IKACOR 40 MG

Israel - English - Ministry of Health

Buy It Now

Active ingredient:
VERAPAMIL HYDROCHLORIDE
Available from:
TEVA PHARMACEUTICAL INDUSTRIES LTD, ISRAEL
ATC code:
C08DA01
Pharmaceutical form:
TABLETS
Composition:
VERAPAMIL HYDROCHLORIDE 40 MG
Administration route:
PER OS
Prescription type:
Required
Manufactured by:
TEVA PHARMACEUTICAL INDUSTRIES LTD, ISRAEL
Therapeutic group:
VERAPAMIL
Therapeutic area:
VERAPAMIL
Therapeutic indications:
Angina pectoris, cardiac arrhythmias, hypertension.
Authorization number:
025 25 21103 00
Authorization date:
2012-01-31

Documents in other languages

Patient Information leaflet Patient Information leaflet - Arabic

26-01-2021

Patient Information leaflet Patient Information leaflet - Hebrew

26-01-2021

Ikacor Tablets, New Format-March 2014 27. 3. 2014

םי חקורה תונקת יפל ןכרצל ןולע

)

םירישכת

(

משתה

"

ו

-

986

1

תה הפור

תק וושמ ע יפ ל דבלב אפור םשרמ

רוקאקיא

תוילבט

בכרה

הליכמ הילבט לכ

רו קאקיא

40

מ

"

ג

תוילבט

רו קאקיא

80

מ

"

ג

תוילבט

רו קאקיא

120

מ

"

ג

תוילבט

Verapamil HCl 40 mg

Verapamil HCl 80 mg

Verapamil HCl 120 mg

תמישרל םיליעפ יתלבה םירמוחה רישכתב

האר ףיעס

"

ףסונ עדימ

"

הפורתב שמתשת םרטב ופוס דע ןולעה תא ןויעב ארק

.

הפורתה לע יתיצמת עדימ ליכמ הז ןולע

שי םא תופסונ תולאש ךל

חקורה לא וא אפורה לא הנפ

ךתלחמב לו פיטל המשרנ וז הפורת

.

ירחאל התוא ריבעת לא

ם

.

הארנ םא וליפא םהל קיזהל הלולע איה המוד םתלחמ יכ ךל

.

תויל וכשא ץימ םע הפורתה לו טיל ןיא

.

1

.

הפורתה תדעוימ המל

?

בלה תקועתב לופיטל

בלה בצקב תוערפה םד ץחל רתיו

תיט יופרת הצובק

:

ןדיס תולעת םסוח

2

.

הפורתב שומישה ינפל

תב שמתשהל ןיא וז הפור

ינמ ךניה רשאכ הק

היביכרממ דחאל תושיגר העודי םא

םא

ןוגכ בלב תויעב ךל שיש עידומ ךאפור

ךומנ םד ץחל

ל תחתמ ילוטסיס ךרע

"

תיפסכ מ

ךומנ דואמ םד ץחל וא

םלה לש הרקמב אמגודל

shock

בל תקיפס יא

רופרפ וא ףורפר תפסונ הכלוה תליסמ תוולתמ וילא ירודסורפ

אמגודל

תעפות

Wolff-Parkinson-White

וא

Lown-Ganong-Levine

תישילש וא היינש הגרדמ בל תמיסח לבוס ךניהש עידומ ךאפורו בל בצוק אשונ ךניא םא

וא תלחמ

sick sinus syndrome

רבעמב המיסח וא ריהמ קפוד יפקתהב םיתיעל הוולמ יתיא קפוד םיילמשחה םייוריגה

אפורל עידוהל ךילע

יטנ םרט חקור חוטב ךניא םא רוקאקיא תל

הפורתב שומישל תועגונה תודחוימ תורהזא

מ רבעב תלבס וא לבוס התא םא לופיטה תלחתה ינפל אפורב ץעוויהל שי

בל ףקתה ףירח הדיריו יטיא קפודב הוולמ םדה ץחלב הלודג

ו בלה דוקפיתב יוקיל

םד ילכ וא

האר הלעמל ףיעס

הילכה וא דבכה

תשה תכרעמ לבוס ךניה םא וא ן םיבצעה תכרעמב הלחממ

םירירש ןווינ ןוגכ

םרירש תשלוח

(myasthenia gravis)

נה תולחמהמ תחא ךל שיש חוטב ךניא םא

"

חקורה וא אפורב ץעוויהל שי

Ikacor Tablets, New Format-March 2014 27. 3. 2014

תופסונ תורהזא

זוטקלל םישיגרה םישנאל היגרלאל םורגל לולעו זוטקל ליכמ רישכתה

קשמ וא תוניי תותשל ןיא וז הפורתב לופיטה תפוקת ךשמב םיפירח תוא

םד ץחל תוקידב ךורעל שי וז הפורתב לופיטה תפוקתב

דבכ דוקפתו בל בצק

יהשלכ הפורתל וא והשלכ ןוזמל שיגר ךניה םא

הפורתה תליטנ ינפל אפורל ךכ לע עידוהל ךילע

חקול התא םא

,

תלטנ םא וא

הנורחאל

,

תורחא תופורת

ופורת ללוכ םשרמ אלל ת

תויחמצ תופורת

ןוזמ יפסותו םינימטיוו

חקורל וא אפורל ךכ לע רפס

שי דחוימב אפורה תא עדייל

םא חקורה וא ךניה

לטונ

צובקהמ הפורת תו אבה תו םא וא הפורתב לופיטה התע הז תרמג

ןיריפסא

םד לולידל תופורת

םד תשירק דגנ

נתשמ תופורת ללוכ םד ץחל תדרוהל תופורת תו

ימסוח

לולורפוטמ וא לולונרפורפ ןוגכ אתיב

וא ןיסוזרפ וא ןיסוזרט ןוגכ אפלא ימסוח

דיניאקלפ ןוגכ בלל תופורת

ןידיניכ

דימריפוסיד

סילטיגיד וא םיטרטינ

ןיליפואית תפורת

המטסאל

ןיפזאמאברק תפורת

תותיוועל

רפימיא ןוגכ העגרהל וא חור יבצמב לופיטל תופורת ןימ

םויתיל

לטיברבונפ

םלוזדימ וא ןוריפסוב

דימלקנבילג ןוגכ תרכוס דגנ תופורת

תוימוהיז תולחמב לופיטל תופורת

ןיצימורתירא ןוגכ

ןיצימורתירלק

ןיפמפיר וא ןיצימורתילט

ןיסיבורוסקוד ןוגכ ןטרסב לופיטל תופורת

ןידיטמיס ןוגכ סוקלואב לופיטל תופורת

יטל תופורת ןיציכלוק ןוגכ ןודגיש לופ

ןוזריפניפלוס

תולתשה תייחד תעינמל תופורת

ןירופסולקיצ ןוגכ

סומילוריס

סומילורקט

סומילורבא וא

ןיטאטסברוטא ןוגכ םדב לורטסלוכ תדרוהל תופורת

ןיטאטסבמיס

ןיטאטסבול וא

תורחא תופורת ןיב תובוגתל תומרוג ןניא הצובקה התואל תוכייתשמה

ורת לימפרווה םע תויתפ

ןה ולא

ןיטאטסבולפ

ןיטאטסברפ

ןיטאטסבוסורו

ןטפירטומלא ןוגכ הנרגימב לופיטל תופורת

תלחמב לופיטל תופורת

AIDS

סוריו וא

םיחותינב שומישל תופורת

שחלאמ זג

םירירש תייפרהל וא

םוקירפיהה חמצ

תוילוכשא ץימו

גל תולולעה תופורת לש וז תמישר תיפוס הניא רוקאקיא םע תויתפורת ןיב תובוגתל םור

אפורב ץעוויהל שי תופורתב שמתשת םרטב חקורה וא ןהשלכ

ןוירה

ןוירהב ךניה םא

ןוירהל סנכיהל ךתנווכב

לימפרווה

רישכתבש ליעפה רמוחה

תכרעממ ךרד רובעל לולע קוניתה לא ךלש םדה

הקנה

וז הפורתב שמתשהל ןיא תא םא נמ הקי

ףיעס האר

הגיהנ

ע םוגפלו תורוחרחס וא שאר באכל םורגל לולע וז הפורתב שומישה

"

תוריהז בייחמ ןכ לעו תונריעב ךכ י בכרב הגיהנ גוסמ תוליעפב

תונריע תבייחמה תוליעפ לכבו תונכוסמ תונוכמ תלעפהב

םידליב שומיש

וז הפורת תדעוימ הניא שומישל םידליב

3

.

מתשת דציכ הפורתב ש

?

אפורה תוארוה יפל הפורתב שמתשהל שי דימת

חוטב ךניא םא חקורה וא אפורה םע קודבל ךילע

Ikacor Tablets, New Format-March 2014 27. 3. 2014

ע עבקנש יפכ םיבוצק םינמזב וז הפורתב שמתשהל שי

"

לפטמה אפורה י

תצלמומה הנמה לע רובעל ןיא

.

ךתואירב בצמב רופיש לח םא םג

צעייתה אלל הפורתב לופיטה תא קיספהל ןיא אפורה םע תו

תורומח תואצותל איבמ לפוטמ וניאש םד ץחל רתי

שומישה ןפוא

סועלל ןיא תוצחל וא שותכל

םימ סוכ םע תוילבטה עולבל

תוחוראה םע הפורתה לוטיל שי בלח םע וא

רתי תנמ תלטנ םא הפורתה ןמ דלי עלב תועטב םא וא

,

תיב לש ןוימ רדחל וא אפורל דימ תונפל שי לו םילוח ךתיא הפורתה תזירא תא איבה

אפורהמ תשרופמ הארוה אלל האקהל םורגת לא

םא םג הבוט ךתשגרה

ינויח אוה ידיימ לופיט

בוצקה ןמזב וז הפורת לוטיל תחכש םא

תרכזנשכ דימ הנמה תא לוטיל שי

יתש לוטיל ןיא ןפוא םושב ךא דחיב תונמ םויה ותואב

טיל ןיא

ךשוחב תופורת ל

ה קודב הנמהו תיוות םעפ לכב ונ ךניהש לט הפורת

ךניה םא םייפקשמ בכרה םהל קוקז

4

.

