Download KIPRES® Tablets 5mg KIPRES® Tablets 10mg KIPRES® OD

Kyorin Pharmaceutical Co., Ltd.
Revised: September 2016 (28th version)
1
Standard Commodity Classification No. of Japan
87449
- LEUKOTRIENE RECEPTOR ANTAGONIST - ANTI-BRONCHIAL ASTHMA AND ALLERGIC RHINITIS DRUG ®
KIPRES Tablets 5mg
KIPRES® Tablets 10mg
< The Japanese Pharmacopoeia Montelukast Sodium tablets >
®
KIPRES OD Tablets 10mg
< Montelukast sodium orally disintegrating tablets >
Storage
Film coated tablets 5mg/10mg: Store at
Approval No.
room temperature, protect from light .
Date of listing in the
OD tablets 10mg: Store at room
NHI reimbursement
temperature
price
Date of initial
Expiration date
marketing in Japan
Indicated on package
Date of latest
(Use up the film cotaed tablets as soon
reexamination
as possible after opening the seal, even
Date of latest approval
if it is before expiration date.)
of indicaion
Film coated tablets 5mg
Film coated tablets 10mg
OD tablets 10mg
22000AMX00010000
22000AMX0040000
22700AMX00773000
April 2008
June 2008
December 2015
April 2008
August 2001
December 2015
March 2016
－
January 2008
－
International birth date
July 1997
－
July 1997
Cautions
See “PRECAUTIONS FOR
HANDLING”.
CONTRAINDICATIONS (This product is contraindicated in the following patients.)
Patients who are hypersensitive to any component of
KIPRES
Product description
Active ingredient
Inactive ingredient
Dosage form
Color
Appearance
Diameter
Weight
Identification code
Brand name
DESCRIPTION
Brand name
Thickness
Active ingredient
KIPRES
KIPRES
Tablets5mg
Tablets10mg
Montelukast 10 mg
Montelukast 5 mg
: The Japanese
: The Japanese
Pharmacopoeia (JP)
Pharmacopoeia (JP)
Lactose monohydrate, crystalline cellulose,
hydroxypropyl cellulose, croscarmellose
sodium, magnesium stearate, hypromellose,
titanium dioxide, red ferric oxide, yellow
ferric oxide, carnauba wax
Film-coated tablets
Beige
Long diameter:7.6 mm
Short diameter:5.6 mm
8.0 mm
Inactive ingredient
Dosage form
Color
2.9mm
About 103mg
KP-374
KIPRES OD
Tablets10mg
Montelukast 10 mg
: The Japanese
Pharmacopoeia (JP)
D-mannitol, gelatin,
sucralose, flavor
Orally disintegrating
tablet
White
Diameter
Appearance
About 9.2mm
Thickness
Weight
Identification code
About 6.2mm
About 34mg
KP-375 (package)
4.1mm
About 205mg
KP-372
2
Kyorin Pharmaceutical Co., Ltd.
INDICATIONS
Bronchial asthma, Allergic rhinitis
DOSAGE AND ADMINISTRATION
< Bronchial asthma>
The usual dosage for adults is 10 mg as montelukast orally
administered once daily at bedtime.
< Allergic rhinitis>
The usual dosage for adults is 5 - 10 mg as montelukast orally
administered once daily at bedtime.
PRECAUTIONS FOR DOSAGE AND ADMINISTRATION
KIPRES Tablets5mg, KIPRES Tablets10mg
Since the montelukast film-coated tablet is not biologically
equivalent to the montelukast chewable tablet, and since the
bioavailability of the montelukast chewable tablet is higher
compared to the montelukast film-coated tablet 1), the
montelukast film-coated 5-mg tablet and the montelukast
chewable 5-mg tablet should not be substituted with each
other.
KIPRES Tablets5mg, KIPRES Tablets10mg, KIPRES OD
Tablets10mg
For adult patients with concomitant bronchial asthma and
allergic rhinitis in whom montelukast should be used to treat
bronchial asthma, 10 mg of montelukast should be given orally
once daily at bedtime.
PRECAUTIONS
1. Important Precautions
1) Patients with asthma should be advised to continue taking
KIPRES not only during periods of worsening asthma, but
also while their asthma is controlled.
2) Because KIPRES differs from bronchial dilators, steroids,
etc., it is not a drug to relieve existing asthma attacks. This
fact must be fully explained to the patients.
3) If a major attack is observed when administering KIPRES
to a bronchial asthma patient, a bronchial dilator or steroid
must be administered.
4) If the patient is receiving long-term steroid treatment and
the plan is to reduce the amount of steroids by administering
KIPRES, this should be accomplished gradually under strict
supervision.
