Overview
Adefovir dipivoxil was developed by Antonín Holý at the Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic. Gilead Sciences formulated the drug for human immunodeficiency virus (HIV). In November 1999, U.S. Food and Drug Administration (FDA) was advised by an expert panel not to approve the drug of the severity of kidney toxicity above 60 or 120-milligram dose.
Following the advice, the FDA refused to approve Adefovir as a treatment for human immunodeficiency virus (HIV). Therefore, its development was discontinued in December 1999 for HIV patients, but it continued for hepatitis B virus (HBV), which is effective with a much lower dose of 10 milligrams. On September 20, 2002, the FDA approved its treatment for hepatitis B. In March 2003, Adefovir was approved for the treatment of hepatitis B in the European Union.
Adefovir is an orally administered nucleotide analog reverse-transcriptase inhibitor. This medication is a nucleotide analog. When formulated with Pivoxil prodrug, it is known as Adefovir dipivoxil. This medication helps to treat a chronic viral infection of the liver, like hepatitis B, in individuals twelve years of age and older. It reduces the virus's growth and helps lower the amount of virus in the body. However, Adefovir dipivoxil does not cure hepatitis B or prevent the spread of hepatitis infection to others.
Indications of Adefovir Dipivoxil:
It is indicated for treating chronic viral liver infection (hepatitis B) in people 12 years and older.
Precautions
The patient must not miss any dose of this medication or run out of Adefovir dipivoxil.The medication must not be discontinued without consulting the doctor because when Adefovir is stopped, it might worsen hepatitis. This usually occurs during the first three months after Adefovir is stopped.
Medical History:
The doctor must be informed if the patient has or has ever had a liver disease apart from hepatitis B or cirrhosis (scarring of the liver). The doctor must be informed immediately in case of the following symptoms:
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Extreme tiredness.
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Weakness.
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Vomiting.
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Loss of appetite.
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Yellowing of the skin or eyes.
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Light-colored bowel movements.
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Muscle or joint pain.
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Dark-colored urine.
Adefovir can cause kidney damage. Hence, the doctor must be informed if the patient has or has ever had kidney disease, diabetes, or high blood pressure.
Drug History:
The doctor must be informed if the patient is taking or has ever taken any of the following medications:
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Aminoglycoside antibiotics like Gentamicin, Kanamycin, Amikacin, Streptomycin, Neomycin, and Tobramycin.
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Nonsteroidal anti-inflammatory drugs (NSAIDs) like Aspirin, Ibuprofen, and Naproxen.
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Cyclosporine.
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Tacrolimus.
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Vancomycin.
Consult the doctor immediately in case of the following symptoms:
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Confusion.
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Decreased urination.
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Swelling of the hands, feet, ankles, or lower legs.
Before Adefovir dipivoxil is administered, the doctor or pharmacist must be informed if the patient is allergic to it or have any other allergies.
The product may contain inactive ingredients, which can cause allergic reactions or other problems. These problems must be discussed with the pharmacist.
The doctor must be informed about the medical history before starting this medication, including HIV infection, liver transplant, and kidney problems.
During pregnancy, this medication must be used only when needed necessarily. Discuss the risks and benefits with the doctor.
For Patients:
How Is Adefovir Dipivoxil Used?
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Adefovir dipivoxil is administered by mouth with or without food as directed by the doctor, usually once a day.
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The dosage is based on the response to treatment and the medical condition of the patient.
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The medication must be used regularly to get the most benefit from it. To help the patient remember, take it at the same time each day.
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Do not alter or stop the dose or medication unless directed by the doctor or pharmacist. Refill your medication before it runs out.
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If both hepatitis B and human immunodeficiency virus (HIV) is present, treatment with Adefovir alone is not adequate.
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A human immunodeficiency virus (HIV) test is advised before and during treatment to ensure appropriate treatment.
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A doctor or pharmacist must consult the doctor for any other essential information.
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Reduced response to the treatment, worsening of the condition, and infection by resistant strains of the virus may occur during or after treatment.
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Tell the doctor immediately if any new symptoms are noticed during or after the treatment.
What Are the Side Effects of Adefovir Dipivoxil?
The side effects of Adefovir dipivoxil include
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Weakness.
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Headache.
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Fever.
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Increased cough.
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Nausea.
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Vomiting.
