Adefovir Dipivoxil

Name: Adefovir Dipivoxil

Description

HEPSERA® is the tradename for adefovir dipivoxil, 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 crystalline 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.

HEPSERA tablets are for oral administration. Each tablet contains 10 mg of adefovir dipivoxil and the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, pregelatinized starch, and talc.

Patient information

HEPSERA®
(hep-SER-rah)

Generic Name: (adefovir dipivoxil) Tablets

Read this information carefully before you start taking HEPSERA. Read and check for new information each time you get more HEPSERA. 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 HEPSERA?

1. Some people who stop taking HEPSERA 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 HEPSERA.

2. HEPSERA 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 HEPSERA. You will need to have regular blood tests to check for kidney function while you are taking HEPSERA.

3. If you get or have HIV that isn't being treated with medicines, HEPSERA 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 HEPSERA. You should get an HIV test before you start taking HEPSERA and anytime after that when there's a chance you were exposed to HIV.

4. Some people who have taken medicines like HEPSERA 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 HEPSERA 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 a long time.

What is HEPSERA?

HEPSERA is a medicine used to treat patients at least 12 years of age with continuing (chronic) infections with active hepatitis B virus. HEPSERA 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.

  • HEPSERA will not cure your chronic hepatitis B.
  • HEPSERA may help lower the amount of hepatitis B virus in your body.
  • HEPSERA may lower the ability of the virus to multiply and infect new liver cells.
  • We do not know if HEPSERA will reduce your chances of getting liver cancer or liver damage (cirrhosis) from chronic hepatitis B.
  • We do not know how long HEPSERA may help your hepatitis. Sometimes viruses change in your body and medicines no longer work. This is called drug resistance.
  • HEPSERA 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 HEPSERA?

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

Tell your doctor if:

  • You are pregnant. We do not know if HEPSERA can harm your unborn child. You and your doctor will need to decide if HEPSERA is right for you. If you take HEPSERA and you are pregnant, talk to your doctor about how you can join the HEPSERA pregnancy registry.
  • You are breast-feeding. We do not know if HEPSERA can pass into your milk and if it can harm your baby. You will need to choose either to breast feed or take HEPSERA, but not both.
  • You have kidney problems now or had them before. Your dose and schedule of HEPSERA 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 HEPSERA works, especially medicines that affect how your kidneys work. HEPSERA can affect how your other medicines work. Your dose of HEPSERA and the other medicines may be changed. Do not take any other medicines while you are taking HEPSERA, unless your doctor has told you it is okay.

How should I take HEPSERA?

  • Your doctor will tell you how much HEPSERA to take.
  • Your doctor will tell you when and how often to take HEPSERA.
  • Take HEPSERA the same time each day that your doctor tells you. If you forget to take HEPSERA, take it as soon as you remember that day. Do not take more than 1 dose of HEPSERA 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 HEPSERA or stop HEPSERA without talking to your doctor. Your hepatitis may get worse if you change doses or stop.
  • You may take HEPSERA with or without food.
  • When your HEPSERA supply gets low, call your doctor or pharmacy for a refill. Do not run out of HEPSERA.
  • If you take too much HEPSERA, 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 HEPSERA (See, “What is the most important information I should know about HEPSERA?”). We don't know how long you should use HEPSERA. You and your doctor will need to decide when it is best for you to stop taking HEPSERA. After you stop taking HEPSERA, 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 HEPSERA?

Avoid doing things that can spread hepatitis B virus since HEPSERA 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 HEPSERA?

HEPSERA can cause the following serious side effects: (See, “What is the most important information I should know about HEPSERA?”)

  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 HEPSERA 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 HEPSERA has been marketed include kidney failure, damage to kidney cells, muscle pain or weakness and weakening of the bones, 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 HEPSERA. For more information, ask your doctor or pharmacist.

General information about the safe and effective use of HEPSERA:

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

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

HEPSERA 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 HEPSERA?