5) If the patient has been able to reduce the amount of steroid
support by administering KIPRES, be cautious about the
possibility of reoccurrence of the original symptoms.
6) Psychiatric symptoms including depression, suicidal
ideation, suicide and aggressive behavior have been
reported although a causal relationship with this drug is not
clear. Therefore, the patient's condition should be
sufficiently observed. (See the "Other Precautions"
subsection)
7) There are reports that Churg-Strauss syndrome-like angiitis
have occurred during use of leukotriene antagonists, which
includes KIPRES. These symptoms are mainly produced
when reducing or suspending the use of oral steroids. When
using KIPRES, be cautious about eosinophil count and
angiitic symptoms (numbness, weakness of limbs, pyrexia,
arthralgia, and infiltration of the lung, etc.)
8) When the efficacy of KIPRES is not observed, therapy with
KIPRES should not be continued randomly for a long-term
period.
2. Drug Interactions
This drug is mainly metabolized by the drug metabolizing
enzymes cytochromes P450 (CYP) 2C8/2C9 and 3A4. [See
the “PHARMACOKINETICS” section.]
[Careful coadministration (This drug should be
coadministered with caution.)]
Drug
Phenobarbital
Signs,
symptoms and
treatment
The action of
Mechanism
factors
and
this drug may be
CYP3A4, thereby
reduced.
promoting the
risk
Phenobarbital induces
metabolism of this
drug.[See the
"PHARMACOKINET
ICS" section.]
3. Adverse Reactions
<Bronchial asthma>
In clinical studies conducted in Japan, 66 adverse reactions
were reported in 46 (8.8%) of 523 patients. The most
frequently reported adverse reactions observed were
diarrhea (9 events, 1.7%), abdominal pain (7 events, 1.3%),
nausea (6 events, 1.1%), heart burn (5 events, 1.0%) and
headache (5 events, 1.0%). Also, 80 abnormalities in
laboratory test findings were observed in 49 patients of 507
patients and the most frequently reported abnormalities
were increased ALT (GPT) (14 events in 505 patients),
increased γ-GTP (9 events in 463 patients) and increased
alkaline phosphatase (8 events in 476 patients). (date at the
time of approval)
In the special drug-use- surveillanceconducted in Japan,
116 cases (including abnormal laboratory test values) of
adverse reactions were observed in 94 patients out of 3,891
patients evaluated for safety (2.4%).
The main adverse reactions were hepatic function
abnormal, increased blood lactate dehydrogenase, increased
blood alkaline phosphatase,rash in 8 cases each
respectively (0.2%), and pruritus in 6 cases (0.2%).[At the
end of reexamination]
< Allergic rhinitis >
In clinical studies conducted in Japan, 88 adverse reactions
were reported in 70 (4.2%) of 1678 patients. The most
frequently reported adverse reactions observed were dry
mouth (14 events, 0.8%), somnolence (13 events, 0.8%),
epigastric discomfort (9 events, 0.5%), headache (5 events,
0.3%), diarrhea (5 events, 0.3%) and malaise (5 events,
0.3%). No adverse reaction more than 1% was reported.
Also, 51 abnormalities in laboratory test findings were
observed in 46 patients of 1672. The most frequently
reported abnormalities were increased ALT (GPT) (9
Kyorin Pharmaceutical Co., Ltd.
events in 1672 patients), white blood cell count increased
(6 events in 1670 patients) and occult hematuria (6 events
in 1671 patients) and similar to the ones observed in
bronchial asthma patients. (date at the time of approval)
In the post-marketing survey(drug use surveillance and
special drug use surveillance) conducted in Japan, 9 cases
(including abnormal laboratory test values) of adverse
reactions were observed in 9 patients out of 1,365 patients
evaluated for safety (0.7%).
The main adverse reactions were somnolence in 2 cases
(0.1%), pruritus generalized in 2 cases (0.1%). [At the end
of reexamination]
1) Clinically significant adverse reactions
(1) Anaphylaxis (frequency unknown)
Since anaphylaxis may occur, close observation
should be maintained. If symptoms appear, this drug
should be discontinued immediately and appropriate
measures should be taken.
(2) Angioedema (frequency unknown)
Since angioedema may occur, close observation
should be maintained. If symptoms appear, this drug
should be discontinued immediately and appropriate
measures should be taken.
(3) Fulminant hepatitis(frequency unknown),
hepatitis(frequency unknown), hepatic
dysfunction(0.01%), jaundice (frequency unknown)
Since fulminant hepatitis, hepatitis, hepatic
dysfunction and jaundice may occur, close
observation should be maintained. If abnormalities are
observed, this drug should be discontinued and
appropriate measures should be taken.
