Mitsubishi Tanabe Pharma Corporation 1

Revised: February 2016 (13th version) D9 Standard Commodity Classification No. of Japan
872171

- Calcium antagonist -
HERBESSER® 10 mg for Injection
HERBESSER® 50 mg for Injection
< Diltiazem hydrochloride preparation >
Powerful and Prescription drug*

Storage 10 mg for 50 mg for

Injection Injection
Store at room temperature.
Approval No. 20100AMZ00343 20100AMZ00344
Date of listing in the NHI reimbursement price November 2009
Expiration date Date of initial marketing in Japan September 1989
The expiration date is indicated on the Date of latest approval of indications December 1998
package and container. Date of latest reexamination June 2000

*Caution – Use under the prescription of a physician, etc

CONTRAINDICATIONS (HERBESSER is contraindi- Description of solution contained in one vial when dissolved in
cated in the following patients.) 5 mL water for injection
1) Patients with severe hypotension or cardiogenic shock Appearance Clear colorless solution
[These symptoms may be aggravated.] pH 5.5 5.1
2) Patients with second or third degree atrioventricular Osmotic pressure
ration
block or sick sinus syndrome (persistent sinus bradycar- 0.30 0.44
(ratio to physiolog-
dia) (less than 50 beats/min), sinus arrest, sinoatrial ical saline)
block, etc.)
[Depression of cardiac stimulation and cardiac conduc- INDICATIONS
tion may occur excessively.] Tachyarrhythmia (supraventricular)
3) Patients with severe congestive cardiac failure Emergency treatment of malignant hypertension during
[Symptoms of cardiac failure may be aggravated.] operation
4) Patients with severe cardiomyopathy Hypertensive emergency
[Symptoms of cardiac failure may be aggravated.] Unstable angina
5) Patients with a history of hypersensitivity to any of the
ingredients of this product DOSAGE AND ADMINISTRATION
6) Pregnant women or women who may possibly be preg- HERBESSER (10 mg or 50 mg of diltiazem hydrochloride)
nant should be dissolved in more than 5 mL of physiological saline
[See “Use during Pregnancy, Delivery or Lactation” or glucose injection before use, and administered as follows:
section.] Tachyarrhythmia (supraventricular)
Usually, for adults, 10 mg of diltiazem hydrochloride is
DESCRIPTION administered intravenously slowly over approx. 3 minutes.
Freeze-dried product. This is solution for injection to be dis- The dosage may be adjusted according to the patient’s age
solved in physiological saline or glucose injection before use. and symptoms.
HERBESSER 10 mg HERBESSER 50 mg Emergency treatment of malignant hypertension during
Brand name
for Injection for Injection
operation
Active ingredient Diltiazem hydrochloride (JP)
(per vial) For one intravenous administration: Usually, for adults,
10 mg 50 mg
D-mannitol 10 mg of diltiazem hydrochloride is administered intrave-
Inactive ingredients nously slowly over approx. one minute. The dosage may
70 mg 75 mg
Container Vial be adjusted according to the patient’s age and symptoms.
Appearance of For intravenous infusion: Usually, for adults, 5 to 15 μg of
White mass or porous solid
preparation diltiazem hydrochloride is infused intravenously per kg
body weight over one minute. Blood pressure should be
2 Mitsubishi Tanabe Pharma Corporation

