ZOMIG RAPIMELT

" עעבקנהזןולעטמרופ " ודילערשואוקדבנונכותותואירבהדרשמי ראוניב 2012 "

=========

ןכרצלןולע םיחקורהתונקתיפל ) םירישכת ( משתה " ו - 1986

אפורםשרמבתבייחוזהפורת

ארק / שמתשתםרטבופוסדעןולעהתאןויעבי / הפורתבי

גימוז טלמיפר ®

תוילבט הפבהסמהל

בכרה

הליכמהילבטלכ :

Zolmitriptan 2.5 mg

םיליעפיתלבםיביכרמ :

Mannitol, microcrystalline cellulose, crospovidone, aspartame *, sodium bicarbonate,

magnesium stearate, citric acid anhydrous, orange flavour-SN027512,Colloidal silicon dioxide

הליכמהילבטלכ 5 מ " םטרפסאג , קפסמה 2.81 מ " םטרפסאלשביכרמאוהשןינלאלינפג .

תיטיופרתהצובק : םינטפירט , טסינוגא יביטקלסיגרנוטורס

) ( 5HT

agonists .

תיאופרתוליעפ

הנרגימבלופיט ילבואםע " הליה " .

רישכתבשמתשהלןיאיתמ ?

היביכרממדחאלתושיגרהעודיםאוזהפורתבשמתשהלןיא .

הםאוזהפורתבשמתשהלןיא י לבוסךנ / מת לופיטלהשקההובגםדץחל , תלחממ תלחממואתימכסיאבל בל

תילילכ ) בלבםיקרועבהשלחםדתמירז ( , לבוסךניהםא / תקועתםשבעודיההזחבםיבאכלשםיוסמגוסמת

לטמזנירפ , םא םיימויואםויךותופלחרשאיחומעוריאלםימודהםינמיסמואיחומעוריאמתלבס ) יחומעוריא

ףלוח (

טלתרחאיהשלכהפורתםעדחיתינמזובוזהפורתלוטילןיא הנרגימבלופי , התואלתוכיישהתורחאתופורתללוכ

הצובקה ) 5HT

agonists ( טוגראהתצובקמםירישכתואןימטוגראו .

לופיטהתלחתהינפלאפורבץעוויהלילבמהפורתבשמתשהלןיא ןוירהבךניהםא , ןוירהלסנכיהלהסנמ ואהקינמוא

בלהדוקפתביוקילמרבעבתלבסםא ללוכ יבאכ הזח , א בלהרירשםטו ) בלףקתה ( , תנומסת Wolff-Parkinson-

White ) ןיקתאלבלבצק ( , םדץחלרתי רבעבתלבסםאוא רשאיחומעוריאלםימודהםינמיסמואיחומעוריאמ

םיימויואםויךותופלח ) ףלוחיחומעוריא ( } האר / קרפבי " רישכתבשמתשהלןיאיתמ " ,{ םאב םייקשךלרמאנ

חמלרבגומןוכיס בלתל רבעבתלבסםאוא יוקלמ דבכהדוקפיתב האירונוטקלינפמוא ) טלמיפרגימוזתוילבט

תוליכמ םטרפסא ןינלאלינפלשרוקמאוהש .(

ךלשםויםויהייחלעהפורתהעיפשתךיא ?

תונוכמליעפהלואגוהנלםילוחהלשםתלוכיבםוגפלרומאוניאוזהפורתבשומיש . תשןובשחבתחקלשיםלוא ןכת

תוינונשי .

תורהזא

שיגרךניהםא / יהשלכהפורתלואוהשלכןוזמלה , הפורתהתליטנינפלאפורלךכלעעידוהלךילע .

הנרגימבענומלופיטלדעוימוניארישכתה .

תונרגימםניאשםיליגרשאריבאכלשםירקמבוזהפורתבשמתשהלןיא .

לאפורבץעוויהלשיהאירונוטקלינפמלבוסךניהםא טלמיפרגימוזבשומישהינפ . הליכמהילבטלכ 2.81 מ " ג

ןינלאלינפ , םטרפסאלשביכרמ .

