..J MR]:*ills'ia' TRANSLAToR cERrrFrcArroN
`
`.15071h Are
`6rh r oor
`\eN York NY l012l
`Tdrt2611.8800
`tdr 2lr 61l0005
`www.momirsr.ns (.,n
`
`To whom this may concern:
`
`This is to certify that l, Shoko Sato, have performed a true and accurate translation ofthe
`document described below.
`. Perdipine 2001 Label (JP)
`
`I am a translator who is bilingual in Japanese and English, and I certify under penalty of perjury
`under the laws ofthe united States ofAmerica that the foregoing is true and correct.
`
`r-t,a/tL
`Executed on 7/)o/
`
`t I
`
`signature of Shoko sato
`
`Accurate Translation Services 2417
`
`Sandoz Exhibit 1012 Page 1
`
`

`

`
`** Revised in September 2001 (6th Edition)
` * Revised in July 2000
`
`Regulatory Classification
`
`Dangerous drug, designated drug
`
`
`
`
`
`Ca Antagonist for Injection
`** Japanese Pharmacopoeia
`Nicardipine hydrochloride injection
`Perdipine ® Injection 2 mg
`Perdipine ® Injection 10 mg
`Perdipine ® Injection 25 mg
`
`
`
`
`
`
`Approval No.
`NHI price
`listing
`Start of
`selling
`Addition of
`indications
`
`Japan standard commodity classification number
`8 7 2 1 4 9
`
`10 mg
`2 mg
`63AM-964
`64AM-965
`November 1988
`
`
`
`25 mg
`21100AMZ00175
`May 1999
`
`July 1999
`January 1989
`September 1994 (hypertensive emergency)
`January 1998 (acute cardiac failure)
`
`
`Storage method: light-shielding, store at
`room temperature
`Expiration date for use: indicated on a case,
`etc.
`
`
`[Contraindication (do not administer to the following patients)]
`(1) Patients who are assumed that hemostasis is not completed in the
`intracranial hemorrhage;
`(2) Patients whose intracranial pressure is increased during their stroke
`acute phase;
`(3) Patients who have a pre-existing condition of hypersensitivity to a
`component of this drug;
`(4) Patients having advanced aortic valve stenosis/ mitral valve stenosis,
`hypertrophic obstructive cardiomyopathy, low blood pressure (systolic
`blood pressure: less than 90 mmHg) or cardiogenic shock [it is possible
`for cardiac output and blood pressure to be further decreased]; and
`(5) Patients with severe acute myocardial infarction where the disease
`condition has not been stabilized in acute cardiac failure immediately
`after onset [in patients with severe acute myocardial infarction, such as
`extensive range of infarction due to triple vessel disease, a drastic
`change in a hemodynamic status, and the disease condition may be
`further worsened.]
`
`rate of 1 µg per 1 kg of body weight in a minute. Furthermore, the infusion
`rate is adjusted within the range of 0.5 µg to 2 µg per 1 kg of body weight
`in a minute according to the disease condition of the patient.
`
`<Precautions relating to Dosage and Administration>
`o In hypertensive emergencies, after the target blood pressure is reached due
`to the administration of this drug, when antihypertensive treatment is
`continuously required and it is possible to orally administer this drug,
`switch to oral administration.
`o In hypertensive emergencies, since the blood pressure may be re-elevated
`after the termination of administration of this drug, gradually reduce the
`dose on the occasion of termination of this drug administration, and
`adequately manage blood pressure even after the termination of
`administration. Furthermore, take notice of re-elevation of blood pressure,
`etc. even after switching to the oral administration.
`o In acute cardiac failure, if any expected improvement is not confirmed even
`with the administration of this drug, stop administration, and adopt any
`necessary measures, such as switching to other therapeutic methods (such
`as diuretic agents, so-called cardiac stimulants having positive inotropic
`activity, intravenous administration or mechanically assisted circulation of
`vasodepressor, etc.).
`o Exemplification of preparation method for this drug upon intravenous
`infusion:
`A 0.01 % to 0.02 % solution of this drug in the case of intravenous infusion
`is prepared by adding a necessary amount of this drug to an infusion
`solution that is blendable with this drug with reference to the
`exemplification in the table below.
`
`Amount of
`infusion solution
`to be blended
`(mL)
`100
`250
`500
`
`Concentration of Perdipine solution to be prepared
`Approx. 0.01 %
`Approx. 0.015 %
`Approx. 0.02 %
`Amount of Perdipine Injection to be added (mL)
`12
`18
`24
`30
`45
`60
`60
`90
`120
`
`
`[Precautions]
`1. Careful administration (carefully administer to the patients below)
`(1) Patients with hepatic/renal function impairment [this drug is
`metabolized by the liver. Further, in patients with severe renal function
`impairment in general, there is a possibility to cause a decrease in the renal
`function in association with drastic depressor action.]
`(2) Patients with aortic valvular stenosis [this drug may worsen symptoms.]
