Biology Reference
In-Depth Information
When used with higher dose regimen (total oral dose of 40 or 60 mg per day), the
most frequent adverse events observed with ibudilast were gastrointestinal symp-
toms (nausea and abdominal discomfort) (Feng et al. 2004 ; Kawasaki et al. 1992 ;
Rolan et al. 2008 ), as well as hyperhidrosis and headache (Rolan et al. 2008 ).
Headache and nausea were most frequently observed early in the multiday dosing
period with ibudilast. In patients with multiple sclerosis, depression occurred more
frequently as an adverse event in year 2 at 60 mg per day ibudilast than with placebo
(Barkhof et al. 2010 ), although ibudilast has been reported to benefit in depression
(Inoue and Harada 2008 ).
No consistent changes from baseline in individual laboratory parameters, vital
signs, or electrocardiogram (ECG) were observed in healthy adult subjects with
supratherapeutic doses (60 mg for 14 days) (Rolan et al. 2008 ). According to the
package insert of Ketas ® (Kyorin Pharmaceutical Co., Ltd., Japan), of 14,968
Asian patients treated, elevated levels of liver enzymes were observed for aspartate
aminotransferase (AST, 0.30%), alanine aminotransferase (ALT, 0.35%), and gamma-
glutamyl transpeptidase ( g GT). Total bilirubin was increased in 0.36% of patients.
Thrombocytopenia, anaemia, and leukopenia may occur as well.
3.3 Cilomilast
Gastrointestinal adverse events were the most frequent adverse events in an overall
analysis of the cilomilast phase III program with COPD patients, with two or
three times higher frequencies with cilomilast ( N
¼
2,088) compared with placebo
( N
1,408) for nausea (16 and 5%), diarrhea (15 and 8%), abdominal pain
(11 and 7%), vomiting (7 and 2%), and dyspepsia (7 and 2%) (Rennard et al.
2008 ). In a long-term safety study, the reported adverse event rates of nausea (44
and 14%), vomiting (21 and 8%), and diarrhea (33 and 13%) were nearly threefold
higher with cilomilast (15 mg BID given as maintenance treatment for COPD over
12 months) than with placebo (study SB207499/121, quoted by Rennard et al. 2008 ),
which is in agreement with tolerability results from a large efficiency study in Asians
where at least a two times higher frequency of gastrointestinal adverse events arose
with cilomilast than with placebo (Rennard et al. 2006 ).
Adverse events are generally transient and more prominent at the beginning of
treatment with cilomilast. The frequency of undesirable gastrointestinal events
was clearly dose-related. Nausea was usually mild to moderate and self-limiting
in a 6-week dose-range study in COPD patients ( N
¼
¼ 424) and occurred in 1, 1,
12, and 11% of patients randomized to receive placebo, low (5 mg), medium
(10 mg), and high doses (15 mg) of cilomilast, respectively. Diarrhea was less
common and occurred in 1, 2, 4, and 9% of the respective treatment groups
(Compton et al. 2001 ).
Overall, gastrointestinal adverse events appear to occur more frequently with
cilomilast than with roflumilast in comparable studies.
No differences in tolerability were observed between young and elderly healthy
adults after single oral doses of cilomilast (10 mg) (Zussman et al. 2001a ).
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