HEPSERA^®
(adefovir dipivoxil)
Tablets

• SEVERE ACUTE EXACERBATIONS OF HEPATITIS HAVE BEEN REPORTED IN PATIENTS WHO HAVE DISCONTINUED ANTI-HEPATITIS B THERAPY INCLUDING HEPSERA^®. HEPATIC FUNCTION SHOULD BE MONITORED CLOSELY WITH BOTH CLINICAL AND LABORATORY FOLLOW-UP FOR AT LEAST SEVERAL MONTHS IN PATIENTS WHO DISCONTINUE ANTI-HEPATITIS B THERAPY. IF APPROPRIATE, RESUMPTION OF ANTI-HEPATITIS B THERAPY MAY BE WARRANTED (SEE WARNINGS).
• IN PATIENTS AT RISK OF OR HAVING UNDERLYING RENAL DYSFUNCTION, CHRONIC ADMINISTRATION OF HEPSERA MAY RESULT IN NEPHROTOXICITY. THESE PATIENTS SHOULD BE MONITORED CLOSELY FOR RENAL FUNCTION AND MAY REQUIRE DOSE ADJUSTMENT (SEE WARNINGS AND DOSAGE AND ADMINISTRATION).
• HIV RESISTANCE MAY EMERGE IN CHRONIC HEPATITIS B PATIENTS WITH UNRECOGNIZED OR UNTREATED HUMAN IMMUNODEFICIENCY VIRUS (HIV) INFECTION TREATED WITH ANTI-HEPATITIS B THERAPIES, SUCH AS THERAPY WITH HEPSERA, THAT MAY HAVE ACTIVITY AGAINST HIV (SEE WARNINGS).
• LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, INCLUDING FATAL CASES, HAVE BEEN REPORTED WITH THE USE OF NUCLEOSIDE ANALOGS ALONE OR IN COMBINATION WITH OTHER ANTIRETROVIRALS (SEE WARNINGS).

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.

The pharmacokinetics of adefovir have been evaluated in healthy volunteers and patients with chronic hepatitis B. Adefovir pharmacokinetics are similar between these populations.

HEPSERA is indicated 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.

This indication is based on histological, virological, biochemical, and serological responses in adult patients with HBeAg+ and HBeAg- chronic hepatitis B with compensated liver function, and in adult patients with clinical evidence of lamivudine resistant hepatitis B virus with either compensated or decompensated liver function.

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

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

In clinical trials of HEPSERA, exacerbations of hepatitis (ALT elevations 10 times the upper limit of normal or greater) occurred in up to 25% of patients after discontinuation of HEPSERA. 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 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 HEPSERA (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 (see ADVERSE REACTIONS).

It is important to monitor renal function for all patients during treatment with HEPSERA, 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). The risks and benefits of HEPSERA treatment should be carefully evaluated prior to discontinuing HEPSERA in a patient with treatment-emergent nephrotoxicity.

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

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 HEPSERA 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).

Since adefovir is eliminated by the kidney, co-administration of HEPSERA with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of either adefovir and/or these co-administered drugs.

Apart from lamivudine, trimethoprim/sulfamethoxazole, acetaminophen, and tenofovir disoproxil fumarate, the effects of co-administration of HEPSERA with drugs that are excreted renally, or other drugs known to affect renal function have not been evaluated (see CLINICAL PHARMACOLOGY).

Patients should be monitored closely for adverse events when HEPSERA is co-administered with drugs that are excreted renally or with other drugs known to affect renal function.

Ibuprofen 800 mg three times daily increased adefovir exposure by approximately 23%. The clinical significance of this increase in adefovir exposure is unknown (see CLINICAL PHARMACOLOGY).

While adefovir does not inhibit common CYP450 enzymes, the potential for adefovir to induce CYP450 enzymes is not known.

The effect of adefovir on cyclosporine and tacrolimus concentrations is not known.

The optimal duration of HEPSERA treatment and the relationship between treatment response and long-term outcomes such as hepatocellular carcinoma or decompensated cirrhosis are not known.

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.

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.

To monitor fetal outcomes of pregnant women exposed to HEPSERA, a pregnancy registry has been established. Healthcare providers are encouraged to register patients by calling 1-800-258-4263.

There are no studies in pregnant women and no data on the effect of HEPSERA on transmission of HBV from mother to infant. Therefore, appropriate infant immunizations should be used to prevent neonatal acquisition of hepatitis B virus.

It is not known whether adefovir is excreted in human milk. Mothers should be instructed not to breast-feed if they are taking HEPSERA.

Safety and effectiveness in pediatric patients have not been established.

Clinical studies of HEPSERA did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. 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.

Assessment of adverse reactions is based on two studies (437 and 438) in which 522 patients with chronic hepatitis B received double-blind treatment with HEPSERA (N=294) or placebo (N=228) for 48 weeks. With extended therapy in the second 48 week treatment period, 492 patients were treated for up to 109 weeks, with a median time on treatment of 49 weeks.

Patients who received HEPSERA beyond week 48 in Study 438 reported adverse reactions similar in nature and severity to those reported in the first 48 weeks of treatment. With increased HEPSERA exposure, the incidence of adverse events related to treatment increased only slightly.