`(3) Patients with severe abnormal cardiac rhythm in acute cardiac failure [it
`is necessary to treat such patients while monitoring the abnormal cardiac
`rhythm in general.]
`(4) Patients with lower blood pressure in acute cardiac failure [there is a
`possibility to further decrease blood pressure. (2. See the section of
`“Important basic cautions”.]
`
`
`2. Important basic cautions
`(1) Since there are individual variations in the effect of this drug, carefully
`administer this drug while adequately managing blood pressure, heart rate, etc.
`(2) Stop administration when overdose of this drug causes obviously low
`blood pressure. Further, administer a vasopressor (norepinephrine) if the
`patient desires to promptly recover his/her blood pressure.
`(3) Administer this drug long term, and change the infusion site if pain or
`reddening, etc. is confirmed at the infusion site.
`(4) Administer this drug while adequately monitoring the general status of
`patients, including blood pressure, heart rate, urinary volume, body fluid and
`electrolyte, and pulmonary artery occlusive pressure, cardiac output and blood
`gas as much as possible, in acute cardiac failure.
`
`
`[Composition/ properties]
`
`Active
`ingredient
`
`Japanese
`Pharmacopoeia
`nicardipine
`hydrochloride
`
`Content
`in one
`tube
`
`2 mg
`
`10 mg
`
`25 mg
`
`Osmotic
`pressure ratio
`
`Approximately
`1.0 (ratio to
`normal saline
`solution)
`
`pH
`
`3.0
`to
`4.5
`
`Tone (in
`amber
`ampule)
`
`Slightly
`yellowish
`clear
`liquid
`
`Additive and
`its content
`
`D-sorbitol
`100 mg
`
`D-sorbitol
`500 mg
`
`D-sorbitol
`1,250 mg
`
`
`[Effect-efficacy]
`Emergency care of abnormal hypertension upon operation
`Hypertensive emergency
`Acute cardiac failure
`
`Sales
`name
`Perdipine
`Injection
`2 mg
`Perdipine
`Injection
`10 mg
`Perdipine
`Injection
`25 mg
`
`
`
`
`
`
`
`[Dosage and Administration]
` Emergency care of abnormal hypertension upon operation
`This drug is diluted with saline or 5 % glucose injection, and a 0.01 % to
`0.02 % (0.1 mg to 0.2 mg per 1 mL) solution as nicardipine hydrochloride
`is intravenously infused. In this case, administration starts at an infusion
`rate of 2 µg to 10 µg per 1 kg of body weight in a minute, and blood
`pressure is decreased to a target value, and thereafter, the infusion rate is
`adjusted while the blood pressure is monitored. Furthermore, when it is
`necessary to promptly decrease the blood pressure, this drug is
`intravenously administered as is at the rate of 10 µg to 30 µg of nicardipine
`hydrochloride per 1 kg of body weight.
` Hypertensive emergency
`This drug is diluted with saline or 5 % glucose injection, and a 0.01 % to
`0.02 % (0.1 mg to 0.2 mg per 1 mL) solution as nicardipine hydrochloride
`is intravenously infused. In this case, administration starts at an infusion
`rate of 0.5 µg to 6 µg per 1 kg of body weight in a minute. Furthermore, on
`the occasion of administration, a dose is started from 0.5 µg per 1 kg of
`body weight in a minute, and the blood pressure is decreased to a target
`value, and thereafter, the infusion rate is adjusted while monitoring the
`blood pressure.
` Acute cardiac failure (including acute exacerbation of chronic cardiac
`insufficiency)
`This drug is diluted with saline or 5 % glucose injection, and a 0.01 % to
`0.02 % (0.1 mg to 0.2 mg per 1 mL) solution as nicardipine hydrochloride
`is intravenously infused. In this case, administration starts at an infusion
`
`
`
`(1)
`
`Sandoz Exhibit 1012 Page 2
`
`

`

`* 4. Side effects
`Out of 6,339 in survey cases in achievement survey at the time of approval
`and post-market, there were 140 cases (2.2 %) where side effects, which are
`suspected to have relevance with this drug (including laboratory
`abnormalities).
`<Acute care of abnormal hypertension upon operation>
`Side effects were confirmed in 109 cases (1.8 %) out of 6,093 cases, and the
`main one was tachycardia in 36 cases (0.6 %).
`<Hypertensive emergency>
`Side effects at the time of approval were confirmed in 10 cases (16.9 %) out
`of 59 cases, and the main one was facial flush in 3 cases (5.1 %).
`<Acute cardiac failure (including acute exacerbation of chronic cardiac
`failure)>
`Side effects at the time of approval were confirmed in 21 cases (11.2 %) out
`of 187 cases, and the main ones were a blood pressure drop in 7 cases (3.7 %)
`and a decrease of partial pressure of oxygen in arterial blood in 7 cases
`(3.7 %).
