Download Azeptin Azeptin

Eisai Co., Ltd.
Revised: January 2010 (12th version)
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Standard Commodity Classification No. of Japan
87449
- Drug for allergic diseases -
Azeptin® Tablets 0.5mg
Azeptin® Tablets 1mg
<Azelastine hydrochloride preparation>
Storage
1) AZEPTIN should be stored at room temperature.
2) AZEPTIN (1mg) package in the bottle should be
protected from light and moisture once the bottle
is opened.
Expiration date
AZEPTIN should be used before the expiration date
indicated on the package or label.
Approval No.
Date of listing in the NHI reimbursement price
Date of initial marketing in Japan
Date of latest reexamination
Date of latest approval of indications
DESCRIPTION
1. Composition
Tablets 0.5 mg:
Each white, sugar coated tablet contains 0.5 mg of azelastine hydrochloride.
It also contains powdered acacia, carnauba wax, hydrated
silicon dioxide, microcrystalline cellulose, titanium oxide, stearic acid, calcium stearate, sucrose, talc, precipitated calcium carbonate, corn starch, lactose hydrate,
white shellac, hydroxypropylcellulose, povidone and
macrogol 6000 as inactive ingredients.
Tablets 1 mg:
Each white, sugar coated tablet contains 1 mg of azelastine hydrochloride.
It also contains carnauba wax, hydrated silicon dioxide,
microcrystalline cellulose, titanium oxide, stearic acid,
calcium stearate, sucrose, talc, precipitated calcium carbonate, corn starch, lactose hydrate, white shellac, hydroxypropylcellulose, pullulan, povidone and macrogol
6000 as inactive ingredients.
2. Product description
Brand
name
AZEPTIN
Tablets
0.5mg
AZEPTIN
Tablets
1mg
Dosage form
and identification code
Appearance
Face
Reverse
Description
Lateral
White
Sugercoated
tablets
232
Diameter
(mm)
6.2
Weight
(mg)
100
Thickness
(mm)
3.5
White
Sugercoated
tablets
233
INDICATIONS
Bronchial asthma
Allergic rhinitis
Diameter
(mm)
6.7
Weight
(mg)
120
Thickness
(mm)
3.7
Tablets 0.5 mg
Tablets 1 mg
16100AMZ03237000 16100AMZ03238000
Jun 1986
Jun 1986
Jun 1986
Jun 1986
Sep 1993
Aug 1990
Urticaria, eczema/dermatitis, atopic dermatitis, pruritus and
prurigo
DOSAGE AND ADMINISTRATION
1. Bronchial asthma
The usual adult dosage for oral use is 2 mg of azelastine
hydrochloride twice a day after breakfast and at bedtime.
The dosage may be adjusted depending on the patient’s age
and symptoms.
2. Allergic rhinitis, urticaria, eczema/dermatitis, atopic
dermatitis, pruritus and prurigo
The usual adult dosage for oral use is 1 mg of azelastine
hydrochloride twice a day after breakfast and at bedtime.
The dosage may be adjusted depending on the patient’s age
and symptoms.
PRECAUTIONS
1. Important Precautions
(1) Since AZEPTIN may induce drowsiness, patients
should be cautioned against engaging in potentially
hazardous activities requiring alertness, such as operating machinery or driving a car.
(2) When a steroid is to be tapered off in a patient undergoing long-term steroid therapy, after initiation of
AZEPTIN, the steroid dosage should be reduced slowly
under close supervision.
(3) If AZEPTIN is administered to patients with bronchial
asthma, it should be explained to them that AZEPTIN
is not a drug that rapidly relieves asthma attacks.
(4) It is recommended that patients with seasonal allergic
diseases be started on AZEPTIN immediately before
the beginning of the unfavorable season and that the
administration be continued until after its end.
2. Adverse Reactions
Adverse reactions were reported in 439 of 14,365 patients.
(At the end of the reexamination period)
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5% >
≥0.1%
<0.1%
Psychoneurologic
Sleepiness and
malaise
Dizziness, headache and numbness of limbs
Gastrointestinal
Thirst and nausea/vomiting
Oral and perioral
roughness, anorexia, heart burn,
stomach discomfort, abdominal
pain, constipation
and diarrhea
Cardiovascular
Facial hot flushes
and palpitations
Respiratory
Nasal dryness and
respiratory distress
Hepatic
Elevation of AST
(GOT) and ALT
(GPT), etc.
