Adefovir Dipivoxil

Name: Adefovir Dipivoxil

Adefovir Dipivoxil Dosage and Administration


Chronic Hepatitis B

The recommended dose of Adefovir Dipivoxil Tablets in chronic hepatitis B patients for patients 12 years of age and older with adequate renal function is 10 mg, once daily, taken orally, without regard to food. The optimal duration of treatment is unknown.

Adefovir Dipivoxil Tablets is not recommended for use in children less than 12 years of age.

Dose adjustment in Renal Impairment

Significantly increased drug exposures were seen when Adefovir Dipivoxil Tablets was administered to adult patients with renal impairment [See Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)]. Therefore, the dosing interval of Adefovir Dipivoxil Tablets should be adjusted in adult patients with baseline creatinine clearance less than 50 mL per minute using the following suggested guidelines (see Table 1). The safety and effectiveness of these dosing interval adjustment guidelines have not been clinically evaluated.

Additionally, it is important to note that these guidelines were derived from data in patients with pre-existing renal impairment at baseline. They may not be appropriate for patients in whom renal insufficiency evolves during treatment with Adefovir Dipivoxil Tablets. Therefore, clinical response to treatment and renal function should be closely monitored in these patients.

Table 1  Dosing Interval Adjustment of Adefovir Dipivoxil Tablets in Adult Patients with Renal Impairment

* Creatinine clearance calculated by Cockcroft-Gault method using lean or ideal body weight.
Creatinine Clearance (mL/min)* Hemodialysis Patients
Greater than or equal to 50 30 to 49 10 to 29
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 following dialysis

The pharmacokinetics of adefovir have not been evaluated in non-hemodialysis patients with creatinine clearance less than 10 mL per minute; therefore, no dosing recommendation is available for these patients.

No clinical data are available to make dosing recommendations in adolescent patients with renal insufficiency [See Warnings and Precautions (5.2)]

Adefovir Dipivoxil Description

Adefovir Dipivoxil is a diester prodrug of adefovir. Adefovir is an acyclic nucleotide analog with activity against human hepatitis B virus (HBV).

The chemical name of Adefovir Dipivoxil is 9-[2-[[bis[(pivaloyloxy)methoxy]-phosphinyl]-methoxy]ethyl]adenine. It has a molecular formula of C20H32N5O8P, a molecular weight of 501.48 and the following structural formula:

Adefovir Dipivoxil is a white to off-white powder with an aqueous solubility of 19 mg/mL at pH 2.0 and 0.4 mg/mL at pH 7.2. It has an octanol/aqueous phosphate buffer (pH 7) partition coefficient (log p) of 1.91.

Adefovir Dipivoxil Tablets are for oral administration. Each tablet contains 10 mg of Adefovir Dipivoxil and the following inactive ingredients: copovidone, anhydrous lactose, microcrystalline cellulose, silicon dioxide, crospovidone and magnesium stearate.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term oral carcinogenicity studies of Adefovir Dipivoxil in mice and rats were carried out at exposures up to approximately 10 times (mice) and 4 times (rats) those observed in humans at the therapeutic dose for HBV infection. In both mouse and rat studies, Adefovir Dipivoxil was negative for carcinogenic findings. Adefovir Dipivoxil was mutagenic in the in vitro mouse lymphoma cell assay (with or without metabolic activation). Adefovir induced chromosomal aberrations in the in vitro human peripheral blood lymphocyte assay without metabolic activation. Adefovir Dipivoxil was not clastogenic in the in vivo mouse micronucleus assay and adefovir was not mutagenic in the Ames bacterial reverse mutation assay using S. typhimurium and E. coli strains in the presence or absence of metabolic activation. In reproductive toxicology studies, no evidence of impaired fertility was seen in male or female rats at systemic exposure approximately 19 times that achieved in humans at the therapeutic dose.

Animal Toxicology and/or Pharmacology

Toxicology Studies

Animal reproduction studies were conducted in rats and rabbits with orally administered Adefovir Dipivoxil and intravenously administered adefovir.