יאוול תועפות

הפורת לכל ומכ

שומישה

וז הפורת תועפותל םורגל לולע קלחב יאוול

םישמתשמהמ

ארקמל להבית לא יאוולה תועפות תמישר

ןהמ תחא ףאמ לובסת אלו ןכתי

ו לופיטה תא קיספהל שי תונפל ורל דימ אפ םיאבה םירקמב

:

הרומח תיגרלא הבוגת

םייפעפעב תוחיפנ דחוימב

ןושלב וא ןורגב

המישנ יישק

ךומנ םד ץחלמ האצותכ ןופליע וא תרוחרחס

תלרח תחתפתמ ובו תיגרלא הבוגת

רועב תבאוכ וא תדרגמ החירפ

תופסונ יאוול תועפות

יא וול תועפות תוחיכש

)

עיפשמ תו לע מ תוחפ

1

תמ ךו

10

םילפוטמ

(

שאר באכ

תורוחרחס

תוריצע

תוליחב

יטיא קפוד

ךומנ םד ץחל

תוימומדא

ףוגב תוחפנתה

םיילגרב וא םיידיב

תוחיכש ןנ יאש יאוול תועפות

)

מ תוחפ לע תועיפשמ

1

ךותמ

100

םי לפוטמ

(

קזח קפוד

ריהמ קפוד

ןטב באכ

תופייע

Ikacor Tablets, New Format-March 2014 27. 3. 2014

יא וול תועפות תורידנ

)

מ תוחפ לע תועיפשמ

1

ךותמ

1000

םילפוטמ

(

לומינ תשוחת

דער

םונמנ

םיינזואב םוזמז

תואקה

תרבגומ העיז

יא וול תועפות םילפוטמ לש עודי אל רפסמב תושרחתמה

רתי תושיגר

םיבצעה תכרעמל תורושקה תועפות

(extrapyramidal)

השק תרוחרחס

(vertigo)

בל תקיפס יא

בלה קפודב תוערפה

תונופמיסה תותיווע

תויעב המישנב

ןטבב תוחונ רסוח

םייכינחה לש תרבגומ החימצ

תוחופנ םייכינח

השק תוריצע לש גוס

םייעמ תמיסח לש הרמחה

ileus

םינפב תוחיפנ

םייתפשב

עולבו ןושלב

תויחופלשו םישושבג

תלחמ

Stevens Johnson

תרירבו רועב תויחופלש

בוא

רעיש ן

דוריג

החירפ

תלרח

ב תדרגמ החירפ רוע

רועב תטירס וא ףושפשל ףחד לש תרבגומ השוחת

םירירש תשלוח

םיקרפמ וא םירירש יבאכ

תונוא ןיא

םיידשהמ הפילדל םרוגה םישנב בלח לש תרבגמ הריצי

רבגב םיידש לש תרבגומ תוחתפתה

דבכה ימיזנא תמרב הילע

הרימחמ יאוולה תועפותמ תחא םא

,

וא ךניה םא אלש יאוול תעפותמ לבוס ןולעב הרכזוה

,

ילע

ך

דימ אפורה םע ץעייתהל

.

5

.

הפורתה תא ןסחאל ךיא

?

הלערה ענמ

שיהל ץוחמ רוגס םוקמב רומשל שי תרחא הפורת לכו וז הפורת

ו םידלי לש םדי

וא תוקונית

הלערה ענמת ךכ ידי לעו

רופמ הארוה אלל האקהל םורגת לא

אפורהמ ת

הגופתה ךיראת ירחא הפורתב שמתשהל ןיא

Exp. Date

הזיראה יבג לע עיפומה

הגופתה ךיראת שדוח ותוא לש ןורחאה םויל סחייתמ

םוקמב וז הפורת רומשל שי ל תחתמ שביו ךושח

בטיה הרוגס דימת היהת הפורתה תזיראש אדוול שי

תוביטרו ריוא תרידח עונמל ידכ תאזו

הזיראה יאנת יפל םג

םיצלמומה הנסחה

נ תופורת דבלב תלבגומ הפוקתל תורמש

ךיראתל בל םישל אנ לש הגופתה

רישכתה

קפס לש הרקמ לכב

הפורתה תא ךל קפיסש חקורב ץעוויהל ךילע

הזירא התואב תונוש תופורת ןסחאל ןיא

Ikacor Tablets, New Format-March 2014 27. 3. 2014

6

.

ףסונ עדימ

םג הליכמ הפורתה ליעפה רמוחה לע ףסונ

:

רוקאקיא

120

מ

"

ג

רוקאקיא

80

מ

"

ג

רוקאקיא

40

מ

"

ג

Lactose monohydrate, starch,

microcrystalline cellulose, gelatin,

talc, sodium starch glycolate,

magnesium stearate,

HPMC

2910,

titanium

dioxide,

polyethylene glycol, brilliant blue

FCF aluminium lake FD&C Blue

No.1.

Lactose

monohydrate,

starch,

microcrystalline

cellulose,

gelatin,

talc,

sodium

starch

glycolate,

magnesium stearate, polydextrose

FCC,

titanium

dioxide,

HPMC

2910,

macrogol/PEG

4000,

polyethylene

glycol,

erythrosine

aluminium lake, brilliant blue FCF

aluminium lake FD&C Blue No.1.

Lactose

monohydrate,

starch,

microcrystalline cellulose, gelatin,

talc,

sodium

starch

glycolate,

magnesium

stearate,

HPMC

2910,

titanium

dioxide,

polyethylene

glycol,

erythrosine

aluminium lake.

הליכמ הילבט לכ

"

זוטקל ג

0.24

"

ןרתנ ג

הליכמ הילבט לכ

80.0

"

זוטקל ג

0.16

"

ןרתנ ג

הליכמ הילבט לכ

40.0

"

זוטקל ג

0.08

"

ןרתנ ג

הזיראה ןכ ות המו הפורתה תיארנ דציכ

:

רוקאקיא

"

דורו עבצב הלוגע הילבט

םידדצה ינשמ הרומכ

רוקאקיא

"

לוגס עבצב הלוגע הילבט

םידדצה ינשמ הרומכ

רוקאקיא

"

ריהב לוחכ עבצב הלוגע הילבט

םידדצה ינשמ הרומכ

ןרצי םושירה לעבו

:

עב תויטבצמרפ תוישעת עבט

"

"

3190

חתפ

הוקת

ע רשואו קדבנ הז ןולע

"

תואירבה דרשמ י

ץרמ

2014

רפסמ

י

פורתה םו שיר תו תואירבה דרשמב יתכלממה תופורתה סקנפב

:

רוקאקיא

"

025 25 21103 00

רוקאקיא

"

040 02 23155 00

רוקאקיא

"

039 47 21913 00

האירקה תלקהלו תוטשפה םשל

רכז ןושלב חסונ הז ןולע

תאז ףא לע

םינימה ינש ינבל תדעוימ הפורתה

Ikacor Tablets- 27 3. 2014 RH

"

ע עבקנ הז ןולע טמרופ

"

רשואו קדבנ ונכותו תואירבה דרשמ י

."

רשואמ ןולע

ץרמ

2014

“This leaflet format has been determined by the Ministry of Health and the content thereof has been

checked and approved.” Date of approval: March 2014.

IKACOR

®

TABLETS

Composition

Ikacor Tablets 40 mg

Each tablet contains:

Active Ingredient

Verapamil HCl

40 mg

Others Ingredients

Lactose monohydrate, starch, microcrystalline cellulose, gelatin, talc, sodium starch

glycolate, magnesium stearate, HPMC 2910, titanium dioxide, polyethylene glycol,

erythrosine aluminium lake.

Each tablet contains: 40.0 mg lactose, 0.08 mg sodium.

Ikacor Tablets 80 mg

Each tablet contains:

Active Ingredient

Verapamil HCl

80 mg

Others Ingredients

Lactose monohydrate, starch, microcrystalline cellulose, gelatin, talc, sodium starch

glycolate, magnesium stearate, polydextrose FCC, titanium dioxide, HPMC 2910,

macrogol/PEG 4000, polyethylene glycol, erythrosine aluminium lake, brilliant blue FCF

aluminium lake FD&C Blue No.1.

Each tablet contains 80.0 mg lactose, 0.16 mg sodium.

Ikacor Tablets 120 mg

Each tablet contains:

Active Ingredient

Verapamil HCl

120 mg

Others Ingredients

Lactose monohydrate, starch, microcrystalline cellulose, gelatin, talc, sodium starch

glycolate, magnesium stearate, HPMC 2910, titanium dioxide, polyethylene glycol,

brilliant blue FCF aluminium lake FD&C Blue No.1.

Each tablet contains 120.0 mg lactose, 0.24 mg sodium.

Action

Pharmacotherapeutic group: Selective calcium channel blockers with direct cardiac

effects, phenylalkylamine derivatives.

ATC-Code: C08DA01

Verapamil is a calcium antagonist which blocks the inward movement of calcium in

cardiac muscle cells, in smooth muscle cells of the coronary and systemic arteries and

in the cells of the intracardiac conduction system. The decrease in systemic and

coronary

vascular

resistance

sparing

effect

intracellular

oxygen

consumption appear to explain the anti-anginal properties of the product.

Because of its effect on the movement of calcium in the intracardiac conduction

system, Verapamil reduces automaticity, decreases conduction velocity and increases

the refractory period.

Ikacor Tablets- 27 3. 2014 RH

Page 2 of 13

Ikacor lowers peripheral vascular resistance with little or no reflex tachycardia. Its

efficacy in reducing both raised systolic and diastolic blood pressures is thought to be

primarily due to this mode of action.

Pharmacokinetic properties

Verapamil hydrochloride is a racemic mixture consisting of equal portions of the R-

enantiomer and the S-enantiomer. Verapamil is extensively metabolized. Norverapamil

is one of 12 metabolites identified in urine, has 10 to 20% of the pharmacologic activity

verapamil

accounts

excreted

drug.

steady-state

plasma

concentrations of norverapamil and verapamil are similar. Steady state after multiple

once daily dosing is reached after three to four days.

Absorption

Greater than 90% of verapamil is rapidly absorbed from the small intestine after oral

administration. Mean systemic availability of the unchanged compound after a single

dose

verapamil

owing

extensive

hepatic

first-pass

metabolism.

Bioavailability is about two times higher with repeated administration. Peak verapamil

plasma levels are reached one to two hours after administration. The peak plasma

concentration of norverapamil is attained approximately one hour after administration.

The presence of food has no effect on the bioavailability of verapamil.

Distribution

Verapamil is widely distributed throughout the body tissues, the volume of distribution

ranging from 1.8–6.8 L/kg in healthy subjects. Plasma protein binding of verapamil is

approximately 90%.

