FDA Label for Hepsera

Warning: Severe Acute Exacerbations Of Hepatitis, Nephrotoxicity, Hiv Resistance, Lactic Acidosis And Severe Hepatomegaly With Steatosis

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 and Precautions (5.1)].

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 Precautions (5.2) and Dosage and Administration (2.2)].

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 and Precautions (5.3)].

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 and Precautions (5.4)].

1 Indications And Usage

HEPSERA is indicated for the treatment of chronic hepatitis B in patients 12 years of age and older 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 with clinical evidence of lamivudine-resistant hepatitis B virus with either compensated or decompensated liver function.

For patients 12 to <18 years of age, the indication is based on virological and biochemical responses in patients with HBeAg+ chronic hepatitis B virus infection with compensated liver function.

2.1 Chronic Hepatitis B

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

HEPSERA is not recommended for use in children less than 12 years of age.

2.2 Dose Adjustment In Renal Impairment

Significantly increased drug exposures were seen when HEPSERA was administered to adult patients with renal impairment [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)]. Therefore, the dosing interval of HEPSERA should be adjusted in adult patients with baseline creatinine clearance <50 mL/min 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 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.

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

3 Dosage Forms And Strengths

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.

4 Contraindications

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

5.1 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 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.

5.2 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 HEPSERA (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 HEPSERA.

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 (2.2)]. The risks and benefits of HEPSERA treatment should be carefully evaluated prior to discontinuing HEPSERA in a patient with treatment-emergent nephrotoxicity.

5.3 Hiv Resistance

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.

5.4 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 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).

5.5 Coadministration With Other Products

HEPSERA should not be used concurrently with VIREAD (tenofovir disoproxil fumarate) or tenofovir disoproxil fumarate-containing products including TRUVADA (emtricitabine/tenofovir disoproxil fumarate combination tablet) and ATRIPLA (efavirenz/emtricitabine/tenofivir disoproxil fumarate combination tablet).

5.6 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 HEPSERA were at greater risk of developing resistance than patients with serum HBV DNA levels below 1000 copies/mL at Week 48 of therapy.

6 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)]

6.1 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 HEPSERA.

Adverse reactions to HEPSERA 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 HEPSERA (n=294) or placebo (n=228) for 48 weeks is presented in Table 2. Patients who received open-label HEPSERA for up to 240 weeks in Study 438 reported adverse reactions similar in nature and severity to those reported in the first 48 weeks.

No patients treated with HEPSERA developed a confirmed serum creatinine increase ≥0.5 mg/dL or confirmed phosphorus decrease ≤2 mg/dL from baseline by Week 48. By Week 96, 2% of HEPSERA-treated patients, by Kaplan-Meier estimate, had increases in serum creatinine ≥0.5 mg/dL from baseline (no placebo-controlled results were available for comparison beyond Week 48). For patients who chose to continue HEPSERA 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 HEPSERA for up to 240 weeks in Study 437, 6 had a confirmed increase in serum creatinine of ≥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.

6.3 Pediatric Patients

Assessment of adverse reactions is based on a placebo-controlled study (Study 518) in which 173 pediatric patients aged 2 to <18 years with chronic hepatitis B and compensated liver disease received double-blind treatment with HEPSERA (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 HEPSERA in patients ≥12 to <18 years of age (n=56) was similar to that observed in adults. No pediatric patients treated with HEPSERA developed a confirmed serum creatinine increase ≥ 0.5 mg/dL or confirmed phosphorus decrease to <2 mg/dL from baseline by Week 48.

6.4 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 (both associated with proximal renal tubulopathy)

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

7 Drug Interactions

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 [see Clinical Pharmacology (12.3)].

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 [see Warnings and Precautions (5.2)].

HEPSERA should not be administered in combination with VIREAD [see Warnings and Precautions (5.5)].

8 Use In Specific Populations

8.2 Labor And Delivery

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.

8.3 Nursing Mothers

It is not known whether adefovir is excreted in human milk.

Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from HEPSERA, a decision should be made whether to discontinue nursing or to discontinue drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

Pediatric patients 12 to <18 years: The safety, efficacy, and pharmacokinetics of HEPSERA in pediatric patients (aged ≥12 to <18 years) were evaluated in a double-blind, randomized, placebo-controlled study (GS-US-103-518, Study 518) in 83 pediatric patients with chronic hepatitis B and compensated liver disease. The proportion of patients treated with HEPSERA who achieved the primary efficacy endpoint of serum HBV DNA <1,000 copies/mL and normal ALT levels at the end of 48 weeks blinded treatment was significantly greater (23%) when compared to placebo-treated patients (0%). [see Clinical Studies (14.4), Dosage And Administration (2) and Adverse Reactions (6.3)].

Pediatric patients 2 to <12 years: Patients 2 to <12 years of age were also evaluated in Study 518. The efficacy of adefovir dipivoxil was not significantly different from placebo in patients less than 12 years of age.

Hepsera is not recommended for use in children below 12 years of age.

8.5 Geriatric Use

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.

8.6 Patients With Impaired Renal Function

It is recommended that the dosing interval for HEPSERA be modified in adult patients with baseline creatinine clearance <50 mL/min. The pharmacokinetics of adefovir have not been evaluated in non-hemodialysis patients with creatinine clearance <10 mL/min or in adolescent patients with renal insufficiency; therefore, no dosing recommendations are available for these patients. [see Dosage And Administration (2.2) and Warning And Precautions (5.2)].

10 Overdosage

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.

11 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:

Chemical Structure - hepsera 01

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.

12.1 Mechanism Of Action

Adefovir is an antiviral drug. [see Clinical Pharmacology (12.4)].

13 Nonclinical Toxicology

13.1 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.

14 Clinical Studies

14.2 Study 435 (Pre- And Post- Liver Transplantation Patients)

HEPSERA was also evaluated in an open-label, uncontrolled study of 467 chronic hepatitis B patients pre- (N=226) and post- (N=241) liver transplantation with clinical evidence of lamivudine- resistant hepatitis B virus (Study 435). At baseline, 60% of pre-liver transplantation patients were classified as Child-Pugh-Turcotte score of Class B or C. The median baseline HBV DNA as measured by the Roche Amplicor Monitor PCR assay (LLOQ = 1000 copies/mL) was 7.4 and 8.2 log₁₀ copies/mL, and the median baseline ALT was 1.8 and 2.0 times the upper limit of normal in pre- and post-liver transplantation patients, respectively. Results of this study are displayed in Table 5. Treatment with HEPSERA resulted in a similar reduction in serum HBV DNA regardless of the patterns of lamivudine-resistant HBV DNA polymerase mutations at baseline. The significance of the efficacy results listed in Table 7 as they relate to clinical outcomes is not known.

14.3 Study 461 (Clinical Evidence Of Lamivudine Resistance)

In Study 461, a double-blind, active controlled study in 59 chronic hepatitis B patients with clinical evidence of lamivudine-resistant hepatitis B virus, patients were randomized to receive either HEPSERA monotherapy or HEPSERA in combination with lamivudine 100 mg or lamivudine 100 mg alone. At Week 48, the mean ± SD decrease in serum HBV DNA as measured by the Roche Amplicor Monitor PCR assay (LLOQ = 1000 copies/mL) was 4.00 ± 1.41 log₁₀ copies/mL for patients treated with HEPSERA and 3.46 ± 1.10 log₁₀ copies/mL for patients treated with HEPSERA in combination with lamivudine. There was a mean decrease in serum HBV DNA of 0.31 ± 0.93 log₁₀ copies/mL in patients receiving lamivudine alone. ALT normalized in 47% of patients treated with HEPSERA, in 53% of patients treated with HEPSERA in combination with lamivudine, and 5% of patients treated with lamivudine alone. The significance of these findings as they relate to clinical outcomes is not known.

