Summary of Product Characteristics

ATELEC Tablets 10
1.

Name of the medicinal product1.1 Product name
ATELEC Tablets 10
1.2 Strength
Each film-coated tablet contains 10mg of cilnidipine
1.3 Pharmaceutical dosage form
Film-coated tablet

2.

Quality and quantitative composition
2.1 Qualitative declaration
Cilnidipine (INN)
2.2 Quantitative declaration
Each film-coated tablet contains 10mg of cilnidipine

3.

Pharmaceutical form
ATELEC Tablets 10 is a white oval film-coated tablet with cleavage line.
Brand
name

Identification code

FaceAppearance
ReverseLateralSize and average weightMjA: ca. 12.3 mm
MnA: ca. 6.0 mm
T : ca. 4.7 mm
W : ca. 0.27 g
T: thickness; W: weight; MjA: major axis; and MnA: minor axis
ATELEC
Tablets 10

4.

AJI 10

Clinical particulars
4.1 Therapeutic indication
ATELEC is indicated for the treatment of hypertension.
4.2 Posology and method of administration
Usually, for adults, 5 to 10 mg is administered as cilnidipine for orally oncea day after breakfast. The dosage may be adjusted according to the patient'sage and symptoms. The dose can be increased up to 20 mg once a day, ifa sufficient response does not appear. For adults with severe hypertension,
ATELEC should be administered 10 to 20 mg once a day for oral use afterbreakfast.
4.3 Contraindication
Patients with hypersensitivity to the active substance or to any of theexcipients.
Pregnant women or women having possibilities of being pregnant (See“Pregnancy and lactation” section).
4.4 Special warning and precautions for use
Careful Administration (ATELEC should be administered with care in
the following patients.)(1) Patients with serious hepatic dysfunction [The plasma concentration maybecome elevated.](2) Patients with a history of serious adverse reactions to calcium antagonists(3) Elderly patients [See “Use in the Elderly” section]
Important Precautions
As it has been reported that sudden withdrawal of a calcium antagonist
caused aggravation of certain symptoms. Therefore, if the discontinuation ofATELEC is necessary, the dosage should be gradually decreased under close
observation.
If ATELEC is withdrawn from a daily dose of 5 mg, appropriate measures,such as replacement with other antihypertensive agents, should be taken.
Direct the patient not to discontinue this drug without physician’sinstructions.
Use in the Elderly
ATELEC should be administered carefully under close observation of thepatient’s condition, taking such measures as starting with a lower dose (e.g.
5mg).
Use in the Elderly is generally acknowledged that the excessive hypotensiveaction should be avoided in the elderly.
Therefore, adverse reactions (including abnormalities in laboratory data) in
the elderly aged 65 years and over, were observed in 152 of 2,863 patientsin the investigation at the time of approval and the postmarketing studies (atthe end of the reexamination period) .
Pediatric Use
The safety of ATELEC in pediatric patients has not been established (noclinical experience).
Precautions concerning Use
When dispensing the drug:
It should be clarified that the patient understands that the tablets must firstbe removed from the PTP blister package before they are ingested. [It isreported that, in case of the ingestion of the PTP blister package, the sharp
hard edges of the package can easily perforate the esophageal mucosa andresult in serious complications, such as mediastinitis.]

4.5 Interaction with other medicinal products and other forms of interactions
ATELEC is chiefly metabolized by the drug-metabolizing enzyme CYP3A4
and in part by CYP2C19.
Precautions for Coadministration (ATELEC and the following drugs
should be coadministered with care.)Names of Drugs
Signs, Symptoms andMechanism and Risk Factors
Treatment
Agents with
There is a possibility that
Drug action is considered tohypotensive effect blood pressure is excessively
be enhanced additively ordecreased.
synergistically.