Metabolism

Verapamil is extensively metabolized. In vitro metabolic studies indicate that verapamil

metabolized

cytochrome

P450

CYP3A4,

CYP1A2,

CYP2C8,

CYP2C9

CYP2C18. In healthy men, orally administered verapamil hydrochloride undergoes

extensive metabolism in the liver, with 12 metabolites having been identified, most in

only trace amounts. The major metabolites have been identified as various N and O-

dealkylated products of verapamil. Of these metabolites, only norverapamil has any

appreciable pharmacological effect (approximately 20% that of the parent compound),

which was observed in a study with dogs.

Elimination

Following intravenous infusion, verapamil is eliminated bi-exponentially, with a rapid

early distribution phase (half-life about four minutes) and a slower terminal elimination

phase (half-life two to five hours). Following oral administration, the elimination half-life

is three to seven hours. Approximately 50% of an administered dose is eliminated

renally within 24 hours, 70% within five days. Up to 16% of a dose is excreted in the

feces. About 3% to 4% of renally excreted drug is excreted as unchanged drug. The

total clearance of verapamil is nearly as high as the hepatic blood

flow, approximately 1 L/h/kg (range: 0.7-1.3 L/h/kg).

Special Populations

Pediatric: Limited information on the pharmacokinetics in the paediatric population is

available. After intravenous dosing, the mean half-life of verapamil was 9.17 hours and

the mean clearance was 30 L/h, whereas it is around 70 L/h for a 70-kg adult. Steady-

state plasma concentrations appear to be somewhat lower in the paediatric population

after oral dosing compared to those observed in adults.

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Geriatrics: Aging may affect the pharmacokinetics of verapamil given to hypertensive

patients. Elimination half-life may be prolonged in the elderly. The antihypertensive

effect of verapamil was found not to be age-related.

Renal

insufficiency:

Impaired

renal

function

effect

verapamil

pharmacokinetics, as shown by comparative studies in patients with end-stage renal

failure and subjects with healthy kidneys.

Verapamil and norverapamil are not significantly removed by hemodialysis.

Hepatic insufficiency: The half-life of verapamil is prolonged in patients with impaired

liver function owing to lower oral clearance and a higher volume of distribution.

Indications

Antianginal

.Angina

rest

including

vasospastic

(Prinzmetal's

variant)

angina

unstable

(crescendo, pre-infarction) angina.

.Chronic stable angina (classic effort-associated angina).

Antiarrhythmic

Ikacor is indicated for the treatment of supraventricular tachyarrhythmias, including:

.Rapid

conversion

sinus

rhythm

paroxysmal

supraventricular

tachycardias,

including those associated with accessory bypass tracts (Wolff-Parkinson-White and

Lown-Ganong-Levine syndrome).

.Temporary control of rapid ventricular rate in atrial flutter or atrial fibrillation.

Hypertension

Ikacor is indicated in the treatment of mild to moderate hypertension, alone or in

conjunction with other antihypertensive drugs.

Contraindications

Known hypersensitivity to verapamil hydrochloride or to any other ingredient of the

preparation.

Heart failure with reduced ejection fraction of less than 35%, and/or pulmonary wedge

pressure

above

(unless

secondary

supraventricular

tachycardia

amenable to verapamil therapy).

Severe left ventricular dysfunction (see Warnings).

Hypotension (less than 90 mm Hg systolic pressure) or cardiogenic shock.

Sick sinus syndrome (except in patients with a functioning artificial ventricular

pacemaker).

Second- or third-degree AV block (except in patients with a functioning artificial

ventricular pacemaker).

Patients with atrial flutter or atrial fibrillation in the presence of an accessory bypass

tract (e.g. Wolff-Parkinson-White, Lown-Ganong-Levine syndromes). These patients

are at risk to develop ventricular tachyarrhythmia including ventricular fibrillation if

verapamil hydrochloride is administered (See Warnings).

Warnings

Acute Myocardial infarction

Use with caution in acute myocardial infarction complicated by bradycardia, marked

hypotension, or left ventricular dysfunction.

Ikacor Tablets- 27 3. 2014 RH

Page 4 of 13

Heart failure

Verapamil has a negative inotropic effect which, in most patients, is compensated by

its afterload reduction (decreased systemic vascular resistance) properties without a

net impairment of ventricular performance. Verapamil should be avoided in patients

with severe left ventricular dysfunction and in patients with any degree of ventricular

dysfunction if they are receiving a beta-adrenergic blocker (see Drug Interactions).

Patients with milder ventricular dysfunction should, if possible, be controlled with

optimum doses of digitalis and/or diuretics before verapamil treatment (see Drug

Interactions).

Heart failure patients with ejection fraction higher than 35% should be compensated

before starting verapamil treatment and should be adequately treated throughout.

Hypotension

Occasionally, the pharmacological action of verapamil may produce a decrease in

blood pressure below normal levels which may result in dizziness or symptomatic

hypotension.

Hypotensive

usually

asymptomatic,

orthostatic,

mild

controlled by a decrease in the Ikacor dose.

HMG-CoA Reductase Inhibitors (“Statins”)

See Drug Interactions.

Elevated Liver Enzymes

Occasional elevations of transaminases and alkaline phosphatases have been

reported.

Patients

receiving

verapamil

should

have

liver

enzymes

monitored

periodically. Use verapamil with caution in patients with severe hepatic impairment.

Atrial Flutter/Fibrillation with Accessory Bypass Tract

Patients with atrial flutter or fibrillation and an accessory AV pathway (e.g. Wolff-

Parkinson-White

Lown-Ganong-Levine

syndromes)

develop

increased

antegrade conduction across the aberrant pathway bypassing the AV node, producing

a very rapid ventricular response after receiving intravenous verapamil (or digitalis).

Although a risk of this occurring with oral verapamil has not been established, such

patients receiving oral verapamil may be at risk and its use in these patients is

contraindicated. Treatment is usually direct current cardioversion. Cardioversion has

been used safely and effectively after oral verapamil.

Heart Block/ 1st Degree AV block/Bradycardia/Asystole

Verapamil hydrochloride affects the AV and SA nodes and prolongs AV conduction

time.

with

caution

development

second-or

third-degree

block

(contraindication) or unifascicular, bifascicular or trifascicular bundle branch block

requires discontinuation in subsequent doses of verapamil hydrochloride and institution

of appropriate therapy, if needed.

Verapamil hydrochloride affects the AV and SA nodes and rarely may produce

second- or third degree AV block, bradycardia, and, in extreme cases, asystole. This is

more likely to occur in patients with a sick sinus syndrome (SA nodal disease), which is

more common in older patients.

Asystole in patients other than those with sick sinus syndrome is usually of short

duration (few seconds or less), with spontaneous return to AV nodal or normal sinus

rhythm. If this does not occur promptly, appropriate treatment should be initiated

immediately. See Adverse Reactions.

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Patients with Hypertrophic Cardiomyopathy (IHSS)

In a total of 120 patients referred to the National Institute of Health (USA) because of

hypertrophic cardiomyopathy (most of them refractory or intolerant to propranolol) a

variety of serious adverse effects were observed following therapy with verapamil at

doses up to 720 mg/day. Three patients died in pulmonary edema: all had severe left

ventricular outflow obstruction and a past history of left ventricular dysfunction.

Eight other patients had pulmonary edema and/or severe hypotension; abnormally

high (over 20 mm Hg) capillary wedge pressure and a marked left ventricular outflow

obstruction were present in most of these patients.

Concomitant administration of quinidine (see Drug Interactions) preceded the severe

hypotension in 3 of the 8 patients (2 of whom developed pulmonary edema).

Sinus bradycardia occurred in 11% of the patients, second-degree AV block in 4%

and sinus arrest in 2%.

It must be appreciated that this group of patients had a serious disease with a high

mortality rate. Most adverse effects responded well to dose reduction and only rarely

did verapamil have to be discontinued.

Antiarrhythmics, Beta-blockers

Mutual potentiation of cardiovascular effects (higher-grade AV block, higher-grade

lowering

heart

rate,

induction

heart

failure

potentiated

hypotension).

Asymptomatic bradycardia (36 beats/minute) with a wandering atrial pacemaker has

been observed in a patient receiving concomitant timolol (a beta-adrenergic blocker)

eye drops and oral verapamil hydrochloride.

Digoxin

If verapamil is administered concomitantly with digoxin, reduce digoxin dosage. See

Drug Interactions

Other Neuromuscular transmission disorders

Verapamil

should

used

with

caution

patients

with

diseases

which

neuromuscular transmission is affected (myasthenia gravis, Lambert-Eaton syndrome,

advanced Duchenne muscular dystrophy).

Use in Pregnancy

There are no adequate and well-controlled studies in pregnant women. Verapamil

crosses the placenta and has been measured in umbilical cord blood. This drug should

be used during pregnancy only if clearly needed.

Verapamil crosses the placental barrier and can be detected in umbilical vein blood at

delivery.

Use in Breastfeeding

Verapamil is excreted in human milk. Limited human data from oral administration

has shown that the infant relative dose of verapamil is low (0.1 –1%of the mother’s oral

dose) and that verapamil use may be compatible with breastfeeding. Due to the

potential for serious adverse reactions in nursing infants, verapamil should only be

used during lactation if it is essential for the welfare of the mother.

Special Populations

Renal impairment

Although impaired renal function has been shown in robust comparator studies to have

no effect on verapamil pharmacokinetics in patients with end-stage renal failure,

several case reports suggest that verapamil should be used cautiously and with close

monitoring in patients with impaired renal function.

Verapamil cannot be removed by hemodialysis.

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Liver impairment

Use with caution in patients with severely impaired liver function (see Dosage)

Preclinical safety data

Reproduction studies have been performed in rabbits and rats at oral verapamil doses

up to 1.5 (15 mg/kg/day) and 6 (60 mg/kg/day) times the human oral daily dose,

respectively, and have revealed no evidence of teratogenicity. In the rat, however, this

multiple

human

dose

embryocidal

retarded

fetal

growth

development, probably because of adverse maternal effects reflected in reduced

weight gains of the dams. This oral dose has also been shown to cause hypotension in

rats.

There are, however, no adequate and well-controlled studies in pregnant women.

Adverse Reactions

The following adverse reactions have been reported with verapamil from clinical

studies, postmarketing surveillance or Phase IV clinical trials and are listed below by

system organ class. Frequencies are defined as: very common (≥1/10); common

(≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very

rare (<1/10,000); not known (cannot be estimated from the available data).

most

commonly

reported

ADRs

were

headache,

dizziness,

gastrointestinal

disorders:

nausea,

constipation

abdominal

pain,

well

bradycardia,

tachycardia, palpitations, hypotension, flushing, edema peripheral and fatigue.