`
`(1) Severe side effects
`1) Paralytic ileus (frequency unknown): Since paralytic ileus may be
`
`developed, when any abnormality is confirmed, stop administration and
`adopt appropriate measures.
`2) Hypoxemia (0.1 % to less than 5 %): Since hypoxemia may be
`developed, when any abnormality is confirmed, stop administration and
`adopt appropriate measures.
`3) Lung edema, breathing difficulty (0.1 % to less than 5 %): Since
`lung edema and/or breathing difficulties may be developed, when any
`abnormality is confirmed, stop administration and adopt appropriate
`measures.
`4) Anginal pain (frequency unknown): There are reports where the
`development or exacerbation of angina pain was confirmed in less than
`1 % of patients with diseases of coronary artery who were treated with
`an injection of this drug in foreign countries. When such symptom is
`confirmed, stop administration and adopt appropriate measures.
`5) Platelet depletion (frequency unknown): Since platelet depletion
`may be developed, carefully monitor patients, and when any abnormality
`is confirmed, stop administration and adopt appropriate measures.
`6) Impaired hepatic function, jaundice (frequency unknown): Since
`impaired hepatic function or jaundice in association with rise of AST
`(GOT), ALT (GPT), γ-GTP may be developed, carefully monitor
`patients, and when any abnormality is confirmed, stop administration
`and adopt appropriate measures.
`
`
`
`
`
`
`
`
`
`
`
`
`(2) Other side effects:
`
`Circulatory
`organ
`
`Liver
`
`Kidney
`Digestive organ
`Others
`
`0.1 % to less than 5 %
`Rapid pulse, palpitation, hot flush, general
`malaise, change on the electrocardiogram;
`blood pressure drop, rise of blood pressure in
`the pulmonary artery, decreased cardiac index,
`ventricular tachycardia, cyanosis, a drop of
`partial pressure oxygen may develop that
`will be developed in acute cardiac failure
`Abnormality of hepatic function (rise of AST
`(GOT), ALT (GPT), etc.)
`BUN increase, creatinine increase
`Sick feeling, vomiting, nausea
`Headache, rise of body temperature, decrease
`in urinary volume, decrease in
`total blood cholesterol, chills, dorsal pain,
`elevation in serum potassium level
`
`Frequency
`unknown
`
`
`
`
`
`
`
`Inflammati
`on of a vein
`
`
`5. Administration to the elderly
`When this drug is used for the elderly, administer from a low dose (for
`example, 0.5 μg/kg/min of intravenous infusion), and carefully administer
`while the progression is carefully observed. [In the elderly, physiology
`(hepatic function, renal function, etc.) is often decreased.]
`
`6. Use during Pregnancy or Lactation
`(1) For pregnant women and women suspected of being pregnant,
`administer this drug only when the therapeutic benefit exceeds the risk.
`[In animal experiments, it is reported that a high dose causes an increase in
`fetal death, dystocia, weight loss of child and suppression of weight gain
`thereafter if this drug is administered at the end of pregnancy.]
`(2)
`It is preferable to avoid administration to women who are lactating,
`but if there is no choice but to administer to these women, avoid breast
`feeding.
`
`In acute cardiac failure, be careful since excessive blood pressure drop
`(5)
`and a drop of partial pressure oxygen may develop due to the vasodilating
`action of this drug. In particular, since this drug has a hypotensive effect,
`when blood pressure is slightly low (less than 100 mg of systolic blood
`pressure is an indication) and circulating blood volume is relatively decreased,
`if blood pressure is strictly monitored and further blood pressure drop is
`confirmed, adopt necessary measures, such as stoppage of administration.
`(6)
`In acute cardiac failure, when a clinical symptom(s) is improved due to
`the administration of this drug and the condition of a patient is stabilized
`(acute state is passed), change to other therapeutic methods without
`unthinkingly administering this drug. Although the administration period will
`vary according to the reactivity of a patient, since there are a few experiences
`of acute cardiac failure exceeding 24 hours, if it becomes necessary to
`administer this drug over 24 hours, carefully administer this drug with careful
`management of hemodynamics and general condition.
`(7) In acute cardiac failure, be careful of obsessive blood pressure drops
`when combining with another vasodepressor.
`(8)
`In acute cardiac failure, when this drug is used for acute cardiac failure
`due to acute myocardial infarction, carefully administer this drug while
`adequately managing hemodynamics and general conditions.
`
` *
`
` 3. Interaction
`[Careful co-administration] (be careful of co-administration):
`Drug name, etc.
`Clinical symptoms(s)/ measures
`Mechanism/ risk factor
`HIV protease inhibitor:
`It is predicted AUC of this drug is
`Competitive inhibitory action on
`Saquinavir, Ritonavir,
`increased.
`hepatic drug-metabolizing
`etc.
`enzyme: P450
`Other depressor
`Due to pharmacological additive
`action, etc. of both drugs
`Due to pharmacological additive
`action, etc. of both drugs;
`(1) Augmentation of a blood-
`pressure-lowering effect
`(2) Augmentation of negative
`inotropic effect 1)
`Mechanism unknown
`
`A blood-pressure-lowering effect
`may be augmented.