ןיבתובוגת - תויתפורת

הנוזתיפסותוםשרמאלל לופיטההתעהזתרמגםאוא לטונךניהםא / הפורתת תפסונ , תורכמנהתופורתללוכ

תרחאהפורתב , יאואםינוכיסעונמלידכלפטמהאפורלחוודלךילע - עי ןיבתובוגתמםיעבונהתולי - תויתפורת ,

תואבהתוצובקהמתופורתיבגלדחוימב : יבכעמתחפשממתופורת MAO

אמגודכןואכידבלופיטל : דימבולקומ , (

תחפשממתופורת SSRIs ) ןינוטורסלשתרזוחהגיפסלשםיביטקלסםיבכעמ ( ןיטסקואולפומכ , ןימסקובולפ ,

ןילרטרסוןיטסקורפ ; תחפשממתופורת SNRIs

) ןירפינפארונןינוטורסלשתרזוחהגיפסלשםיבכעמ ( ומכ

ןיטסקולודואןיסקפלנו , ס ןידיטמי ) הביקביכלולוכיעיישקל ( , םינולוניקהתחפשממהקיטויביטנא ) ןוגכ :

ןיצסקולפורפיצ ( , םוטרופרפםוקירפיה ) St. John’s Wort ( , תופורתללוכהנרגימבלופיטלתרחאיהשלכהפורת

תורחא הצובקההתואלתוכיישה ) 5HT

agonists ( לשןמזקרפןיתמהלשי 24 תורחאתופורתתליטנרחאלתועש

םינטפירטהתחפשממ ) ןטפירטמוס , ןטפירפטרנ ( גימוזתליטנןיבל טלמיפר 2.5 מ " ג , קרפןיתמהלשיהמודןפואבו

לשןמז 24 גימוזתליטנרחאלתועש טלמיפר 2.5 מ " חאתופורתתליטנןיבלג םינטפירטהתחפשממתור .

טוגראהתצובקמםירישכתואןימטוגרא ) ןוגכ : גרסיתמואןימטוגראורדיהיד ' די ( -

לשןמזקרפןיתמהלשי תוחפל 24 ויתורזגנואןימטוגראתליטנןיבתועש ) הנרגימל ( טלמיפרגימוזתליטנל

ןיפוליחלו , ןיתמהל לשןמזקרפ תוחפל 6 תליטנןיבתועש ז ויתורזגנואןימטוגראירישכתלשהליטנלטלמיפרגימו .

יאוולתועפות

הפורתהלשהיוצרהתוליעפלףסונב , יאוולתועפשהעיפוהלתולולעהבשומישהןמזב . תוצופניאוולתועפות ) עיפשמ

לע 1%-10% םילוחהמ (

תשגרה

הליחב , תואקה , ןטביבאכ , תרוחרחס , םונמנ , םוחתשגרה , ואהשלוח הפבשבוי ,

שאריבאכ , תויצטיפלפ ) רידסאלבלקפוד ( . תודבכלשהשגרה , ץחל , ןורגבבאכ , ראווצב , הזחב , םיילגרבואתועורזב ,

םירירשבהשלוחואםיבאכוםישוחימוא , העילבבישוקואםיילגרהתופכבוםיידיהתועבצאברורקדוא . תועפות

רצקןמזרחאלתופלוחותולקללכךרדבןהולא .

.

תוצופנתוחפיאוולתועפות ) לעעיפשמ 0.1%-1% םילוחהמ :( הידרקיכט ) ריהמבלבצק ( , חווטלםדהץחלבהילע

רצק , ןתשהתורידתבהילע .

םירידנםירקמב ) לעעיפשמ 0.01%-0.1% םילוחהמ :( תדפריסללוכרתיתושיגרלשתובוגת ) דוריגבהוולמהחירפ ( ,

המדאויגנא ) הפהתוחפנתה , הוןושלה ראווצ , תומקרבלזונתואצמהםע ( , תויטקליפנאתובוגתו ) הבוגתלשגוס

תיניצרתיגרלא .( תידיימתיאופרהרזעקיעזהלשיהפלביבסתוחפנתההלחםא .