Adverse

reactions

reported

from

clinical

studies

with

verapamil

and

post-

marketing surveillance activities

MedDRA

System

Organ

Class

Common

Uncommon

Rare

Unknown

Immune

system

disorders

Hypersensitivity

Nervous system

disorders

Dizziness,

Headache

Paresthesia

Tremor

Extrapyramidal

disorder,

paralysis

(tetraparesis)

Seizures

Psychiatric

disorders

Somnolence

Ear and labyrinth

disorders

Tinnitus

vertigo

Cardiac

disorders

Bradycardia

Palpitations,

Tachycardia

Atrioventricular

block (1°, 2°, 3°),

Cardiac failure,

Sinus

arrest, Sinus

bradycardia;

asystole

Vascular

disorders

Flushing,

Hypotension

Ikacor Tablets- 27 3. 2014 RH

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MedDRA

System

Organ

Class

Common

Uncommon

Rare

Unknown

Respiratory,

thoracic and

mediastinal

disorders

Bronchospasm

Gastrointestinal

disorders

Constipation,

Nausea

Abdominal pain

vomiting

Abdominal

discomfort,

Gingival

hyperplasia,

Ileus

Skin and

subcutaneous

tissue disorders

Hyperhidrosis

Angioedema,

Stevens-

Johnson

syndrome,

Erythema

multiforme,

Alopecia,

Itching, Pruritus,

Purpura, Rash

maculopapular,

Urticaria

Musculoskeletal

and connective

tissue disorders

Arthralgia,

Muscular

weakness,

Myalgia

Reproductive

system and

breast disorders

Erectile

dysfunction,

Galactorrhea,

Gynecomastia

General

disorders and

administration

site conditions

Edema

peripheral

Fatigue

Investigations

Blood

prolactin

increased,

Hepatic enzymes

increased

There has been a single postmarketing report of paralysis (tetraparesis) associated with the combined

use of verapamil and colchicine. This may have been caused by colchicine crossing the blood-brain barrier

due to CYP3A4 and P-gp inhibition by verapamil. See Drug Interactions

Reporting of suspected adverse reactions

Reporting

suspected

adverse

reactions

important

gather

more

information to continuously monitor the benefit/risk balance of the medicinal product.

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Page 8 of 13

Precautions

Treatment of Acute Cardiovascular Adverse Reactions

The frequency of cardiovascular adverse reactions which require therapy is rare;

hence, experience with their treatment is limited. Whenever severe hypotension or

complete AV block occurs following oral administration of verapamil, the appropriate

emergency measures should be applied immediately, e.g. intravenously administered

isoproterenol HCl; levarterenol bitartrate, atropine (all in the usual doses), or calcium

gluconate (10% solution). In patients with hypertrophic cardiomyopathy (IHSS), alpha-

adrenergic agents (phenylephrine, metaraminol bitartrate or methoxamine) should be

used to maintain blood pressure and isoproterenol and levarterenol should be avoided.

If further support is necessary, inotropic agents (dopamine or dobutamine) may be

administered. Actual treatment and dosage should depend on the severity of the

clinical situation and the judgment and experience of the treating physician.

Use in Patients with Impaired Hepatic Function

Since

verapamil

highly

metabolized

liver,

should

be administered

cautiously to patients with impaired hepatic function. Severe liver dysfunction prolongs

the elimination half-life of verapamil to about 14 to 16 hours; hence, approximately 30%

of the dose given to patients with normal liver function should be administered to these

patients. Careful monitoring for abnormal prolongation of the PR interval or other signs

of excessive pharmacologic effects (see Overdosage) should be carried out.

Use in Patients with Impaired Renal Function

About 70% of an administered dose of verapamil is excreted as metabolites in the

urine. Verapamil is not removed by hemodialysis. Until further data are available,

verapamil should be administered cautiously to patients with impaired renal function.

These patients should be carefully monitored for abnormal prolongation of the PR

interval or other signs of overdosage (see Overdosage).

Use in Patients with Attenuated (Decreased) Neuromuscular Transmission

It has been reported that verapamil decreases neuromuscular transmission in

patients with Duchenne's muscular dystrophy, and that verapamil prolongs recovery

from the neuromuscular blocking agent vecuronium. It may be necessary to decrease

dosage

verapamil

when

administered

patients

with

attenuated

neuromuscular transmission.

Drug Interactions

In vitro metabolic studies indicate that verapamil hydrochloride is metabolized by

cytochrome P450 CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18. Verapamil

has been shown to be an inhibitor of CYP3A4 enzymes and P-glycoprotein (P-gp).

Clinically significant interactions have been reported with inhibitors of CYP3A4 causing

elevation of plasma levels of verapamil hydrochloride while inducers of CYP3A4 have

caused a lowering of plasma levels of verapamil hydrochloride, therefore, patients

should be monitored for drug interactions.

Potential drug interactions

Verapamil/Prazosin/Terazosin (Alpha Blockers):

Prazosin: Increase of about 40% in Cmax with no effect on half-life.

Terazosin: Increase of about 24% in AUC and 25% in Cmax.

In both cases there is additive hypotensive effect.

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Verapamil/Colchicine:

Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein

(Pgp). Verapamil is known to inhibit CYP3A and P-gp. When verapamil and colchicine

are administered together, inhibition of P-gp and/or CYP3A by verapamil may lead to

increased exposure to colchicine. Colchicine levels may rise , AUC (approximately

2 fold) as well as C

(approximately 1.3 fold). Reduce colchicine dose.

Verapamil/Flecainide:

A study in healthy volunteers showed that the concomitant

administration of flecainide and verapamil may have additive effects on myocardial

contractility, AV conduction, and repolarization. Concomitant therapy with flecainide

and verapamil may result in additive negative inotropic effect and prolongation of

atrioventricular conduction. Effect on flecainide plasma clearance is minimal; no effect

on verapamil clearance.

Verapamil/Quinidine

Pulmonary

edema

occur

patients

with

hypertrophic

obstructive cardiomyopathy (IHSS). Elevation of quinidine plasma level may occur. In a

small number of patients with IHSS, concomitant use of verapamil and quinidine

resulted in significant hypotension. Until further data are obtained, combined therapy of

verapamil and quinidine in patients with hypertrophic cardiomyopathy should probably

be avoided. Oral quinidine clearance decreases by about 35%.

Verapamil/Theophylline

Concomitant

verapamil

patients

receiving

theophylline has resulted in decreased oral and systemic clearance of theophylline by

about 20% , elevated serum theophylline concentrations, and a prolonged serum half-

life of the bronchodilator.

smokers,

reduction

theophylline

clearance

lessened

(about

11%).

Patients receiving theophylline should be closely monitored for signs of theophylline

toxicity

when

verapamil

administered

concomitantly;

serum

theophylline

levels

should be monitored and dosage of the bronchodilator reduced if indicated.

Verapamil/Carbamazepine/Antiepileptics:((e.g.

Phenytoin)

Verapamil

therapy

increase carbamazepine concentrations during combined therapy. This may produce

carbamazepine side effects such as diplopia, headache, ataxia or dizziness

Carbamazepine AUC may increase by about 46% in refractory partial epilepsy patients.

Verapamil plasma concentrations may be decreased upon combination with phenytoin.

Verapamil/Antidepressants

: Imipramine AUC may increase by about 15%.There was no

effect on the level of the active metabolite, desipramine.

Verapamil/Antidiabetics:

Glibenclamide

increases

about

28%,

Glibenclamide AUC increases by about 26%.

Verapamil/Erythromycin

: Verapamil levels may possibly rise.

Verapamil/Clarithromycin

: Concomitant administration may lead to a possible rise in

verapamil levels.

Verapamil/Rifampin:

Therapy

with

rifampin

markedly

reduce

oral

verapamil

bioavailability by about 92%, verapamil AUC by about 97%, and verapamil C

about 94%.The blood pressure lowering effect may be reduced.

Verapamil/Telithromycin:

Verapamil levels may possibly rise.

Verapamil/Doxorubicin

: In patients with small cell lung cancer doxorubicin AUC rose by

104% and doxorubicin Cmax by 61% with oral verapamil administration. In patients

with advanced neoplasma there was no significant change in doxorubicin PK with

intravenous verapamil administration

Verapamil/Phenobarbital:

Phenobarbital therapy may increase oral verapamil clearance

by about 5 fold.

Verapamil/Buspirone

: Buspirone AUC and C

may increase by 3.4 fold.

Verapamil/Midazolam:

Elevation of midazolam AUC by about 3 fold and its Cmax by

about 2 fold.

Ikacor Tablets- 27 3. 2014 RH

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Verapamil/Beta Blockers

: Controlled studies in a small number of patients suggest that

the concomitant use of Ikacor and oral beta- blocker agents may be beneficial in

certain patients with chronic stable angina or hypertension but available information is

not sufficient to predict with confidence the effects of concurrent treatment in patients

with

left

ventricular

dysfunction

cardiac

conduction abnormalities. Concomitant

therapy with beta-adrenergic blockers and verapamil may result in additive negative

effects on heart rate, atrioventricular conduction and/or cardiac contractibility. Induction

of heart failure and potentiated hypotension may also occur.

Metoprolol AUC increased by about 32.5%, metoprolol Cmax increased by about 41%

in angina patients.

Propranolol AUC increased by about 65% and propranolol Cmax increased by about

94% in angina patients.

Verapamil/Digoxin

/Digitoxin

:

Clinical use of verapamil in digitalized patients has shown

the combination to be well tolerated if digoxin doses are properly adjusted. Digoxin

Cmax increases by about 44%, digoxin C

(about 53%) in healthy subjects, Css

increases by about 44% and AUC increases by about 50%. In patients with hepatic

cirrhosis the influence of verapamil on digoxin kinetics is magnified.

Digitoxin total body clearance and extrarenal clearance are reduced by about 27% and

29%, respectively.

Maintenance digitalization doses should be reduced when verapamil is administered,

and the patient should be carefully monitored to avoid over- or underdigitalization.

Whenever overdigitalization is suspected, the daily dose of digoxin should be reduced

or the drug temporarily discontinued. Upon discontinuation of verapamil the patient

should be monitored to avoid underdigitalization.

Verapamil/Cimetidine:

Possible elevation of verapamil hydrochloride plasma levels

AUC of R-verapamil increases by about 25%, that of the S-verapamil by about 40%

with corresponding decrease in R-and S-verapamil clearance.

Verapamil/Immunologics/

Immunosuppressives:

Verapamil/Cyclosporine

Verapamil

therapy

increase

serum

levels

cyclosporine (AUC, C

by ~45%).