Digoxin

It has been reported that some The mechanism is notother calcium antagonists
completely clarified yet, but is(e.g., nifedipine) increased
thought to lie in decreased renal
the plasma concentration ofand extrarenal clearances.
digoxin.
If any toxic signs/symptoms
attributable to digoxin (e.g.,nausea, vomiting, headache,abnormal vision, arrhythmia)
are observed, appropriate
measures should be instituted
such as digoxin dose adjustment
or discontinuation of ATELEC,depending on the patient’scondition.
Cimetidine
It has been reported that
It is thought that cimetidine
effects of some other calcium decreases hepatic blood
antagonists (e.g., nifedipine)
flow with the consequent
were enhanced.
suppression of the emzymatic
metabolism of calcium
antagonists in liver microsomes,
and at the same time cimetidine
lowers gastric acid output andthus increases absorption ofcalcium antagonists.
Rifampicin
It has been reported that effects It is generally thought thatof other calcium antagonists
hepatic drug-metabolizing(e.g., nifedipine) were reduced. enzyme (cytochrome P-450)
induced by rifampicin
facilitates metabolism ofcalcium antagonists and thusincreases the clearance of theseagents.
Antifungal azoles: The blood concentration of
Antimycotic azoles are thought
Itraconazole,
ATELEC may be elevated.
to inhibit CYP3A4, a drugmiconazole, etc.
metabolizing enzyme for
ATELEC.
Grapefruit juice
It has been demonstrated that Details of the underlying
the plasma concentration ofmechanism remain toATELEC is elevated.
be elucidated, but someconstituents in grapefruit juice
may inhibit CYP3A4, a drugmetabolizing enzyme forATELEC.
4.6 Pregnancy and lactation
ATELEC should not be administered to pregnant women or women having
possibilities of being pregnant. [It has been reported that ATELEC prolongs
the gestation period and delivery time in animal experiments (in rats).]
It is advisable to avoid the administration of ATELEC to nursing mothers.
However, if the administration is indispensable, the patient should beinstructed to discontinue lactation. [Transfer of this drug to mother’s milk
has been reported in animal experiments (in rats).]
4.7 Effects on ability to drive and use machine
The symptoms, such as dizziness may occur because of the hypotensive
action from this drug. Give warning against engaging in hazardous activities
requiring alertness, such as working at a height, operating machinery or
driving motor vehicles.
4.8 Undesirable effects
Adverse reactions, including abnormalities in laboratory data, were observedin 414 (6.95%) of 5,958 patients in the investigations at the time of approval
and the postmarketing studies (at the end of the reexamination period).
Clinically significant adverse reactions
1) Hepatic dysfunction and jaundice (frequency unknown): Hepaticfunction disorder and jaundice accompanied with increased AST (GOT),ALT (GPT) and γ-GTP may occur. Therefore, close observation should be
made, and if any abnormality is observed, appropriate measures, such as
discontinuation of ATELEC, should be taken.
2) Thrombocytopenia (incidence: <0.1%): Since thrombocytopenia mayoccur, close observation should be made, and if any abnormality isobserved, appropriate measures, such as discontinuation of ATELEC,
should be taken.
Other adverse reactions
If any of the following adverse reactions occur, appropriate measures should
be taken depending on the symptoms.
0.1 to <5%<0.1%

Increases in AST
ALP increased(GOT), ALT (GPT),
LDH, etc.
Renal
Increases in creatinine Urinary sedimentor urea nitrogen,present
urinary protein
positive
Psychoneurological Headache, headache Sleepiness, insomnia,dull, dizziness,
tremor finger,dizziness on standing forgetfulness
up, shoulder muscle
stiffness

Incidenceunknown

HepaticNote 1)

Numbness

7. Effect on Cardiovascular Disturbance Associated with Hypertension(1) In stroke-prone spontaneously hypertensive rats, a single daily dose ofcilnidipine suppressed the appearance of stroke and improved the survival
rate. In addition, it lessened cardiac hypertrophy (increased heart weight),
thickening of the ventricular wall, myocardial fibrosis and lesions in thekidney. Moreover, it depressed medial thickening in the coronary arterial
wall and decreased calcium content in the aorta.
(2) In patients with essential hypertension, cilnidipine decreased theatherosclerotic index and serum lipid peroxide.
8. Mechanisms of Action(1) Experimental data suggest that cilnidipine binds to the dihydropyridine
binding sites of L-type voltage dependent calcium channel and inhibits
Ca2+ influx across the cell membranes of vascular smooth muscle cells
via this channel (rabbits in vitro).
Consequently, vascular smooth muscle is relaxed, causing vasodilation.
Through this mechanism, cilnidipine is considered to have an hypotensiveaction.
(2) Cilnidipine inhibits Ca2+ influx via N-type voltage dependent calcium
channels in the sympathetic nerve cell membrane. The inhibition of Ca2+
influx via N-type voltage dependent calcium channel was observed overa similar range of drug concentrations to those inhibiting L-type voltage
dependent Ca2+ channels (rats in vitro).
Consequently, release of norepinephrine from sympathetic nerve
terminals would be inhibited. Cilnidipine is considered to suppress thereflex increase in heart rate which may be mediated by sympathetic
activation after blood pressure reduction and to inhibit stress-related
hypertension through this mechanism.
5.2 Pharmacokinetic properties
1. Plasma Drug Levels
When a single dose of 5 mg, 10mg or 20mg cilnidipine was orally
administered to six healthy male volunteers, the Cmax was found to be
4.7 ng/mL, 5.4 ng/mL and 15.7 ng/mL, respectively, and the AUC0-24 tobe 23.7 ng·hr/mL, 27.5 ng·hr/mL and 60.1 ng·hr/mL, respectively. Thus,
both parameters increased in a dose-dependent manner.
When a single dose of 10 mg of cilnidipine was repeatedly administeredonce a day to six healthy male volunteers, pharmacokinetic parameters ofcilnidipine were indicated as follows. The plasma concentration reacheda steady state from Day 4 of the administration and there was no evidenceof the accumulation.