In rats and rabbits, no embryotoxicity or teratogenicity was shown from oral administration of Adefovir Dipivoxil at maternal doses producing systemic exposures approximately 23 times (rats) and 40 times (rabbits) that achieved in humans at the therapeutic dose of 10 mg/day.

When pregnant rats were administered intravenous adefovir at maternally toxic doses associated with systemic exposure 38 times that in humans, embryotoxicity and an increased incidence of fetal malformations (anasarca, depressed eye bulge, umbilical hernia, and kinked tail) were observed. No adverse effects on development were seen with intravenous adefovir administered to pregnant rats at a systemic exposure 12 times that in humans.

Animal Toxicology Studies

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 to 10 times higher than those in humans at the recommended therapeutic dose of 10 mg/day.

How supplied / storage and handling

Adefovir Dipivoxil is available as tablets. Each tablet contains 10 mg of Adefovir Dipivoxil. The tablets are white are to off-white, round, flat faced beveled edged tablets, debossed "∑ 3" on one side and plain on the other side. They are packaged as follows: Bottles of 30 tablets (NDC 42794-003-08) containing polyester and desiccant and closed with a child-resistant closure.

Store in original container at 25 °C (77 °F), excursions permitted to 15° to 30 °C (59° to 86 °F) (see USP Controlled Room Temperature).

Do not use if seal over bottle opening is broken or missing.

FDA-Approved Patient Labeling

PATIENT INFORMATION

Adefovir Dipivoxil (a-DEF-oh-vir dip-ih-VOX-il) TABLETS

Read this information carefully before you start taking Adefovir Dipivoxil Tablets. Read and check for new information each time you get more Adefovir Dipivoxil Tablets. This information does not take the place of talking with your doctor about your medical condition or your treatment.

What is the most important information I should know about Adefovir Dipivoxil Tablets?

  1. Some people who stop taking Adefovir Dipivoxil get a very serious hepatitis. This usually happens within 12 weeks after stopping. You will need to have regular blood tests to check for liver function and hepatitis B virus levels if you stop taking Adefovir Dipivoxil Tablets
  2. Adefovir Dipivoxil Tablets may cause a severe kidney problem called nephrotoxicity. It usually happens in people that already have a kidney problem, but it can happen to anyone that uses Adefovir Dipivoxil Tablets. You will need to have regular blood tests to check for kidney function while you are taking Adefovir Dipivoxil Tablets.
  3. If you get or have HIV that isn't being treated with medicines, Adefovir Dipivoxil Tablets may increase the chances your HIV infection cannot be helped with usual HIV medicines. This can happen if you get or have HIV and don't know it, or if your HIV is not being treated while you are taking Adefovir Dipivoxil Tablets. You should get an HIV test before you start taking Adefovir Dipivoxil Tablets and anytime after that when there's a chance you were exposed to HIV.
  4. Some people who have taken medicines like Adefovir Dipivoxil Tablets that are called nucleoside or nucleotide analogs have developed a serious condition called lactic acidosis (build up of an acid in the blood). Lactic acidosis is a medical emergency and must be treated in the hospital. Call your doctor right away if you get any of the following signs of lactic acidosis:
    • You feel very weak or tired.
    • You have unusual (not normal) muscle pain.
    • You have trouble breathing.
    • You have stomach pain with nausea and vomiting.
    • You feel cold, especially in your arms and legs.
    • You feel dizzy or lightheaded.
    • You have a fast or irregular heartbeat.

Some people who have taken medicines like Adefovir Dipivoxil Tablets have developed serious liver problems called hepatotoxicity, with liver enlargement (hepatomegaly) and fat in the liver (steatosis). Call your doctor right away if you get any of the following signs of liver problems.

  • Your skin or the white part of your eyes turns yellow (jaundice).
  • Your urine turns dark.
  • Your bowel movements (stools) turn light in color.
  • You don't feel like eating food for several days or longer.
  • You feel sick to your stomach (nausea).
  • You have lower stomach pain.