Hypersensitivitynote)
Rash
Hematologic
Bitter taste
and taste disorder
7. Other Precautions
Because of the bitterness of the drug itself, a bitter taste
and taste disorder may be experienced.
PHARMACOKINETICS
Elevation of
Al-P
Leucocytosis
Urinary
Others
Incidence
unknown
Pollakiuria
Dysuria and
hematuria
Edema
Menstrual
disorder
1. Blood concentration
When AZEPTIN was administered orally to healthy male
adult volunteers at a single doses of 1 mg (4 men), 2 mg (4
men), 3 mgnote) (6 men) and 4 mgnote) (4 men), the peak
plasma concentrations were 0.6, 1.1, 2.0 and 2.1 ng/mL,
respectively. The times to reach the peak plasma concentration were 4 hr after administration of 1 to 3note) mg and 6
hr after administration of 4 mg note).
When AZEPTIN was repeatedly administered orally to 6
healthy male adult volunteers at dose of 3 mg twice a day,
the plasma concentration reached a steady state within 6
days and the biological half-life was found to be about 16.5
hr.
Note) In the event of such symptoms, treatment should be
discontinued.
3. Use in the Elderly
Since the elderly often have a physiological hypofunction,
it is advisable to take measures, such as reduction in dosage, under careful supervision.
4. Use during Pregnancy, Delivery or Lactation
(1) AZEPTIN should only be used in pregnant women or
women suspected of being pregnant if the expected
therapeutic benefits outweigh the possible risk of
treatment.
[AZEPTIN has been reported to be potentially teratogenic at large doses (greater than 370 times the recommended clinical dose) in an animal study (in rats).
(2) It is advisable to avoid administration to nursing mothers. When AZEPTIN must be used, breast feeding
should be discontinued during treatment.
[It has been reported that AZEPTIN is excreted in
breast milk in an animal study (in rats).]
5. Pediatric Use
Safety in low birth weight infants, neonates, nursing infants
and infants has not been established (insufficient clinical
experience).
6. Precautions concerning Use
Caution in handing over drug
For drugs that are dispensed in a press-through package
(PTP), instruct the patient to remove the drug from the
package prior to use. [It has been reported that, if the PTP
sheet is swallowed, the sharp corners of the sheet may
puncture the esophageal mucosa, causing perforation and
resulting in serious complications such as mediastinitis.]
2. Excretion
When AZEPTIN was administered orally to 3 healthy male
adult volunteers at a single dose of 4 mgnote), excretion of
the unchanged drug in the urine within 72 hr of administration accounted for 2.5% and that in the feces for 1.2%.
[References]
When 4.4 mgnote) of 14C-azelastine hydrochloride was administered orally to healthy male adult volunteers outside
Japan, excretion of radioactivity in the urine within 120 hr
of administration accounted for 26.2% and that in the feces
for 53.2%.
Note) Single doses of 3, 4, and 4.4 mg are unapproved.
CLINICAL STUDIES
Clinical efficacy
The efficacy rate (“remarkably effective+effective”) was 31.2%
(138/443 patients) for broncial asthma. It increased 66.4%
(294/443 patients) when fairly to remarkably effective was
taken into account.1)
The efficacy rate (“remarkably effective+effective”) was 49.8%
(309/620 patients) for allergic rhinitis. It increased 80.2%
(497/620 patients) when fairly to remarkably effective was
taken into account.2,3)
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The efficacy rate (“remarkably effective+effective”) was 64.5%
(142/220 patients) for dermatoses (urticaria, eczema/dermatitis,
atopic dermatitis, pruritus cutaneous and prurigo). It increased
83.2% (183/220 patients) when fairly to remarkably
effective was taken into account.4,5)
The usefulness of AZEPTIN has been established in double
blind clinical trials.
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PHYSICOCHEMISTRY
Nonproprietary name: Azelastine Hydrochloride
Chemical name:
4-[(4-Chlorophenyl)methyl]-2-[(4RS)-(1-methylazepan-4yl)]phthalazin –1(2H)-one monohydrochloride
Molecular formula: C22H24ClN3O ⋅ HCl
Molecular weight: 418.36
Structural formula:
PHARMACOLOGY
1. Mechanisms of Action
(1) Inhibition of the production and release of leukotrienes and antagonism to leukotrienes
Azelastine hydrochloride inhibits the production and
release of leukotrienes C4, D4 and B4 in guinea pig lung
sections and human neutrophils and eosinophils.
