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Study No:112331(ZEAA)
Title: Drug Use Investigation of Zefix Tablets
Rationale: This post-marketing surveillance (PMS) was conducted to collect efficacy and safety
data of Zefix administered in the Japanese population by regulatory requirements of the
Japanese authorities.
Phase: Post-Marketing Surveillance (PMS)
Period: June 2001-June 2006
Design: Open label, multi-centre, post-marketing surveillance
Centres: 204 centres in Japan
Indication: Chronic hepatitis B
Treatment: The standard duration of treatment and observation was set at 16 weeks from the
starting day of treatment for prospective patients, and from the starting day of treatment to the
day of completing the survey sheet for retrospective patients.
Objectives: This investigation was carried out to obtain the information listed below, and
examine the presence/absence of necessity of special investigation or post-marketing clinical
trials.
1) Unexpected ADRs (especially, significant ADRs)
2) Status of onset of ADRs under the actual clinical use of Zefix
3) Factors that may affect the safety, efficacy, etc.
Safety Outcome/Variable(s): Presence/absence of AEs, diagnosis or symptoms, date of onset,
outcome, date of outcome, seriousness, reason why it was assessed as serious, severity,
causal relationship with Zefix, and other suspicious factors than Zefix (concomitant drugs,
diseases, or therapies, etc.)
Efficacy Outcome/Variable(s): The investigator made an overall assessment of the patient’s
condition based on a 2-rating 3-category scale, “resp onsive,” “unr esponsive,” an d
“un assessable,”. I f the assessment resulted in unassessable, the reason was investigated.
Statistical Method: Since this surveillance was not designed to test any statistical hypothesis,
basic descriptive statistics were presented.
Study population: This investigation targeted patients with chronic hepatitis B, which is the
indication of Zefix.
Number of Subjects:
Planned, N
3,000
Entered, N
1,877
Completed, n (%)
1,757 (93.61%)
Demographics
N (ITT safety population)
1,740
Female (%): Male (%)
481 (27.64%) : 1,255 (72.13%)
Age, years, n (%)
<15 (children)
0 (0.00%)
≥15 ~ <65 (adults)
1,610 (92.53%)
≥65 (elderly)
130 (7.47%)
Race, n (%)
Japanese
1,740(100.00%)
others
0 (0.00%)
unknown
0 (0.00%)
Indication for use, n (%)
Chronic hepatitis B
1,520 (87.36%)
Chronic hepatitis B and hepatic cirrhosis
19 (1.09%)
Hepatic cirrhosis
150 (8.62%)
Others
49 (2.82%)
Unknown
2 (0.11%)
Histological diagnosis
(new Inuyama classification: F)
F0
8(0.46%)
F1
106(6.09%)
F2
91(5.23%)
F3
129(7.41%)
F4
38(2.18%)
Unknown
1,368 (78.62%)
Histological diagnosis
(new Inuyama classification: A)
A0
4 (0.23%)
A1
94 (5.40%)
A2
195 (11.21%)
A3
75 (4.31%)
Unknown
1,372 (78.85%)
Complications, n (%)
Absent
1,245 (71.55%)
Present
495 (28.45%)
Medical history of hepatic diseases
Absent
1510 (86.78%)
Present
225 (12.93%)
Unknown
5 (0.29%)
Concurrent medications, n (%)
Absent
625 (35.92%)
Present
1,114 (64.02%)
Unknown
1 (0.06%)
Safety Results: (ITT Safety population)
Overall incidence of adverse events related, n
73 events, 66 subjects (3.79%)
(%)
Unexpected adverse events related, n (%)
26 events, 22 subjects
Serious adverse events related, n (%)
21 events, 18 subjects
Safety Outcome Variable(s):
Summary of risk factors by incidence of
Adverse events, n (%)
adverse events
Covariates
Gender, n (%)
Male
50 (3.98%)
Female
16 (3.33%)
UNK
0 (0.00%)
Diagnosis, n (%)
Chronic hepatitis B
56 (3.68%)
Chronic hepatitis B and hepatic cirrhosis
2 (10.53%)
Hepatic cirrhosis
7 (4.67%)
Others
1 (2.04%)
Unknown
0 (0.00%)
Histological diagnosis(new Inuyama
classification: F)
F0
1 (12.50%)
F1
10 (9.43%)
F2
5 (5.49%)
F3
7 (5.43%)
F4
3 (7.89%)
Unknown
Histological diagnosis(new Inuyama
classification: A)
A0
A1
A2
A3
Unknown
Most Frequent Adverse Events – OnTherapy, n (%)
Subjects with any AE(s), n (%)
infections and infestations
investigations
hepatobiliary disorders
nervous system disorders
general disorders and administration site
conditions
gastrointestinal disorders
40 (2.92%)
1 (25.00%)
6 (6.38%)
15 (7.69%)
4 (5.33%)
40 (2.92%)
Zefix (n=1,740)
66 (3.79%)
