Adefovir

Uses

Adefovir is used for the treatment of chronic hepatitis B in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease.

Adefovir is also used to associated treatment for these conditions: Hepatitis B Chronic Infection

How Adefovir works

Adefovir dipivoxil is a prodrug of adefovir. Adefovir is an acyclic nucleotide analog of adenosine monophosphate which is phosphorylated to the active metabolite adefovir diphosphate by cellular kinases. Adefovir diphosphate inhibits HBV DNA polymerase (reverse transcriptase) by competing with the natural substrate deoxyadenosine triphosphate and by causing DNA chain termination after its incorporation into viral DNA. The inhibition constant (Ki) for adefovir diphosphate for HBV DNA polymerase was 0.1 μM. Adefovir diphosphate is a weak inhibitor of human DNA polymerases α and γ with Ki values of 1.18 μM and 0.97μM, respectively.

Dosage

Adefovir dosage

The recommended dose of Adefovir for the treatment of chronic hepatitis B in adolescent & adults (age ≥ 12 year) with adequate renal function is 10 mg, once daily, taken orally, without regard to food

Dose Adjustment in Renal Impairment: Significantly increased drug exposures are seen when Adefovir is administered to patients with renal impairment. Therefore, the dosing interval of Adefovir should be adjusted in patients with baseline creatinine clearance < 50 mL/min using the following suggested guidelines-

Dosing interval adjustment of Adefovir in patients with renal impairment

Creatinine clearance(mL/min)

> 50

20 to 49

10 to 19

< 10 Hemodialysis or CAPD

Recommended dose and dosing interval

10 mg every 24 hours

10 mg every 48 hours

10 mg every 72 hours

10 mg every 7 days

Side Effects

Treatment-related clinical adverse events that occurred in 3% or greater of Adefovir-treated patients compared with placebo are asthenia, headache, abdominal pain, nausea, flatulence, diarrhea, dyspepsia.

Toxicity

Renal tubular nephropathy characterized by histological alterations and/or increases in BUN and serum creatinine was the primary dose-limiting toxicity associated with administration of adefovir dipivoxil in animals. Nephrotoxicity was observed in animals at systemic exposures approximately 3–10 times higher than those in humans at the recommended therapeutic dose of 10 mg/day.

Precaution

Severe acute exacerbation of hepatitis has been reported in patients who have discontinued anti-hepatitis B therapy, including therapy with Adefovir. Patients who discontinue Adefovir should be monitored at repeated intervals over a period of time for hepatic function. If appropriate, resumption of anti-hepatitis B therapy may be warranted.

Chronic administration of Adefovir (10 mg once daily) may result in nephrotoxicity. The overall risk of nephrotoxicity in patients with adequate renal function is low.

However, this is of special importance in patients at risk of or having underlying renal dysfunction and patients taking concomitant nephrotoxic agents such as cyclosporine, tacrolimus, aminoglycosides, vancomycin and non-steroidal anti-inflammatory drugs.

Interaction

The pharmacokinetics of adefovir was unchanged when adefovir dipivoxil was coadministered with lamivudine, trimethoprim/ sulfamethoxazole and acetaminophen. When adefovir dipivoxil was co-administered with ibuprofen (800 mg three times daily), increases in adefovir Cmax (33%), AUC (23%) and urinary recovery were observed due to higher oral bioavailability of adefovir.

Food Interaction

• Take with or without food. The absorption is unaffected by food.

Volume of Distribution

• 392 ± 75 mL/kg [Vd at steady state, intravenous administration of 1.0 mg/kg/day]
• 352 ± 9 mL/kg [Vd at steady state, intravenous administration of 3.0 mg/kg/day]

Elimination Route

The approximate oral bioavailability of adefovir from HEPSERA is 59%. When a single oral 10 mg dose is given to chronic hepatitis B patients, the peak plasma concentration (Cmax) of adefovir was 18.4 ± 6.26 ng/mL. This occurred between 0.58 - 4 hours post dose (Tmax). The adefovir area under the plasma concentration-time curve (AUC0–∞) was 220 ± 70.0 ng∙h/mL. Food does not affect the exposure of adeforvir.

Half Life

Plasma adefovir concentrations declined in a biexponential manner with a terminal elimination half-life of 7.48 ± 1.65 hours.

Clearance

• 469 ± 99.0 mL/min [Patients with Unimpaired renal Function receiving a 10 mg single dose]
• 356 ± 85.6 mL/min [Patients with mild renal impairement receiving a 10 mg single dose]
• 237 ± 118 mL/min [Patients with moderate renal impairement receiving a 10 mg single dose]
• 91.7 ± 51.3 mL/min [Patients with severe renal impairement receiving a 10 mg single dose]

Elimination Route

Adefovir is renally excreted by a combination of glomerular filtration and active tubular secretion.

Pregnancy & Breastfeeding use

Pregnancy: There are no adequate and well-controlled studies in pregnant women. Therfore, Adefovir should be used during pregnancy only if clearly needed and after careful consideration of the risks and benefits.

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.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

In general, caution should be exercised when prescribing to elderly patients since they have greater frequency of decreased renal or cardiac function due to concomitant disease or other drug therapy.

Contraindication

Adefovir dipivoxil is contraindicated in patients with previously demonstrated hypersensitivity to any of the components of the product.

Special Warning

Pediatric use: Safety and effectiveness in pediatric patients have not been established.

Geriatric use: In general, caution should be exercised when prescribing to elderly patients since they have greater frequency of decreased renal or cardiac function due to concomitant disease or other drug therapy.

Dose Adjustment in Renal Impairment: the dosing interval of Adefovir should be adjusted in patients with baseline creatinine clearance <50 ml/min using the following suggested guidelines:

• CrCl ≤ 50 ml/min: 10 mg
• CrCl 20-49 ml/min: 10 mg every 48 hours
• CrCl 10-19 ml/min: 10 mg every 72 hours
• Haemodialysis patients: 10 mg every 7 days following dialysis

Acute Overdose

If overdose occurs the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary.

Storage Condition

Store at cool and dry place. Protect from light and moisture. Keep all the medicines out of the reach of children.

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