רתויבםירידנםירקמב ) מתוחפ – 0.01% םילוחהמ ( , הזגוסמםירחאםירישכתלהמודב ) 5HT

agonists ( , וחווד

הניגנאלשםירקמ , ) םיבאכ הזחב ( , בלהרירשםטוא ) בלףקתה , םיבבלהםדהילכלשתורציה ) םילולעםינימסת

המישנרצוקוהזחבםיבאכלולכל ( , ןתשהתומכבהילע , יעמבםדהילכלשתורציה ) לושלשלולכלםילולעםינימסת

ןטבבאכואימד .(

וזחמבתומייוסמתויעבלןוכיסבאצמיהלםילולעתונרגיממםילבוסהםישנא חומבםדהר , אמגודל : יחומךותםומיד

םייחומםיעוריאוא . הזגוסמםירחאםירישכתלהמודב , רתויבםירידנםירקמבוחוודוללהתויעבה .

תדחוימתוסחייתהתובייחמהתועפות

התאםא / שחתא / בה הזחבםיבאכ ךלשאפורהםעתוצעייתהרחאלדעטלמיפרגימוזלוטילקיספהלךילע .

ובשהרקמלכב שיגרמךניה / תיללכהךתשגרהביונישלחםאואהזןולעבונייוצאלשיאוולתועפותה , ץעייתהלךילע

דימאפורהםע .

ןונימ

דבלבאפורהתוארוהיפל .

מהלערובעלןיא ןוני למומה ץ .

אפורהמתרחאהארוהרדעהבץלמומןונימ :

תחאהילבט ) 2.5 מ " ג ( הנרגימהתליחתםעדיימ . אלהנרגימהםא ךותבהרזחםאואםייתעשרחאלהפלח 24 תועש ,

חק / תפסונהילבטי .

חוודתועיפשמןניאתוילבטהםא / אפורלי , לופיטהיונישלעטילחיוןכתירשא .

הניאוזהפורת תצלמומ ללכךרדב ליגלתחתמםירגבתמוםידליל 18 ליגלעמםירגובמלו 65

שומישהןפוא

שלהלעססומתהלהילבטלרשפאלשי קורהםעעלבהלוןו . םימתותשלךרוצןיא .

הילבטהתאררחשלתנמלעםוינימולאהדידרתאףלקלשי . םוינימולאהדידרךרדהילבטהלעץוחללןיא .

*******************************************

* לכותדציכ / לופיטהתחלצהלעייסלי ? *

****************************************** *

םינושארההנרגימהינמיסתעפוהםעדימהילבטלוטילץלמומ . רשאכדימלוטילשיתאזתושעלךתורשפאבןיאםא

לטינאוהובבלשלכבתמגפנהניארישכתהלשותוליעיורחאמירשפאהז .

ענמ / הלערהי !

וםידלילשםדיגשיהלץוחמרוגסםוקמברומשלשיתרחאהפורתלכווזהפורת / ניתוא ענמתךכידילעותוקו

הלערה .

הפורתהןמדליעלבתועטבםאוארתיתנמתלטנםא , הנפ / אבהוםילוחתיבלשןוימרדחלדימי / הפורתהתזיראי

ךתיא .

םורגתלא / י האקהל אפורהמתשרופמהארוהאלל !

ךתלחמבלופיטלהמשרנוזהפורת ; רחאהלוחב ) ת ( , קיזהלהלולעאיה .

ןתיתלא / י וזהפורת ךיבורקל , ךירכמואךינכש .

ךשוחבתופורתלוטילןיא ! קודב / הנמהותיוותהי םעפלכב לטונךניהש / ת הפורת . בכרה / ךניהםאםייפקשמי

קוקז / םהלה .

א הנסח

לעהלועהניאשהרוטרפמטבןסחאלשי 30ºC הזיראהיאנתיפלםג / םיצלמומההנסחה , הפוקתלתורמשנתופורת

תלבגומ דבלב . שלאנ רישכתהלשהגופתהךיראתלבלםי ! קפסלשהרקמלכב , תאךלקפיסשחקורבץעוויהלךילע

הפורתה .

הזיראהתואבתונושתופורתןסחאלןיא .