dropped to a target level, and then infusion rate should be should be discontinued immediately, and ap-
adjusted while monitoring the blood pressure. propriate therapeutic measures should be taken.
Hypertensive emergency 3) Prolonged QT and ventricular arrhythmia have been
Usually, for adults, 5 to 15 μg of diltiazem hydrochloride is reported in coadministration of terfenadine with other
infused intravenously per kg body weight over one minute. antiarrhythmic agents (disopyramide phosphate)
Blood pressure should be dropped to a target level, and 4) In case of severe angina attack such as persisting for
then infusion rate should be adjusted while monitoring the more than 15 minutes, other treatments (such as PTCA,
blood pressure. CABG, etc.) should be considered as needed.
Unstable angina 3. Drug Interactions
Usually, for adults, 1 to 5 μg of diltiazem hydrochloride is This product is metabolized mainly by cytochrome P450
infused intravenously per kg body weight over one minute. 3A4 (CYP3A4) metabolizing enzyme.
Administration should be started at a lower dosage, and the Precautions for coadministration (HERBESSER should
dosage should be adjusted according to the patient’s symp- be administered with care when coadministered with
toms. The maximum dosage should be up to 5 μg per kg the following drugs.)
body weight over one minute. Sings, Symptoms, and Mechanism and
Drugs
Treatment Risk Factors
PRECAUTIONS Drugs with anti- Antihypertensive effects may Antihypertensive
1. Careful Administration (HERBESSER should be ad- hypertensive ef- be intensified. effects may be
ministered with care in the following patients.) fects (antihyper- Blood pressure should be intensified addi-
tensive drugs, ni- measured to adjust the dosage. tively.
1) Patients with congestive cardiac failure
tric acid prepara-
[Symptoms of cardiac failure may be aggravated.]
tions, etc.)
2) Patients with cardiomyopathy
Beta blockers Bradycardia, atrioventricular Depression of
[Symptoms of cardiac failure may be aggravated.] (bisoprolol block, sinoatrial block, etc. cardiac stimula-
3) Patients with acute myocardial infarction fumarate, pro- may occur. tion and cardiac
[Symptoms of cardiac failure may be aggravated.] pranolol hydro- Electrocardiogram should be conduction, nega-
4) Patients with bradycardia or first degree atrioventricu- chloride, atenolol, monitored. If any abnormali- tive inotropic ef-
lar block etc.) ties are observed, the dosage fects, and antihy-
[Depression of cardiac stimulation and cardiac conduc- Rauwolfia should be reduced or admin- pertensive effects
tion may occur excessively.] preparations istration should be discontin- may be intensified
5) Patients with hypotension (reserpine, etc.) ued. additively. Partic-
[Blood pressure may be further decreased.] ular attention
should be given to
6) Patients with atrial fibrillation or atrial flutter associat-
triple therapy us-
ed with WPW or LGL syndromes
ing this product
[Increased heart rate or venticular fibrillation associat- with digitalis
ed with hypotension may occur.] preparation and
7) Patients being treated with beta blocker beta blocker or
[Bradycardia or depression of cardiac conduction may rauwolfia prepa-
occur excessively.] ration.
8) Patients with severe hepatic or renal impairment Digitalis prepara- Bradycardia, atrioventricular Depression of
[The metabolism and excretion of this product may be tions (digoxin, block, etc. may occur. In ad- cardiac stimula-
prolonged, and effects may be intensified.] methyldigoxin) dition, toxic symptoms (nau- tion and cardiac
2. Important Precautions sea, vomiting, headache, diz- conduction may
ziness, abnormal vision, etc.) be intensified ad-
1) Electrocardiogram and blood pressure should be
including the above arrhythmic ditively. Partic-
monitored continuously.
symptoms may occur due to ular attention
2) Since complete atrioventricular block, severe brad-
increased blood concentration should be given to
ycardia may occur, possibly leading to cardiac ar- of digitalis preparation. triple therapy us-
rest, adequate attention should be paid to the following Electrocardiogram should be ing this product
points. [See “Adverse Reactions” section.] monitored. In addition, pres- with digitalis
(1) The patients should be treated with minimum ence or absence of digitalis preparation and
dosage for treatment. In case of intravenous infu- toxicity should be observed beta blocker.
sion, the dosing should be limited to the minimum periodically, and blood con- This product may
duration of time. centration of digitalis prepara- increase blood
(2) The patients should be observed carefully during tion should be measured as concentrations of
needed. If any abnormalities digitalis prepara-
and after the administration for early detection of
are observed, the dosage tions.
these symptoms.
should be reduced or admin-
(3) Prior to administration, adequate preparations
istration should be discontin-
should be made to treat these symptoms. If any ued.
abnormalities are observed, administration
 Mitsubishi Tanabe Pharma Corporation 3