Active Ingredient: adefovir dipivoxil

Inactive Ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, pregelatinized starch, and talc

Cautions for Adefovir Dipivoxil

Contraindications

  • Known hypersensitivity to adefovir or any ingredient in the formulation.1

Warnings/Precautions

Warnings

Exacerbations of Hepatitis

Clinical and laboratory evidence of severe acute exacerbations of hepatitis have occurred following discontinuance of HBV therapy, including adefovir therapy.1

Exacerbations of hepatitis (ALT elevations at least 10 times the ULN) reported in up to 25% of patients following discontinuance of adefovir, usually within 12 weeks after discontinuance.1 These exacerbations generally occurred in the absence of HBeAg seroconversion and presented as elevations in ALT and reemergence of viral replication.1

Although these exacerbations may be self-limited or resolve with reinitiation of therapy, severe exacerbations (including fatalities) have been reported.1

In patients with compensated liver function, exacerbations have not generally been accompanied by hepatic decompensation.1 However, patients with advanced liver disease or cirrhosis may be at higher risk for hepatic decompensation than those with compensated liver function.1

Closely monitor hepatic function at repeated intervals with both clinical and laboratory follow-up for several months or longer after adefovir is discontinued.1 If appropriate, resumption of anti-HBV therapy may be warranted.1

Nephrotoxicity

Nephrotoxicity, characterized by a delayed onset, is the principal dose-limiting toxicity of adefovir and also may occur in patients receiving chronic (long-term) therapy with recommended dosage of the drug.1

Delayed onset of gradual increases in serum creatinine and decreases in serum phosphorus were the treatment-limiting toxicities of adefovir in clinical studies evaluating use of high dosages for treatment of HIV infection† (60 or 120 mg daily) or use of high dosages for treatment of chronic HBV infection (30 mg daily).1

Long-term administration in dosages recommended for the treatment of HBV infection (10 mg daily) also may result in delayed nephrotoxicity.1 By week 96 or week 240, 2 or 3% of patients who received adefovir had serum creatinine increases of ≥0.5 mg/dL from baseline (by Kaplan Meier estimates), respectively.1

In pre- or post-liver transplantation patients receiving the usually recommended dosage (10 mg daily), most of whom had some degree of baseline renal insufficiency, 37 or 32% had increases in serum creatinine concentrations of 0.3 mg/dL or greater from baseline by week 48, respectively, and 53 or 51% had serum creatinine increases of 0.3 mg/dL or greater from baseline by week 96, respectively.1

Although overall risk of nephrotoxicity is low in patients with adequate renal function, consider possibility of nephrotoxicity in patients at risk of or having underlying renal dysfunction and in those receiving concomitant therapy with nephrotoxic agents.1 (See Nephrotoxic Drugs or Drugs Eliminated by Renal Excretion under Interactions.)

Closely monitor renal function in all patients receiving adefovir, especially those with preexisting renal impairment or other risks for renal impairment.1 Dosage adjustments may be necessary.1 (See Renal Impairment under Dosage and Administration.)

Individuals Coinfected with HBV and HIV

Use of adefovir for the treatment of chronic HBV infection in patients with unrecognized or untreated HIV infection may result in emergence of HIV resistance.1 Although adefovir has in vitro activity against HIV,22 dosage of the drug used for treatment of HBV infection (10 mg daily) has not been shown to suppress HIV RNA levels in HIV-infected patients.1 14 16

Offer HIV antibody testing to all patients prior to initiating adefovir.1

Lactic Acidosis and Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis (including some fatalities) reported in patients receiving nucleoside analogs alone or in conjunction with antiretrovirals.1 Most reported cases have involved women; obesity and long-term therapy with nucleoside reverse transcriptase inhibitors (NRTIs) also may be risk factors.1

Nucleoside analogs should be used with particular caution in patients with known risk factors for liver disease; however, lactic acidosis and severe hepatomegaly with steatosis have been reported in patients with no known risk factors.1

Discontinue adefovir in any patient with clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).1

Clinical Resistance

Resistance to adefovir may result in viral load rebound of HBV, which may lead to exacerbation of HBV infection; if the patient has impaired hepatic function, this may lead to liver decompensation and death.1

To reduce risk of clinical resistance in patients with lamivudine-resistant HBV, use adefovir in conjunction with lamivudine; do not use adefovir monotherapy1 9

Patients with serum HBV DNA levels >1000 copies/mL after 48 weeks of adefovir treatment are at greater risk of developing clinical resistance.1 To reduce risk of clinical resistance in patients receiving monotherapy with the drug, consider treatment modification if serum HBV DNA levels remain >1000 copies/mL with continued treatment.1