סמ . הפורתהםושיר 125693047200

ערצוימ " י תודבעמ ס המי קניא הרא " ב

עבהילגנאהקנזהרטסארובע " מ ,

דליפסלקמ , הילגנא .

וםושירלעב ןאובי

עהלארשיהקנזהרטסא " מ

" ד 4070

הננער 43656

ZOMIG RAPIMELT approved 0509

Page of 10

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

approved 01.2012.”

SUMMARY OF PRODUCT CHARACTERISTICS

ZOMIG 2.5 MG SOLUBLE IN MOUTH

1.

TRADENAME OF THE MEDICINAL PRODUCT

‘Zomig Rapimelt’

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Tablets soluble in mouth containing 2.5 mg of zolmitriptan.

For excipients: see Section 6.1

3.

PHARMACEUTICAL FORM

Tablets soluble in mouth.

4.

CLINICAL PARTICULARS

4.1

Therapeutic Indications

‘Zomig Rapimelt’ is indicated for the acute treatment of migraine with or without

aura.

4.2

Posology and Method of Administration

The recommended dose of ‘Zomig Rapimelt’ to treat a migraine attack is 2.5 mg.

‘Zomig Rapimelt’ rapidly dissolves when placed on the tongue and is swallowed

with the patient’s saliva. A drink of water is not required when taking ‘Zomig

Rapimelt’. ‘Zomig Rapimelt’ can be taken when water is not available thus

allowing early administration of treatment for a migraine attack. This formulation

may also be beneficial for patients who suffer from nausea and are unable to drink

during a migraine attack, or for patients who do not like swallowing conventional

tablets.

If symptoms persist or return within 24 hours, a second dose of zolmitriptan has

been shown to be effective. If a second dose is required, it should not be taken

within 2 hours of the initial dose.

If a patient does not achieve satisfactory relief with 2.5 mg doses, subsequent

attacks can be treated with 5 mg doses of ‘Zomig Rapimelt’. In those patients who

respond, significant efficacy is apparent within 1 hour of dosing with zolmitriptan.

Zolmitriptan is equally effective whenever the tablets are taken during a migraine

attack; although it is advisable that ‘Zomig Rapimelt’ is taken as early as possible

after the onset of migraine headache.

ZOMIG RAPIMELT approved 0509

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In the event of recurrent attacks, it is recommended that the total intake of ‘Zomig

Rapimelt’ in a 24 hour period should not exceed 10 mg.

‘Zomig Rapimelt’ is not indicated for prophylaxis of migraine.

ZOMIG RAPIMELT approved 0509

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Use in Children (under 12 year of age)

Safety and efficacy of ‘Zomig Rapimelt’ in paediatric patients have not been evaluated.

Use of Zomig Rapimelt tablets in childrens is therefore not recommended.

Adolescents (12-17 years of age)

The efficacy of Zomig tablets was not demonstrated in placebo controlled clinical trial for

patients ages 12 to 17 years. Use of Zomig Rapimelt tablets in adolescents is therefore

not recommended.

Use in Patients Aged Over 65 years

Safety and efficacy of ‘Zomig Rapimelt’ in individuals aged over 65 years have not

been established.

Patients with Hepatic Impairment

Metabolism is reduced in patients with hepatic impairment (See Section 5.2

Pharmacokinetic properties). Therefore for patients with moderate or severe

hepatic impairment a maximum dose of 5 mg in 24 hours is recommended.

Patients with Renal Impairment

No dosage adjustment required (see Section 5.2 Pharmacokinetic Properties).

4.3

Contraindications

‘Zomig Rapimelt’ is contraindicated in patients with:

Known hypersensitivity to any component of the product.

Uncontrolled hypertension.

Ischaemic heart disease.

Coronary vasospasm/Prinzmetal’s angina.

A history of cerebrovascular accident (CVA) or transient ischaemic attack

(TIA).

Concomitant

administration

Zomig

with

ergotamine

ergotamine

derivatives or other 5-HT

receptor agonists.