Antiarrhythmic Bradycardia, atrioventricular Depression of Midazolam Symptoms (intensified sedative This product may
agents (amioda- block, sinus arrest, etc. may cardiac stimula- and hypnotic effects, etc.) may inhibit the metab-
rone hydrochlo- occur. tion and cardiac occur due to increased blood olizing enzyme
ride, mexiletine Electrocardiogram should be conduction may concentration of midazolam. (cytochrome
hydrochloride, monitored. If any abnormali- be intensified ad- Clinical symptoms should be P450) of these
etc.) ties are observed, the dosage ditively. observed periodically. If any drugs, and in-
should be reduced or admin- abnormalities are observed, the crease their blood
istration should be discontin- dosage should be reduced or concentrations.
ued. administration should be dis-
Fingolimod hy- Severe bradycardia or heart Both diltiazem continued.
drochloride block may occur by concomi- hydrochloride and Carbamazepine Symptoms (sleepiness, nausea,
tant use of this product during fingolimod hy- vomiting, dizziness, etc.) may
the initiation of fingolimod hy- drochloride may occur due to increased blood
drochloride. induce bradycar- concentration of carbamaze-
dia or heart block. pine.
Aprindine hy- Symptoms (bradycardia, atrio- Each drug may Clinical symptoms should be
drochloride ventricular block, sinus arrest, affect a common observed periodically. If any
tremor, dizziness, lightheaded- metabolizing en- abnormalities are observed, the
ness, etc.) may occur due to zyme (cyto- dosage should be reduced or
increased blood concentrations chrome P450), administration should be dis-
of both drugs. and increase continued.
Electrocardiogram should be blood concentra- Selegiline hydro- Effects and toxicity of sele-
monitored. In addition, clini- tion of each drug. chloride giline hydrochloride may be
cal symptoms should be ob- intensified.
served periodically. If any Clinical symptoms should be
abnormalities are observed, the observed periodically. If any
dosage should be reduced or abnormalities are observed, the
administration should be dis- dosage should be reduced or
continued. administration should be dis-
Dihydropyridine Symptoms (intensified antihy- This product may continued.
calcium antago- pertensive effects, etc.) may inhibit the metab- Theophylline Symptoms (nausea, vomiting,
nists (nifedipine, occur due to increased blood olizing enzyme headache, insomnia, etc.) may
amlodipine be- concentration of dihydro- (cytochrome occur due to increased blood
silate, etc.) pyridine calcium antagonist. P450) of these concentration of theophylline.
Clinical symptoms should be drugs, and in- Clinical symptoms should be
observed periodically. If any crease their blood observed periodically. If any
abnormalities are observed, the concentrations. abnormalities are observed, the
dosage should be reduced or dosage should be reduced or
administration should be dis- administration should be dis-
continued. continued.
Simvastatin Rhabdomyolysis or myopathy Cilostazol Effects of cilostazol may be
may occur due to increased intensified.
blood concentration of Clinical symptoms should be
simvastatin. observed periodically. If any
Clinical symptoms should be abnormalities are observed, the
observed periodically. If any dosage should be reduced or
abnormalities are observed, administration should be dis-
administration should be dis- continued.
continued. Apixaban Effects of apixaban may be in-
Triazolam Symptoms (prolonged sleeping tensified.
time, etc.) may occur due to Clinical symptoms should be
increased blood concentration observed periodically. If any
of triazolam. abnormalities are observed, the
Clinical symptoms should be dosage should be reduced or
observed periodically. If any administration should be dis-
abnormalities are observed, the continued.
dosage should be reduced or
administration should be dis-
continued.
4 Mitsubishi Tanabe Pharma Corporation