Cardiovascular

Flushed face,
Chest pain,
Extrasystole,
palpitation, feelingcardiothoracic ratio
bradycardia
hot, electrocardiogram increased, tachycardia,
abnormal (STatrioventricular block,depressed, inverted T feeling coldwaves), blood pressure
decreased
Gastrointestinal
Nausea, vomiting,Constipation, bloating,abdominal pain
thirst, gingival
hypertrophy, heartburn,diarrhoeaRedness, itching
Photosensitivity
HypersensitivityNote 2) Rash
Hematologic
Up or down in WBC, Up or down in RBC,
neutrophils andhematocrit, eosinophils
hemoglobin
and lymphocytes
Other
Oedema (facial, lower Feelings of weakness, Tinnitus
leg, etc.), generalgastrocnemius
malaise, pollakiuria, muscle cramps,
increased serum
periophthalmiccholesterol, up ordryness, ocular
down in CK (CPK),
hyperemia and feelinguric acid, serum K and of irritation, dysgeusia,
serum Purine sugar positive,
up or down in fastingblood sugar, totalprotein, serum Ca andCRP, coughNote 1): The patient should be carefully monitored for these symptoms, andif any abnormality is noted, ATELEC should be discontinued.
Note 2): If any such symptom appears, ATELEC should be discontinued.
Inform your doctor of undesirable effects occurred during the use ofdrug.
4.9 Overdose
Overdosage of ATELEC may cause excessive reduction in blood pressure.
If reduction in blood pressure is remarkable, appropriate measures such as
lifting lower extremities, fluid therapy and administration of vasopressors
should be taken. Hemodialytical removal of the drug is not effective becauseof its high rate of protein binding.
5.

Pharmacological properties
5.1 Pharmacodynamic properties
1. Antihypertensive Effect(1) In various hypertensive animal models (spontaneously hypertensiverats, renal hypertensive rats and dogs, DOCA salt hypertensive rats,
and stroke-prone spontaneously hypertensive rats), a single oral doseof cilnidipine showed a gradual and long-lasting hypotensive actionthat was dose-dependent at 1mg/kg or more. In contrast, it showed
a weak hypotensive action in normotensive rats. The duration of theaction was not prolonged by an excessive dosage. In renal hypertensive
dogs, cilnidipine showed an additive effect when coadministered with aβ-blocker or an angiotensin-converting enzyme inhibitor.
(2) In stroke-prone spontaneously hypertensive rats and renally hypertensive
dogs, repeated oral doses of cilnidipine had a stable hypotensive action
which did not show attenuatetion. Discontinuation of cilnidipine did notcause a rebound in blood pressure.
(3) In conscious and unrestrained spontaneously hypertensive rats, cilnidipine
did not increase the heart rate during hypotension. Cilnidipine did notincrease the plasma noradrenaline level during hypotension, nor did it
cause a significant decrease, which an adrenergic blocker (guanethidinesulfate) did. Cilnidipine did not cause orthostatic hypotension, although aganglion blocker (pentolinium) did in a tilt test using rabbits.
(4) In patients with essential hypertension, a single daily dose of cilnidipine
showed a hypotensive action that maintained for 24 hours and was still
evident early in the next morning. Power spectral analysis of the R-Rintervals of 24 hours electrocardiogram revealed that cilnidipine did notincrease sympathetic activity or the heart rate as a reflex response to thereduction of blood pressure.
2. Inhibitory action on Stress induced Pressor Response(1) In conscious and unrestrained spontaneously hypertensive rats,
cilnidipine inhibited the elevation of blood pressure and plasma
norepinephrine levels induced by cold stress. Cilnidipine also inhibitedthe elevation of blood pressure induced by air jet stress (mental stress) inrats.
(2) In healthy adult male volunteers whose blood pressure was elevated by
20% or more in cold stress test, cilnidipine suppressed the elevation ofblood pressure induced by cold stress.
3. Inhibitory action on Sympathetic Stimulation induced Pressor
Response(1) In pithed spontaneously hypertensive rats, cilnidipine supressed theelevation of blood pressure induced by electrical sympathetic stimulation.
(2) In isolated and perfused mesenteric arterial vascular preparation in
spontaneously hypertensive rats, cilnidipine also inhibited the release of
norepinephrine induced by electrical sympathetic stimulation.
4. Effect on Cerebral Circulation(1) In spontaneously hypertensive rats, cilnidipine did not decrease cerebral
blood flow even if the dose which decrease blood pressure by 30-40%
in rats was administered. The autoregulation of cerebral blood flow wassatisfactorily maintained while the blood pressure was decreased.
(2) In hypertensive patients comlicated by cerebrovascular disease, thecerebral blood flow was maintained while blood pressure was lowered.
5. Effects on Cardiac Function(1) In dogs, cilnidipine decreased heart rate and myocardial contractility at ahigher dose than that inducing an increased flow of arterial blood.
(2) In anesthetized open chest dogs, cilnidipine decreased the myocardial
oxygen consumption at dose inducing hypotension. At the time, it neither
caused tachycardia nor affected cardiac contractility.
(3) In patients with essential hypertension, cilnidipine did not affectheart rate while the blood pressure was decreased and in patients withabnormal cardiothoracic ratio (CTR), it improved the CTR.
6. Effects on Renal Function(1) In anesthetized spontaneously hypertensive rats, cilnidipine increased theurinary volume, renal blood flow and glomerular filtration rate at the dose
inducing hypotension. Cilnidipine also increased the urinary volume,
renal blood flow and glomerular filtration rate, when the renal function
was depressed by endothelin.
(2) In patients with essential hypertension, cilnidipine did not affect renal
function while the blood pressure was decreased.