4.4

Special Warnings and Special Precautions for Use

‘Zomig Rapimelt’ should only be used where a clear diagnosis of migraine has

been established. Care should be taken to exclude other potentially serious

neurological conditions. There are no data on the use of ‘Zomig Rapimelt’ in

hemiplegic

basilar

migraine.

Migraneurs

risk

certain

cerebrovascular

events.

Cerebral

haemorrhage,

subarachnoid

haemorrhage,

stroke, and other cerebrovascular events have been reported in patients treated

with 5HT

1B/1D

agonists.

‘Zomig

Rapimelt’

should

given

patients

with

symptomatic

Wolff-

Parkinson-White syndrome or arrhythmias associated with other cardiac accessory

conduction pathways.

In very rare cases, as with other 5HT

1B/1D

agonists,

coronary vasospasm, angina

pectoris, and myocardial infarction have been reported. In patients with risk

factors

ischaemic

heart

disease,

cardiovascular

evaluation

prior

commencement of treatment with this class of compounds, including ‘Zomig

Rapimelt’,

recommended

(see

Section

Contraindications).

These

evaluations, however, may not identify every patient who has cardiac disease, and

ZOMIG RAPIMELT approved 0509

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in very rare cases, serious cardiac events have occurred in patients without

underlying cardiovascular disease.

As with other 5HT

1B/1D

agonists, atypical sensations over the precordium (see

Section 4.8 Undesirable Effects) have been reported after the administration of

zolmitriptan. If chest pain or symptoms consistent with ischaemic heart disease

occur, no further doses of zolmitriptan should be taken until after appropriate

medical evaluation had been carried out.

As with other 5HT

1B/1D

agonists, transient increases in systemic blood pressure

have been reported in patients with and without a history of hypertension; very

rarely these increases in blood pressure have been associated with significant

clinical events.

As with other 5HT

1B/1D

agonists, there have been rare reports of

anaphylaxis/anaphylactoid reactions in patients receiving Zomig

Patients with phenylketonuria should be informed that ‘Zomig Rapimelt’ contains

phenylalanine (a component of aspartame). Each 2.5 mg orally dispersible tablet

contains 2.81 mg of phenylalanine.

Excessive use of an acute anti-migraine medicinal product may lead to an increased

frequency of headache, potentially requiring withdrawal of treatment.

Serotonin Syndrome has been reported with combined use of triptans, and Selective

Serotonin Reuptake Inhibitors (SSRIs) and Serotonin Norepinephrine Reuptake

Inhibitors (SNRIs). Serotonin Syndrome is a potentially life-threatening condition,

and it may include signs and symptoms such as: mental status changes (e.g. agitation,

hallucinations, coma), autonomic instability, (e.g. tachycardia, labile blood-pressure,

hyperthermia), neuromuscular aberrations (e.g. hyperreflexia, in-coordination), and/or

gastrointestinal symptoms (e.g. nausea, vomiting, diarrhoea). Careful observation of the

patient is advised, if concomitant treatment with Zomig and an SSRI or SNRI is clinically

warranted, particularly during treatment initiation and dosage increases (See section

4.5).

4.5

Interactions with Other Medicaments and Other Forms of Interaction

There is no evidence that concomitant use of migraine prophylactic medications

has any effect on the efficacy or unwanted effects of zolmitriptan (for example beta

blockers, oral dihydroergotamine, pizotifen).

pharmacokinetics

tolerability

‘Zomig’,

when

administered

conventional tablet, were unaffected by acute symptomatic treatments such as

paracetamol, metoclopramide and ergotamine. Concomitant administration of

other 5HT

1B/1D

agonists within 24 hours of 'Zomig Rapimelt' treatment should be

avoided.

Data from healthy subjects suggest there are no pharmacokinetic or clinically

significant interactions between Zomig and ergotamine, however, the increased

risk of coronary vasospasm is a theoretical possibility. Therefore, it is advised to

wait at least 24 hours following the use of ergotamine containing preparations

before administering Zomig .

. Conversely it is advised to wait at least six hours

following use of Zomig before administering any ergotamine-containing preparation

(see Section 4.3 Contraindications).