Specific Populations

Pregnancy

Category C.1

Pregnancy registry at 800-258-4263.1

Data not available regarding the effect of adefovir therapy during pregnancy on transmission of HBV to the infant;1 such infants should receive HBV vaccine according to the usual childhood immunization schedule to prevent neonatal acquisition of HBV.1

Lactation

Not known whether adefovir is distributed into milk.1 Discontinue nursing or drug, taking into account the importance of the drug to the woman.1

Pediatric Use

Safety and efficacy not established in children <12 years of age.1

Geriatric Use

Experience in those ≥65 years of age insufficient to determine whether they respond differently than younger adults.1

Use with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1

Renal Impairment

Dosage adjustments recommended for adults if Clcr <50 mL/minute.1 5 (See Renal Impairment under Dosage and Administration.)

Has not been evaluated in adolescents 12–17 years of age with renal impairment.1 Use caution in such adolescents and monitor renal function closely.1

Common Adverse Effects

Asthenia, headache, abdominal pain, nausea, flatulence, diarrhea, dyspepsia.1

Interactions for Adefovir Dipivoxil

Adefovir does not inhibit CYP isoenzymes, including CYP1A2, 2C9, 2C19, 2D6, and 3A4.1 Adefovir is not a substrate for CYP isoenzymes; potential of the drug to induce these enzymes is unknown.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interactions with drugs affecting or metabolized by CYP isoenzymes unlikely.1

Nephrotoxic Drugs or Drugs Eliminated by Renal Excretion

Concomitant use with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of adefovir and/or the other drug.1 Monitor closely for adverse effects if adefovir is used concomitantly with drugs excreted renally or with drugs known to affect renal function.1

Specific Drugs

Drug

Interaction

Comments

Acetaminophen

No pharmacokinetic interaction1

Co-trimoxazole

No pharmacokinetic interaction1

Didanosine

No pharmacokinetic interaction with didanosine delayed-release capsules containing enteric-coated pellets1

Entecavir

No pharmacokinetic interaction24

Ibuprofen

No effect on pharmacokinetics of ibuprofen;1 increased adefovir plasma concentrations and AUC;1 may occur because of increased oral bioavailability of adefovir;1

Clinical importance unknown1

Immunosuppressive agents (cyclosporine, tacrolimus)

Cyclosporine: Effect on adefovir concentrations unknown1

Tacrolimus: No pharmacokinetic interaction1

Lamivudine

No pharmacokinetic interaction1

Additive antiviral effects against HBV1

Telbivudine

No pharmacokinetic interaction25

In vitro evidence of additive antiviral effects against HBV25

Tenofovir

No pharmacokinetic interaction1

Should not be used concomitantly for treatment of chronic HBV infection20

Adefovir Dipivoxil Pharmacokinetics

Absorption

Bioavailability

Following oral administration of adefovir dipivoxil, approximate bioavailability of adefovir is 59%.1 Peak plasma concentration of adefovir attained within 0.58–4 hours.1

Food

Food does not affect AUC of adefovir.1

Special Populations

Adolescents 12–17 years of age with compensated liver disease: Peak plasma concentrations and AUC similar to those reported in adults.1

Distribution

Extent

Not known whether adefovir distributed into human milk.1

Plasma Protein Binding

≤4%.1

Elimination

Metabolism

Following oral administration, adefovir dipivoxil is converted to the active adefovir.1

Adefovir is not metabolized by CYP isoenzymes.1

Elimination Route

Adefovir is excreted in urine by glomerular filtration and active tubular secretion.1

Following oral administration of adefovir dipivoxil, 45% of dose eliminated in urine as adefovir over 24 hours at steady-state.1

Removed by hemodialysis; effect of peritoneal dialysis unknown.1

Half-life

Terminal elimination half-life of adefovir: 7.48 hours.1

Special Populations

In adults with nonchronic HBV infection and hepatic impairment, no substantial differences in pharmacokinetics in those with moderate to severe hepatic impairment compared with those without hepatic impairment.1

In adults with moderate to severe renal impairment or end-stage renal disease requiring hemodialysis, clearance decreased and half-life prolonged.1