Verapamil/Sirolimus/Tacrolimus/Everolimus

Possible

increase

sirolimus,

tacrolimus, or everolimus levels.

Everolimus

: AUC increase (about 3.5 fold), C

(about 2.3 fold); verapamil: C

trough

increases by about 2.3 fold). Concentration determinations and dose adjustments of

everolimus may be necessary.

Sirolimus

: increased sirolimus AUC (about 2.2 fold); S-verapamil AUC increases by

about 1.5 fold). Concentration determinations and dose adjustments of sirolimus

may be necessary.

Tacrolimus

: possible increase in tacrolimus levels.

Verapamil/Lipid Lowering Agents (HMG Co-A Reductase Inhibitors, i.e. “Statins”, e.g.,

Atorvastatin,

Lovastatin, Simvastatin

)

:

Concomitant use of these agents with verapamil

hydrochloride may increase the serum levels of atorvastatin (as well as increase in

AUC of verapamil by about 43%), simvastatin or lovastatin. For simvastatin: a rise in

AUC (about 2.6 fold), C

(about 4.6 fold). Lovastatin levels may possibly rise;

verapamil AUC may rise (63%), Cmax (32%)

Treatment

with

reductase

inhibitors

(e.g.,

simvastatin,

atorvastatin, or

lovastatin) in a patient taking verapamil should be started at the lowest possible dose

and titrated upwards. If verapamil treatment is to be added to patients already taking an

HMG CoA reductase inhibitor (e.g., simvastatin/atorvastatin/lovastatin), consider a

reduction in the statin dose and retitrate against serum cholesterol concentrations.

Fluvastatin, pravastatin and rosuvastatin are not metabolized by CYP3A4 and are less

likely to interact with verapamil.

Ikacor Tablets- 27 3. 2014 RH

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Verapamil/Almotriptan (Serotonin Receptor Agonist):

There is an increase in almotriptan

AUC by about 20%, and its Cmax about 24%.

Verapamil/Sulfinpyrazone (Uricosuric):

Oral verapamil clearance increases by about 3

fold, with a decrease in of about 60% in its bioavailability. The blood pressure lowering

effect may be reduced.

Verapamil/Grapefruit juice:

Grapefruit juice may increase the plasma levels of

verapamil hydrochloride (AUC for R-verapamil increases by about 49% and for S-

verapamil by about 37% verapamil AUC. C

for R-verapamil increases by about 75%

and for the S-verapamil by about 51%. Elimination half-life and renal clearance not

affected. Grapefruit juice should therefore not be ingested with verapamil

Verapamil/St.John’s

Wort

: Verapamil AUC decreases: R-verapamil by about 78% and

S-verapamil by about 80% with corresponding reductions in Cmax.

Other Drug Interactions and Additional Drug Interaction Information

(see also

Potential drug interactions.

Antiarrhythmics, beta-blockers

Mutual potentiation of cardiovascular effects (higher-grade AV block, higher-grade

lowering of heart rate, induction of heart failure and potentiated hypotension).

HIV Antiviral Agents

Due to the metabolic inhibitory potential of some of the HIV antiviral agents, such as

ritonavir, plasma concentrations of verapamil may increase. Caution should be used or

dose of verapamil may be decreased.

Verapamil Protein-Bound Drugs:

As verapamil is highly bound to plasma proteins, it

should be administered with caution to patients receiving other highly protein-bound

drugs, such as oral anticoagulants.

Verapamil/Antihypertensive Agents

: Verapamil administered concomitantly with oral

antihypertensive agents (e.g., vasodilators, angiotensin-converting enzyme inhibitors,

diuretics, beta blockers) will usually have an additive effect on lowering blood pressure.

Patients receiving these combinations should be appropriately monitored.

Concomitant use of agents that attenuate

-adrenergic function with verapamil may

result in a reduction in blood pressure, which may be excessive in some patients. Such

an effect has been observed in one study following the concomitant administration of

verapamil and prazosin.

Verapamil/Disopyramide

: Until data on possible interactions between verapamil and

disopyramide phosphate are obtained, disopyramide should not be administered within

48 hours before or 24 hours after verapamil administration.

Verapamil/Nitrates

: Verapamil has been given concomitantly with short- and long-

acting nitrates without any undesirable drug interactions. The pharmacologic profile of

both drugs and the clinical experience suggest beneficial interactions.

Verapamil/Acetylsalicylic acid :

Increased tendency to bleed

Verapamil/Ethanol (alcohol):

Elevation of ethanol plasma levels

Verapami/ Lithium:

Increased sensitivity to the effects of lithium (neurotoxicity) has

been reported during concomitant verapamil hydrochloride-lithium therapy with either

change

increase

serum

lithium

levels.

addition

verapamil

hydrochloride, however, has also resulted in the lowering of the serum lithium levels in

patients receiving chronic stable oral lithium. Patients receiving both drugs should be

monitored carefully.

Verapamil/Inhalation Anesthetic Agents/ Neuromuscular Blocking Agents:

Clinical data

and animal studies suggest that verapamil may potentiate the activity of inhalation

anesthetics and neuromuscular blocking agents (curare-like and depolarizing). It may

be necessary to decrease the dose of verapamil hydrochloride and/or the dose of the

neuromuscular blocking agent when the drugs are used concomitantly..

Ikacor Tablets- 27 3. 2014 RH

Page 12 of 13

Effects on ability to drive and use machines

Due to its antihypertensive effect, depending on the individual response, verapamil

hydrochloride may affect the ability to react to the point of impairing the ability to drive a

vehicle, operate machinery or work under hazardous conditions. This applies all the

more at the start of treatment, when the dose is raised, when switching from another

drug and in conjunction with alcohol. Verapamil may increase the blood levels of

alcohol and slow its elimination. Therefore, the effects of alcohol may be exaggerated.

Dosage and Administration

The dose of verapamil must be individualized by titration.

Ikacor should be administered with food.

Ikacor tablets should be taken whole. They should not be crushed, sucked, chewed,

or divided.

Angina

120 mg, 3 times daily is recommended.

80 mg, 3 or 4 times daily may be satisfactory in some patients with angina of effort.

The total daily dosage ranges from 240 - 480 mg.

The optimum daily dosage for most patients ranges from 320 - 480 mg.

Dosage may be increased at daily (e.g., patients with unstable angina) or weekly

intervals until optimum clinical response is obtained. In general, maximum effects of

any given dosage would be apparent during the first 24 to 48 hours of therapy, but note

that between 24 to 48 hours the half-life of verapamil increases, hence maximum

response may be delayed.

Arrhythmia

40 -120 mg, 3 times daily according to the severity of the condition.

Hypertension

240 - 480 mg daily in divided doses.

Overdosage

Symptoms

Hypotension,

bradycardia

high

degree

block

sinus

arrest,

hyperglycemia, stupor, metabolic acidosis Fatalities have occurred as a result of

overdose.

Treatment

Treatment of overdosage should be supportive.

Beta-adrenergic

stimulation

parenteral

administration

calcium

solutions may

increase calcium ion flux across the slow channel, and have been used effectively in

treatment of deliberate overdosage with verapamil.

Verapamil cannot be removed by hemodialysis.

Clinically significant hypotensive reactions or high degree AV block should be treated

with vasopressor agents or cardiac pacing, respectively. Asystole should be handled by

usual

measures

including

beta

adrenergic

stimulation

(e.g.,

isoproterenol

hydrochloride), other vasopressor agents or cardiopulmonary resuscitation.

Ikacor Tablets- 27 3. 2014 RH

Page 13 of 13

Storage

Store in a dark and dry place (under 25

Registration Numbers

Ikacor 40 mg tablets : 025 25 2113 00.

Ikacor 80 mg tablets: 040 02 23155 00.

Ikacor 120 mg tablets: 039 47 21913 00.

Manufacturer

Teva Pharmaceutical Industries Ltd

P.O.B. 3190, Petach Tikva.

העדוה העדוה

לע לע

הרמחה הרמחה

(

(

עדימ עדימ

ןולעב )תוחיטב ןולעב )תוחיטב

ל

ל

אפור אפור

ןכרצלו ןכרצלו

ןכדועמ( ןכדועמ(

05.2013

05.2013

ךיראת

_______

_

October 15, 2013

_

םש

רישכת

תילגנאב

ירפסמו

םושירה

IKACOR Tablets 40 mg: 025 25 2113 0; 80mg: 040 02 23155 00, 120 mg: 039 47 21913 00

םש

לעב

םושירה

__

Teva Pharmaceutical Industries Ltd., P.O.Box 3190, Petach Tikva

ןולעב ןולעב

אפור אפור דבלב תורמחהה טורפל דעוימ הז ספוט

תורמחהה

תושקובמה קרפ

ןולעב טסקט

יחכונ טסקט

שדח

Indication

contraindications

Known

hypersensitivity

verapamil

hydrochloride or to any other ingredient of

the preparation.

Acute

myocardial

infarction

with

complications.

Congestive heart failure.

Severe left

ventricular dysfunction (see Warnings).

Hypotension (less than 90 mm Hg systolic

pressure) or cardiogenic shock.

Sick sinus syndrome (except in patients

with

functioning

artificial

ventricular

pacemaker).

Second- or third-degree AV block (except

in patients with a functioning artificial

ventricular pacemaker).

Patients

with

atrial

flutter

atrial

fibrillation and an accessory bypass tract (e.g.

Wolff-Parkinson-White,

Lown-Ganong-

Levine syndromes). (See Warnings).

Known hypersensitivity to verapamil hydrochloride or to any

other ingredient of the preparation.

Acute myocardial infarction with complications.

Congestive heart failure. Heart failure with reduced ejection

fraction of less than 35%, and/or pulmonary wedge pressure

above 20 mm Hg (unless secondary to a supraventricular

tachycardia amenable to verapamil therapy).

Severe left ventricular dysfunction (see Warnings).

Hypotension (less than 90 mm Hg systolic pressure) or

cardiogenic shock.

Sick sinus syndrome (except in patients with a functioning

artificial ventricular pacemaker).

Second- or third-degree AV block (except in patients with a

functioning artificial ventricular pacemaker).

Patients with atrial flutter or atrial fibrillation in the presence

of and an accessory bypass tract (e.g. Wolff-Parkinson-White,

Lown-Ganong-Levine syndromes). These patients are at risk to

develop ventricular tachyarrhythmia including ventricular

fibrillation if verapamil hydrochloride is administered (See

Warnings).