Following administration of moclobemide, a specific MAO-A inhibitor, there was a

small increase (26%) in AUC for zolmitriptan and a 3-fold increase in AUC of the

active metabolite. Therefore, a maximum intake of 5 mg ‘Zomig Rapimelt’ in

24 hours is recommended in patients taking an MAO-A inhibitor.

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Following the administration of cimetidine, a general P450 inhibitor, the half life of

zolmitriptan was increased by 44% and the AUC increased by 48%. In addition

the half life and AUC of the active N-desmethylated metabolite (183C91) were

doubled. A maximum dose of 5 mg 'Zomig Rapimelt' in 24 hours is recommended

patients

taking

cimetidine.

Based

overall

interaction

profile,

interaction with inhibitors of the cytochrome P450 isoenzyme CYP1A2 cannot be

excluded.

Therefore,

same

dosage

reduction

recommended

with

compounds of this type, such as fluvoxamine and the quinolone antibiotics (eg

ciprofloxacin).

Fluoxetine

does

affect

pharmacokinetic

parameters

zolmitriptan.

Therapeutic

doses

specific

serotonin

reuptake

inhibitors,

fluoxetine,

sertraline, paroxetine and citalopram do not inhibit CYP1A2.

However, Serotonin Syndrome has been reported during combined use of triptans, and

SSRIs (e.g. fluxetine, paroxetine, sertraline) and SNRIs (e.g. venlafaxine, duloxetine) (see

section 4.4).

As with other 5HT

1B/1D

agonists, there is the potential for dynamic interactions with

the herbal remedy St John’s wort (Hypericum perforatum) which may result in an

increase in undesirable effects.

4.6

Pregnancy and Lactation

Pregnancy

‘Zomig Rapimelt’ should be used in pregnancy only if the benefits to the mother

justify potential risk to the foetus. There are no studies in pregnant women, but

there

evidence

teratogenicity

animal

studies.

(See

Section

Preclinical Safety Data).

Lactation

Studies have shown that zolmitriptan passes into the milk of lactating animals. No

data exist for passage of zolmitriptan into human breast milk. Therefore, caution

should be exercised when administering ‘Zomig Rapimelt’ to women who are

breast-feeding.

4.7

Effects on Ability to Drive and Use Machines

There was no significant impairment of performance of psychomotor tests with

doses up to 20 mg zolmitriptan. Use is unlikely to result in an impairment of the

ability of patients to drive or operate machinery. However it should be taken into

account that somnolence may occur.

4.8

Undesirable Effects

Zolmitriptan is well tolerated. Adverse reactions are typically mild/moderate,

transient, not serious and resolve spontaneously without additional treatment.

Possible adverse reactions tend to occur within 4 hours of dosing and are no more

frequent following repeated dosing.

The following definitions apply to the incidence of the undesirable effects:

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

(≥1/10,000 < 1/1,000); very rare (<1/10,000).

The following undesirable effects have been reported following administration with

zolmitriptan:

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Table 1

Table of Adverse Drug Reactions

System Organ Class

Frequency

Undesirable Effect

Immune system

disorders

Rare

Anaphylaxis/Anaphylactoid Reactions;

Hypersensitivity reactions

Nervous system disorder

Common

Abnormalities or disturbances of

sensation;

Dizziness;

Headache;

Hyperaesthesia;

Paraesthesia;

Somnolence;

Warm sensation

Cardiac disorders

Common

Palpitations

Uncommon

Tachycardia

Very rare

Angina pectoris;

Coronary vasospasm;

Myocardial infarction

Vascular disorders

Uncommon

Transient increases in systemic blood

pressure

Gastrointestinal

disorders

Common

Abdominal pain;

Dry mouth;

Nausea;

Vomiting

Very rare

Bloody diarrhoea;

Gastrointestinal infarction or necrosis;

Gastrointestinal ischaemic events;

Ischaemic colitis;

Splenic infarction

Skin and subcutaneous

tissue disorders

Rare

Angioedema;

Urticaria

Musculoskeletal and

connective tissue

disorders

Common

Muscle weakness;

Myalgia

Renal and urinary

disorders

Uncommon

Polyuria;

Increased urinary frequency

Very rare

Urinary urgency

General disorders

Common

Asthenia;

Heaviness, tightness, pain or pressure in

throat, neck, limbs or chest

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4.9

Overdose

Volunteers receiving single oral doses of 50 mg commonly experienced sedation.

elimination

half-life

zolmitriptan

hours,

(see

Section

Pharmacokinetic Properties) and therefore monitoring of patients after overdose

with ‘Zomig Rapimelt’ should continue for at least 15 hours or while symptoms or

signs persist.

