Is There Resistance to Hepsera?
Drug resistance is a primary concern of infectious disease specialists around the world. Any virus can develop drug resistance, and may even develop resistance to more than one drug. Resistance occurs when viruses acquire ways to survive the effects of the drugs that were designed to weaken them. Resistance to antiviral drugs presents an obstacle to providing effective long-term treatment of viral diseases, such as chronic hepatitis B.
Hepsera® was studied in clinical trials to find out whether or not resistance would develop. Through 144 weeks (about 3 years), resistance mutations were identified that may reduce the effectiveness of Hepsera. After 3 years of continuous treatment, 4/100 patients developed resistance to Hepsera in clinical trials.
In clinical trials, Hepsera was found to work well in people who had hepatitis B virus that was resistant to the currently approved chronic hepatitis B treatment, lamivudine.
Important Safety Information about Hepsera
Severe acute exacerbations of hepatitis have been reported with discontinuation of 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. Patients with advanced liver disease or cirrhosis may be at a 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.1
Chronic administration of Hepsera may result in nephrotoxicity in patients at risk of or having underlying renal dysfunction. These patients should be monitored closely for renal function and may require dose adjustment.
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.
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.
Frequently Asked Questions About Hepsera
Q: What is the indication for Hepsera?A: 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-positive and HBeAg-negative 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.Q: What is the dosing for Hepsera?A: The dosing for Hepsera is one 10 mg tablet once daily, without regard to food. The optimal duration of treatment is unkown. Dose adjustments can be made for patients with renal impairment(see table below).
The pharmacokinetics of adefovir have not been evaluated in non-hemodialysis patients with creatinine clearence < name="5">Q: What are the efficacy data of Hepsera?A: The efficacy and safety of Hepsera compared to placebo were evaluated in two large controlled clinical trials enrolling adult patients with chronic hepatitis B. In both studies, patients received Hepsera or matching placebo once a day for 48 weeks, with therapy extended for a second 48-week treatment period.Q: What were the most common side effects for Hepsera in clinical trials?A: The most common adverse events seen with Hepsera in clinical trials were headache, pharyngitis, asthenia, abdominal pain and flu syndrome; no patients discontinued drug due to these events. One percent of patients receiving Hepsera discontinued drug due to an adverse event. Q: How many patients have participated in clinical trials for Hepsera?A: To date, over 800 people have received Hepsera in clinical trials.Q: Has Hepsera been associated with drug resistance?A: Long-term resistance analyses (96–144 weeks) performed by genotyping samples from all adefovir dipivoxil-treated patients with detectable serum HBV DNA identified 2 adefovir resistance-associated mutations. The rtN236T mutation resulted in 4- to 14-fold reduced adefovir susceptibility in vitro and serum HBV DNA rebound in 6/6 patients who developed this mutation in their HBV. The rtA181V mutation conferred 2.5 to 3-fold reduced susceptibility to adefovir in vitro and serum HBV DNA rebound in 2/3 patients who developed this mutation in their HBV. There was a cumulative probability of 3.9% in developing adefovir resistance at year 3. At 96 weeks, 5.1% (4/79) of adefovir dipivoxil-treated patients experienced a confirmed increase of >1 log10 HBV DNA copies/mL from nadir (Study 438).1Q: Are there any significant drug interactions associated with Hepsera?A: No significant drug interactions have been observed with Hepsera. Hepsera has been evaluated in healthy volunteers in combination with lamivudine, trimethoprim/sulfamethoxazole, acetominophen, tenofovir disoproxil fumarate or ibuprofen. Hepsera was not found to alter the pharmacokinetics of any of these agents.1Q: Is Hepsera safe for use in children?A: The safety and effectiveness of Hepsera in pediatric patients have not been established. Q: Where can I find out more about Hepsera?A: To find out more about Hepsera, you cana) review the content of www.Hepsera.com, b) read the full prescribing information, or c) contact Gilead to speak with the clinical information department or set up a meeting with a Gilead Representative.