`In patients with congestive heart
`failure, excessive blood pressure
`drop and deterioration of heart
`function may be developed. Reduce
`either dose or stop administration as
`needed.
`With anesthesia of fentanyl, a
`combination of β-blockers and this
`drug may cause a blood-pressure
`drop 2). Reduce either dose or stop
`administration as needed.
`Action of this drug may be
`augmented, and a blood pressure
`drop and rapid pulse, etc. may be
`developed. Reduce the dose of this
`drug as needed.
`This drug may augment digoxin 4),
`and toxic symptom(s) (nausea,
`vomiting, dizziness, bradycardia,
`abnormal cardiac rhythm, etc.) may
`be developed. Reduce digoxin as
`needed.
`Action of immunosuppressant may
`be augmented 5), and toxic
`symptom(s) (especially, abnormality
`of kidney function) may be
`developed. Further, action of this
`drug is augmented and a blood
`pressure drop, rapid pulse, etc. may
`be developed. Reduce doses of the
`immunosuppressant and this drug as
`needed.
`(1) Action of phenytoin may be
`augmented, and a (neurological)
`toxic symptom(s) may be
`developed. Reduce the dose of
`phenytoin as needed.
`(2) Action of this drug may be
`reduced. Increase the dose of this
`drug if needed.
`Action of this drug may be reduced.
`Reduce the dose of this drug as
`needed.
`
`There are reports where ventricular
`fibrillation and circulatory collapse
`were observed in animal
`experiments with other calcium
`antagonist agents (verapamil, etc.).
`There are reports where a blood-
`pressure-lowering effect was
`augmented in animal experiments.
`
`There are reports where
`atrioventricular block was
`developed in animal experiments.
`Action of muscular relaxation may
`be augmented. Be careful of a
`muscle relaxant effect, and reduce
`doses of both drugs or stop
`administration if any abnormality is
`confirmed.
`
`
`β-blocker:
`Propranolol, etc.
`
`
`Fentanyl
`
`Cimetidine
`
`Digoxin
`
`Immunosuppressant:
`Cyclosporine
`Tacrolimus hydrate,
`etc.
`
`Phenytoin
`
`Rifampicin
`
`Dantrolene sodium
`
`Tandospirone citrate
`
`Nitroglycerin
`
`Muscle relaxant agent:
`Pancuronium bromide
`Vecuronium bromide,
`etc.
`
`
`
`
`
`Cimetidine inhibits hepatic drug-
`metabolizing enzyme: P450, and
`the blood level of this drug is
`increased 3).
`
`This drug decreases clearance
`mainly at the kidneys, and blood
`concentration of digoxin is
`increased.
`
`The hepatic drug-metabolizing
`enzyme: P450 is inhibited by this
`drug or an immunosuppressor, and
`blood concentration of the
`immunosuppressor or this drug is
`increased.
`
`(1) Since a protein binding ratio of
`this drug is high, free phenytoin is
`increased due to plasma-protein
`binding competition.
`(2) Phenytoin induces hepatic
`drug-metabolizing enzyme: P450,
`and metabolism of this drug is
`accelerated 6) 7).
`Rifampicin induces hepatic drug-
`metabolizing enzyme: P450, and
`metabolism of this drug is
`accelerated.
`It is believed that this drug causes
`hyperkalemia.
`
`Tandospirone citrate has a central
`blood-pressure-lowering effect,
`and shows additive
`antihypertensive effect 8).
`Mechanism unknown
`
`It is believed that this drug
`suppresses acetylcholine release
`before or after synapse at the
`nerve-muscle junction, and
`reduces contractile strength of
`muscle itself due to Ca isolation
`suppression at the sarcoplasmic
`reticulum of skeletal muscles 9),
`etc.
`
`(2)
`
`Sandoz Exhibit 1012 Page 3
`
`

`

`[It is reported that this drug is transferred to breast milk according to
`animal experiments.]
`
`
`7. Administration to children, etc.
`Safety to low-birth-weight babies, newborn, infants, young children and
`children has not been established yet.
`
`
`8. Precautions of application
` Upon preparation:
`(1) When this drug is intravenously infused, be careful because this drug
`may be deposited due to high pH depending upon an infusion solution to
`be blended. Furthermore, as a result of a blending test with this drug, it
`was possible for the following infusion solutions to blended with this
`drug:
`Saline, 5 % glucose injection, 10 % EL No. 3, 5 % Fructon injection,
`KN replacement fluid 1A, KN replacement fluid 4A, Solita-T No. 1,
`
`Solita-T No. 3, Physiosol‐F No. 3, Physiosol‐F No. 4, Potacol R,
`
`15 % mannitol injection TM, mannitol No. F-2, Lactec D Injection,
`Ringer's solution, Ringer glucose injection, 10 w/v % Rheomacrodex
`2) Do not mix because it has been confirmed by now that this drug
`causes a blending variation with the following injections:
`Fursemide, potassium canrenoate, aminophylline, bucladesine sodium,
`amrinone, lidocaine, iohexol, , iopamidol, tranexamic acid,
`carbazochrome sodium sulfonate, heparin sodium, urokinase,
`tisokinase, alteplase, fosfomycin, cefotiam hydrochloride, cefuzonam
`sodium, imipenem, flomoxef sodium, sodium hydrogen carbonate
`3) Although this drug is one-point cut ampoules, it is preferable to cut
`after bed bath of the ampoule cut portions with ethanol cotton, etc.