31 (1.78%)
12 (0.69%)
7 (0.40%)
6 (0.34%)
4 (0.23%)
3 (0.17%)
Serious Adverse Events (SAEs) – OnZefix (n=1,740)
Therapy
60 events, 52 subjects (2.99%)
n (%), [n considered by the investigator to
[21 events, 18 subjects]
be related to study medication]
4 events, 3 subjects (0.17%)
Subjects with fatal SAE(s)
Safety: In this investigation, the incidence of ADRs in 1,740 patients in the safety analysis
population was 3.79% (66/1,740 patients), and significantly lower than 65.30% (303/464
patients), the incidence of ADRs obtained in clinical studies conducted up to the time of
approval of Zefix (p<0.001). The ADRs frequently reported in this investigation were 29
episodes of “hep atitis B” , of which, 26 episodes were reported as exacerbation of hepatitis B
due to the emergence of YMDD variants.
Eighteen patients reported 21 ADRs assessed as serious, and the outcome of these serious
ADRs were assessed as resolved or abated except a total of 8 episodes in 7 patients, i.e., 4
episodes in 3 patients resulting in “d eaths” (1 episode each of hepatic failure, acute renal failure,
sepsis, and hepatitis B), and 4 episodes in 4 patients with the outcome assessed as “persis tent”
or “unk nown” (2 episodes of hepatitis B and 1 episode each of platelet count decreased and
jaundice). Of 4 episodes in 3 patients resulting in “d eaths,” 3 episodes in 2 patients, i.e.,
“he patic failure and acute renal failure” and “sepsis,”
were considered to have occurred during
the natural course of the underlying disease or due to complications, and it was difficult to clarify
the causal relationship with Zefix. As for 1 patient who developed “h epatitis B,” the investigator
assessed that the involvement of YMDD variants could not be ruled out. It is reported that
YMDD variant HBV emerges during the treatment with Zefix, and caution about this issue is
therefore raised by including the following description in “Imp ortant Precautions” in Section
“Prec autions” in the package insert of Zefix: If therapeutic benefits can no longer be attained
due to the emergence of YMDD variants, concomitant use of adefovir dipivixil, which exhibits an
antiviral effect against Zefix-resistant HBV, or discontinuation of treatment with Zefix should be
considered.
No specific tendency in the incidence or onset trend of ADRs, or no clinically significant findings
were observed in special populations such as pediatric patients, elderly patients, pregnant and
parturient women, and patients with renal dysfunction.
Consequently, no emerging issues or concerns with respect to the safety of Zefix were found in
this investigation.
Efficacy Results:
Efficacy: In this investigation, the response rate in 1,463 patients in the efficacy analysis
population was 91.87% (1,344/1,463 patients), and significantly higher than 78.51% (190/242
patients), the response rate (rate of improvement in HBV-DNA) obtained in clinical studies
conducted up to the time of approval of Zefix (p<0.001). A comparable response rate was
obtained in special populations such as pediatric patients, elderly patients, pregnant and
parturient women, and patients with renal dysfunction.
Consequently, no emerging issues or concerns with respect to the efficacy of Zefix were found
in this investigation.
Conclusion: In this investigation, the incidence of ADRs in 1,740 patients in the safety analysis
population was 3.79% (66/1,740 patients). The ADRs frequently reported in this investigation
were 29 episodes of “h epatitis B”. Eighteen patients reported 21 ADRs assessed as serious. No
specific tendency in the incidence or onset trend of ADRs, or no clinically significant findings
were observed in special populations such as pediatric patients, elderly patients, pregnant and
parturient women, and patients with renal dysfunction. No emerging issues or concerns with
respect to the safety of Zefix were found in this investigation.
In this investigation, the response rate in 1,463 patients in the efficacy analysis population was
91.87% (1,344/1,463 patients). No emerging issues or concerns with respect to the efficacy of
Zefix were found in this investigation.
Publication: No publication