Adverse Events
Safety profile through 48 weeks
Laboratory abnormalities occurred at similar rates with Hepsera vs placebo in placebo-controlled studies (Studies 437 and 438)
No patients developed a serum creatinine increase ≥ 0.5 mg/dL from baseline by week 48; increases in serum creatinine ≥ 0.3 mg/dL occurred in 4% of patients receiving Hepsera vs 2% with placebo by week 48
By week 96, increases in serum creatinine ≥ 0.3 mg/dL and ≥ 0.5 mg/dL from baseline occurred in 10% and 2%, respectively, of patients receiving Hepsera†1
Elevations in serum creatinine > 0.3 mg/dL from baseline resolved on continued treatment (20/29), remained unchanged (8/29), or resolved following treatment discontinuation (1/29). In total, only one patient discontinued treatment due to an increase in creatinine
Exacerbations of hepatitis (ALT ≥ 10 x ULN) occurred in up to 25% of patients after discontinuation of Hepsera
Exacerbations were not generally accompanied by hepatic decompensation in HBeAg+ and HBeAg- patients with compensated liver function. Patients with advanced liver disease or cirrhosis may be at a 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 reported1
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. 1* No placebo control beyond 48 weeks.† Based on Kaplan-Meier estimates.Discontinuation due to adverse events Treatment-related adverse events
The most common treatment-related adverse events occurred at rates similar to placebo1
Adverse events in patients receiving Hepsera beyond week 48 in Study 438 were similar in nature and severity to those reported through week 48. With increased Hepsera exposure, the incidence of adverse events related to treatment increased only slightly
Drug interactions
Adefovir does not inhibit common cytochrome P450 enzymes; the potential for adefovir to induce cytochrome P450 enzymes is not known1
The effect of adefovir on cyclosporine and tacrolimus concentrations is not known1
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 drugs1
Safety and tolerability in pre- and post-liver transplantation patients
The most common treatment-related adverse events (2% or higher) with Hepsera were asthenia, abdominal pain, headache, fever, nausea, vomiting, diarrhea, flatulence, hepatic failure, increases in ALT and AST, abnormal liver function, increased cough, pharyngitis, sinusitis, pruritus, rash, increases in creatinine, renal failure, and renal insufficiency1
Increases in serum creatinine ≥ 0.3 mg/dL from baseline were observed in 26% of patients by week 48 and 37% by week 96‡1
Increases in serum creatinine ≥ 0.5 mg/dL from baseline were observed in 16% of patients by week 48 and 31% by week 96 (N=41) ‡
Elevations in serum creatinine ≥ 0.5 mg/mL from baseline resolved on continued treatment (7/41), remained unchanged (18/41), or had not resolved (16/41) 1
Due to the presence of multiple concomitant risk factors for renal dysfunction at baseline or during treatment in these patients, the contributory role of Hepsera to these changes in serum creatinine is difficult to assess 1% (3/324) of patients discontinued Hepsera due to renal eventsImportant safety informationSevere acute exacerbations of hepatitis have been reported with discontinuation of 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. Patients with advanced liver disease or cirrhosis may be at a 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.
1In 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 a dose adjustment.1HIV 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. 1Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with antiretrovirals.1
Dosing
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 optimum duration of treatment is unknown.
Dose Adjustment in Renal Impairment:
Significantly increased drug exposures were seen when Hepsera was administered to patients with renal impairment. 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 below). The safety and effectiveness of these dosing interval adjustment guidelines have not been clinically evaluated. Therefore, the clinical response to treatment and renal function should be closely monitored in patients with creatinine clearance below 50 mL/min.
*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 dosing recommendation is available for non-hemodialysis patients with creatinine clearance< 10 mL/min.
Hepsera® was studied in clinical trials to find out whether or not resistance would develop. Through 144 weeks (about 3 years), resistance mutations were identified that may reduce the effectiveness of Hepsera. After 3 years of continuous treatment, 4/100 patients developed resistance to Hepsera in clinical trials.
In clinical trials, Hepsera was found to work well in people who had hepatitis B virus that was resistant to the currently approved chronic hepatitis B treatment, lamivudine.
Important Safety Information about Hepsera
Severe acute exacerbations of hepatitis have been reported with discontinuation of 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. Patients with advanced liver disease or cirrhosis may be at a 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.1
Chronic administration of Hepsera may result in nephrotoxicity in patients at risk of or having underlying renal dysfunction. These patients should be monitored closely for renal function and may require dose adjustment.
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.
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.
Frequently Asked Questions About Hepsera
Q: What is the indication for Hepsera?A: 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-positive and HBeAg-negative 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.Q: What is the dosing for Hepsera?A: The dosing for Hepsera is one 10 mg tablet once daily, without regard to food. The optimal duration of treatment is unkown. Dose adjustments can be made for patients with renal impairment(see table below).