Posology, dosage &

administration

Special Warnings and

Special Precautions for

Use

Atrioventricular Block

The effect of verapamil on AV conduction

and the SA node may lead to asymptomatic

first-degree

block

transient

bradycardia,

sometimes

accompanied

nodal

escape

rhythms.

interval

prolongation is correlated with verapamil

plasma concentrations, especially during the

early titration phases of therapy. Higher

degrees

block,

however,

were

infrequently (0.8%) observed. Marked first-

degree block or progressive development to

second- or third-degree AV block requires a

reduction in dosage or, in rare instances,

discontinuation

verapamil

institution of appropriate therapy depending

upon the clinical situation.

Acute Myocardial infarction

Use with caution in acute myocardial infarction complicated by

bradycardia, marked hypotension, or left ventricular

dysfunction.

Heart failure patients with ejection fraction higher than 35%

should be compensated before starting verapamil treatment and

should be adequately treated throughout.

Heart Block/ 1st Degree AV block/Bradycardia/Asystole

Verapamil hydrochloride affects the AV and SA nodes and

prolongs AV conduction time. Use with caution as development

of second-or third-degree AV block (contraindication) or

unifascicular, bifascicular or trifascicular bundle branch block

requires discontinuation in subsequent doses of verapamil

hydrochloride and institution of appropriate therapy, if needed.

Verapamil hydrochloride affects the AV and SA nodes and

rarely may produce second- or third degree AV block,

bradycardia, and, in extreme cases, asystole. This is more likely

to occur in patients with a sick sinus syndrome (SA nodal

disease), which is more common in older patients.

Other

Verapamil should be used with caution in

patients

with

diseases

which

neuromuscular

transmission

affected

(myasthenia

gravis,

Lambert-Eaton

syndrome,

advanced

Duchenne

muscular

dystrophy).

Asystole in patients other than those with sick sinus syndrome

is usually of short duration (few seconds or less), with

spontaneous return to AV nodal or normal sinus rhythm. If this

does not occur promptly, appropriate treatment should be

initiated immediately. See Adverse Reactions.

Atrioventricular Block

The effect of verapamil on AV conduction and the SA node

may lead to asymptomatic first-degree AV block and transient

bradycardia, sometimes accompanied by nodal escape rhythms.

PR interval prolongation is correlated with verapamil plasma

concentrations, especially during the early titration phases of

therapy. Higher degrees of AV block, however, were

infrequently (0.8%) observed. Marked first-degree block or

progressive development to second- or third-degree AV block

requires

reduction

dosage

rare

instances,

discontinuation of verapamil HCl and institution of appropriate

therapy depending upon the clinical situation.

Antiarrhythmics, Beta-blockers

Mutual potentiation of cardiovascular effects (higher-grade

AV block, higher-grade lowering of heart rate, induction of

heart failure and potentiated hypotension). Asymptomatic

bradycardia

beats/minute)

with

wandering

atrial

pacemaker

been

observed

patient

receiving

concomitant timolol (a beta-adrenergic blocker) eye drops and

oral verapamil hydrochloride.

Digoxin

If verapamil is administered concomitantly with digoxin,

reduce digoxin dosage. See Drug Interactions

Others Neuromuscular transmission disorders

Verapamil should be used with caution in patients with

diseases in which neuromuscular transmission is affected

(myasthenia

gravis,

Lambert-Eaton

syndrome,

advanced

Duchenne muscular dystrophy).

Special Populations

Renal impairment

Although impaired renal function has been shown in robust

comparator

studies

have

effect

verapamil

pharmacokinetics in patients with end-stage renal failure,

several case reports suggest that verapamil should be used

cautiously and with close monitoring in patients with impaired

renal function.

Verapamil cannot be removed by hemodialysis.

Liver impairment

Use with caution in patients with severely impaired liver

function (see Dosage)

Effects on ability to

drive and use machines

Depending on the individual response,

verapamil may affect the ability to react to

the point of impairing the ability to drive a

vehicle, operate machinery or work under

hazardous conditions. This applies all the

more at the start of treatment, when the dose

is raised, when switching from another drug

and in conjunction with alcohol.

Due to its antihypertensive effect, depending on the individual

response, verapamil hydrochloride may affect the ability to

react to the point of impairing the ability to drive a vehicle,

operate machinery or work under hazardous conditions. This

applies all the more at the start of treatment, when the dose is

raised, when switching from another drug and in conjunction

with alcohol. Verapamil may increase the blood levels of

alcohol and slow its elimination. Therefore, the effects of

alcohol may be exaggerated.

Depending on the individual response, verapamil may affect

the ability to react to the point of impairing the ability to drive a

vehicle, operate machinery or work under hazardous conditions.

This applies all the more at the start of treatment, when the dose

is raised, when switching from another drug and in conjunction

with alcohol.

Interaction with Other

Medicaments and Other

Forms of Interaction

Verapamil/Colchicine:

Colchicine is a substrate for both CYP3A and

the efflux transporter, P-glycoprotein (Pgp).

Verapamil is known to inhibit CYP3A and P-

gp. When verapamil and colchicine are

administered together, inhibition of P-gp and/

or CYP3A by verapamil may lead to

increased exposure to colchicine.. Combined

use is not recommended.

Verapamil/Carbamazepine

Verapamil

therapy

increase

carbamazepine

concentrations during combined therapy. This

may produce carbamazepine side effects such

as diplopia, headache, ataxia or dizziness

Carbamazepine AUC may increase by about

46% in refractory partial epilepsy patients.

Verapamil/Doxorubicin: In patients with

small cell lung cancer doxorubicin AUC rose

by 89% and doxorubicin Cmax by 61% with

oral verapamil administration. In patients

with advanced neoplasma there was no

significant change in doxorubicin PK with

intravenous verapamil administration

Verapamil/Digoxin/Digitoxin: Clinical

of verapamil in digitalized patients has shown

the combination to be well tolerated if

digoxin doses are properly adjusted. Digoxin

Cmax increases by about 45-53%, in healthy

subjects, Css increases by about 42% and

AUC increases by about 52%. In patients

with

hepatic

cirrhosis

influence

verapamil on digoxin kinetics is magnified.

Digitoxin total body clearance and extrarenal

clearance are reduced by about 27% and

29%, respectively.

Verapamil/Immunologics/:

Verapamil/Cyclosporine:

Verapamil

therapy may increase serum levels of

cyclosporine (AUC, C

by ~45%).

Verapamil/Sirolimus/Tacrolimus/

Everolimus:

Possible

increase

sirolimus, tacrolimus, or everolimus

levels.

Verapamil/Lipid Lowering Agents (HMG

Co-A Reductase Inhibitors, i.e. “Statins”,

e.g., Atorvastatin, Lovastatin, Simvastatin):

Concomitant

these

agents

with

verapamil hydrochloride may increase the

serum levels of atorvastatin (as well as

increase in AUC of verapamil by about

42.8%),

simvastatin

lovastatin.

simvastatin: a rise in AUC (about 2.6 fold),

(about 4.6 fold).

Verapamil/Colchicine:

Colchicine is a substrate for both CYP3A and the efflux

transporter, P-glycoprotein (Pgp). Verapamil is known to

inhibit CYP3A and P-gp. When verapamil and colchicine are

administered together, inhibition of P-gp and/or CYP3A by

verapamil may lead to increased exposure to colchicine.

Colchicine levels may rise , AUC (approximately 2 fold) as

well as Cmax (approximately 1.3 fold). Reduce colchicine dose.

Combined use is not recommended.

Verapamil/Carbamazepine/Antiepileptics:((e.g. Phenytoin)

Verapamil therapy may increase carbamazepine concentrations

during combined therapy. This may produce carbamazepine

side effects such as diplopia, headache, ataxia or dizziness

Carbamazepine AUC may increase by about 46% in refractory

partial epilepsy patients.

Verapamil plasma concentrations may be decreased upon

combination with phenytoin.

Verapamil/Doxorubicin: In patients with small cell lung cancer

doxorubicin AUC rose by 104% 89% and doxorubicin Cmax by

61% with oral verapamil administration. In patients with

advanced neoplasma there was no significant change in

doxorubicin PK with intravenous verapamil administration

Verapamil/Digoxin/Digitoxin: Clinical use of verapamil in

digitalized patients has shown the combination to be well

tolerated if digoxin doses are properly adjusted. Digoxin Cmax

increases by about 44 45-53%, digoxin C12h (about 53%) in

healthy subjects, Css increases by about 44 42% and AUC

increases by about 50 52%. In patients with hepatic cirrhosis

the influence of verapamil on digoxin kinetics is magnified.

Digitoxin total body clearance and extrarenal clearance are

reduced by about 27% and 29%, respectively.

Verapamil/Immunologics/Immunosuppressives:

Verapamil/Cyclosporine: Verapamil therapy may increase

serum levels of cyclosporine (AUC, C

by ~45%).

Verapamil/Sirolimus/Tacrolimus/Everolimus:

Possible

increase in sirolimus, tacrolimus, or everolimus levels.

Everolimus: AUC increase (about 3.5 fold), Cmax (about

2.3 fold); verapamil: Ctrough increases by about 2.3 fold).

Concentration determinations and dose adjustments of

everolimus may be necessary.

Sirolimus: increased sirolimus AUC (about 2.2 fold); S-

verapamil AUC increases by about 1.5 fold).

Concentration determinations and dose adjustments of

sirolimus may be necessary.

Tacrolimus: possible increase in tacrolimus levels.

Verapamil/Lipid Lowering Agents (HMG Co-A Reductase

Inhibitors, i.e. “Statins”, e.g., Atorvastatin, Lovastatin,

Simvastatin): Concomitant use of these agents with verapamil

hydrochloride may increase the serum levels of atorvastatin (as

well as increase in AUC of verapamil by about 43 42.8%),

simvastatin or lovastatin. For simvastatin: a rise in AUC (about

2.6 fold), C

(about 4.6 fold). Lovastatin levels may possibly

rise; verapamil AUC may rise (63%), Cmax (32%)

Verapamil/Grapefruit juice: Grapefruit juice may increase the

plasma levels of verapamil hydrochloride (AUC for R-

verapamil increases by about 49% and for S-verapamil by about

37% verapamil AUC. Cmax for R-verapamil increases by about

75% and for the S-verapamil by about 51%. Elimination half-

life and renal clearance not affected. Grapefruit juice should

therefore not be ingested with verapamil

Verapamil/Grapefruit juice: Grapefruit juice

may increase the plasma levels of verapamil

hydrochloride (AUC for R-verapamil

increases by about 49% and for S-verapamil

by about 37% verapamil AUC. Cmax for R-

verapamil increases by about 75% and for the

S-verapamil by about 51%.

Verapami/ Lithium:

Oral verapamil therapy may result in a

lowering of serum lithium levels in patients

receiving chronic, stable oral lithium therapy.