Its inhibitory action is considered to reside in its ability
to inhibit calcium ion influx into the cell, inhibit
5-lipoxygenase activity, increase intracellular cyclic
AMP and stabilize the cell membrane, etc. Azelastine
hydrochloride has also been shown to inhibit the contraction of isolated guinea pig ileum and bronchial
muscle induced by leukotrienes C4 and D4, and the migration of neutrophils induced by leukotriene B4.6-9)
(2) Inhibition of histamine release and antagonism to
histamine
Azelastine hydrochloride inhibits histamine release
from human and rabbit basophils, and rat mast cells,
and exhibits an antihistaminic action in the contraction
reaction of guinea pig bronchial muscle and ileum.9-14)
(3) Inhibition of the migration and infiltration of inflammatory cells and production of active oxygen
Azelastine hydrochloride inhibits the migration of human neutrophils induced by leukotriene B4, and the
migration and infiltration of guinea pig eosinophils induced by PAF. Azelastine hydrochloride also exhibits a
marked inhibitory effect on the production of active
oxygen in guinea pig neutrophils.8,15,16)
2. Inhibition of experimental allergic reactions
Azelastine hydrochloride inhibits the following over a long
period of time at low oral doses: passive cutaneous anaphylactic reactions (PCA) in guinea pigs and rats, experimental asthma in guinea pigs due to the inhalation of leukotriens, PAF and histamine, experimental allergy rhinitis
in dogs and Arthus reaction (type III allergy reaction) in
guinea pigs.17-19)
3. Reduction of hypersensitivity in airways and nasal mucosa
It has been demonstrated in airways and nasal mucosal hypersensitivity tests that azelastin hydrochloride reduces
airway and nasal mucosal hypersensitivity in patients with
asthma or allergic rhinitis.20,21)
And enantiomer
Description:
Azelastine hydrochloride occurs as a white crystalline
powder. It is soluble in formic acid, slightly soluble in water and in ethanol (99.5).
Azelastine hydrochloride shows no optical rotation.
Melting point: about 225°C (decomposition)
PACKAGING
AZEPTIN Tablets 0.5 mg:
Boxes of 100 and 500 in press-through packages
AZEPTIN Tablets 1 mg:
Boxes of 100, 280 (28 Tabs. × 10), 500, 1,000, 1,400 (28
Tabs. × 50) and 3,000 tablets in press-through packages,
and bottles of 500
REFERENCES
1) Makino S. et al.: Jpn. J.Clin. Exp. Med, 62, 1623, 1985.
2) Okuda M. et al.: Oto-rhino-Laryngol. Tokyo, 26(S,6),
563, 1983.
3) Okuda M. et al.: ibid., 26(S,6), 606, 1983.
4) Kameda H. et al.: Jpn. J. Clin. Exp. Med., 58, 2719,
1981.
5) Nisimoto M. et al.: J. New Remed. Clin., 35, 2111,
1986.
6) Katayama S. et al.: Prog. Med., 6, 1173, 1986.
7) Matsumura. M. et al.: Respiration Res., 9, 206, 1990.
8) Origasa E. et al.: Prog. Med., 9, 2272, 1989.
9) Tomooka M. et al.: Jpn. J. Allergol. 37, 213, 1988.
10) Little M. M. et al.: J. Allergy Clin. Immunol., 79, 204,
1987.
11) Chand N. et al.: Eur. J. Pharmacol., 96, 227, 1983.
12) Chand N. et al.: Int. Archs. Allergy Appl. immunol.,
77, 451, 1985.
13) Yamanaka T. et al.: Arzneim.-Forsch., 31, 1203, 1981.
14) Akagi M. et al.: Pharmacometrics, 26, 191, 1983.
15) Takahashi R. et al.: Prog. Med., 9, 2479, 1989.
16) Yamai T. et al.: 2th Azeptin Research Report, 2, 12,
1989.
17) Tasaka K. et al.: Arzneim.-Forsch., 29, 488, 1979.
18) Katayama S. et al.: ibid., 31, 1196, 1981.
19) Tanigawa T.et al.: ibid., 31, 1212, 1981.
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20) Iwata M. et al.: Jpn. J. Allergol. 39, 428, 1989.
21) Harada I. et al.: Oto-Rhino-Laryngol. Tokyo, 35(S,6),
469, 1992.
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Fax: 03-3811-2710
Eisai Co., Ltd.
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BE MADE TO:
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Free Dial: 0120-419-497
Eisai Co., Ltd.
Manufactured and marketed by:
Eisai Co., Ltd.
6-10, Koishikawa 4-chome, Bunkyo-ku, Tokyo, 112-8088