(4) Toxic epidermal necrolysis (TEN) (frequency
unknown), oculomucocutaneous syndrome
(Stevens-Johnson syndrome) (frequency unknown),
erythema multiforme (0.01%)
Since toxic epidermal necrolysis,
oculomucocutaneous syndrome and erythema
multiforme may occur, close observation should be
maintained. If abnormalities are observed, this drug
should be discontinued and appropriate measures
should be taken.
(5)Thrombocytopenia(frequency unknown)
Thrombocytopenia (initial symptoms: bleeding
tendency such as purpura, nose bleeding and gingival
bleeding) may occur. Therefore, if such a symptom as
this occurs, this drug should be discontinued and
appropriate measures should be taken.
2) Other Adverse Reactions
If the following symptoms or abnormalities appear,
appropriate measures such as discontinuation of therapy
should be considered.
0.1% <1%
Hyper-
Rash,
sensitivity
pruritus
<0.1%
Urticaria
Incidence
unknown
3
Psychiatric
Headache,
Restlessness,
Dream
and nervous
somnolence
insomnia,
abnormalities,
hallucination,
irritability,
dizziness,
seizure,
sensory
agitation,
abnormality
tremor,
(numbness)
somnambu-
system
lism,
disorientation,
mental
concentration
decreased,
memory
impairment,
delirium
Respiratory
Pulmonary
eosinophilia
Gastro-
Diarrhea,
Heartburn,
intestinal
abdominal
vomiting,
system
pain,
constipation,
epigastric
stomatitis
discomfort,
nausea
Hepatic
Hepatic
function
abnormal,
increased
AST
(GOT),
increased
ALT
(GPT),
increased
alkaline
phosphatase
, increased
γ-GTP,
increased
total
bilirubin
Musculoske
Myalgia
letal system
including
muscle
cramps,
arthralgia
Others
Dry mouth,
Hematuria,
bruise,
occult
sugar urinary,
weakness,
hematuria
edema,
fatigue,
malaise, white
enuresis
blood cell
count
increased,
protein urine,
blood
Hepatic
triglycerides
eosinophilic
increased,
infiltration
Dyspepsia
4
Kyorin Pharmaceutical Co., Ltd.
bleeding,tend
ency (nose
bleeding,
purpura),
palpitation,
urinary
frequency,
pyrexia,
alopecia
The adverse reaction frequency was calculated based on
clinical studies, post-marketing surveys (drug-use-results
survey, specific drug-use-results survey, and post
marketing clinical studies) of Tablets, Chewable Tablets
and Fine Granules conducted in Japan.
4. Use during Pregnancy, Delivery or Lactation
1) KIPRES should be administered to pregnant women or
women suspected of being pregnant only when it is
judged that the benefits from the treatment exceed the
possible risks.
[The safety of KIPRES in pregnant women has not been
established. During worldwide marketing experience,
congenital limb malformations have been reported in the
offspring of women being treated with KIPRES during
pregnancy. Most of these women were also taking
other asthma medications during their pregnancy. A
causal relationship between these events and KIPRES
has not been established.]
2) Caution should be used in the administration of KIPRES
to nursing mothers.
[In animal studies (rats), it has been reported that
KIPRES is secreted into breast milk.]
5. Pediatric Use
<Bronchial asthma>
1) For pediatric patients ≥6 years of age, montelukst
chewable tablet 5-mg should be administered once daily
at bedtime.
2) For pediatrics ≥1 year and <6 years of age, montelukast
fine granules 4-mg should be administered once daily at
bedtime.
3) The safety of montelukast formulations in babies under 1
year of age, newborns and premature babies has not been
fully established.
[Due to lack of domestic experience with montelukast
formulations]
<Allergic rhinitis>
The safety of montelukast formulations in children has
not been established.
[Due to lack of domestic experience with montelukast
formulations]
6. Precautions concerning Use
1) KIPRES Tablets5mg, KIPRES Tablets10mg
At the time of delivery:When drugs packed in a PTP
sheet are used, patients should be instructed to take the
drugs out of the sheet.
[It has been reported that when patients mis-swallowed
drugs with a PTP sheet (after failing to take the drugs out
of the sheet), a hard, sharply angled edge of the sheet
struck to the esophageal mucosa. Furthermore, if
perforation occurred, serious complications, such as
mediastinitis were reported.]
2) KIPRES OD Tablets10mg
(1) At the time of delivery: The following instructions
should be provided:
①The drug must be removed from the blister sheet
before ingestion. [If the blister packaging is
swallowed, the sharp corners of the packaging may
puncture the esophageal mucosa, resulting in severe
complications such as mediastinitis.]
