Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 06 September 2018

Indication(s)

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 less than 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.

HEPSERA is a nucleotide analogue indicated for the treatment of chronic hepatitis B in patients 12 years of age and older.

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Advisory information

contraindications
4 CONTRAINDICATIONS HEPSERA is contraindicated in patients with previously demonstrated hypersensitivity to any of the components of the product. HEPSERA is contraindicated in patients with previously demonstrated hypersensitivity to any of the components of the product. (4)
Adverse reactions

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)] Most common adverse reaction (incidence greater than 10 %) in compensated disease patients is asthenia and in pre - and post-transplantation lamivudine-resistant liver disease patients is increased creatinine.

(6) To report SUSPECTED ADVERSE REACTIONS, contact Gilead at (1-800-GILEAD-5) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 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 can not 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.

Table 2 Adverse Reactions (Grades 1-4) Reported in?3 % of All HEPSERA-Treated Patients in Pooled Studies 437-438 Studies (0-48 Weeks)In these studies, the overall incidence of adverse reactions with HEPSERA 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 HEPSERA 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 HEPSERA developed a confirmed serum creatinine increase greater than or equal to 0.5 mg/dL from baseline or a confirmed phosphorus decrease to 2 mg/dL or less by Week 48.

By Week 96, 2 % of HEPSERA-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 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 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.

6.2 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 HEPSERA 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 HEPSERA 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 HEPSERA due to renal adverse events.

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 less than 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 less than 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 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.

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 can not 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

Usage information

Dosing and administration

2 DOSAGE AND ADMINISTRATION One tablet containing 10 mg adefovir dipivoxil once daily orally with or without food.

(2.1) Dose adjustment in renal impairment for adults (2.2) Creatinine Clearance (mL/min)Creatinine clearance calculated by Cockcroft-Gault method using lean or ideal body weight.

Greater than or equal to 50 30-49 10-29 Hemodialysis Patients Recommended dose and dosing interval 10 mg every 24 hours 10 mg every 48 hours 10 mg every 72 hours 10 mg every 7 days following dialysis No dose recommendations for (2.1): Non-hemodialysis patients with creatinine clearance less than 10mL per minute.

Adolescent patients with renal impairment.

2.1 Chronic Hepatitis B The recommended dose of HEPSERA in chronic hepatitis B patients for patients 12 years of age and older with adequate renal function is 10 mg, once daily, taken orally, without regard to food.

The optimal duration of treatment is unknown.

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 less than 50 mL per minute using the following suggested guidelines (See Table 1).

The safety and effectiveness of these dosing interval adjustment guidelines have not been clinically evaluated.

Additionally, it is important to note that these guidelines were derived from data in patients with pre-existing renal impairment at baseline.

They may not be appropriate for patients in whom renal insufficiency evolves during treatment with HEPSERA.

Therefore, clinical response to treatment and renal function should be closely monitored in these patients.

Table 1 Dosing Interval Adjustment of HEPSERA in Adult Patients with Renal Impairment

Creatinine Clearance (mL/min)Creatinine clearance calculated by Cockcroft-Gault method using lean or ideal body weight.

Greater than or equal to 50 30-49 10-29 Hemodialysis Patients Recommended dose and dosing interval 10 mg every 24 hours 10 mg every 48 hours 10 mg every 72 hours 10 mg every 7 days following dialysis The pharmacokinetics of adefovir have not been evaluated in non-hemodialysis patients with creatinine clearance less than 10 mL per minute; therefore, no dosing recommendation is available for these patients.

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

Use in special populations

8 USE IN SPECIFIC POPULATIONS Nursing Mothers: Unknown if present in human milk (8.3) Pediatrics: Not recommended in children less than 12 years of age.

(8.4, 2.1,14.4) Renal Impairment: Dose adjustment may be required.

(2.2) 8.1 Pregnancy Teratogenic Effects: Pregnancy Category C There are no adequate and well-controlled studies of HEPSERA in pregnant women.

Chronic hepatitis B is a serious condition that requires treatment.

HEPSERA should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

Reproduction studies with oral administration of adefovir dipivoxil to pregnant rats and rabbits showed no evidence of embryotoxicity or teratogenicity at systemic exposures equivalent to 23 times (rats) and 40 times (rabbits) that achieved in humans at the therapeutic dose.

However, embryotoxicity and an increased incidence of fetal malformations (anasarca, depressed eye bulge, umbilical hernia and kinked tail) occurred when adefovir was administered intravenously to pregnant rats at 38 times the human therapeutic exposure.

These adverse reproductive effects did not occur following an intravenous dose where exposure was 12 times the human therapeutic exposure.

Because animal reproduction studies are not always predictive of human response, HEPSERA should be used during pregnancy only if clearly needed and after careful consideration of the risks and benefits [See Nonclinical Toxicology (13.2)].

Pregnancy Registry 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.

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 less than 18 years: The safety, efficacy, and pharmacokinetics of HEPSERA in pediatric patients (aged 12 to less than 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 less than 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 less than 12 years: Patients 2 to less than 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 less than 50 mL per minute.

The pharmacokinetics of adefovir have not been evaluated in non-hemodialysis patients with creatinine clearance less than 10 mL per minute or in adolescent patients with renal insufficiency; therefore, no dosing recommendations are available for these patients [See Dosage and Administration (2.2) and Warnings and Precautions (5.2)].

Pregnancy and lactation
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.

Interactions

7 DRUG INTERACTIONS Since adefovir is eliminated by the kidney, coadministration of HEPSERA with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of either adefovir and/or these coadministered drugs [See Clinical Pharmacology (12.3)].

Patients should be monitored closely for adverse events when HEPSERA is coadministered 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)].

Coadministration with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of adefovir or the coadministered drug.

Monitor for HEPSERA associated adverse events.

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More information

Category Value
Authorisation number NDA021449
Orphan designation No
Product NDC 61958-0501
Date Last Revised 24-09-2013
Type HUMAN PRESCRIPTION DRUG
RXCUI 881343
Storage and handling 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.
Marketing authorisation holder Gilead Sciences, Inc.
Warnings

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)].

WARNING:

SEVERE ACUTE EXACERBATIONS OF HEPATITIS, NEPHROTOXICITY, HIV RESISTANCE, LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS See full prescribing information for complete boxed warning.

Severe acute exacerbations of hepatitis may occur in patients who discontinue HEPSERA. Monitor hepatic function closely in these patients.

(5.1) Chronic use of HEPSERA may result in nephrotoxicity in patients at risk of renal dysfunction or having underlying renal dysfunction.

Monitor renal function closely in these patients.

Dose adjustment may be required.

(5.2) HIV resistance may emerge in chronic hepatitis B patients with unrecognized or untreated HIV infection.

(5.3) Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues.

(5.4)