Pharmacokinetics not studied in geriatric adults.1

Pharmacokinetics not studied in adolescents 12–17 years of age with renal impairment.1

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Adefovir Dipivoxil

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

10 mg

Hepsera

Gilead

Warnings and Precautions


Exacerbation of Hepatitis after Discontinuation of Treatment

Severe acute exacerbation of hepatitis has been reported in patients who have discontinued anti-hepatitis B therapy, including therapy with Adefovir Dipivoxil Tablets. Hepatic function should be monitored at repeated intervals with both clinical and laboratory follow-up for at least several months in patients who discontinue Adefovir Dipivoxil Tablets. If appropriate, resumption of anti-hepatitis B therapy may be warranted.

In clinical trials of Adefovir Dipivoxil Tablets, exacerbations of hepatitis (ALT elevations 10 times the upper limit of normal or greater) occurred in up to 25% of patients after discontinuation of Adefovir Dipivoxil Tablets. These events were identified in studies GS-98-437 and GS-98-438 (N=492). Most of these events occurred within 12 weeks of drug discontinuation. These exacerbations generally occurred in the absence of HBeAg seroconversion, and presented as serum ALT elevations in addition to re-emergence of viral replication. In the HBeAg-positive and HBeAg-negative studies in patients with compensated liver function, the exacerbations were not generally accompanied by hepatic decompensation. However, patients with advanced liver disease or cirrhosis may be at higher risk for hepatic decompensation. Although most events appear to have been self-limited or resolved with re-initiation of treatment, severe hepatitis exacerbations, including fatalities, have been reported. Therefore, patients should be closely monitored after stopping treatment.

Nephrotoxicity

Nephrotoxicity characterized by a delayed onset of gradual increases in serum creatinine and decreases in serum phosphorus was historically shown to be the treatment-limiting toxicity of Adefovir Dipivoxil therapy at substantially higher doses in HIV-infected patients (60 and 120 mg daily) and in chronic hepatitis B patients (30 mg daily). Chronic administration of Adefovir Dipivoxil Tablets (10 mg once daily) may result in delayed 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 [See Adverse Reactions (6.2) and Clinical Pharmacology (12.3)].  It is recommended that creatinine clearance is calculated in all patients prior to initiating therapy with Adefovir Dipivoxil Tablets.

It is important to monitor renal function for all patients during treatment with Adefovir Dipivoxil Tablets, particularly for those with pre-existing or other risks for renal impairment. Patients with renal insufficiency at baseline or during treatment may require dose adjustment [See Dosage and Administration (2.2)]. The risks and benefits of Adefovir Dipivoxil Tablets treatment should be carefully evaluated prior to discontinuing Adefovir Dipivoxil Tablets in a patient with treatment-emergent nephrotoxicity.

Pediatric Patients

The efficacy and safety of Adefovir Dipivoxil Tablets have not been studied in patients less than 18 years of age with different degrees of renal impairment and no data are available to make dosage recommendations in these patients [See Dosage and Administration (2.2)]. Caution should be exercised when prescribing Adefovir Dipivoxil Tablets to adolescents with underlying renal dysfunction, and renal function in these patients should be closely monitored.

HIV Resistance

Prior to initiating Adefovir Dipivoxil therapy, HIV antibody testing should be offered to all patients. Treatment with anti-hepatitis B therapies, such as Adefovir Dipivoxil Tablets, that have activity against HIV in a chronic hepatitis B patient with unrecognized or untreated HIV infection may result in emergence of HIV resistance. Adefovir Dipivoxil Tablets has not been shown to suppress HIV RNA in patients; however, there are limited data on the use of Adefovir Dipivoxil Tablets to treat patients with chronic hepatitis B co-infected with HIV.

Lactic Acidosis/Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with antiretrovirals.

A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with Adefovir Dipivoxil Tablets therapy should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

Coadministration with Other Products

Adefovir Dipivoxil Tablets should not be used concurrently with VIREAD (tenofovir disoproxil fumarate) or tenofovir disoproxil fumarate-containing products including ATRIPLA® (efavirenz/emtricitabine/tenofovir disoproxil fumarate combination tablet), COMPLERA® (emtricitabine/rilpivirine/tenofovir disoproxil fumarate combination tablet), STRIBILD™ (elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate combination tablet), and TRUVADA® (emtricitabine/tenofovir disoproxil fumarate combination tablet).