`
`
`9. Other precautions
`During the recovery management period after open-heart operations, it is
`known that circulatory failure may develop depending upon cases and a
`patient may fall into a cardiac failure state, but there are a few experiences
`of this drug under the situation (21 cases in total) and the effectiveness has
`not been established.
`
`
`[Pharmacokinetics]
`1. Unchanged drug concentration in plasma … pharmacokinetic parameters
`a-1) Healthy adults: 0.01 to 0.02 mg/kg, iv, single administration 10)11)
`AUC
`Vdβ
`Dose (mg/kg iv)
`n
`t1/2β (min)
`(ng·h/mL)
`(mL/kg)
`23.3
`644
`38.3
`641
`
`0.01
`0.02
`
`2
`2
`
`63
`50
`
`
`a-2) Patients under general anesthesia:
`administration 11)
`Dose (mg/kg iv)
`
`n
`
`t1/2β (min)
`
`0.01
`0.02
`0.03
`
`7
`5
`4
`
`28
`22
`45
`
`0.01 to 0.03 mg/kg, iv, single
`
`AUC
`(ng·h/mL)
`21.8
`29.8
`68.7
`
`Vdβ
`(mL/kg)
`321
`495
`609
`
`
`b-1) Healthy adults: Repeated administration of 2-hour continuous dosing
`at 4 mg/h (rate of approximately 1.1 μg/kg/min) once a day for 5 days 12)
`CL tot
`Dose
`t1/2β (min)
`Vdβ (mL/kg)
`(mL/kg/min)
`10.7
`
`1st day n=5
`
`109
`
`1,683
`
`b-2) Patients with hypertension emergency: 5 to 24-hour continuous
`intravenous administration at 0.5 μg/kg/min, and sequentially increase or
`decrease of dose 12)
`Dose
`t1/2β (min)
`
`CL tot (mL/kg/min)
`
`Vdβ (mL/kg)
`
`n=5
`
`160
`
`14.2
`
`3,083
`
`b-3) Patients with acute cardiac failure: 2-hour continuous intravenous
`administration at 1.0 μg/kg/min 13)
`Dose
`CL tot (mL/kg/min)
`t1/2β (min)
`
`Vdβ (mL/kg)
`
`n = 5
`
`130
`
`11.5
`
`2,091
`
`
`
`
`
`
`
`
`
`(3)
`
`2. Principal metabolite in urine in healthy adults was a conjugate of M-11
`(a metabolite where an N-benzyl-N-methyl amino group is detached, and is
`oxidized to a pyridine body) 14).
`3. Binding ratio with plasma protein was 90 % or greater of all in vitro
`(healthy adults) 15), in vitro (patients with acute cardiac failure) 13) and in vivo
`(patients under general anesthesia) 16).
`
`
`[Clinical Performance]
`
`
`<Clinical effects>
`
`
`
`Test method
`
`Decision of usefulness
`
`Efficacy rate
`per
`administration
`method
`
`Single
`intravenous
`Intravenous
`infusion
`
`Emergency
`care of
`abnormal
`hyperten-
`sion upon
`surgery
`Double-
`blind
`compara-
`tive study,
`etc. 17)-22)
`82.9 %
`(557/672)
`useful or
`greater
`78.6 %
`(301/383)
`88.6 %
`(256/289)
`
`[Pharmacological Action]
`
`
`Hyper-
`tensive
`emer-
`gency
`
`Single
`blind
`compara-
`tive study,
`etc. 23)24)
`94.4 %
`(51/54)
`slightly
`useful or
`greater
`—
`94.4 %
`(51/54)
`
`Acute
`cardiac
`failure
`
`Double-
`blind
`compara-
`tive study,
`etc. 25)-29)
`71.7 %
`(86/120)
`useful or
`greater
`
`—
`72.3 %
`(102/141)
`
`
`
`<Pharmacological Action>
`1. Blood-pressure-lowering effect
`(1) Blood-pressure-lowering effect
`
`In anesthetized dogs, this drug showed a dose-dependent blood-pressure-
`lowering effect, and a slope of the dose-action curve was gradual. This
`does not cause an excess blood pressure drop in blood pressure
`management, and suggests that it excels in regulation 30).
`Even in non-anesthetized dogs, this drug showed a dose-dependent
`blood-pressure-lowering effect without suppressing an impulse
`conducting system 31).