If any of these side effects worsen, the doctor must be informed. Therefore, this medication is prescribed after the doctor has calculated the benefits and the risk of side effects.
Many people using this medication do not show serious side effects.
The doctor must be informed immediately if the patient has any serious side effects, like changes in the amount of urine (kidney problems). However, a severe allergic reaction to this drug is rare.
However, medical help must be taken immediately. If there are symptoms of a serious allergic reaction, including
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Rash.
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Itching or swelling involving the face, tongue, or throat).
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Severe dizziness.
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Trouble breathing.
Interactions
Drug interactions can alter the action of the medication and increase the risk of severe side effects. The drug must not be started or discontinued without consulting the doctor. Some products that can interact with this drug include
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Cidofovir.
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Nonsteroidal anti-inflammatory drugs like Ibuprofen.
What Shoud Be Done in Case of an Overdose?
In case of an overdose or certain serious symptoms like trouble breathing or fainting, the poison control cell should be contacted immediately. This medication should not be shared with others.
Medical or laboratory tests like kidney function, liver function tests, and human immunodeficiency virus tests may be done while this medication is administered.
What Should Be Done Is a Dose Is Missed?
If they miss a dose, it must be taken as soon as the patient remembers. If it is time for the next dose missed dose can be skipped. However, the next dose must be taken on the routine time and should not be doubled to compensate for a missed dose.
How Is Adefovir Dipivoxil Stored?
The original container must be stored at room temperature, away from moisture and light.
All medications must be kept away from children and pets. The medication must be properly discarded when it's expired or not needed. Consult the pharmacist or local waste disposal company. The medications must not be flushed down the toilet or into a drain.
For Doctors:
Indications:
Adefovir dipivoxil is indicated for treating chronic hepatitis B in adult patients with active viral replication and elevations in serum aminotransferases (ALT or AST) or another histologically active disease.
The indication is based on virological, histological, serological, and biochemical responses in adult patients with
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Clinical evidence of Lamivudine-resistant hepatitis B virus.
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HBe Ag+ and HBe Ag- chronic hepatitis B with compensated liver function in adult patients.
Dosage and Administration:
The recommended dose of Adefovir dipivoxil in chronic hepatitis B patients with normal renal function is 10 milligrams (oral) once a day, without regard to food. The ideal duration of treatment is still unknown.
Dose Adjustment in Renal Impairment:
When Adefovir dipivoxil was administered to patients with renal impairment, a significant increase in drug exposure was observed. Therefore, the dosage interval of Adefovir dipivoxil must be adjusted according to the baseline creatinine clearance in patients.
Mechanism of Action
Adefovir is an acyclic analog of adenosine monophosphate phosphorylated to the active metabolite Adefovir diphosphate by cellular kinases. Adefovir diphosphate stops hepatitis B virus (HBV) DNA (deoxyribonucleic acid) polymerase by contending with the natural substrate (deoxyadenosine triphosphate) that leads to DNA chain termination after it is incorporated into a viral DNA.
Pharmacology
Pharmacokinetics:
Absorption: Adefovir dipivoxil is regarded as a diester prodrug of the active Adefovir. The oral bioavailability of Adefovir is approximately 59 percent.
Peak Adefovir Plasma Concentration (Cmax): 18.4 ± 6.26 ng/mL.
Effects of Food on Oral Absorption: Adefovir exposure remains unaffected with a 10-milligram single dose with food (an approximately 1000 kcal high-fat meal).
Distribution: In vitro binding of Adefovir to human plasma or human serum proteins is less than or equal to four percent over the Adefovir concentration of 0.1 to 25 µg/mL.
The distribution volume at a steady state after intravenous administration is
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1.0 mg/kg/day: 392 ± 75 mL/kg.
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3.0 mg/kg/day: 352 ± 9 mL/kg.
Metabolism and Elimination: Adefovir dipivoxil is converted to Adefovir after oral administration.
Special Populations:
Gender: The pharmacokinetics of Adefovir is similar in female and male patients.
Race: The pharmacokinetics of Adefovir is comparable in Caucasians and Asians. Pharmacokinetic data are unavailable for other racial groups.
Pediatric and Geriatric Patients: Pharmacokinetic studies have not been performed in children or the elderly.