Vinorelbine tar- Effects of vinorelbine tartrate This product may observed periodically, and if (cytochrome
trate may be intensified. inhibit the metab- possible, blood concentration P450) of this
Clinical symptoms should be olizing enzyme of this product should be product , and de-
observed periodically. If any (cytochrome measured. If any abnormali- crease blood con-
abnormalities are observed, the P450) of these ties are observed, appropriate centration of this
dosage should be reduced or drugs, and in- therapeutic measures such as product.
administration should be dis- crease their blood changing to other drugs or in-
continued. concentrations. creasing the dosage of this
Ciclosporin Symptoms (renal disorder, etc.) product should be taken.
may occur due to increased Anesthetic drugs Bradycardia, atrioventricular Depression of
blood concentration of ciclo- (isoflurane, en- block, sinus arrest, etc. may cardiac stimula-
sporin. flurane, halo- occur. tion and cardiac
Clinical symptoms should be thane, etc.) Electrocardiogram should be conduction may
observed periodically, and monitored. If any abnormali- be intensified ad-
blood concentration of ciclo- ties are observed, the dosage ditively.
sporin should be measured. If should be reduced or admin-
any abnormalities are observed, istration should be discontin-
the dosage should be reduced ued.
or administration should be Muscle relaxants Effects of muscle relaxants This product may
discontinued. (pancuronium may be intensified. inhibit the ace-
Tacrolimus Symptoms (renal disorder, etc.) bromide, Caution should be exercised to tylcholine release
hydrate may occur due to increased vecuronium muscle relaxant action. If any from the presyn-
blood concentration of tacro- bromide, etc.) abnormalities are observed, the aptic terminals at
limus. dosage should be reduced or the neuromuscu-
Clinical symptoms should be administration should be dis- lar junction.
observed periodically, and continued.
blood concentration of tacro-
limus should be measured. If 4. Adverse Reactions
any abnormalities are observed, Adverse reactions were reported in 266 (4.1%) of 6,543 pa-
the dosage should be reduced tients tested. The major adverse reactions were bradycar-
or administration should be
dia (1.1%), decreased blood pressure (0.7%), first degree
discontinued.
atrioventricular block (0.4%), second degree atrioventricu-
Phenitoin Symptoms (ataxia, dizziness, This product may
lar block (0.3%), atrioventricular junctional rhythm (0.3%),
nystagmus, etc.) may occur due inhibit the metab-
to increased blood concentra- olizing enzyme etc. (at the time of latest reexamination).
tion of phenitoin. (cytochrome (1) Clinically significant adverse reactions (occasionally:
Clinical symptoms should be P450) of phenit- 5% > ≥ 0.1%, rarely: < 0.1%)
observed periodically. If any oin, and increase 1) Complete atrioventricular block, severe brady-
abnormalities are observed, the blood concentra- cardia (early symptom: bradycardia, dizziness,
dosage should be reduced or tion of phenitoin. lightheadedness, etc.) may occasionally occur, pos-
administration should be dis- In addition, phen- sibly leading to cardiac arrest. Therefore, ade-
continued. itoin may stimu- quate preparations should be made to treat these
Effects of this product may be late metabolism
symptoms prior to administration. If these ab-
attenuated. of this product ,
normalities are observed, administration should be
and decrease
discontinued at once, and the following appropriate
blood concentra-
tion of this prod- therapeutic measures should be taken.
uct . Complete atrioventricular block, severe bradycar-
Cimetidine Symptoms (intensified antihy- These drugs may dia: Atropine sulfate hydrate, isoprenaline, etc.
pertensive effect, bradycardia, inhibit the metab- should be administered or appropriate therapeutic
HIV protease etc.) may occur due to in- olizing enzyme measures such as cardiac pacing should be taken as
inhibitors creased blood concentration of (cytochrome needed.
(ritonavir, this product. P450) of this Cardiac arrest: Resuscitate measures such as cardi-
saquinavir Blood pressure should be drug, and increase ac massage, administration of catecholamine such
mesylate, etc.) measured, and electrocardio- blood concentra- as adrenaline, etc. should be taken.
gram should be monitored. If tion of this prod-
2) Congestive cardiac failure may occur rarely. If
any abnormalities are observed, uct .
any signs of congestive cardiac failure are ob-
the dosage should be reduced
served, administration should be discontinued, and
or administration should be
discontinued. appropriate therapeutic measures should be taken.
Rifampicin Effects of this product may be Rifampicin may
attenuated. induce the metab-
Clinical symptoms should be olizing enzyme
 Mitsubishi Tanabe Pharma Corporation 5

(2) Other adverse reactions Atropine sulfate hydrate, isoprenaline, etc. should be
If any adverse reactions are observed, appropriate administered or cardiac pacing should be performed.
therapeutic measures such as discontinuation of treat- 2) Cardiac failure, hypotension
ment should be taken. Cardiotonic drug, vasopressor, infusion, etc. should
Incidence Incidence un-
5% > ≥ 0.1% < 0.1%
be administered or assisted circulation should be
Type known performed.
Cardiovascular Bradycardia, Sinoatrial block,
9. Precautions concerning Use
atrioventricular bundle branch
block, decreased block, palpitation,
Precautions in preparation:
blood pressure, dizziness, transi- Caution should be exercised in case where pH exceeds 8
atrioventricular ent tachycardia due to combination with other drugs, since diltiazem pre-
junctional rhythm, cipitation may occur.
extrasystoles, si-
nus arrest, facial
flushing
PHARMACOKINETICS
Psychoneurotic Headache, nausea, Plasma concentrations
vomiting An elimination half-life (elimination phase) of diltiazem after
Hepatic Increased AST Increased Al-P single intravenous administration was about 1.9 hours.
(GOT), increased The plasma concentration reached a steady state within 5 to 6
ALT (GPT), in-
hours after intravenous infusion.
creased LDH
Decreased urine Intravenous administration 1) Intravenous infusion 2)
Renal
8 patients with cardiac diseases Simulation curve calculated based on
output, increased actual measured values when 5, 10 or
10 mg of diltiazem hydrochloride ad-
serum creatinine, ministered intravenously over one mi- 15 μg/kg/minute of diltiazem hydro-
increased BUN nute chloride was administered to 5 pa-
tients who had not received
Hypersensitivity Photosensitivity* Rash, pruritus open-heart surgery