`(2) Abnormal hypertensive suppression action
`In anesthetized dogs, this drug dose-dependently suppressed blood
`pressure elevation by an endogenous hypertensive substance
`(noradrenaline or angiotensin II), which is believed to be a cause of
`onset of incidental abnormal hypertension upon anesthesia 30).
`In non-anesthetized dogs that are in an induced hypertensive state by
`continuous dosing of a hypertensive substance (angiotensin II), this drug
`was dose-dependently lowered the blood pressure without affecting the
`impulse conducting system 31).
`2. Effect on the cardiovascular system
`(1) Cardiac hemodynamics
`
`In anesthetized dogs, this drug has strong coronary dilating effects, and
`lowers peripheral vascular resistance along with increasing coronary
`blood flow, and lowers myocardial oxygen consumption by reducing
`afterload 32).
`(2) Effect on the cardiovascular system in various anesthetized
`conditions 33)34)
`Even in dogs and monkeys anesthetized with any of pentobarbital, GOF
`and NLA, this drug showed substantially the same level of
`antihypertensive action. With a dose to lower the blood pressure by
`approximately 30 %, under the pentobarbital anesthesia or NLA
`anesthesia, this drug caused a slight increase in the reflective cardiac rate
`and heart contractility, but the drug affected none of these conditions
`under the GOF anesthesia. In the meantime, with a high dose to lower
`the blood pressure by 50 % or more, even in any anesthesia method, this
`drug caused a decrease in heart contractility and extended
`atrioventricular conduction as well.
`3. Anti-cardiac failure action
`(1) Anti-cardiac failure action
`
`In anesthetized dog models with ischemic acute cardiac failure induced
`by coronary ligation and anesthetized dog models with acute cardiac
`failure induced by administration of angiotensin II in addition to
`coronary ligation, the acute cardiac failure condition was improved by
`dose-dependently increasing a cardiac output and a stroke output without
`
`Sandoz Exhibit 1012 Page 4
`
`

`

`
`
`lowering cardiac contractile force, and by developing afterload reduction
`action 35).
`In patients with acute cardiac failure, an increase in a cardiac index, a
`decrease in total peripheral vascular resistance, and lowering of
`pulmonary artery occlusive pressure were confirmed without affecting
`the cardiac rate 27).
`(2) Effect on myocardial metabolism
`In anesthetized dog models with ischemic acute cardiac failure induced
`by coronary ligation, anti-cardiac failure action was developed, and, an
`oxygen difference, a carbon dioxide difference and a pH difference
`between/among coronary arteries and veins, and myocardial oxygen
`consumption were decreased. At this time, this drug did not affect a
`myocardial lactic acid intake ratio 36).
`4. Splanchnic circulation and blood gas
`In anesthetized cats, this drug lowered the blood pressure, and, increased
`a cardiac output and increased a blood flow of various organs including
`the brain and the heart 37).
`In anesthetized humans and dogs 38), this drug hardly caused any change
`in the blood gas (Po2, Pco2 and pH).
`5. Diuretic action
`In hypnopompic and anesthetized humans, this drug increased the renal
`blood flow and glomerular filtration rate, and an increase in urinary
`volume was confirmed 39).
`
`<Action Mechanism>
`Nicardipine hydrochloride demonstrates vasodilating action by suppressing
`an intake of Ca++ into vascular smooth muscle cells 40). Nicardipine
`hydrochloride demonstrated 30,000 times stronger Ca++ antagonistic action
`of cardiac muscles in the vascular smooth muscle, and the vascular
`selectivity was higher than that of other calcium antagonists 41).
`
`
`Generic name:
`Chemical name:
`
`**[Physicochemical properties regarding active ingredient]
`
`Nicardipine Hydrochloride
`2-(N-Benzyl-N-methylamino) ethyl methyl (RS)-1,4-
`dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-
`dicarboxylate monohydrochloride
`Molecular formula: C26H29N3O6 · HCl
`Molecular weight:
`515.99
`Melting point:
`167 °C to 171 °C
`Structural formula:
`
`Properties:
`
`
`Nicardipine hydrochloride is a slightly greenish yellow
`crystalline powder. It is soluble in methanol or acetic
`acid (100), and is sparingly-soluble in ethanol (99.5),
`and least soluble in water, acetonitrile or acetic acid
`anhydride. This drug in a methanol solution (1  20)
`is not optically active. It will gradually change.
`
`[Package]
`Perdipine Injection 2 mg (2 mL)
`Perdipine Injection 10 mg (10mL)
`Perdipine Injection 25 mg (25mL)
`
`10 tubes
`10 tubes, 50 tubes
`5 tubes
`
`[Main References and Contact for References]
`<Main references>
`1)
`Supervised by Planning Section, Pharmaceutical Affairs Bureau:
`Handbook of Drug Interactions, Yakugyo Jiho, Inc., 1996, P96
`Physician’s Desk Reference 51Ed. Med. Econom. Co., Montvale.