Clinical Resistance

Resistance to Adefovir Dipivoxil can result in viral load rebound which may result in exacerbation of hepatitis B and, in the setting of diminished hepatic function, lead to liver decompensation and possible fatal outcome.

In order to reduce the risk of resistance in patients with lamivudine resistant HBV, Adefovir Dipivoxil should be used in combination with lamivudine and not as Adefovir Dipivoxil monotherapy.

In order to reduce the risk of resistance in all patients receiving Adefovir Dipivoxil monotherapy, a modification of treatment should be considered if serum HBV DNA remains above 1000 copies/mL with continued treatment.

Long-term (144 week) data from Study 438 (N=124) show that patients with HBV DNA levels greater than 1000 copies/mL at Week 48 of treatment with Adefovir Dipivoxil were at greater risk of developing resistance than patients with serum HBV DNA levels below 1000 copies/mL at Week 48 of therapy.

Adverse Reactions

The following adverse reactions are discussed in other sections of the labeling:

  • Severe acute exacerbations of Hepatitis [See Boxed Warning, Warnings and Precautions (5.1)]
  • Nephrotoxicity [See Boxed Warning, Warnings and Precautions (5.2)]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of treatment with Adefovir Dipivoxil Tablets.

Adverse reactions to Adefovir Dipivoxil Tablets identified from placebo-controlled and open label studies include the following: asthenia, headache, abdominal pain, diarrhea, nausea, dyspepsia, flatulence, increased creatinine, and hypophosphatemia.

The incidence of these adverse reactions in studies 437 and 438, where 522 patients with chronic hepatitis B and compensated liver disease received double-blind treatment with Adefovir Dipivoxil Tablets (N=294) or placebo (N=228) for 48 weeks is presented in Table 2. Patients who received open-label Adefovir Dipivoxil Tablets for up to 240 weeks in Study 438 reported adverse reactions similar in nature and severity to those reported in the first 48 weeks.

Table 2 Adverse Reactions (Grades 1–4) Reported in ≥3% of All Adefovir Dipivoxil Tablets-Treated Patients in Pooled Studies 437–438 Studies (0–48 Weeks)*
* In these studies, the overall incidence of adverse reactions with Adefovir Dipivoxil Tablets was similar to that reported with placebo. The incidence of adverse reactions is derived from treatment-related events as identified by the study investigators.
Adverse Reaction Adefovir Dipivoxil Tablets 10 mg (N=294) Placebo (N=228)
Asthenia 13% 14%
Headache 9% 10%
Abdominal Pain 9% 11%
Nausea 5% 8%
Flatulence 4% 4%
Diarrhea 3% 4%
Dyspepsia 3% 2%

No patients treated with Adefovir Dipivoxil Tablets developed a confirmed serum creatinine increase greater than or equal to 0.5 mg/dL from baseline or confirmed phosphorus decrease to 2 mg/dL or less by Week 48. By Week 96, 2% of Adefovir Dipivoxil Tablets-treated patients, by Kaplan-Meier estimate, had increases in serum creatinine greater than or equal to 0.5 mg/dL from baseline (no placebo-controlled results were available for comparison beyond Week 48). For patients who chose to continue Adefovir Dipivoxil Tablets for up to 240 weeks in Study 438, 4 of 125 patients (3%) had a confirmed increase of 0.5 mg/dL from baseline. The creatinine elevation resolved in 1 patient who permanently discontinued treatment and remained stable in 3 patients who continued treatment. For 65 patients who chose to continue  Adefovir Dipivoxil Tablets for up to 240 weeks in Study 437, 6 had a confirmed increase in serum creatinine of greater than or equal to 0.5 mg/dL from baseline with 2 patients discontinuing from the study due to the elevated serum creatinine concentration. See Adverse Reactions (6.2)  for changes in serum creatinine in patients with underlying renal insufficiency at baseline.