There is no specific antidote to zolmitriptan. In cases of severe intoxication,

intensive

care

procedures

recommended,

including

establishing

maintaining a patent airway, ensuring adequate oxygenation and ventilation, and

monitoring and support of the cardiovascular system.

It is unknown what effect haemodialysis or peritoneal dialysis has on the serum

concentrations of zolmitriptan.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic Properties

Pharmacotherapeutic group: Selective serotonin (5HT

) agonists.

ATC code: N02CC03

In pre-clinical studies, zolmitriptan has been demonstrated to be a selective

agonist for the vascular human recombinant 5HT

and 5HT

receptor subtypes.

Zolmitriptan is a high affinity 5HT

1B/1D

receptor agonist with modest affinity for

receptors.

Zolmitriptan

significant

affinity

measured

radioligand binding assays) or pharmacological activity at 5HT

-, 5HT

-, 5HT

alpha

alpha

beta

adrenergic;

histaminic;

muscarinic;

dopaminergic

, or dopaminergic

receptors. The 5HT

receptor is predominately

located

presynaptically

both

peripheral

central

synapses

trigeminal nerve and preclinical studies have shown that zolmitriptan is able to act

at both these sites.

One controlled clinical trail in 696 adolescents with migraine failed to demonstrate

superiority of zolmitriptan tablets at doses of 2.5 mg, 5 mg and 10 mg over placebo.

Efficacy was not demonstrated.

5.2

Pharmacokinetic Properties

Following oral administration of ‘Zomig’ conventional tablets zolmitriptan is rapidly

and well absorbed (at least 64%) in man. The mean absolute bioavailability of the

parent compound is approximately 40%. There is an active metabolite (183C91,

the N-desmethyl metabolite) which is also a 5HT

IB/1D

agonist and is 2 to 6 times as

potent, in animal models, as zolmitriptan.

In healthy subjects, when given as a single dose, zolmitriptan and its active

metabolite 183C91, display dose-proportional AUC and C

over the dose range

2.5 to 50 mg. Absorption is rapid with 75% of C

achieved within 1 hour and

plasma concentrations are sustained subsequently for 4 to 6 hours. Zolmitriptan

absorption is unaffected by the presence of food. There is no evidence of

accumulation on multiple dosing of zolmitriptan.

Zolmitriptan is eliminated largely by hepatic biotransformation followed by urinary

excretion of the metabolites. There are three major metabolites: the indole acetic

acid, (the major metabolite in plasma and urine), the N-oxide and N-desmethyl

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analogues. The N-desmethylated metabolite (183C91) is active whilst the others

are not. Plasma concentrations of 183C91 are approximately half those of the

parent drug, hence it would therefore be expected to contribute to the therapeutic

action of ‘Zomig Rapimelt’. Over 60% of a single oral dose is excreted in the urine

(mainly as the indole acetic acid metabolite) and about 30% in faeces, mainly as

unchanged parent compound.

study

evaluate

effect

liver

disease

pharmacokinetics

zolmitriptan showed that the AUC and C

were increased by 94% and 50%

respectively in patients with moderate liver disease and by 226% and 47% in

patients with severe liver disease compared with healthy volunteers. Exposure to

the metabolites, including the active metabolite, was decreased. For the 183C91

metabolite, AUC and C

were reduced by 33% and 44% in patients with

moderate liver disease and by 82% and 90% in patients with severe liver disease.

The plasma half-life (t½) of zolmitriptan was 4.7 hours in healthy volunteers,

7.3 hours in patients with moderate liver disease and 12 hours in those with severe

liver disease. The corresponding t½ values for the 183C91 metabolite were

5.7 hours, 7.5 hours and 7.8 hours respectively.