Parameter
Day ofdosing
Day 1
Day 4
Day 7

Cmax
(ng/mL)Tmax(hr)

T1/2 (α)(hr)

T1/2 (β)(hr)

AUC0-∞(ng·hr/mL)

9.5±1.6
13.5±5.0
16.5±7.92.8±1.0
3.7±0.8
3.0±1.3

1.0±0.2−
1.1±0.6

5.2±2.0−
8.1±2.751.4±12.7
101.8±29.0
95.5±34.5(Mean ± S.D.)

The pharmacokinetics of this drug have also been evaluated in patientswith impaired renal function (serum creatinine:1.5-3.1mg/dL) following
a single oral dose of 10mg in the hypertensive patients, and no significant
differences were found in the pharmacokinetic profile of this drug
compared with that in patients with normal renal function.
Repeated oral administration of this drug at a dose of 10mg once a dayfor 7days in patients with impaired renal function caused no differencesin the pharmacokinetic profile compared with that in patients with normal
renal function.
2. Metabolism and Excretion
From the metabolites identified in the plasma and urine of healthy malevolunteers, it is considered that the major route of cilnidipine metabolism
is demethylation of the methoxyethyl group followed by hydrolysis of thecinnamyl ester and oxidation of the dihydropyridine ring. It is consideredthat CYP3A4 is mainly involved and CYP2C19 is partly involved in thedemethylation of the methoxyethyl group (in vitro).
The calcium channel blocking action of the metabolite with thedemethylated methoxyethyl group was only 1/100 of that of the parent
compound (in rabbits).
When a single oral dose of 10mg of cilnidipine was repeatedlyadministrated to healthy male volunteers once a day for 7days, nounchanged compound of cilnidipine but 5.2% of the dose was excreted
in the urine as metabolites. (The approved administration of ATELEC isorally once a day after breakfast.)
An in vitro experiment showed that cilnidipine was 99.3% bound tohuman serum protein.
5.3 Preclinical safety data
In studies on acute toxicity, subacute toxicity, chronic toxicity, reproduction,
antigenicity, mutagenicity, carcinogenicity, and general pharmacology toevaluate the safety of cilnidipine, there was no finding of particular concern.
6.

Pharmaceutical particulars
6.1 List of excipient
Lactose Hydrate, Microcrystalline Cellulose, Macrogol 400, Magnesium
Aluminometasilicate, Croscarmellose Sodium, Hydroxypropylcellulose,
Hypromellose Phthalate, Talc, Magnesium Stearate, Hypromellose,Ethylcellulose, Macrogol 6000, Macrogol 600, Titanium Oxide andCarnauba Wax.
6.2 Incompatibilities
Since ATELEC tablets 10 is a tablet preparation, it is not applicable
6.3 Shelf life
36 months from manufacturing date
6.4 Special precautions for storage
Store below 30°C, protect from light.
6.5 Nature and contents of container
Blister: CPP, Aluminum

7.

Name and address of importer
DKSH (Thailand) Limited
Bangkok, Thailand

8. Thai registration number
1C 9/61 (NC)9.

Date of authorization
3 April 2018

10. Date of revision of the text
4 June 2018