Chemical formula: C₈H₁₂N₅O₄P Molecular mass: 501.471 g/mol PubChem compound: 60871
Adefovir dipivoxil interacts in the following cases:
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.
It is recommended to administer adefovir dipivoxil (10 mg) 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.
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 (10 mg) may be administered every 72 hours; for haemodialysis patients, adefovir dipivoxil (10 mg) 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 non-haemodialysed patients with creatinine clearance less than 10 ml/min.
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.
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.
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.
Adefovir dipivoxil should not be administered concurrently with tenofovir disoproxil fumarate.
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.
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.
The use of adefovir dipivoxil must be accompanied by the use of effective contraception.
There are limited 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 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.
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.
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.
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.
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%).
Assessment of adverse reactions is based on experience from post-marketing surveillance and from three pivotal clinical studies in patients with chronic hepatitis B:
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).
Summary of adverse reactions associated with adefovir dipivoxil based on clinical study and post-marketing experience:
Common: Headache
Common: Diarrhoea, vomiting, abdominal pain, dyspepsia, nausea, flatulence
Not known: Pancreatitis
Common: Rash, pruritus
Not known: Osteomalacia (manifested as bone pain and infrequently contributing to fractures) and myopathy, both associated with proximal renal tubulopathy
Very common: Increases in creatinine
Common: Renal failure, abnormal renal function, hypophosphatemia
Not known: Fanconi syndrome, proximal renal tubulopathy
Very common: Asthenia
Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of treatment with 10 mg adefovir dipivoxil.
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.
Based on post-marketing data, long-term treatment with adefovir dipivoxil may lead to progressive alteration of renal function resulting in renal impairment.
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.
Because of insufficient data on safety and efficacy, adefovir dipivoxil should not be used in children under the age of 18 years.
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