There may be increased sensitivity to lithium

causing enhanced neurotoxicity. A dose

adjustment of the lithium may be necessary.

Verapamil/Inhalation Anesthetic Agents/

Neuromuscular Blocking Agents: Clinical

data

animal

studies

suggest

that

verapamil may potentiate the activity of

inhalation

anesthetics and neuromuscular

blocking agents .

Verapami/ Lithium: Increased sensitivity to the effects of

lithium (neurotoxicity) has been reported during concomitant

verapamil hydrochloride-lithium therapy with either no change

or an increase in serum lithium levels. The addition of

verapamil hydrochloride, however, has also resulted in the

lowering of the serum lithium levels in patients receiving

chronic stable oral lithium. Patients receiving both drugs should

be monitored carefully.

Oral verapamil therapy may result in a lowering of serum

lithium levels in patients receiving chronic, stable oral lithium

therapy. There may be increased sensitivity to lithium causing

enhanced neurotoxicity. A dose adjustment of the lithium may

be necessary.

Verapamil/Inhalation Anesthetic Agents/

Neuromuscular

Blocking Agents: Clinical data and animal studies suggest that

verapamil may potentiate the activity of inhalation anesthetics

neuromuscular

blocking

agents

(curare-like

depolarizing). It may be necessary to decrease the dose of

verapamil hydrochloride and/or the dose of the neuromuscular

blocking agent when the drugs are used concomitantly..

Fertility, pregnancy

and Lactation

Use in Pregnancy

There are no adequate and well-controlled

studies

pregnant

women.

Verapamil

crosses the placenta and has been measured in

umbilical cord blood. This drug should be

used during pregnancy only if clearly needed.

Use in Pregnancy

There are no adequate and well-controlled studies in pregnant

women. Verapamil crosses the placenta and has been measured

in umbilical cord blood. This drug should be used during

pregnancy only if clearly needed.

Verapamil crosses the placental barrier and can be detected in

umbilical vein blood at delivery.

Preclinical Data

Reproduction studies have been performed in rabbits and rats at

oral verapamil doses up to 1.5 (15 mg/kg/day) and 6 (60 mg/kg/

day) times the human oral daily dose, respectively, and have

revealed no evidence of teratogenicity. In the rat, however, this

multiple of the human dose was embryocidal and retarded fetal

growth and development, probably because of adverse maternal

effects reflected in reduced weight gains of the dams. This oral

dose has also been shown to cause hypotension in rats.

There are, however, no adequate and well-controlled studies in

pregnant women.

Adverse events

Serious adverse reactions are uncommon

when verapamil therapy is initiated with

upward

dose

titration

within

recommended single and total daily dose.

The following reactions occurred at rates

greater than 1% or appeared in lower rates

but appeared clearly drug-related in clinical

trials.

The following adverse reactions have been reported with

verapamil from clinical studies, postmarketing surveillance or

Phase IV clinical trials and are listed below by system organ

class. Frequencies are defined as: very common (≥1/10);

common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100);

rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known

(cannot be estimated from the available data).

The most commonly reported ADRs were headache, dizziness,

gastrointestinal disorders: nausea, constipation and abdominal

pain,

well

bradycardia,

tachycardia,

palpitations,

hypotension, flushing, edema peripheral and fatigue.

Adverse reactions reported from clinical studies with verapamil

Cardiovascular

Hypotension, edema, congestive heart

failure or pulmonary edema, bradycardia

(HR<50/min.), AV block, flushing.

Central Nervous System

Dizziness, headache, fatigue.

Gastrointestinal

Constipation, nausea.

Pulmonary

Dyspnea.

Skin

Rash.

Other

Elevated liver enzymes have been reported

(see WARNINGS).

The following reactions, reported in 1% or

less of patients, occurred under conditions

where a causal relationship is uncertain

They are listed to alert the physician to a

possible relationship:

Angina pectoris, atrioventricular dissociation,

chest

pain,

claudication,

myocardial

infarction, palpitations, purpura (vasculitis),

syncope; diarrhea, dry mouth, gastrointestinal

distress, gingival hyperplasia; ecchymosis or

bruising; cerebrovascular accident, confusion,

equilibrium

disorders,

insomnia,

muscle

cramps, paresthesia, psychotic symptoms,

shakiness (tremor), extrapyramidal disorder,

somnolence;

hair

loss,

hyperkeratosis,

maculae,

sweating,

Stevens-Johnson

syndrome,

erythema

multiforme;

blurred

vision;

increased

urination,

spotty

menstruation.

Other Adverse Reactions

Immune system disorders

Hypersensitivity.

Ear and labyrinth disorders

Vertigo, tinnitus

Cardiac disorders

Atrioventricular block (1

), sinus

arrest, tachycardia. Heart failure may develop

or existing heart failure may be exacerbated;

edema peripheral.

Gastrointestinal disorders

Vomiting, ileus, abdominal pain/discomfort

Skin and subcutaneous tissue disorders

Pruritus, urticaria, angioedema, rash

maculopapular.

Musculoskeletal

and

connective

tissue

disorders

Muscular weakness or muscle and joint

pain.

and post-marketing surveillance activities

MedDR

System

Organ

Class

Common

Uncomm

Rare

Unknow

Immune

system

disorders

Hyperse

nsitivity

Nervous

system

disorders

Dizzines

Headach

Paresthe

Tremor

Extrapyr

amidal

disorder,

paralysis

(tetrapar

esis)

Seizures

Psychiatr

disorders

Somnole

Ear and

labyrinth

disorders

Tinnitus

vertigo

Cardiac

disorders

Bradycar

Palpitati

ons,

Tachycar

Atrioven

tricular

block

(1°, 2°,

3°),

Cardiac

failure,

Sinus

arrest,

Sinus

bradycar

dia;

asystole

Vascular

disorders

Flushing,

Hypoten

sion

Respirat

ory,

thoracic

mediasti

disorders

Broncho

spasm

Gastroint

estinal

disorders

Constipa

tion,

Nausea

Abdomi

nal pain

vomiting

Abdomin

discomfo

Gingival

hyperpla

sia, Ileus

Skin and

subcutan

eous

tissue

disorders

Hyperhi

drosis

Angioed

ema,

Stevens-

Johnson

syndrom

Erythem

multifor

Alopecia

Itching,

Pruritus,

Purpura,

Rash

maculop

apular,

Reproductive system and breast disorders

Impotence, gynecomastia, galactorrhea.

Nervous system disorders

There has been a single postmarketing

report of paralysis (tetraparesis) associated

with

combined

verapamil

colchicine. This may have been caused by

colchicine crossing the blood-brain barrier

due to CYP3A4 and P-gp inhibition by

verapamil. Combined use of verapamil and

colchicine is not recommended.

Investigations

Elevated prolactin levels.

Urticaria

Musculo

skeletal

connecti

ve tissue

disorders

Arthralgi

Muscular

weaknes

Myalgia

Reprodu

ctive

system

breast

disorders

Erectile

dysfuncti

Galactorr

hea,

Gyneco

mastia

General

disorders

administ

ration

site

conditio

Edema

peripher

Fatigue

Investiga

tions

Blood

prolactin

increased

, Hepatic

enzymes

increased

There has been a single postmarketing report of paralysis

(tetraparesis) associated with the combined use of verapamil

and colchicine. This may have been caused by colchicine

crossing the blood-brain barrier due to CYP3A4 and P-gp

inhibition by verapamil. See Drug Interactions

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions is an important way to

gather

more

information

continuously

monitor

benefit/risk balance of the medicinal product.

Serious adverse reactions are uncommon when verapamil

therapy is initiated with upward dose titration within the

recommended single and total daily dose.

The following reactions occurred at rates greater than 1% or

appeared in lower rates but appeared clearly drug-related in

clinical trials.

Cardiovascular

Hypotension, edema, congestive heart failure or pulmonary

edema, bradycardia (HR<50/min.), AV block, flushing.

Central Nervous System

Dizziness, headache, fatigue.

Gastrointestinal

Constipation, nausea.

Pulmonary

Dyspnea.

Skin

Rash.

Other

Elevated

liver

enzymes

have

been

reported

(see

WARNINGS).

The following reactions, reported in 1% or less of patients,

occurred under conditions where a causal relationship is

uncertain

They are listed to alert the physician to a possible relationship:

Angina pectoris, atrioventricular dissociation, chest pain,

claudication,

myocardial

infarction,

palpitations,

purpura

(vasculitis), syncope; diarrhea, dry mouth, gastrointestinal

distress,

gingival

hyperplasia;

ecchymosis

bruising;

cerebrovascular accident, confusion, equilibrium disorders,

insomnia, muscle cramps, paresthesia, psychotic symptoms,

shakiness (tremor), extrapyramidal disorder, somnolence; hair

loss,

hyperkeratosis,

maculae,

sweating,

Stevens-Johnson

syndrome, erythema multiforme; blurred vision; increased

urination, spotty menstruation.

Other Adverse Reactions

Immune system disorders

Hypersensitivity.

Ear and labyrinth disorders

Vertigo, tinnitus

Cardiac disorders

Atrioventricular block (1

), sinus arrest, tachycardia.

Heart failure may develop or existing heart failure may be

exacerbated; edema peripheral.

Gastrointestinal disorders

Vomiting, ileus, abdominal pain/discomfort

Skin and subcutaneous tissue disorders

Pruritus, urticaria, angioedema, rash maculopapular.

Musculoskeletal and connective tissue disorders

Muscular weakness or muscle and joint pain.

Reproductive system and breast disorders

Impotence, gynecomastia, galactorrhea.

Nervous system disorders

There has been a single postmarketing report of paralysis

(tetraparesis) associated with combined use of verapamil and

colchicine. This may have been caused by colchicine crossing

the blood-brain barrier due to CYP3A4 and P-gp inhibition by

verapamil. Combined use of verapamil and colchicine is not

recommended.

Investigations

Elevated prolactin levels.

Mechanism of

Action/Pharmacodynanics/

Pharmacokinetics

Pharmacotherapeutic group: Selective calcium channel blockers

with direct cardiac effects, phenylalkylamine derivatives. ATC-

Code: C08DA01

Pharmacokinetic properties

Verapamil hydrochloride is a racemic mixture consisting of

equal portions of the R-enantiomer and the S-enantiomer.

Verapamil is extensively metabolized. Norverapamil is one of

12 metabolites identified in urine, has 10 to 20% of the

pharmacologic activity of verapamil and accounts for 6% of

excreted drug. The steady-state plasma concentrations of

norverapamil and verapamil are similar. Steady state after

multiple once daily dosing is reached after three to four days.

