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Section 4.6 has been updated
4.6
Pregnancy Fertility, pregnancy and lactation
There
Women of childbearing potential: given that the potential risks to the developing foetus are
unknown, women of childbearing potential should use effective contraception.
Pregnancy:
there are no adequate data from the use of entecavir in pregnant women. Studies in
animals have shown reproductive toxicity at high doses (see section 5.3). The potential risk for
humans is unknown. Baraclude should not be used during pregnancy unless clearly necessary.
There are no data on the effect of entecavir on transmission of HBV from mother to newborn infant.
Therefore, appropriate interventions should be used to prevent neonatal acquisition of HBV.
Given that the potential risks to the developing foetus are unknown, women of child-bearing potential
should use effective contraception.
It
Breastfeeding: it is unknown whether entecavir is excreted in human breast milk. Animal studies
Available toxicological data in animals
have shown excretion of entecavir in breast milk (for details
see section 5.3). A risk to the infants cannot be excluded
. Breastfeeding is not recommendedshould be
discontinued
during treatment with Baraclude.
Fertility:
toxicology studies in animals administered entecavir have shown no evidence of impaired
fertility (see section 5.3).
Section 4.8 has been updated
4.8 Undesirable effects
Assessment of adverse reactions is based on four clinical studies in which 1,720 patients with chronic
hepatitis B infection received double-blind treatment with entecavir 0.5 mg/day (n = 679), entecavir
1 mg/day (n = 183), or lamivudine (n = 858) for up to 107 weeks. The safety profiles of entecavir and
lamivudine, including laboratory test abnormalities, were comparable in these studies.
The
a. Summary of the safety profile
In clinical studies in patients with compensated liver disease, the
most common adverse reactions of
any severity with at least a possible relation to entecavir were headache (9%), fatigue (6%), dizziness
(4%) and nausea (3%).
Exacerbations of hepatitis during and after discontinuation of entecavir therapy
have also been reported (see section 4.4 and
c. Description of selected adverse reactions).
b. Tabulated list of adverse reactions
Assessment of adverse reactions is based on experience from postmarketing surveillance and four
clinical studies in which 1,720 patients with chronic hepatitis B infection and compensated liver
disease received double-blind treatment with entecavir (n = 862) or lamivudine (n = 858) for up to
107 weeks (see section 5.1). In these studies, the safety profiles, including laboratory abnormalities,
were comparable for entecavir 0.5 mg daily (679 nucleoside-naive HBeAg positive or negative
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patients treated for a median of 53 weeks), entecavir 1 mg daily (183 lamivudine-refractory patients
treated for a median of 69 weeks), and lamivudine.
Adverse reactions considered at least possibly related to treatment with entecavir are listed by body
system organ class. Frequency is defined as very common (
≥ 1/10); common (≥ 1/100, to < 1/10);
uncommon (
≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000). Within each frequency grouping,
undesirable effects are presented in order of decreasing seriousness.
Experience in nucleoside naive patients (HBeAg positive and negative):
The safety profile is based on treatment exposure to entecavir 0.5 mg once daily for a median of
53 weeks.
Immune system disorders:
rare: anaphylactoid reaction
Psychiatric disorders:
common: insomnia
Nervous system disorders:
common: headache, dizziness, somnolence
Gastrointestinal disorders:
common: vomiting, diarrhoea, nausea, dyspepsia
General
Hepatobiliary disorders and
administration site conditions:
common:
fatigue increased transaminases
Psychiatric
Skin and subcutaneous tissue
disorders:
common: insomnia
uncommon: rash, alopecia
General disorders and administration site
conditions:
common: fatigue
Laboratory test abnormalities: 2% of patients had ALT elevations both > 10 times upper limit of the
normal range (ULN) and > 2 times baseline, 5% had ALT elevations > 3 times baseline, and < 1% had
ALT elevations > 2 times baseline together with total bilirubin > 2 times ULN and > 2 times baseline.
Albumin levels < 2.5 g/dl occurred in < 1% of patients, amylase levels > 3 times baseline in 2%, lipase
levels > 3 times baseline in 11% and platelets < 50,000/mm
3 in < 1%.
Cases of lactic acidosis have been reported, often in association with hepatic decompensation, other
serious medical conditions or drug exposures (see section 4.4).
Treatment beyond 48 weeks: continued treatment with entecavir for a median duration of 96 weeks did
not reveal any new safety signals.
Experience in lamivudine-refractory patients:
The safety profile is based on treatment exposure to entecavir 1 mg once daily for a median
c.
Description
of 69 weeks.
selected adverse reactions
Nervous system disorders:
very common: headache
common: dizziness, somnolence
Gastrointestinal disorders:
common: vomiting, diarrhoea, nausea, dyspepsia
General disorders and administration site
conditions:
common: fatigue
Psychiatric disorders:
common: insomnia
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Laboratory test abnormalities:
In clinical studies with nucleoside-naive patients, 5% had ALT
elevations > 3 times baseline, and < 1% had ALT elevations >
2 times baseline together with total
bilirubin > 2 times ULN and > 2 times baseline. Albumin levels < 2.5 g/dl occurred in < 1
% of
patients
had ALT elevations both > 10 times ULN and > 2 times baseline, amylase levels > 3 times
baseline in 2%, lipase levels > 3 times baseline in 11% and platelets < 50,000/mm
3 in < 1%.
In clinical studies with lamivudine-refractory patients
, 4% had ALT elevations > 3 times baseline, and
< 1% had ALT elevations > 2 times baseline together with total bilirubin > 2 times ULN and > 2 times
baseline. Amylase levels > 3 times baseline occurred in 2% of patients, lipase levels > 3 times baseline
in 18% and platelets < 50,000/mm
3 in < 1%.
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