You may be more likely to get lactic acidosis or serious liver problems if you are very overweight (obese) or have been taking nucleoside analog medicines [ATRIPLA® (efavirenz plus emtricitabine plus tenofovir disoproxil fumarate)], COMPLERA® (emtricitabine plus rilpivirine plus tenofovir disoproxil fumarate), Combivir (zidovudine plus lamivudine), EMTRIVA® (emtricitabine), Epivir, Epivir-HBV (lamivudine), Epzicom (abacavir plus lamivudine) Hivid (zalcitabine), Retrovir (zidovudine), STRIBILD™ (elvitegravir plus cobicistat plus emtricitabine plus tenofovir disoproxil fumarate), Trizivir (zidovudine plus lamivudine plus abacavir), TRUVADA® (emtricitabine plus tenofovir disoproxil fumarate), Videx (didanosine), VIREAD® (tenofovir disoproxil fumarate), Zerit (stavudine), and Ziagen (abacavir)] for long time.

What are Adefovir Dipivoxil Tablets?

Adefovir Dipivoxil Tablets is a medicine used to treat patients at least 12 years of age with continuing (chronic) infections with active hepatitis B virus. Adefovir Dipivoxil Tablets has not been studied in adults over the age of 65 and is not recommended for use in children less than 12 years of age.

  • Adefovir Dipivoxil Tablets will not cure your chronic hepatitis B.
  • Adefovir Dipivoxil Tablets may help lower the amount of hepatitis B virus in your body.
  • Adefovir Dipivoxil Tablets may lower the ability of the virus to multiply and infect new liver cells.
  • We do not know if Adefovir Dipivoxil Tablets will reduce your chances of getting liver cancer or liver damage (cirrhosis) from chronic hepatitis B.
  • We do not know how long Adefovir Dipivoxil Tablets may help your hepatitis. Sometimes viruses change in your body and medicines no longer work. This is called drug resistance.
  • Adefovir Dipivoxil Tablets does not stop you from spreading hepatitis B virus to others by sex or sharing needles. So practice safe sex and needle use.

Who should not take Adefovir Dipivoxil Tablets?

  • Do not take Adefovir Dipivoxil Tablets if you are allergic to any of the ingredients in Adefovir Dipivoxil Tablets. The active ingredient in Adefovir Dipivoxil Tablets is Adefovir Dipivoxil. See the end of this leaflet for a complete list of all the ingredients in Adefovir Dipivoxil Tablets.
  • Do not take Adefovir Dipivoxil Tablets if you are already taking ATRIPLA, COMPLERA, STRIBILD, TRUVADA, or VIREAD.

Tell your doctor if:

  • You are pregnant. We do not know if Adefovir Dipivoxil Tablets can harm your unborn child. You and your doctor will need to decide if Adefovir Dipivoxil Tablets is right for you. If you take Adefovir Dipivoxil Tablets and you are pregnant, talk to your doctor about how you can join the Adefovir Dipivoxil Tablets pregnancy registry.
  • You are breast-feeding. We do not know if Adefovir Dipivoxil Tablets can pass into your milk and if it can harm your baby. You will need to choose either to breast feed or take Adefovir Dipivoxil Tablets, but not both.
  • You have kidney problems now or had them before. Your dose and schedule of Adefovir Dipivoxil Tablets may be reduced. Blood tests will need to be done regularly to see how your kidneys are working.

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Some medicines may affect how Adefovir Dipivoxil Tablets works, especially medicines that affect how your kidneys work. Adefovir Dipivoxil Tablets can affect how your other medicines work. Your dose of Adefovir Dipivoxil Tablets and the other medicines may be changed. Do not take any other medicines while you are taking Adefovir Dipivoxil Tablets, unless your doctor has told you it is okay.

How should I take Adefovir Dipivoxil Tablets?