Others Phlebitis Injection site red-

Plasma diltiazem concentrations

Plasma diltiazem concentrations

ness
* Case reports of oral preparation of this product
5. Use in the Elderly
Since elderly patients often have reduced physiological
function, HERBESSER should be administered with care
such as starting from lower dosage while carefully moni-
toring the patient’s condition.
6. Use during Pregnancy, Delivery or Lactation
1) HERBESSER should not be administered to pregnant
women or women who may possibly be pregnant.
[Animal studies have shown teratogenicity (mice, rats,
rabbits: skeletal abnormality, appearance abnormality)
and embryotoxicity (mice, rats, rabbits: fatality).]
2) Use of this product in lactating women is not recom-
mended. If treatment with this product is judged to be
essential, breast feeding must be discontinued during
treatment.
[It has been reported that diltiazem is excreted in hu-
man breast milk.]
7. Pediatric Use
The safety of HERBESSER in children has not been estab-
lished.
8. Overdosage
Symptoms:
Bradycardia, complete atrioventricular block, cardiac fail-
ure, hypotension, etc. may occur after overdosage of
HERBESSER. These symptoms have been also reported
as adverse reactions.
Treatment:
In case of overdosage, administration should be discontin-
ued, and the following appropriate therapeutic measures
should be taken.
1) Bradycardia, complete atrioventricular block
15 μg/kg/minute
10 μg/kg/minute
5 μg/kg/minute
Time Time after infusion (hours)
CLINICAL STUDIES
1. Tachyarrhythmia (supraventricular)
Clinical studies including placebo-controlled, double-blind
comparative study 3) have shown the usefulness of
HERBESSER for paroxysmal supraventricular tachycardia,
rapid ventricular atrial fibrillation, and rapid ventricular
atrial flutter. The efficacy rate (more than effective) was
86.4% (184/213) in paroxysmal supraventricular tachycar-
dia, and 87.2% (130/149) in rapid ventricular atrial fibrilla-
tion, and rapid ventricular atrial flutter.
2. Emergency treatment of malignant hypertension during
operation
Clinical studies including single blind comparative study
using nitroglycerin (injection) as a control 4) have shown
the usefulness of this product for emergency treatment of
malignant hypertension during operation. The efficacy
rate (more than effective) was 94.0% (315/335).
3. Hypertensive emergency
The efficacy rate (more than effective) was 100.0% (28/28)
for hypertensive emergency such as malignant hyperten-
sion, hypertensive encephalopathy, dissecting aortic aneu-
rysm, acute left cardiac failure, etc. 5)
6 Mitsubishi Tanabe Pharma Corporation
4. Unstable angina
A randomized single blind comparative study 6) has shown
the usefulness of this product for unstable angina. The ef-
ficacy rate (more than mild improvement) was 80.0%
(32/40).
PHARMACOLOGY
This product exerts vasodilating action and slows atrioventric-
ular nodal conduction by inhibiting calcium channel influx to
cells in vascular smooth muscles such as peripheral vessels,
coronary vessels, etc. and atrioventricular node, and shows the
efficacy for hypertension, arrhythmia, and angina pectoris.
1. Action on blood pressure
1) It decreases high blood pressure under anesthetized and
unanesthetized conditions. The antihypertensive effect
is more potent under anesthetized condition than under
unanesthetized condition. 7) In addition, it exerts strong-
er antihypertensive action on higher blood pressure than
on normal levels (rats). 8, 9)
2) It reduces peripheral vascular resistance and myocardial
oxygen consumption due to decreased blood pressure,