②To remove the drug from the blister sheet, peel off the
sheet from the back of the foil completely
and take the drug out carefully. Do not push a OD
tablet though the foil without first peeling off the
sheet because breakage may occur since OD tablets
are characteristically soft compared to regular
tablets. If chipping or breakage occurs, all pieces of
the OD tablets should be ingested.
③The drug should only be removed from the blister
sheet immediately before use since this drug
absorbs moisture.
(2) At time of administration: Since KIPRES OD tablets
will disperse after placement on the tongue, it can be
swallowed without or with water.
3) KIPRES Tablets5mg, KIPRES Tablets10mg, KIPRES
OD Tablets10mg
KIPRES may be taken with or without food.
7. Other Precautions
The result of a pooled analysis of 41 placebo-controlled
clinical studies indicated that while suicidal ideation was
observed in one out of 9,929 patients in the montelukast
group, no suicidal ideation was observed in 7,780 patients in
the placebo group.2)
Also, the result of a separate pooled analysis of 46 placebocontrolled clinical studies indicated that behavior-related
adverse experiences (including insomnia and irritability)
were observed in 319 (2.73%) out of 11,673 patients in the
montelukast group and 200 (2.27%) out of 8,827 patients in
the placebo group. No statistically significant difference was
observed between them.3)
PHARMACOKINETICS
1. Blood Concentration
1) Results of Domestic Clinical Studies
(1) Following a single oral dose of montelukast filmcoated tablets 10-mg to 8 healthy adults in the fasted
state, the peak plasma concentration (Cmax, 526
ng/mL) of montelukast was reached in 3.9 hours
(Tmax), and plasma concentrations declined with an
apparent half-life (t1/2) of 4.6 hours (Figure 1). Cmax
and the area under the plasma concentration-time
curve (AUC0→∞ ) increased proportionally with dose
in the range of 2 to 50 mg (Table 1). 4)
Kyorin Pharmaceutical Co., Ltd.
5
(fasted condition)
Fig.1 Plasma Concentration Profile Following Single Oral Administration
of Montelukast Film-coated Tablets 10mg in Healthy Adults
(ng/mL)
1000
10mg
10 mg
n=8：平均値±標準偏
差n=8, Mean±S.D.
Plasma concentration
◆
血
漿
中
濃 100
度
Table 2 Pharmacokinetic Parameters in Healthy Adults
(fasted condition)
With
water
(hr)
10
Table 01 Pharmacokinetic
in16Healthy 20Adults
4
8 Parameters
12
時間
Dose
(mg)
Tmax
(hr)
2
2.8±0.9
108±23.1
10
3.9±1.5
50
3.6±1.2
Cmax Time t1/2
(ng/mL)
(hr)
24
AUC0→∞
(ng·hr/mL)
4.34±0.76
753±242
526±138
4.57±0.39
3840±906
2550±
4.63±0.41
19100±
1250
7910
(2) Administration of montelukast film-coated tablets 10mg after meal to 8 healthy adults resulted in a 24%
increase in AUC0→∞ from 3,420 ± 598 ng · hr/mL to
4,240 ± 1,120 ng · hr/mL compared with
administration in the fasted state. No differences in
Tmax (fasting: 4.0 ± 1.1 hr, after meal: 4.4 ± 1.8 hr)
and t1/2 (fasting: 4.31 ± 0.58 hr, after meal: 4.30 ±
0.35 hr) were observed when administered after meal
and in the fasted state. 4)
(3) When montelukast film-coated tablets 10-mg was
orally given once daily to 8 healthy adults at a 10-mg
dose for 7 consecutive days, the Cmax was 580 ± 136
ng/mL on the 1st day and 660 ± 124 ng/mL on the 7th
day. No clinically important accumulation of KIPRES
was observed due to multiple administration, as the
AUC 0-24 hr on 7th day agrees well with the AUC0→∞
on 1st day. 4)
(4) Following the administration of a single oral dose of
montelukast OD tablets 10 mg (1 tablet without or
with water) or montelukast film-coated tablet 10 mg 1
tablet with water in healthy adult males (120 subjects)
in a fasted state in a crossover trial, pharmacokinetic
parameters and change in plasma concentrations of
montelukast were as shown below. The results
demonstrate bioequivalence of montelukast OD 10
mg (without and with water) relative to montelukast
film-coated tablet 10 mg since the 90% confidence
intervals of the geometric mean ratios for Cmax and
AUC0-t were within log (0.8) and log (1.25).5)
Fig.2 Plasma Concentration Profile Following Single Oral
Administration of Montelukast OD tablets 10mg and
Montelukast Film-coated Tablets 10mg in Healthy Adults
OD tablet
10mg
Mean±S.D.
