients with cirrhosis may be at a higher risk for hepatic decompensation following hepatitis exacerbation, and therefore should be monitored closely during therapy. 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 treated with 10 mg adefovir dipivoxil were not accompanied by clinical and laboratory changes associated with liver decompensation. Although most events appear to have been self-limiting or resolved with re-initiation of treatment, severe hepatitis flares, including fatalities, have been reported in some cases. The relationship of exacerbation of hepatitis to discontinuation of adefovir dipivoxil is unknown. 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. In patients with decompensated liver disease or cirrhosis, treatment cessation is not recommended. 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. 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. |
| Interactions : | 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. Concomitant administration of 10 mg adefovir dipivoxil and 100 mg lamivudine did not alter the pharmacokinetic profile of either medicinal product. Adefovir did not alter the pharmacokinetics of trimethoprim/sulfamethoxazole, paracetamol, ibuprofen and tenofovir disoproxil fumarate, four 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 Special Precautions). Concomitant administration of 10 mg adefovir dipivoxil and 800 mg ibuprofen 3 times daily resulted in increases in AUC and Cmax 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. Adefovir is excreted renally, by a combination of glomerular filtration and active tubular secretion. Apart from ibuprofen, lamivudine, paracetamol, trimethoprim/sulfamethoxazole and tenofovir disoproxil fumarate 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. 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 Special Precautions). 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. No data on the concomitant use with other medicinal products (including interferon) are available. Pregnancy and lactation Pregnancy: There are no adequate data on the use of adefovir dipivoxil in pregnant women. Studies in animals administered adefovir intravenously have shown reproductive toxicity. Studies in orally dosed animals do not indicate teratogenic or foetotoxic effects. 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. Given that the potential risks to developing human foetuses are unknown, it is recommended that women of child-bearing potential treated with adefovir dipivoxil use effective contraception. Lactation: It is not known whether adefovir is excreted in human milk. Mothers should be instructed not to breast-feed if they are taking adefovir dipivoxil tablets. |
| Adverse Reactions : | Experience in patients with compensated liver disease: Assessment of adverse reactions is based on 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. With extended therapy 492 of these 522 patients were treated with 10 mg adefovir dipivoxil for up to 109 weeks, with a median duration of treatment of 49 weeks. The adverse reactions considered at least possibly related to treatment in the first 48 weeks of treatment are listed below, by body system organ class, and absolute frequency. Frequencies are defined as very common (> 1/10) or common (> 1/100, < 1/10). Gastrointestinal: Common (> 1/100, < 1/10): nausea, flatulence, diarrhoea, dyspepsia. Body as a whole: Very common (> 1/10): asthenia. Common (> 1/100, < 1/10): abdominal pain, headache. There was no clinically relevant difference in laboratory abnormalities observed in these studies in the 10 mg adefovir dipivoxil and placebo-treated groups with the exception of hepatic transaminase elevations, which occurred more frequently in the placebo-treated group. With extended treatment, mild to moderate increases in serum creatinine were observed uncommonly (< 1/100) in patients with chronic hepatitis B and compensated liver disease treated with 10 mg adefovir dipivoxil for a median of 49 weeks and a maximum of 109 weeks. These increases in serum creatinine resolved, one with continuation of adefovir dipivoxil therapy and one following discontinuation of therapy. Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of treatment with 10 mg adefovir dipivoxil (See Special Precautions). Experience in patients pre- and post-transplantation with lamivudine-resistant HBV: Pre- (n=128) and post-liver transplantation patients (n=196) with chronic hepatitis B and lamivudine-resistant HBV were treated in an open-label study with 10 mg adefovir dipivoxil once daily, for up to 129 weeks,with a median time on treatment of 19 and 56 weeks, respectively. The adverse reactions considered at least possibly related to treatment are listed below, by body system organ class, and absolute frequency. Frequencies are defined as very common (> 1/10) or common (> 1/100, < 1/10). Gastrointestinal: Common (> 1/100, < 1/10): nausea, flatulence, diarrhoea, dyspepsia. Body as a whole: Common (> 1/100, < 1/10): asthenia, abdominal pain, headache. Urogenital system: Very common (> 1/10): increases in creatinine. Common (> 1/100, < 1/10): renal insufficiency and renal failure. Changes in serum creatinine were observed very commonly. These changes were seen in patients with multiple risk factors for changes in renal function, including concomitant use of cyclosporin and tacrolimus, and were generally mild to moderate in severity, although some cases of renal failure have been reported. Experience post-marketing: In addition to adverse drug reaction reports from clinical trials the following possible adverse reactions have also been identified during post-approval use of adefovir dipivoxil. Skin and subcutaneous tissue disorders: Rash, pruritus. |
| Manufacturer : | Gilead Sciences International |
| Drug Availability : | (POM) |
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