14.4 Study 518 (Pediatric Study)

Study 518 was a double-blind, placebo-controlled, study in which 173 pediatric patients (ages 2 to <18 years) with chronic hepatitis B (CHB) infection and elevated ALT were randomized 2:1 (115 receiving adefovir dipivoxil and 58 receiving placebo). Randomization was stratified by prior treatment and age 2 to <7 years old (cohort 1), 7 to <12 years old (cohort 2), and 12 to <18 years old (cohort 3). All patients in cohort 3 received 10 mg tablet formulation; all patients in cohorts 1 and 2 received an investigational suspension formulation (0.3 mg/kg/day cohort 1, 0.25 mg/kg/day cohort 2) once daily. The primary efficacy endpoint was HBV DNA <1000 copies/mL plus normalization of ALT at the end of Week 48.

In cohort 3 (n=83), significantly more patients treated with HEPSERA achieved the primary efficacy endpoint at the end of 48 weeks of blinded treatment (23%) when compared to placebo-treated patients (0%). The proportion of patients from cohorts 1 and 2 who responded to treatment with adefovir dipivoxil was not statistically significant when compared to the placebo arm, although the adefovir plasma concentrations in these patients were comparable to those observed in older patients. Overall, 22 of 115 (19%) of pediatric patients who received adefovir dipivoxil vs. 1 of 58 (2%) of placebo treated patients responded to treatment by Week 48 [see Adverse Reactions (6.3), Use In Special Populations (8.4) and Clinical Pharmacology (12.3, 12.4)].

16 How Supplied / Storage And Handling

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.

17.1 Instructions For Safe Use

See FDA-approved patient labeling

• Physicians should inform patients of the potential risks and benefits of HEPSERA and of alternative modes of therapy.
• Physicians should instruct their patients to
  • –Read the Patient Package Insert before starting HEPSERA therapy.
  • –Follow a regular dosing schedule to avoid missing doses.
  • –Immediately report any severe abdominal pain, muscle pain, yellowing of the eyes, dark urine, pale stools, and/or loss in appetite.
  • –Inform their doctor or pharmacist if they develop any unusual symptom(s), or if any known symptom persists or worsens.
  • Patients should remain under the care of a physician when using HEPSERA.
  • Patients should be advised that
    • –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.
    • –Patients should not discontinue Hepsera without first informing their physician [See Warnings and Precautions. (5.1)]
    • –Routine laboratory monitoring and follow-up with a physician is important during HEPSERA therapy.
    • –Obtaining HIV antibody testing prior to starting HEPSERA is important [See Warnings and Precautions. (5.3)]
    • –HEPSERA should not be administered concurrently with VIREAD or TRUVADA or ATRIPLA [See Warnings and Precautions. (5.5)]
    • –Lamivudine-resistant patients should use HEPSERA in combination with lamivudine and not as HEPSERA monotherapy [See Warnings and Precautions. (5.6)]
    
    

17.2 Pregnancy And Breastfeeding

• Physicians should inform women of childbearing age about the risks associated with exposure to HEPSERA during pregnancy.
• Patients should inform their physician if they become pregnant while using HEPSERA.
• Pregnant patients using HEPSERA should be informed about the HEPSERA pregnancy registry and offered the opportunity to enroll.
• Patients should be informed that it is not known whether HEPSERA is excreted into human milk or if it can harm a nursing infant. Therefore, a decision should be made whether to discontinue breastfeeding or drug.

Spl Patient Package Insert

FDA-Approved Patient Labeling

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), Combivir (zidovudine plus lamivudine), Emtriva^® (emtricitabine), Epivir, Epivir-HBV (lamivudine), Epzicom (abacavir plus lamivudine), Hivid (zalcitabine), Retrovir (zidovudine), 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 VIREAD, TRUVADA or ATRIPLA.

  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 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 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

  
  

Package Label.Principal Display Panel

PRINCIPAL DISPLAY PANEL - 30 CT Representative Label

HEPSERA^® (ADEFOVIR DIPIVOXIL 10 MG)
TABLETS, 30 CT - BRITESTOCK

STORE BELOW 25°C

Part Number: 7000003

Lot Number: 1005247

Quantity: 080

CONTENTS MADE IN GERMANY
MANUFACTURED FOR:
GILEAD SCIENCES LIMITED
CORK, IRELAND

4000738.00

PRINCIPAL DISPLAY PANEL - 30 tablet bottle - hepsera 02