No
Yes
N
12
0
11
9
Film-coated
11
tablets 10mg
Yes
9
Mean±S.D.
OD tablet 10 mg (without
water) /
Film-coated tablet 10 mg
Geometric mean ratio
(90% CI)
OD tablet 10 mg (with water) /
Film-coated tablet 10 mg
Geometric mean ratio
(90% CI)
Cmax
(ng/mL)
588±
129
531±
138
AUC0-t
(ng/hr/mL)
3917±
1001
3638±
1036
Tmax
(hr)
2.4±
1.1
2.1±
0.9
t1/2
(hr)
4.6±
2.4
4.2±
0.5
495±
105
3517±
878
3.6±
1.4
4.2±
0.6
1.17
(1.10 to
1.24)
1.10
(1.05 to
1.15)
－
－
1.06
(1.01 to
1.11)
1.03
(0.99 to
1.07)
－
－
2) Results of Clinical Studies Conducted Overseas
(Reference)
(1) Following a single oral dose of montelukast filmcoated tablets 10-mg to the healthy elderly (65 to 73
years of age), the Cmax (495 ng/mL) was achieved
in 2.8 hours, and plasma concentrations declined
with a t1/2 of 6.6 hours. AUC0→∞ in the elderly
(3,423.2 ± 1,344.7 ng · hr/mL) was not significantly
different from that in the healthy non-elderly
(3,624.0 ± 1,257.8 ng · hr/mL, 20 to 48 years of age).
6)
(2) Following a single oral dose of montelukast filmcoated tablets 10-mg to patients with mild-tomoderate hepatic insufficiency and clinical evidence
of cirrhosis, the Cmax (313 ng/mL) was achieved in
4.0 hours, and plasma concentrations declined with a
t1/2 of 8.6 hours. The t1/2 of the patients was slightly
longer compared with 4.7 hours in healthy adults,
and the AUC0→∞ increased by 41% from 2,248.7 ±
812.1 ng · hr/mL to 3,167.2 ± 1,300.5 ng · hr/mL. 7)
(3) Bioavailability of KIPRES in healthy adults was
58% to 67%.8)
2. Distribution
The binding of montelukast with human plasma proteins
was 99.6%. Montelukast was more than 99% bound to both
albumin and α1-acid glycoproteins at physiological
concentrations. 9)
6
Kyorin Pharmaceutical Co., Ltd.
3. Metabolism
The main metabolites of montelukast in human are side
chain methyl hydroxylated metabolites and benzylic
methylene hydroxylated metabolites. Cytochromes P450
(CYP) molecular species CYP2C8/2C9 and 3A4 are
involved in the formation of these metabolites, and
CYP2C8 is the main enzyme in the metabolism of
montelukast. It has been confirmed that side chain methyl
hydroxylated metabolites are further metabolized
oxidatively to carboxylic acid metabolites. Based on further
in vitro results, therapeutic plasma concentrations of
montelukast do not inhibit CYP3A4, 2C9, 1A2, 2A6, 2C19,
or 2D6. 10) ~13)
Also, other in vitro studies have shown that montelukast is
an inhibitor of CYP2C8. However, data from an overseas
clinical drug-drug interaction study involving montelukast
and a representative drug primarily metabolized by
CYP2C8 (rosiglitazone) demonstrated that montelukast
does not inhibit CYP2C8 in vivo. 14) Therefore montelukast
is not anticipated to alter the metabolism of drugs
metabolized by this enzyme (e.g. paclitaxel.)
4. Excretion
1) Results of Domestic Clinical Studies
Following single 400-mg oral administration of
montelukast capsules to healthy adults, unchanged drug
was not detected in the urine. 4)
2) Results of Clinical Studies Conducted Overseas
(Reference)
During the 5 days after single oral administration of 102
mg of radiolabeled montelukast capsules to healthy adults,
86 % of the radioactivity was recovered in feces and 0.1 %
in urine. 15)
5. Coadministration with other agents (Results of Clinical
Studies Conducted Overseas, Reference)
1) Phenobarbital 16)
When 100 mg phenobarbital (repeated administration for
14 days) was administered to healthy adults and then
montelukast film-coated tablets 10 mg (single
administration) was orally coadministered, the AUC0-∞
of montelukast was reduced by approximately 40%.