Absorption

Greater than 90% of verapamil is rapidly absorbed from the

small intestine after oral administration. Mean systemic

availability of the unchanged compound after a single dose of

verapamil is 22% owing to an extensive hepatic first-pass

metabolism. Bioavailability is about two times higher with

repeated administration. Peak verapamil plasma levels are

reached one to two hours after administration. The peak plasma

concentration of norverapamil is attained approximately one

hour after administration. The presence of food has no effect on

the bioavailability of verapamil.

Distribution

Verapamil is widely distributed throughout the body tissues, the

volume of distribution ranging from 1.8–6.8 L/kg in healthy

subjects. Plasma protein binding of verapamil is approximately

90%.

Metabolism

Verapamil is extensively metabolized.

In vitro metabolic

studies indicate that verapamil is metabolized by cytochrome

P450 CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18.

In healthy men, orally administered verapamil hydrochloride

undergoes extensive metabolism in the liver, with 12

metabolites having been identified, most in only trace amounts.

The major metabolites have been identified as various N and O-

dealkylated products of verapamil. Of these metabolites, only

norverapamil has any appreciable pharmacological effect

(approximately 20% that of the parent compound), which was

observed in a study with dogs.

Elimination

Following intravenous infusion, verapamil is eliminated bi-

exponentially, with a rapid early distribution phase (half-life

about four minutes) and a slower terminal elimination phase

(half-life two to five hours). Following oral administration, the

elimination half-life is three to seven hours. Approximately

50% of an administered dose is eliminated renally within 24

hours, 70% within five days. Up to 16% of a dose is excreted in

the feces. About 3% to 4% of renally excreted drug is excreted

as unchanged drug. The total clearance of verapamil is nearly as

high as the hepatic blood

flow, approximately 1 L/h/kg (range: 0.7-1.3 L/h/kg).

Special Populations

Pediatric: Limited information on the pharmacokinetics in the

paediatric population is available. After intravenous dosing, the

mean half-life of verapamil was 9.17 hours and the mean

clearance was 30 L/h, whereas it is around 70 L/h for a 70-kg

adult.

Steady-state

plasma

concentrations

appear

somewhat lower in the paediatric population after oral dosing

compared to those observed in adults.

Geriatrics:

Aging

affect

pharmacokinetics

verapamil given to hypertensive patients. Elimination half-life

may be prolonged in the elderly. The antihypertensive effect of

verapamil was found not to be age-related.

Renal insufficiency: Impaired renal function has no effect on

verapamil pharmacokinetics, as shown by comparative studies

in patients with end-stage renal failure and subjects with

healthy kidneys.

Verapamil and norverapamil are not significantly removed by

hemodialysis.

Hepatic insufficiency: The half-life of verapamil is prolonged in

patients with impaired liver function owing to lower oral

clearance and a higher volume of distribution.

Overdose

Symptoms

Hypotension, bradycardia up to high degree

AV block and sinus arrest, hyperglycemia,

stupor, metabolic acidosis

Fatalities have

occurred as a result of overdose.

Treatment

Treatment

overdosage

should

supportive.

Beta-adrenergic

stimulation

parenteral

administration of calcium solutions may

increase calcium ion flux across the slow

Symptoms

Hypotension, bradycardia up to high degree AV block and

sinus

arrest,

hyperglycemia,

stupor,

metabolic

acidosis

Fatalities have occurred as a result of overdose.

Treatment

Treatment of overdosage should be supportive.

channel, and have been used effectively in

treatment of deliberate overdosage with

verapamil.

Verapamil

cannot

removed

hemodialysis.

Clinically significant hypotensive reactions

or high degree AV block should be treated

with vasopressor agents or cardiac pacing,

respectively. Asystole should be handled by

usual

measures

cardiopulmonary

resuscitation

Beta-adrenergic stimulation or parenteral administration of

calcium solutions may increase calcium ion flux across the slow

channel, and have been used effectively in treatment of

deliberate overdosage with verapamil.

Verapamil cannot be removed by hemodialysis.

Clinically significant hypotensive reactions or high degree AV

block should be treated with vasopressor agents or cardiac

pacing, respectively. Asystole should be handled by the usual

measures

including

beta

adrenergic

stimulation

(e.g.,

isoproterenol hydrochloride), other vasopressor agents or

cardiopulmonary resuscitation.

ןולעב ןולעב

ןכרצל ןכרצל

ספוט

הז

דעוימ

טורפל

תורמחהה

דבלב

תורמחהה

תושקובמה

קרפ

ןולעב טסקט

יחכונ טסקט

שדח תויוותה

שמתשהל ןיא יתמ

?

רישכתב םא

:ןוגכ בלב תויעב ךל שיש עידומ ךאפור -ל תחתמ ילוטסיס ךרע) ךומנ םד ץחל

אמגודל ) ךומנ דואמ םד ץחל וא (תיפסכ מ"מ

םלה לש הרקמב

shock

,בל תקיפס יא ,( תוולתמ וילא ירודסורפ רופרפ וא ףורפר תעפות :אמגודל) תפסונ הכלוה תליסמ

Wolff-Parkinson-White

וא

Lown-

Ganong-Levine

םא

ךרע) ךומנ םד ץחל :ןוגכ בלב תויעב ךל שיש עידומ ךאפור -ל תחתמ ילוטסיס

ךומנ דואמ םד ץחל וא (תיפסכ מ"מ םלה לש הרקמב אמגודל )

shock

םיכוביס םע בל ףקתה

יא , תליסמ תוולתמ וילא ירודסורפ רופרפ וא ףורפר ,בל תקיפס תעפות :אמגודל) תפסונ הכלוה

Wolff-Parkinson-White

וא

Lown-Ganong-Levine

תודחוימ תורהזא

שומישל תועגונה

:

הפורתב

שמתשהל ןיא

ילבמ הפורתב

ינפל אפורב ץעוויהל

:

לופיטה תלחתה .םדה ץחלב הלודג הדיריו יטיא קפודב הוולמ דח בל ףקתה-

:

תויתופורת ןיב תובוגת

:

הקנהו ןוירה

שמתשת דציכ

:

הפורתב :יאוול תועפות תועפות

יאוול

תורחא

תמיסח לש הרמחה ללוכ , תוריצע .םייעמ

.החירפ

.ךומנ םד ץחל

.יטיא קפוד

.ריהמ קפוד

.בל תקיפס יא

.תומימדא תופסונ יאוול תועפות

2

מ תוחפ לע תועיפשמ( תוחיכש יאוול תועפות

1

ךותמ

10

)םילפוטמ

שאר באכ

תורוחרחס

.תוליחב ,תוריצע

יטיא קפוד

ךומנ םד ץחל

םיילגרב וא םיידיב ,ףוגב תוחפנתה תוימומדא

.םיילגרב וא םיידיב ,ףוגב תוחפנתה

.תואירב לזונ תורבטצה

.תורוחרחס

.שאר באכ

.תופייע

.הליחב

.המישנב תויעב

השק תרוחרחס

vertigo

.םיינזואב םוזמז

תכרעמל

תורושקה תועפות םיבצעה

extrapyramidal

.האקה

םייכינחה לש תרבגומ החימצ .(תוחופנ םייכינח)

.ןטב באכ

.םרירש תשלוח

.םיקרפמ וא םירירש יבאכ

םיידש לש תרבגומ תוחתפתה .רבגב

םישנב בלח לש תרבגמ הריצי .(םיידשהמ הפילדל םרוגה

.היצנטופמיאמ ולבסי םירבגו ןכתי

החירפ) תלרח תויגרלא תובוגת .עיפוהל תולולע (רועב תדרגמ שחרתהל םג תולולע דבכב תויעב מ תוחפ לע תועיפשמ( תוחיכש ןניאש יאוול תועפות

1

ךותמ

100

)םילפוטמ

קזח קפוד

ריהמ קפוד

ןטב באכ

תופייע מ תוחפ לע תועיפשמ( תורידנ יאוול תועפות

1

ךותמ

1000

)םילפוטמ

לומינ תשוחת

דער

םונמנ

םיינזואב םוזמז

תואקה

תרבגומ העיז םילפוטמ לש עודי אל רפסמב תושרחתמה יאוול תועפות

רתי תושיגר

םיבצעה תכרעמל

תורושקה

תועפות

extrapyramidal

השק תרוחרחס

vertigo

.בל תקיפס יא

בלה קפודב תוערפה

(המישנב תויעב) תונופמיסה תותיווע

ןטבב תוחונ רסוח

.(תוחופנ םייכינח) םייכינחה לש תרבגומ החימצ

םייעמ תמיסח לש הרמחה) השק תוריצע לש גוס

ileus

עולבו ןושלב ,םייתפשב ,םינפב תוחיפנ

תויחופלשו םישושבג

תלחמ

Stevens Johnson

(תרירבו רועב תויחופלש)

רעיש ןדבוא

דוריג

החירפ

(רועב תדרגמ החירפ) תלרח

רועב תטירס וא ףושפשל ףחד לש תרבגומ השוחת

םירירש תשלוח

.םיקרפמ וא םירירש יבאכ

תונוא ןיא

הפילדל םרוגה םישנב בלח לש תרבגמ הריצי .(םיידשהמ

רבגב םיידש לש תרבגומ תוחתפתה

דבכה ימיזנא תמרב הילע תורחא יאוול תועפות

.םייעמ תמיסח לש הרמחה ללוכ , תוריצע

.החירפ

.ךומנ םד ץחל

.יטיא קפוד

.ריהמ קפוד

.בל תקיפס יא

.תומימדא

.םיילגרב וא םיידיב ,ףוגב תוחפנתה

.תואירב לזונ תורבטצה

.תורוחרחס

.שאר באכ

.תופייע

.הליחב

.המישנב תויעב

השק תרוחרחס

vertigo

.םיינזואב םוזמז

םיבצעה תכרעמל

תורושקה

תועפות

extrapyramidal

.האקה

.(תוחופנ םייכינח) םייכינחה לש תרבגומ החימצ

.ןטב באכ

.םרירש תשלוח

.םיקרפמ וא םירירש יבאכ

.רבגב םיידש לש תרבגומ תוחתפתה

הפילדל םרוגה םישנב בלח לש תרבגמ הריצי .(םיידשהמ

.היצנטופמיאמ ולבסי םירבגו ןכתי

תולולע (רועב תדרגמ החירפ) תלרח תויגרלא תובוגת .עיפוהל

םינתינ רשא ,שחרתהל םג תולולע דבכב תויעב .תויאופר תוקידב י"ע ןוחבאל

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