Clinical Trials on Lamivudine Resistance:
A double-blind, active-controlled study was conducted on 59 chronic hepatitis B patients with evidence of Lamivudine-resistant hepatitis B virus. These patients were randomly given either Adefovir monotherapy or Adefovir in combination with Lamivudine 100 milligrams or Lamivudine 100 milligrams alone. A mean decrease in serum HBV DNA of 0.31 ± 0.93 log10 copies/mL was reported in patients who received Lamivudine alone.
Alanine transaminase (ALT) was reported to be normal in the following situations:
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Patients treated with Adefovir: 47 percent.
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Patients treated with Adefovir in combination with Lamivudine: 53 percent.
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Patients treated with Lamivudine alone: 5 percent.
Contraindications:
Adefovir is contraindicated in patients with a history of hypersensitivity to any of the product's ingredients.
Warnings:
1) Exacerbations of Hepatitis after Discontinuation of Treatment: Severe acute exacerbation of hepatitis has been documented in patients who have stopped anti-hepatitis B therapy, including Adefovir therapy. Hepatic function tests must be performed at regular intervals with proper follow-up for at least several months in patients who discontinue Adefovir.
The clinical trials have shown Adefovir exacerbations of hepatitis with ALT elevations around ten times or greater than the normal upper limit in 25 percent of patients after Adefovir was discontinued. However, patients with cirrhosis or advanced liver disease are at a higher risk for hepatic deterioration. Most cases are usually self-limiting and resolved by starting the treatment again. However, in severe hepatitis exacerbations, fatalities have also been reported. Hence, the patients must be monitored after the discontinuation of the treatment.
2) Nephrotoxicity: Nephrotoxicity leads to a delayed onset of a gradual increase in serum creatinine and a decrease in serum phosphorus. Chronic administration of Adefovir dipivoxil (10 mg once a day) may cause delayed nephrotoxicity. The universal risk of nephrotoxicity is usually low in patients with adequate renal function. However, this is of immense significance in patients at risk of or with underlying renal dysfunction and receiving nephrotoxic agents like Cyclosporine, Tacrolimus, Aminoglycosides, Vancomycin, and non-steroidal anti-inflammatory drugs (NSAIDs). Nephrotoxicity has previously been documented as treatment-limiting toxicity of Adefovir dipivoxil at higher doses. For instance,
- In HIV-infected patients - 60 and 120 mg daily.
- In chronic hepatitis B patients - 30 mg daily.
All patients' renal function must be monitored during treatment with Adefovir dipivoxil. The risks and benefits of Adefovir dipivoxil treatment must be evaluated carefully before it is discontinued in treating-emergent nephrotoxicity.
3) HIV Resistance Before Starting Adefovir Dipivoxil Therapy: HIV antibody testing must be done before initiating Adefovir therapy in all patients. Treatment with anti-hepatitis B therapies that show activity against HIV in patients with a chronic hepatitis B infection and an untreated or unrecognized HIV infection may cause the emergence of HIV resistance.
4) Others: The following problems may also be reported in patients with the use of nucleoside analogs alone or in combination with antiretrovirals:
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Lactic acidosis.
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Severe hepatomegaly.
These cases are mainly reported in women. Risk factors include
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Obesity.
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Prolonged nucleoside exposure.
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Liver disease.
Treatment with Adefovir dipivoxil must be discontinued immediately in patients in any patient who show clinical or laboratory findings related to lactic acidosis or pronounced hepatotoxicity, including hepatomegaly and steatosis, even in the absence of marked transaminase elevations.
Overdosage:
The following dosage of Adefovir dipivoxil is associated with gastrointestinal side effects:
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Five hundred milligrams daily for two weeks.
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Two hundred fifty milligrams daily for 12 weeks.
In the case of an overdose, the patient must be monitored for toxicity, and standard supportive treatment must be given. For a ten-milligram dose of Adefovir dipivoxil, a four-hour hemodialysis session helps remove around 35 percent of the Adefovir dose.
Drug Interactions:
The effects of co-administration of Adefovir dipivoxil with the following drugs have only been evaluated.
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Lamivudine.
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Trimethoprim or Sulfamethoxazole.
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Tenofovir disoproxil fumarate.
Since Adefovir dipivoxil is eliminated by the kidneys if it is co-administered with other drugs that compete for active tubular secretion or decrease renal function might increase their serum concentrations. Eight hundred milligrams of Ibuprofen thrice daily increases Adefovir exposure by around 23 percent.