2) Theophylline 17)
When a high oral dose of montelukast capsules (200 mg
qd repeated administration for 6 weeks or 200 mg tid
repeated administration for 8 days) was coadministered
with an oral dose of theophylline (250 mg single
administration) to healthy adults or coadministered with
an intravenous dose of theophylline (5 mg/kg single
administration), a decrease in plasma concentrations of
theophylline was observed. Theophylline plasma
concentrations did not change when an oral 10-mg dose
of montelukast film-coated tablets (repeated
administration for 10 days) was coadministered with an
intravenous dose of 5 mg/kg theophylline (single
administration).
3) Prednisone, Prednisolone
Following oral coadministration of 200 mg montelukast
capsules (repeated administration for 6 weeks) with 20
mg prednisone (single administration) to healthy adults,
the AUC0-∞ of prednisone was significantly lowered
compared with placebo group. However, the AUC0-∞ of
prednisone was not changed between before and after the
administration of 200 mg montelukast capsules within
the same subjects. The pharmacokinetics of the active
metabolite prednisolone was not changed.
Coadministration of 200 mg montelukast capsules
(repeated administration for 6 weeks) with 20 mg
intravenous prednisolone (single administration) to
healthy adults had no effect on the pharmacokinetics of
either prednisone or prednisolone.
4) Oral contraceptives 18) (ethinyl
estradiol/norethindrone 35 μg/1 mg)
Following oral coadministration of 100 mg montelukast
capsules (repeated administration for 8 days) with oral
contraceptives (ethinyl estradiol/norethindrone 35 μg/1
mg single administration) to healthy adults, the
pharmacokinetics of either ethinyl estradiol or
norethindrone was not affected.
5) Digoxin 19)
Following oral coadministration of montelukast filmcoated tablets 10 mg (repeated administration for 7 days)
with 0.5 mg digoxin (single administration) to healthy
adults, the pharmacokinetics of immunoreactive digoxin
was not affected.
6) Warfarin 20)
Following oral coadministration of montelukast filmcoated tablets 10 mg (repeated administration for 7 days)
with 30 mg warfarin (single administration) to healthy
adults, the plasma total drug concentrations of warfarin
were not affected. Also, no effect on prothrombin time of
warfarin was observed.
(Note)
The approved dosage of KIPRES for adult bronchial
asthma is 10 mg.
The approved dosage of KIPRES for adult allergic
rhinitis is 5 - 10 mg.
CLINICAL STUDIES
In clinical studies conducted in Japan, the tolerability of
KIPRES has been shown to be up to 400 mg/day in healthy
adults. 4)
<Bronchial asthma>
1. In clinical studies including a double-blind comparative
study conducted in Japan, the efficacy rate of KIPRES 10
mg group was 55.6% (145/261 patients) for definitive
general improvement in adult patients with bronchial
asthma. Also, the efficacy was 56.1% (32/57 patients) in
patients 65 years of age and older and was similar to that for
patients less than 65 years of age (113/204 patients, 55.4%).
Furthermore, the incidence of adverse reactions in patients
65 years of age and older was 9.0 % (10/111 patients) and
Kyorin Pharmaceutical Co., Ltd.
was similar to the incidence of 8.7% in patients less than 65
years of age (36/412 patients).
2. In double-blind, comparative Phase III clinical studies in
patients with bronchial asthma, the efficacy rate for KIPRES
10 mg group in final general improvement is 58.5% (83/142
patients) and that for pranlukast hydrate (450 mg) is 46.0%
(63/137 patients). The non-inferiority (non-inferiority
margin Δ=10%) of KIPRES to pranlukast were
demonstrated. 21)
<Allergic rhinitis>
1. In a phase II dose-finding study in approximately 900
patients with seasonal allergic rhinitis, the change from
baseline (LS mean) of composite nasal symptoms score
[average of daytime nasal symptoms score* and nighttime
nasal symptoms score** (average over the 2-week treatment
period)] are -0.47 in montelukast film-coated tablets 5 mg
group and -0.47 in montelukast film-coated tablets 10 mg
group. Both group showed significant improvement of
composite nasal symptoms score compared with placebo (0.37). 22)
2. In a phase III double blind study in approximately 1400
patients with seasonal allergic rhinitis, the change from
baseline (LS mean) of composite nasal symptoms score
[average of daytime nasal symptoms score* and nighttime
nasal symptoms score** (average over the 2-week treatment
period)] are -0.19 in montelukast film-coated tablets 5 mg
group, -0.19 in montelukast film-coated tablets 10 mg group,
and -0.20 in pranlukast hydrate 450 mg group. The noninferiority (non-inferiority margin Δ=0.085) of KIPRES to
pranlukast hydrate were demonstrated. 23)
*: Compilation of the symptoms score of nasal congestion,
rhinorrhea, and sneezing
**: Compilation of the symptoms score of nasal congestion,
difficulty going to sleep, and nighttime awakening
(Note)
The approved dosage of KIPRES for adult bronchial
asthma is 10 mg.