and increases cardiac output (dogs). 10)
3) It does not reduce blood flow in the brain, coronary ves-
sels, and kidney, while decreases blood pressure. It also
exerts natriuretic action (dogs and monkeys).10-12)
2. Action on arrhythmia
1) It slows conduction, effective refractory period, and
functional refractory period of the atrioventricular node,
and exerts effects on supraventricular tachyarrhythmia
(dogs). 13)
2) It inhibits supraventricular tachyarrhythmia induced by
atrial electric stimulation (rabbits). 14)
3. Action on myocardial ischaemia
1) Improvement of myocardial oxygen demand and supply
balance
(1) It dilates large coronary vessels and collateral chan-
nels, and increases blood flow to myocardial is-
chaemic lesions (dogs). 12, 15-17)
(2) It inhibits coronary artery spasm (pigs and humans).
18, 19)
2) Myocardial protective action
It maintains cardiac function and myocardial energy me-
tabolism, and reduces the extension of infarct lesions by
inhibiting calcium channel influx to cells at the time of
myocardial ischaemia (dogs and cats). 20, 21)
PHYSICOCHEMISTRY
Nonproprietary name: Diltiazem Hydrochloride (JAN)
Chemical name: (2S,3S)-5-[2-(Dimethylamino) ethyl]-2-
(4-methoxyphenyl)-4-oxo-2,3,4,5-tetrahydro-
1,5-benzothiazepin-3-yl-acetate monohydro-
chloride
Description:
- Diltiazem Hydrochloride occurs as white crystal or crystal-
line powder. It is odorless.
- It is very soluble in formic acid, freely soluble in water, in
methanol and in chloroform, sparingly soluble in acetonitrile,
slightly soluble in acetic anhydride and in ethanol (99.5), and
practically insoluble in diethyl ether.
20
- Optical rotation [α] D : +115 - +120º (after drying, 0.20 g, wa-
ter, 20 mL, 100 mm)
- Melting point: 210 - 215ºC (with decomposition)
PACKAGING
HERBESSER 10 mg for Injection:
10 mg 10 vials
HERBESSER 50 mg for Injection:
50 mg 10 vials
REFERENCES
1) Eto A., et al.: Clin. Rep. 1980;14(10) :3082-3088
2) Mizobe M. et al.: Clin. Rep. 1987;21(11) :4623-4628
3) Hashiba K. et al.: Progress in Medicine 1987;7(6):
1155-1177
4) Yamamura H. et al.: Jpn. Pharmacol. Ther. 1987;
15(7) :2941-2960
5) Omae T. et al.: Jpn. J. Clin. Exp. Med. 1987;
64(10) :3221-3236
6) Kinoshita M. et al.: J. Clin. Exp. Med. (IGAKU NO
AYUMI) 1997;181(2) :173-198
7) Sato T. et al.: Folia Pharmacol. Japon. 1979;75 :99-106
8) Takada Y. et al.: Clin. Exp. Hypertens. 1983;A5(6) :
827-847
9) Yamaguchi I. et al.: Folia Pharmacol. Japon. 1979;75 :
191-199
10) Nagao T. et al.: Folia Pharmacol. Japon.
1981;77 :195-203
11) Murata S. et al.: Jpn. J. Pharmacol. 1982;32 :1033-1040
12) Sato T. et al.: Arzneimittelforschung 1971;21(9):
1338-1343
13) Nakaya H. et al.: Folia Pharmacol. Japon. 1980;76 :
697-707
14) Adaniya H. et al.: Respiration and Circulation 1987;
35(5) :561-567
15) Nagao T. et al.: Jpn. J. Pharmacol. 1977;27 :330-332
16) Nagao T. et al.: J. Mol. Cell. Cardiol. 1980;12 :29-43
17) Nagao T. et al.: Jpn. J. Pharmacol. 1975;25 :281-288
 Mitsubishi Tanabe Pharma Corporation 7

18) Shimokawa H. et al.: Science 1983;221 :560-562

19) Yasue H. et al.: Circulation 1978;58(1) :56-62
20) Kinoshita M. et al.: Jpn. Circ. J. 1985;49 :179-189
21) Bush LR. et al.: J. Pharmacol. Exp. Ther. 1981;
218(3):653-661

REQUEST FOR LITERATURE SHOULD BE MADE TO:

Safety Information Department
Pharmacovigilance & Quality Assurance Division
Mitsubishi Tanabe Pharma Corporation
3-2-10, Dosho-machi, Chuo-ku, Osaka 541-8505, Japan

Manufactured and Distributed by:

Mitsubishi Tanabe Pharma Corporation
3-2-10, Dosho-machi, Chuo-ku, Osaka 541-8505, Japan

This document is an English translation of the Japanese package insert.