Following

intravenous

administration,

mean

total

plasma

clearance

approximately

ml/min/kg,

which

third

renal

clearance.

Renal

clearance

greater

than

glomerular

filtration

rate

suggesting

renal

tubular

secretion. The volume of distribution following intravenous administration is 2.4

L/kg. Plasma protein binding is low (approximately 25%). The mean elimination

half-life of zolmitriptan is 2.5 to 3 hours. The half-lives of its metabolites are similar,

suggesting their elimination is formation-rate limited.

Renal clearance of zolmitriptan and all its metabolites is reduced (7 to 8 fold) in

patients with moderate to severe renal impairment compared to healthy subjects,

although the AUC of the parent compound and the active metabolite were only

slightly higher (16 and 35% respectively) with a 1 hour increase in half-life to 3 to

3.5 hours. These parameters are within the ranges seen in healthy volunteers.

In a small group of healthy individuals there was no pharmacokinetic interaction with

ergotamine. Concomitant administration of zolmitriptan with ergotamine/caffeine was well

tolerated and did not result in any increase in adverse events or blood pressure changes

as compared with zolmitriptan alone. (see section 4.5 for precautions regarding

ergotamine use).

Following the administration of rifampicin, no clinically relevant differences in the

pharmacokinetics of zolmitriptan or its active metabolite were observed.

Selegiline, an MAO-B inhibitor, and fluoxetine (a selective serotonin reuptake inhibitor;

SSRI) had no effect on the pharmacokinetic parameters of zolmitriptan. .

(see section 4.4

for warnings and precautions regarding concomitant use with SSRIs).

The pharmacokinetics of zolmitriptan in healthy elderly subjects were similar to

those in healthy young volunteers.

‘Zomig Rapimelt’ was demonstrated to be bioequivalent with the conventional

tablet in terms of AUC and C

for zolmitriptan and its active metabolite 183C91.

Clinical pharmacology data show that the t

for zolmitriptan can be later for the

orally dispersible tablet (range 0.6 to 5h, median 3h) compared to the conventional

tablet (range 0.5 to 3h, median 1.5h). The t

for the active metabolite was

similar for both formulations (median 3h).

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5.3

Preclinical Safety Data

An oral teratology study of zolmitriptan has been conducted. At the maximum

tolerated doses, 1200 mg/kg/day (AUC 605

g/ml.h : approx. 3700 x AUC of the

human maximum recommended daily intake of 15 mg) and 30 mg/kg/day (AUC

g/ml.h : approx. 30 x AUC of the human maximum recommended daily intake

rats

rabbits,

respectively,

signs

teratogenicity

were

apparent.

Five genotoxicity tests have been performed. It was concluded that ‘Zomig

Rapimelt’ is not likely to pose any genetic risk in humans.

Carcinogenicity studies in rats and mice were conducted at the highest feasible

doses and gave no suggestion of tumorogenicity.

Reproductive studies in male and female rats, at dose levels limited by toxicity,

revealed no effect on fertility.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of Excipients

Each 'Zomig Rapimelt' oro-dispersible tablet contains the following excipients:

Aspartame

Citric Acid Anhydrous

Colloidal silicon dioxide

Crospovidone

Magnesium Stearate

Mannitol

Microcrystalline Cellulose

Orange Flavour SN027512

Sodium bicarbonate

6.2

Incompatibilities

None known

6.3

Shelf life

2 years

6.4 Special Precautions for Storage

Do not store above 30

6.5

Presentation

Packs of 2, 6 tablets

Not all pack sizes may be marketed.

6.8

Instructions for Use/Handling

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The blister pack should be peeled open as shown on the foil (tablets should not be

pushed through the foil). The ‘Zomig Rapimelt’ tablet should be placed on the tongue,

where it will dissolve and be swallowed with the saliva.

7.

MANUFACTURER

Manufactured by CIMA Laboratories USA for

AstraZeneca UK Limited, Cheshire, United Kingdom

8.

License holder and IMPORTER

AstraZeneca Israel Ltd.

POB 4070, RAANANA 43656

Zomig Rapimelt is a trademark of the AstraZeneca Group of Companies