The approved dosage of KIPRES for adult allergic rhinitis
is 5 - 10 mg.
PHARMACOLOGY
Mechanism of Action
<Bronchial asthma>
Montelukast binds with high selectivity to type 1 cysteinyl
leukotriene (CysLT1) receptors, thereby inhibiting the
pathophysiologic actions (bronchoconstriction, vascular
permeability, and mucus secretion) of the pro-inflammatory
mediators LTD4 and LTE4. Due to this mechanism of action,
montelukast significantly improves parameters of asthmatic
inflammation contributing to its anti-asthmatic effect.
<Allergic rhinitis>
In allergic rhinitis, CysLTs are released from the nasal
mucosa after allergen exposure during both early- and latephase reactions and are associated with symptoms of allergic
rhinitis. Intranasal challenge with CysLTs has been shown to
increase nasal airway resistance and symptoms of nasal
obstruction. Montelukast blocks the actions of leukotriene
7
receptors, which suggestively play an important role in relief
of the symptoms of allergic rhinitis.
1. LT Receptor Antagonism (Receptor Binding Studies)
In receptor binding studies using membranes isolated from
guinea pig lung, U937 and THP-1 cells, the binding of
LTD4 to receptors was shown to be strongly inhibited by
KIPRES and this inhibition was not affected by the
presence of blood ingredients. On the other hand, a weak
receptor antagonism against LTC4 and LTB4 was
observed24).
2. Inhibitory Effect on Bronchoconstriction (Isolated Tissues
and Animal Studies)
The LTD4-induced contractions were competitively
inhibited by KIPRES in isolated guinea pig trachea.
KIPRES was also shown to have a potent, continuous
inhibitory action against LTD4-induced bronchoconstriction
reactions in guinea pigs and squirrel monkeys. On the other
hand, KIPRES did not block contraction of isolated tissues
induced by LTC4 (in the absence of LTC4 metabolism).
Also, there was almost no inhibition of bronchoconstriction
in guinea pigs induced by histamine, arachidonic acid,
serotonin and acetylcholine. 24)
3. Inhibitory Effect on Antigen-Induced Bronchoconstriction
KIPRES inhibited antigen-induced bronchoconstriction
reactions in sensitized inbred asthmatic rats, guinea pigs
and squirrel monkeys when administered intravenously or
orally. 24)
In overseas clinical studies, KIPRES inhibited early and
late-phase bronchoconstriction due to antigen challenge by
75% and 57%, respectively. 25)
4. Inhibitory Effect on Immediate and Delayed Bronchoconstriction Reactions
KIPRES inhibited antigen-induced immediate and delayed
bronchoconstriction reactions in sensitized squirrel
monkeys when administered orally. 24)
5. Inhibitory Effect on Anaphylactic Shock
KIPRES partly inhibited anaphylactic shock induced by
egg albumin in sensitized guinea pigs. 26)
6. Inhibitory Effect on the Increase of Allergen-induced
Nasal Resistance (Nasal Congestion)
KIPRES inhibited the increase of ovalbumin-induced nasal
resistance (nasal congestion) in sensitized guinea pigs, by
55% and 85% at 1 mg/kg and 3 mg/kg (intraperitoneal
treatment), respectively. 27)
7. Improvement of Pulmonary Function
KIPRES improved the forced expiratory volume in 1
second and peak expiratory flow in patients with mild-tomoderate chronic bronchial asthma. 28)
8. Effect on Eosinophils
8
Kyorin Pharmaceutical Co., Ltd.