Special Risk Patients

Pre- and Post-Liver Transplantation Patients

Additional adverse reactions observed from an open-label study (Study 435) in pre- and post- liver transplantation patients with chronic hepatitis B and lamivudine-resistant hepatitis B administered Adefovir Dipivoxil Tablets once daily for up to 203 weeks include: abnormal renal function, renal failure, vomiting, rash, and pruritus.

Changes in renal function occurred in pre-and post-liver transplantation patients with risk factors for renal dysfunction, including concomitant use of cyclosporine and tacrolimus, renal insufficiency at baseline, hypertension, diabetes, and on-study transplantation. Therefore, the contributory role of Adefovir Dipivoxil Tablets to these changes in renal function is difficult to assess.

Increases in serum creatinine greater than or equal to 0.3 mg/dL from baseline were observed in 37% and 53% of pre-liver transplantation patients by Weeks 48 and 96, respectively, by Kaplan-Meier estimates. Increases in serum creatinine greater than or equal to 0.3 mg/dL from baseline were observed in 32% and 51% of post-liver transplantation patients by Weeks 48 and 96, respectively, by Kaplan-Meier estimates. Serum phosphorus values less than 2 mg/dL were observed in 3/226 (1.3%) of pre-liver transplantation patients and in 6/241 (2.5%) of post-liver transplantation patients by last study visit. Four percent (19 of 467) of patients discontinued treatment with Adefovir Dipivoxil Tablets due to renal adverse events.

Pediatric Patients

Assessment of adverse reactions is based on a placebo-controlled study (Study 518) in which 173 pediatric patients aged 2 to less than 18 years with chronic hepatitis B and compensated liver disease received double-blind treatment with Adefovir Dipivoxil Tablets (N=115), or placebo (N=58) for 48 weeks [See Clinical Studies (14.4) and Use In Specific Populations (8.4)].

The safety profile of Adefovir Dipivoxil Tablets in patients 12 to less than 18 years of age (N=56) was similar to that observed in adults. No pediatric patients treated with Adefovir Dipivoxil Tablets developed a confirmed serum creatinine increase to greater than or equal to 0.5 mg/dL from baseline or a confirmed phosphorus decrease to less than 2 mg/dL by Week 48.

Post-Marketing Experience

In addition to adverse reaction reports from clinical trials, the following possible adverse reactions have also been identified during post-approval use of Adefovir Dipivoxil. Because these events have been reported voluntarily from a population of unknown size, estimates of frequency cannot be made.

Metabolism and Nutrition Disorders: hypophosphatemia

Gastrointestinal Disorders: pancreatitis

Musculoskeletal System and Connective Tissue Disorders: myopathy, osteomalacia (manifested as bone pain and may contribute to fractures), both associated with proximal renal tubulopathy.

Renal and Urinary Disorders: renal failure, Fanconi syndrome, proximal renal tubulopathy

What should i discuss with my healthcare provider before taking adefovir (hepsera)?

You should not take adefovir if you are allergic to it.

Some people develop a life-threatening condition called lactic acidosis while taking adefovir. You may be more likely to develop lactic acidosis if you are overweight or have liver disease, if you are a woman, or if you have taken HIV or AIDS medications for a long time. Talk with your doctor about your individual risk.

The following drugs should not be used while you are taking adefovir:

  • tenofovir (Viread);
  • emtricitabine and tenofovir (Truvada);
  • efavirenz, emtricitabine, and tenofovir (Atripla); or
  • emtricitabine, rilpivirine, and tenofovir (Complera).

Tell your doctor if you have been exposed to HIV, or if you have untreated HIV or AIDS. Taking medicines to treat chronic hepatitis B can cause HIV infection to become resistant to the standard HIV and AIDS medications. You may need to be tested for HIV before you start taking adefovir.

To make sure you can safely take adefovir, tell your doctor if you have kidney or liver disease.

FDA pregnancy category C. It is not known whether adefovir will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication.

Your name may need to be listed on an antiviral pregnancy registry when you start using this medication.

It is not known whether adefovir passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

What should i avoid while taking adefovir (hepsera)?

Taking this medication will not prevent you from passing hepatitis B to other people. Avoid having unprotected sex or sharing razors or toothbrushes. Talk with your doctor about safe ways to prevent hepatitis transmission during sex. Sharing drug or medicine needles is never safe, even for a healthy person.

(web3)