`1995 P2816
`3) Edited by Juzo Matsuda: Side effects of co-prescribing of several
`drugs by this drug, Ishiyaku Publishing. 1994, P96
`4) Edited by Juzo Matsuda: Side effects of co-prescribing of several
`drugs by this drug, Ishiyaku Publishing. 1994, P78
`
`
`
`2)
`
`
`
`5) Tatsuji Iga, et al.: The Journal of Therapy, 76: 2322, 1994
`6) Capewell, S. et al.: Lancet 2: 480, 1988
`7) Woodcock, B. G. et al.: N. Engl. J. Med. 325: 1179, 1991
`8) Hiroshi Shimizu, et al.: Basic Principles and Clinical Applications 26:
`1681, 1992
`9) Masaki Nishida et al.: Journal of The Japan Society for Clinical
`Anesthesia 23: 1793, 1999
`10) Higuchi, S. et al.: Xenobiotica. 10: 447, 1980
`11) Toshiya Ebata et al.: Journal of The Japan Society for Clinical
`Anesthesia 9: 1071, 1985
`12) Takao Chiyo et al.: Journal of Japanese Pharmacology &
`Therapeutics 23: 717, 1995
`13) Kunihiko Hirasawa et al.: Journal of Japanese Pharmacology &
`Therapeutics 23: 901, 1995
`14) Akira Shiina et al.: Basic Principles and Clinical Applications 20:
`1114, 1986
`15) Higuchi, S. et al.: Xenobiotica. 10: 889, 1980
`16) Yamanouchi Pharmaceutical’s research report: D9700856-1, 1997
`17) Yoichi Tanaka et al.: Journal of The Japan Society for Clinical
`Anesthesia 7: 1399, 1983
`18) So Ishii et al.: Basic Principles and Clinical Applications 20: 503,
`1986
`Ikuto Yoshiya et al.: The Japanese Journal of Anesthesiology 35: 520,
`1986
`20) Nobuo Matsumoto et al: Journal of Japan Society of Circulation
`Control in Medicine 7: 737, 1986
`21) Noriko Sakuma et al.: Journal of The Japan Society for Clinical
`Anesthesia 9: 407, 1985
`22) Nao Tamai et al.: The Japanese Journal of Anesthesiology 35: 528,
`1986
`23) Kaoru Yoshinaga et al.: Clinical Pharmacology and Therapeutics 3:
`245, 1993
`24) Kaoru Yoshinaga et al.: Journal of Clinical and Experimental
`Medicine 165: 437, 1993
`25) Nasahiko Kinoshita et al: Journal of Japanese Pharmacology &
`Therapeutics 23: 345, 1995
`26) Yuzo Hirota et al: Journal of Japanese Pharmacology & Therapeutics
`23: 357, 1995
`27) Toshiaki Kumata et al.: Journal of Japanese Pharmacology &
`Therapeutics 23: 375, 1995
`28) Yuzo Hirota et al.: Journal of Japanese Pharmacology & Therapeutics
`23: 703, 1995
`29) Hiroshi Ogawa et al.: Journal of Japanese Pharmacology &
`Therapeutics 23: 887, 1995
`30) Masayuki Shibazaki et al.: Basic Principles and Clinical Applications
`19: 7044, 1985
`31) Shuichi Sato et al.: Clinical Pharmacology and Therapeutics 3: 309,
`1993
`32) Tohichi Takenaka: Basic Principles and Clinical Applications 14:
`4477, 1980
`33) Masayuki Shibazaki et al.: Basic Principles and Clinical Applications
`20: 177, 1986
`34) Masayuki Shibazaki et al.: Basic Principles and Clinical Applications
`22: 6327, 1988
`35) Hideyuki Tanaka et al.: Clinical Pharmacology and Therapeutics 5:
`371, 1995
`Itaru [or Chikashi] Saito et al.: Clinical Pharmacology and
`Therapeutics 5: 381, 1995
`37) Hof, R. P.: Br. J. Pharmacol. 78: 375, 1983
`Isao Kosugi et al.: Basic Principles and Clinical Applications 13:
`38)
`1186, 1979
`39) Takashi Momose: Basic Principles and Clinical Applications 20:
`3867, 1986
`40) Terai, M. et al.: Biochem. Pharmacol. 30: 375, 1981
`42) Bristow, M. R. et al.: Br. J. Pharmacol. 82: 309, 1984
`
`19)
`
`36)
`
`
`<Contact for references>
`Pharmaceutical Affairs Dept., Yamanouchi Pharmaceutical Co., Ltd.
`2-3-11, Nihonbashihon-cho, Chuo-ku, Tokyo 103 -8411
`
`** Manufacturer Yamanouchi Pharmaceutical Co., Ltd.