KIPRES significantly reduced the sputum eosinophil to
total leukocyte ratio in patients with mild-to-moderate
chronic bronchial asthma, compared with placebo.29)
Similarly, KIPRES significantly reduced the peripheral
blood eosinophil to total leukocyte ratio in adult asthmatic
patients, 28) and pediatric asthmatic patients. 30), 31)
PHYSICOCHEMISTRY
Nonproprietary name:
Montelukast Sodium (JAN)
Chemical name:
Monosodium (1-{[((1R )-1-{3-[(1E )-2-(7chloroquinolin-2-yl)ethenyl]phenyl}-3-[2-(1-hydroxy1-methylethyl)phenyl]propyl)sulfanyl]methyl}
cyclopropyl)acetate
Molecular formula:
C35H35ClNNaO3S
Molecular weight:
608.17
Structural formula:
1) Knorr, B. et al.: J. Clin. Pharmacol., 39(8): 786,1999
2) Philip, G., et al.: J. Allergy Clin. Immunol., 124(4): 691, 2009
3) Philip, G., et al.: J. Allergy Clin. Immunol., 124(4): 699, 2009
4) Ohnishi, A. et al.: J. Clin. Ther. Med., 17 (4): 443, 2001
5) Bioequivalence study of montelukast (In-house data)
6) Zhao, J.J. et al.: Biopharm. Drug Dispos., 18(9):769,1997
7) Pharmacokinetics of montelukast in patients with hepatic
insufficiency (In-house data)
8) Bioavailability of montelukast (In-house data)
9) Binding of montelukast with proteins (In-house data)
10) Filppula, A. M. et al.: Drug Metab. Dispos., 39(5): 904, 2011
11) Karonen, T. et al.: Br. J. Clin. Pharmacol., 73(2): 257, 2012
12) Karonen, T. et al.: Clin. Pharmacol. Ther., 88(2): 223, 2010
13) Chiba, M. et al.: Drug Metab. Dispos., 25(9):1022,1997
14) Friedman, E. et al.: Clin. Pharmacol. Ther., 79(2):72, 2006
15) Balani, S. K. et al.: Drug Metab. Dispos., 25 (11): 1282, 1997
16) Holland, S. et al.: Clin. Pharmacol. Ther., 63(2):231,1998
17) Malmstrom, K. et al.: Am. J. Ther., 5(3):189, 1998
18) Schwartz, J. et al.: Clin. Pharmacol. Ther., 61(2):162,1997
19) Depre, M. et al.: J. Clin. Pharmacol., 39(9):941,1999
20) Van Hecken, A. et al.: J. Clin. Pharmacol., 39(5):495,1999
CO2Na
H
Cl
REFERENCES
N
S
21) Miyamoto, T. et al.: J. Clin. Ther. Med., 17 (4): 519, 2001
22) Okubo, K. et al.: Allergol. Int., 57(3): 247, 2008
23) Okubo, K. et al.: Allergol. Int., 57(4): 383, 2008
OH
CH3
CH3
Description:
Montelukast Sodium occurs as a white to pale yellow-white
powder.
It is very soluble in methanol and in ethanol (99,5), and
freely soluble in water.
It is hygroscopic.
It turns yellow on exposure to light.
It shows a crystal polymorphism.
24) Jones, T.R. et al.: Can. J. Physiol. Pharmacol., 73(2):191, 1995
25) Diamant, Z. et al.: Clin. Exp. Allergy, 29(1):42, 1999
26) Inhibitory effects of montelukast on anaphylactic shock (In-house
data)
27) Inhibitory effects of montelukast on the increase of allergen-induced
nasal resistance (nasal congestion) (In-house data)
28) Miyamoto, T. et al.: J. Clin. Ther. Med., 17 (4): 577, 2001
29) Minoguchi. K. et al.: Chest, 121 (3): 732, 2002
30) Furusyo, K. et al.: J. Clin. Ther. Med., 17 (4): 609, 2001
31) Furusyo, K. et al.: J. Clin. Ther. Med., 21 (10): 1019, 2005
Partition coefficient:
Log KD=2.3±0.2 in 1-octanol/phosphate buffered system
(pH7)
PRECAUTIONS FOR HANDLING
Storage conditions:Protect from moisture after opening the
seal.
PACKAGING
KIPRES Tablets 5 mg:
PTP: 28 Tablets (14 Tablets x 2)
100 Tablets (10 Tablets x 10)
140 Tablets (14 Tablets x 10)
KIPRES Tablets 10mg:
PTP: 28 Tablets (14 Tablets x 2)
100 Tablets (10 Tablets x 10)
140 Tablets (14 Tablets x 10)
420 Tablets (14 Tablets x 30)
500 Tablets (10 Tablets x 50)
KIPRES OD Tablets 10mg:
Blister sheet
60 Tablets (10 Tablets x 6)
200 Tablets (10 Tablets x 20)
REQUEST FOR LITERATURE SHOULD BE
MADE TO:
A request for in-house data mentioned in the References can
also be made to the following.
Kyorin Pharmaceutical Co, Ltd. Drug Information Center
6, Kanda surugadai 4-chome, Chiyoda-ku, Tokyo 101-8311,
Japan
TEL: 0120-409-341 (Toll-free)
9:00 to 17:30 (Monday through Friday exclusive of national
holidays)
Manufactured and marketed by:
Kyorin Pharmaceutical Co., Ltd.
6, Kanda surugadai 4-chome, Chiyoda-ku, Tokyo 101-8311,
Japan