In addition to specific adverse events described under the WARNINGS section, all treatment-related clinical adverse events that occurred in 3% or greater of HEPSERA-treated patients compared with placebo are uled in Table 6. A summary of grade 3 and 4 laboratory abnormalities during therapy with HEPSERA compared with placebo is uled in Table 7.

In patients with adequate renal function, increases in serum creatinine ≥0.3 mg/dL from baseline were observed in 4% of patients treated with HEPSERA 10 mg daily compared with 2% of patients in the placebo group at week 48. No patients developed a serum creatinine increase ≥0.5 mg/dL from baseline by week 48. By week 96, 10% and 2% of HEPSERA-treated patients, by Kaplan-Meier estimate, had increases in serum creatinine ≥0.3 mg/dL and ≥0.5 mg/dL from baseline, respectively (no placebo-controlled results were available for comparison beyond week 48). Of the 29 of 492 patients with elevations in serum creatinine ≥0.3 mg/dL from baseline, 20 out of 29 resolved on continued treatment (≤0.2 mg/dL from baseline), 8 of 29 remained unchanged and 1 of 29 resolved on discontinuing treatment (see Special Risk Patients section below for changes in serum creatinine in patients with underlying renal insufficiency at baseline).

Pre- (N=128) and post-liver transplantation patients (N=196) with chronic hepatitis B and clinical evidence of lamivudine-resistant hepatitis B virus were treated in an open-label study with HEPSERA for up to 129 weeks, with a median time on treatment of 19 and 56 weeks, respectively. The majority of these patients had some degree of underlying renal insufficiency at baseline or other risk factors for renal dysfunction during treatment. Increases in serum creatinine ≥0.3 mg/dL from baseline were observed in 26% of these patients by week 48 and 37% by week 96 by Kaplan-Meier estimates. Increases in serum creatinine ≥0.5 mg/dL from baseline were observed in 16% of these patients by week 48 and 31% by week 96. Of the 41 of 324 patients with elevations in serum creatinine ≥0.5 mg/dL from baseline, 7 of 41 resolved on continued treatment (≤0.3 mg/dL from baseline), 18 of 41 remained unchanged and 16 of 41 had not resolved. Additionally, decreases in serum phosphorus were observed in 4% of these patients by week 48, and 6% by week 96 by Kaplan-Meier estimates. One percent (3 of 324) of pre- and post-liver transplantation patients discontinued HEPSERA due to renal events.

Due to the presence of multiple concomitant risk factors for renal dysfunction in these patients, the contributory role of HEPSERA to these changes in serum creatinine and serum phosphorus is difficult to assess.

The most common treatment-related adverse events reported in pre- and post-liver transplantation patients treated with HEPSERA with a 2% frequency or higher include:

Body as a whole: asthenia, abdominal pain, headache, fever

Gastrointestinal: nausea, vomiting, diarrhea, flatulence, hepatic failure

Metabolic and Nutritional: increases in ALT and AST, abnormal liver function

Respiratory: increased cough, pharyngitis, sinusitis

Skin and Appendages: pruritus, rash

Urogenital: increases in creatinine, renal failure, renal insufficiency

Doses of adefovir dipivoxil 500 mg daily for 2 weeks and 250 mg daily for 12 weeks have been associated with gastrointestinal side effects. If overdose occurs the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary.

Following a 10 mg single dose of HEPSERA, a four-hour hemodialysis session removed approximately 35% of the adefovir dose.

The recommended dose of HEPSERA in chronic hepatitis B patients with adequate renal function is 10 mg, once daily, taken orally, without regard to food. The optimal duration of treatment is unknown.

Significantly increased drug exposures were seen when HEPSERA was administered to patients with renal impairment (see Pharmacokinetics). Therefore, the dosing interval of HEPSERA should be adjusted in patients with baseline creatinine clearance <50 mL/min using the following suggested guidelines (see Table 8). 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 HEPSERA. Therefore, clinical response to treatment and renal function should be closely monitored in these patients.

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

HEPSERA is available as tablets. Each tablet contains 10 mg of adefovir dipivoxil. The tablets are white and debossed with "10" and "GILEAD" on one side and the stylized figure of a liver on the other side. They are packaged as follows: Bottles of 30 tablets (NDC 61958-0501-1) containing desiccant (silica gel) and closed with a child-resistant closure.

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

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

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?

• 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.
• 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.
• 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.
• 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 [Combivir^® (zidovudine plus lamivudine), Emtriva^® (emtricitabine), Epivir^®, Epivir-HBV^® (lamivudine), Hivid^® (zalcitabine), Retrovir^® (zidovudine), Trizivir^® (zidovudine plus lamivudine plus abacavir), 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 adults with continuing (chronic) infections with active hepatitis B virus. HEPSERA has not been studied in adults over the age of 65 or in children.

• 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 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 ul of all the ingredients in HEPSERA.

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 be on the HEPSERA pregnancy registry.
• You are breast-feeding. We do not know if HEPSERA can pass through 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 since HEPSERA doesn't stop you from passing the infection to others.

• Do not share needles or other injection equipment.
• Do not share personal lis 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?")

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

The most common side effects of HEPSERA are weakness, headache, stomach pain, and nausea. The most common side effects in patients with liver transplants and chronic hepatitis B are weakness, headache, stomach pain, and itching. Some patients with liver transplants also had changes in the way their kidneys worked.

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