Baraclude (Entecavir) - Side Effects and Adverse Reactions

Clinical Trial 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.

Assessment of adverse reactions is based on four studies (AI463014, AI463022, AI463026, and AI463027) in which 1720 subjects with chronic hepatitis B virus infection received double-blind treatment with BARACLUDE 0.5 mg/day (n=679), BARACLUDE 1 mg/day (n=183), or lamivudine (n=858) for up to 2 years. Median duration of therapy was 69 weeks for BARACLUDE-treated subjects and 63 weeks for lamivudine-treated subjects in Studies AI463022 and AI463027 and 73 weeks for BARACLUDE-treated subjects and 51 weeks for lamivudine-treated subjects in Studies AI463026 and AI463014. The safety profiles of BARACLUDE and lamivudine were comparable in these studies. The safety profile of BARACLUDE 1 mg (n=51) in HIV/HBV co-infected subjects enrolled in Study AI463038 was similar to that of placebo (n=17) through 24 weeks of blinded treatment and similar to that seen in non-HIV infected subjects [see Warnings and Precautions ].

The most common adverse reactions of any severity (≥3%) with at least a possible relation to study drug for BARACLUDE-treated subjects were headache, fatigue, dizziness, and nausea. The most common adverse reactions among lamivudine-treated subjects were headache, fatigue, and dizziness. One percent of BARACLUDE-treated subjects in these four studies compared with 4% of lamivudine-treated subjects discontinued for adverse events or abnormal laboratory test results.

Clinical adverse reactions of moderate-severe intensity and considered at least possibly related to treatment occurring during therapy in four clinical studies in which BARACLUDE was compared with lamivudine are presented in Table 2.

Table 2: Clinical Adverse Reactionsa of Moderate-Severe Intensity (Grades 2-4) Reported in Four Entecavir Clinical Trials Through 2 Years
	Nucleoside-Naiveb		Lamivudine-Refractoryc
Body System/   Adverse Reaction	BARACLUDE 0.5 mg n=679	Lamivudine 100 mg n=668	BARACLUDE 1 mg n=183	Lamivudine 100 mg n=190
a Includes events of possible, probable, certain, or unknown relationship to treatment regimen.
b Studies AI463022 and AI463027.
c Includes Study AI463026 and the BARACLUDE 1-mg and lamivudine treatment arms of Study AI463014, a Phase 2 multinational, randomized, double-blind study of three doses of BARACLUDE (0.1, 0.5, and 1 mg) once daily versus continued lamivudine 100 mg once daily for up to 52 weeks in subjects who experienced recurrent viremia on lamivudine therapy.
Any Grade 2-4 adverse reactiona	15%	18%	22%	23%
Gastrointestinal
Diarrhea	<1%	0	1%	0
Dyspepsia	<1%	<1%	1%	0
Nausea	<1%	<1%	<1%	2%
Vomiting	<1%	<1%	<1%	0
General
Fatigue	1%	1%	3%	3%
Nervous System
Headache	2%	2%	4%	1%
Dizziness	<1%	<1%	0	1%
Somnolence	<1%	<1%	0	0
Psychiatric
Insomnia	<1%	<1%	0	<1%

Laboratory Abnormalities

Frequencies of selected treatment-emergent laboratory abnormalities reported during therapy in four clinical trials of BARACLUDE compared with lamivudine are listed in Table 3.

Table 3: Selected Treatment-Emergenta Laboratory Abnormalities Reported in Four Entecavir Clinical Trials Through 2 Years
	Nucleoside-Naiveb		Lamivudine-Refractoryc
Test	BARACLUDE 0.5 mg n=679	Lamivudine 100 mg n=668	BARACLUDE 1 mg n=183	Lamivudine 100 mg n=190
a On-treatment value worsened from baseline to Grade 3 or Grade 4 for all parameters except albumin (any on-treatment value <2.5 g/dL), confirmed creatinine increase ≥0.5 mg/dL, and ALT >10 X ULN and >2 X baseline.
b Studies AI463022 and AI463027.
c Includes Study AI463026 and the BARACLUDE 1-mg and lamivudine treatment arms of Study AI463014, a Phase 2 multinational, randomized, double-blind study of three doses of BARACLUDE (0.1, 0.5, and 1 mg) once daily versus continued lamivudine 100 mg once daily for up to 52 weeks in subjects who experienced recurrent viremia on lamivudine therapy.
d Includes hematology, routine chemistries, renal and liver function tests, pancreatic enzymes, and urinalysis.
e Grade 3 = 3+, large, ≥ 500 mg/dL; Grade 4 = 4+, marked, severe.
f Grade 3 = 3+, large; Grade 4 = ≥ 4+, marked, severe, many.
ULN=upper limit of normal
Any Grade 3-4 laboratory abnormalityd	35%	36%	37%	45%
ALT >10 X ULN and >2 X baseline	2%	4%	2%	11%
ALT >5.0 X ULN	11%	16%	12%	24%
Albumin <2.5 g/dL	<1%	<1%	0	2%
Total bilirubin >2.5 X ULN	2%	2%	3%	2%
Lipase ≥2.1 X ULN	7%	6%	7%	7%
Creatinine >3.0 X ULN	0	0	0	0
Confirmed creatinine increase ≥0.5 mg/dL	1%	1%	2%	1%
Hyperglycemia, fasting >250 mg/dL	2%	1%	3%	1%
Glycosuriae	4%	3%	4%	6%
Hematuriaf	9%	10%	9%	6%
Platelets <50,000/mm3	<1%	<1%	<1%	<1%

Among BARACLUDE-treated subjects in these studies, on-treatment ALT elevations greater than 10 times the upper limit of normal (ULN) and greater than 2 times baseline generally resolved with continued treatment. A majority of these exacerbations were associated with a ≥2 log₁₀/mL reduction in viral load that preceded or coincided with the ALT elevation. Periodic monitoring of hepatic function is recommended during treatment.

Exacerbations of Hepatitis after Discontinuation of Treatment [see also Warnings and Precautions ]

An exacerbation of hepatitis or ALT flare was defined as ALT greater than 10 times ULN and greater than 2 times the subject’s reference level (minimum of the baseline or last measurement at end of dosing). For all subjects who discontinued treatment (regardless of reason), Table 4 presents the proportion of subjects in each study who experienced post-treatment ALT flares. In these studies, a subset of subjects was allowed to discontinue treatment at or after 52 weeks if they achieved a protocol-defined response to therapy. If BARACLUDE is discontinued without regard to treatment response, the rate of post-treatment flares could be higher.

Table 4: Exacerbations of Hepatitis During Off-Treatment Follow-up, Subjects in Studies AI463022, AI463027, and AI463026
	Subjects with ALT Elevations >10 X ULN and >2 X Referencea
	BARACLUDE	Lamivudine
a Reference is the minimum of the baseline or last measurement at end of dosing. Median time to off-treatment exacerbation was 23 weeks for BARACLUDE-treated subjects and 10 weeks for lamivudine-treated subjects.
Nucleoside-naive
HBeAg-positive	4/174 (2%)	13/147 (9%)
HBeAg-negative	24/302 (8%)	30/270 (11%)
Lamivudine-refractory	6/52 (12%)	0/16

Postmarketing Experience

The following adverse reactions have been reported during postmarketing use of BARACLUDE. Because these reactions were reported voluntarily from a population of unknown size, it is not possible to reliably estimate their frequency or establish a causal relationship to BARACLUDE exposure.

Immune system disorders: Anaphylactoid reaction.

Skin and subcutaneous tissue disorders: Alopecia, rash.