`
`Head Office: 2-3-11, Nihonbashi-honcho, Chuo-ku, Tokyo 103-8411
`
`
`
`(4)
`
`Sandoz Exhibit 1012 Page 5
`
`

`

`注射用Ｃa 拮抗剤
`＊＊
`日本薬局方　塩酸ニカルジピン注射液
`
`日本標準商品分類番号
`８７２１４９
`
`＊
`＊2001年９月改訂（第６版）
`＊2000年７月改訂
`
`規制区分
`　劇薬、指定医薬品
`
`貯　　法　遮光、室温保存
`使用期限　外箱等の表示を参照　
`
`〔禁　忌（次の患者には投与しないこと）〕
`　‚頭蓋内出血で止血が完成していないと推定される患者［出血を
`促進させる可能性がある。］
`　„脳卒中急性期で頭蓋内圧が亢進している患者［頭蓋内圧を高め
`るおそれがある。］
`　”本剤の成分に対し過敏症の既往歴のある患者
`　»急性心不全において、高度な大動脈弁狭窄・僧帽弁狭窄、肥大
`型閉塞性心筋症、低血圧（収縮期血圧90mmHg未満）、心原性
`ショックのある患者［心拍出量及び血圧が更に低下する可能性
`がある。］
`　…急性心不全において、発症直後で病態が安定していない重篤な
`急性心筋梗塞患者［広範囲、３枝病変による梗塞等の重篤な急
`性心筋梗塞患者では血行動態の急激な変化を生じることがあり、
`更に病態が悪化するおそれがある。］
`
`〔組 成・性 状〕
`
`名売販
`
`分成効有
`
`の中管１
`量含
`
`比圧透浸
`
`ｐＨ
`
`調　色
`プンア色褐（
`）り入ル　
`
`ンピジルペ
`液射注
`２ gm
`
`ンピジルペ
`液射注
`gm01
`
`ンピジルペ
`液射注
`gm52
`
`　　　局日
`ルカニ酸塩
`　　ンピジ
`
`２ gm
`
`gm01
`
`gm52
`
`約 .1 0
`( 食理生
`対に液塩
`比るす )
`
`0.3 〜 5.4
`
`な明澄
`色黄微
`
`物加添
`そび及
`量含の
`
`D ルソ−
`ルートビ
`gm001
`
`D ルソ−
`ルートビ
`gm005
`
`D ルソ−
`ルートビ
`gm052,1
`
`〔効 能・効 果〕
`
`　　　　　・手術時の異常高血圧の救急処置
`　　　　　・高血圧性緊急症　　　　　　　
`　　　　　・急性心不全（慢性心不全の急性増悪を含む）
`
`〔用 法・用 量〕
`
`○手術時の異常高血圧の救急処置
`　本剤は、生理食塩液又は５％ブドウ糖注射液で希釈し、塩酸ニカ
`ルジピンとして0.01〜0.02％（１mL当たり0.1〜0.2mg）溶液を点滴
`静注する。この場合１分間に、体重１kg当たり２〜10μgの点滴速
`度で投与を開始し、目的値まで血圧を下げ、以後血圧をモニター
`しながら点滴速度を調節する。なお、急速に血圧を下げる必要が
`ある場合には、本剤をそのまま体重１kg当たり塩酸ニカルジピン
`として10〜30μgを静脈内投与する。
`○高血圧性緊急症
`　本剤は、生理食塩液又は５％ブドウ糖注射液で希釈し、塩酸ニカ
`ルジピンとして0.01〜0.02％（１mL当たり0.1〜0.2mg）溶液を点滴
`静注する。この場合１分間に、体重１kg当たり0.5〜６μgの点滴速
`度で投与する。なお、投与に際しては１分間に、体重１kg当たり
`0.5μgより開始し、目的値まで血圧を下げ、以後血圧をモニターし
`ながら点滴速度を調節する。
`
`25
`
`２mg
`10mg
`25mg
`承 認 番 号
`21100AMZ00175
`63AM−965
`63AM−964
`1999 年５月
`1988年11月
`薬 価 収 載
`1999 年７月
`1989年１月
`販 売 開 始
`効 能 追 加 1994年９月（高血圧性緊急症）
`1998年１月（急性心不全）
`　　
`
`○急性心不全（慢性心不全の急性増悪を含む）
`　本剤は、生理食塩液又は５％ブドウ糖注射液で希釈し、塩酸ニカル
`ジピンとして0.01〜0.02％（１mL当たり0.1〜0.2mg）溶液を点滴静
`注する。この場合１分間に、体重１kg当たり１μgの点滴速度で投
`与する。なお、患者の病態に応じて１分間に、体重１kg当たり0.5
`〜２μgの範囲で点滴速度を調節する。
`
`＜用法・用量に関連する使用上の注意＞
`○高血圧性緊急症においては、本剤投与により目的の血圧が得られた
`後、引き続いて降圧治療が必要で経口投与が可能な場合には、経
`口投与に切り替えること。
`○高血圧性緊急症において、本剤投与終了後に血圧が再上昇すること
`があるので、本剤の投