  • Your doctor will tell you how much Adefovir Dipivoxil Tablets to take.
  • Your doctor will tell you when and how often to take Adefovir Dipivoxil Tablets.
  • Take Adefovir Dipivoxil Tablets the same time each day that your doctor tells you. If you forget to take Adefovir Dipivoxil Tablets, take it as soon as you remember that day. Do not take more than 1 dose of Adefovir Dipivoxil Tablets in a day. Do not take 2 doses at the same time. Call your doctor or pharmacist if you are not sure what to do.
  • Do not change your dose of Adefovir Dipivoxil Tablets or stop Adefovir Dipivoxil Tablets without talking to your doctor. Your hepatitis may get worse if you change doses or stop.
  • You may take Adefovir Dipivoxil Tablets with or without food.
  • When your Adefovir Dipivoxil Tablets supply gets low, call your doctor or pharmacy for a refill. 
  • Do not run out of Adefovir Dipivoxil Tablets.
  • If you take too much Adefovir Dipivoxil Tablets, call your local poison control center or emergency room right away.

Some patients get worse or very serious hepatitis B symptoms when they stop taking Adefovir Dipivoxil Tablets (see, "What is the most important information I should know about Adefovir Dipivoxil Tablets?"). We don't know how long you should use Adefovir Dipivoxil Tablets. You and your doctor will need to decide when it is best for you to stop taking Adefovir Dipivoxil Tablets. After you stop taking Adefovir Dipivoxil Tablets, your doctor will still need to check your health and take blood tests to check your liver for a few months.

What should I avoid while taking Adefovir Dipivoxil Tablets?

Avoid doing things that can spread hepatitis B virus since Adefovir Dipivoxil Tablets doesn't stop you from passing the infection to others.

  • Do not share needles or other injection equipment.
  • Do not share personal items that can have blood or body fluids on them, like toothbrushes or razor blades.
  • Do not have any kind of sex without protection. Practice "safe sex" using condoms and dental dams.

What are the possible side effects of Adefovir Dipivoxil Tablets?

Adefovir Dipivoxil Tablets can cause the following serious side effects: (See, "What is the most important information I should know about Adefovir Dipivoxil Tablets?")

  1. a very serious hepatitis if you stop taking it.
  2. a severe kidney problem called nephrotoxicity.
  3. increase your chance of developing a form of HIV that cannot be treated with usual HIV medicines.
  4. lactic acidosis and liver problems.

The most common side effects of Adefovir Dipivoxil Tablets are weakness, headache, stomach pain, nausea, flatulence (intestinal gas), diarrhea, indigestion and changes in the way the kidneys work. Additional side effects in liver transplant patients with chronic hepatitis B are vomiting, rash and itching. Some patients with liver transplants also had undesirable effects on their kidneys, including failure of the kidneys.

Other side effects reported since Adefovir Dipivoxil Tablets has been marketed include kidney failure, damage to kidney cells, muscle pain or weakness and weakening of the bone, which could cause them to break (both associated with kidney problems), and inflammation of the pancreas.

These are not all of the possible side effects of Adefovir Dipivoxil Tablets. For more information, ask your doctor or pharmacist.

General information about the safe and effective use of Adefovir Dipivoxil Tablets:

Medicines are sometimes prescribed for conditions not mentioned in patient information leaflets. Do not use Adefovir Dipivoxil Tablets for a condition for which it was not prescribed. Do not give Adefovir Dipivoxil Tablets to other people, even if they have the same symptoms that you have.

This leaflet summarizes the most important information about Adefovir Dipivoxil Tablets. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Adefovir Dipivoxil Tablets that is written for health professionals.

Adefovir Dipivoxil Tablets Tablets should be stored at room temperature and should be stored in their original container.

Do not use if seal over bottle opening is broken or missing.

What are the Ingredients of Adefovir Dipivoxil Tablets?

Active Ingredient: Adefovir Dipivoxil

Inactive Ingredients: copovidone, anhydrous lactose, microcrystalline cellulose, silicon dioxide, crospovidone and magnesium stearate.

Manufactured by:

Sigmapharm Laboratories,LLC

Bensalem, PA 19020

OS003-06 REV.0913

COMPLERA, EMTRIVA, HEPSERA, STRIBILD, TRUVADA and VIREAD are trademarks or registered trademarks of Gilead Sciences, Inc., or its related companies. ATRIPLA is a trademark of Bristol-Myers Squibb & Gilead Sciences, LLC. Other brands listed are the trademarks of their respective owners.

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