The pharmacokinetics of adefovir have not been evaluated in non-hemodialysis patients with creatinine clearence < name="5">Q: What are the efficacy data of Hepsera?A: The efficacy and safety of Hepsera compared to placebo were evaluated in two large controlled clinical trials enrolling adult patients with chronic hepatitis B. In both studies, patients received Hepsera or matching placebo once a day for 48 weeks, with therapy extended for a second 48-week treatment period.Q: What were the most common side effects for Hepsera in clinical trials?A: The most common adverse events seen with Hepsera in clinical trials were headache, pharyngitis, asthenia, abdominal pain and flu syndrome; no patients discontinued drug due to these events. One percent of patients receiving Hepsera discontinued drug due to an adverse event. Q: How many patients have participated in clinical trials for Hepsera?A: To date, over 800 people have received Hepsera in clinical trials.Q: Has Hepsera been associated with drug resistance?A: Long-term resistance analyses (96–144 weeks) performed by genotyping samples from all adefovir dipivoxil-treated patients with detectable serum HBV DNA identified 2 adefovir resistance-associated mutations. The rtN236T mutation resulted in 4- to 14-fold reduced adefovir susceptibility in vitro and serum HBV DNA rebound in 6/6 patients who developed this mutation in their HBV. The rtA181V mutation conferred 2.5 to 3-fold reduced susceptibility to adefovir in vitro and serum HBV DNA rebound in 2/3 patients who developed this mutation in their HBV. There was a cumulative probability of 3.9% in developing adefovir resistance at year 3. At 96 weeks, 5.1% (4/79) of adefovir dipivoxil-treated patients experienced a confirmed increase of >1 log10 HBV DNA copies/mL from nadir (Study 438).1Q: Are there any significant drug interactions associated with Hepsera?A: No significant drug interactions have been observed with Hepsera. Hepsera has been evaluated in healthy volunteers in combination with lamivudine, trimethoprim/sulfamethoxazole, acetominophen, tenofovir disoproxil fumarate or ibuprofen. Hepsera was not found to alter the pharmacokinetics of any of these agents.1Q: Is Hepsera safe for use in children?A: The safety and effectiveness of Hepsera in pediatric patients have not been established. Q: Where can I find out more about Hepsera?A: To find out more about Hepsera, you cana) review the content of www.Hepsera.com, b) read the full prescribing information, or c) contact Gilead to speak with the clinical information department or set up a meeting with a Gilead Representative.
Adverse Events
Safety profile through 48 weeks
Laboratory abnormalities occurred at similar rates with Hepsera vs placebo in placebo-controlled studies (Studies 437 and 438)
No patients developed a serum creatinine increase ≥ 0.5 mg/dL from baseline by week 48; increases in serum creatinine ≥ 0.3 mg/dL occurred in 4% of patients receiving Hepsera vs 2% with placebo by week 48
By week 96, increases in serum creatinine ≥ 0.3 mg/dL and ≥ 0.5 mg/dL from baseline occurred in 10% and 2%, respectively, of patients receiving Hepsera†1
Elevations in serum creatinine > 0.3 mg/dL from baseline resolved on continued treatment (20/29), remained unchanged (8/29), or resolved following treatment discontinuation (1/29). In total, only one patient discontinued treatment due to an increase in creatinine
Exacerbations of hepatitis (ALT ≥ 10 x ULN) occurred in up to 25% of patients after discontinuation of Hepsera
Exacerbations were not generally accompanied by hepatic decompensation in HBeAg+ and HBeAg- patients with compensated liver function. Patients with advanced liver disease or cirrhosis may be at a 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 reported1
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. 1* No placebo control beyond 48 weeks.† Based on Kaplan-Meier estimates.Discontinuation due to adverse events Treatment-related adverse events
The most common treatment-related adverse events occurred at rates similar to placebo1
Adverse events in patients receiving Hepsera beyond week 48 in Study 438 were similar in nature and severity to those reported through week 48. With increased Hepsera exposure, the incidence of adverse events related to treatment increased only slightly
Drug interactions
Adefovir does not inhibit common cytochrome P450 enzymes; the potential for adefovir to induce cytochrome P450 enzymes is not known1
The effect of adefovir on cyclosporine and tacrolimus concentrations is not known1
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 drugs1
Safety and tolerability in pre- and post-liver transplantation patients
The most common treatment-related adverse events (2% or higher) with Hepsera were asthenia, abdominal pain, headache, fever, nausea, vomiting, diarrhea, flatulence, hepatic failure, increases in ALT and AST, abnormal liver function, increased cough, pharyngitis, sinusitis, pruritus, rash, increases in creatinine, renal failure, and renal insufficiency1
Increases in serum creatinine ≥ 0.3 mg/dL from baseline were observed in 26% of patients by week 48 and 37% by week 96‡1
Increases in serum creatinine ≥ 0.5 mg/dL from baseline were observed in 16% of patients by week 48 and 31% by week 96 (N=41) ‡
Elevations in serum creatinine ≥ 0.5 mg/mL from baseline resolved on continued treatment (7/41), remained unchanged (18/41), or had not resolved (16/41) 1
Due to the presence of multiple concomitant risk factors for renal dysfunction at baseline or during treatment in these patients, the contributory role of Hepsera to these changes in serum creatinine is difficult to assess 1% (3/324) of patients discontinued Hepsera due to renal eventsImportant safety informationSevere acute exacerbations of hepatitis have been reported with discontinuation of 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. Patients with advanced liver disease or cirrhosis may be at a 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.
1In 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 a dose adjustment.1HIV 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. 1Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with antiretrovirals.1
Dosing
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 optimum duration of treatment is unknown.
Dose Adjustment in Renal Impairment:
Significantly increased drug exposures were seen when Hepsera was administered to patients with renal impairment. 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 below). The safety and effectiveness of these dosing interval adjustment guidelines have not been clinically evaluated. Therefore, the clinical response to treatment and renal function should be closely monitored in patients with creatinine clearance below 50 mL/min.
*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 dosing recommendation is available for non-hemodialysis patients with creatinine clearance< 10 mL/min.
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