ZYPADHERA 210 MG

Israel - English - Ministry of Health

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Active ingredient:
OLANZAPINE 210 MG
Available from:
ELI LILLY ISRAEL LTD
ATC code:
N05AH03
Pharmaceutical form:
POWDER FOR SUSPENSION FOR INJECTION
Administration route:
I.M
Manufactured by:
LILLY PHARMA FERT. & DISTRIB. GmbH & Co. KG
Therapeutic group:
OLANZAPINE
Therapeutic indications:
Zypadhera is indicated for the treatment of schizophrenia.The use of Zypadhera is limited to patients who have been diagnosed as non-compliant regarding taking prescribed medicines and as a consequence are prone to outbursts of psychotic episodes .Zypadhera is NOT to be used in patients whose condition is adequately controlled with oral Zyprexa .Zypadhera is available only through a restricted program which will be conducted according to Zypadhera EU Risk Management Plan.For a patient to receive treatment, the prescribers , injection administrators, pharmacists and patients must all be trained on the appropriate elements of the Zypadhera Risk Management Plan. The Zypadhera Risk Management plan has been developed to enable the safe use of Zypadhera in patients, including the management of those patients who develop Post-Injection Delirium and Sedation Syndrome. In addition to mandating label language around this risk, this plan includes education and training activities to the following target audience as appr
Authorization number:
145013198701
Authorization date:
2010-12-01

Documents in other languages

Patient Information leaflet Patient Information leaflet - Arabic

27-01-2021

Patient Information leaflet Patient Information leaflet - Hebrew

27-01-2021

PATIENT PACKAGE INSERT INACCORDANCE WITH THE PHARMACISTS' REGULATIONS (PREPARATIONS) – 1986

The dispensing of this medicine requires a doctor's prescription

ZYPADHERA210 mg

Powder and solvent for

preparation of prolonged release

suspension for injection

Active ingredient and its amount:

Each vial of powder contains:

Olanzapine pamoate monohydrate

equivalent to 210 mg Olanzapine

The reconstituted suspension contains:

Olanzapine 150 mg/ml ZYPADHERA300 mg

Powder and solvent for

preparation of prolonged release

suspension for injection

Each vial of powder contains:

Olanzapine pamoate monohydrate

equivalent to 300 mg Olanzapine

The reconstituted suspension contains:

Olanzapine 150 mg/ml ZYPADHERA405 mg

Powder and solvent for

preparation of prolonged release

suspension for injection

Each vial of powder contains:

Olanzapine pamoate monohydrate

equivalent to 405 mg Olanzapine

The reconstituted suspension

contains:

Olanzapine 150 mg/ml

For a list of the inactive ingredients, please see section 6.

Read this package insert carefully in its entirety before using this medicine.

This package insert contains concise information regarding this medicine. If you

have additional questions, please contact your doctor or pharmacist.

This medicine has been prescribed for the treatment of your ailment. Do not give

this medication to others, it might harm them even if you think your ailment is

similar.

ZypAdhera is usually not intended for children and adolescents under the age of

18, since there is limited experience with this group.

Forwhat is this medicine intended?

ZypAdheraisanantipsychoticpreparation,administeredasaprolongedrelease

injection, for the treatment ofschizophrenic patients.

Therapeutic group:

Atypical antipsychotic medicines.

Before using this medicine:

This preparation should not be usedif:

Youhave aknownsensitivitytoOlanzapineoroneoftheotheringredients

ofthedrug.Signsofanallergicreactioninclude:rash,difficultyswallowingor

breathing, swelling ofthe lips, face, throat, or tongue.

You are breastfeeding.

You suffer from or have the potential to develop narrowangle glaucoma.

You suffer from dementia-related psychosis.

Your conditionis properly controlled with orally administered Zyprexa.

Special warningsregarding the use of this medicine:

Avoid situations which mayinvolve an excessive rise in body temperature and

dehydration, suchas increased physical activity or frequent stay in warm places.

On the day of the injection you must remain under medical supervision at the

medical center for at least 3 hours from the time of the injection.You must have

someone accompany you when you are discharged from the medical center.

Before treatment with ZypAdhera tell the doctor if:

You are allergic to any food or medicine.

You suffer or have suffered in the past from impaired function of: the heart (e.g.,

heart attack, heart disease, abnormal heart rate, angina pectoris)and/or vascular

system (e.g., if you or your family members suffer / have suffered from blood

clots).

You suffer or have suffered in the past from a stroke.

You suffer from problems in the eyes (e.g., glaucoma, in particular narrow-

angle glaucoma), the liver, the kidneys, the digestive system (e.g., intestinal

obstruction),thebloodsystem,thenervoussystem(Parkinson'sdisease),the

bone marrow,Alzheimer's disease, breast cancer, suicidal thoughts.

You suffer or have suffered in the past from an enlarged prostate gland.

You sufferfromepilepsy,diabetes,highorlowbloodpressure,highcholesterol or

triglyceride levels in the blood.

Ifyouaretakingotherdrugsconcomitantly,includingnon-

prescriptionmedicinesornutritionalsupplements,informthedoctor

or pharmacist. It isespecially important to notify the doctor or

pharmacist if youare taking:

DrugseffectingCYP1A2suchasFluvoxamine(anantidepressant),Ciprofloxacin

(an antibiotic) or Carbamazepine (an antiepileptic and mood stabilizer) – there

might be a need to adjust the dosage of ZypAdhera.

Drugs affecting the central nervous system, such as: Sedatives (e.g., Diazepam),

hypnotics or antidepressants – concomitant use may cause drowsiness.

Certainantihypertensivedrugs–concomitantusewithZypAdheramayincrease

their effect.

Drugs for Parkinson’s disease (levodopa) – concomitant use may exacerbate the

symptoms of Parkinson's disease.

Antiepileptics, anesthetics for surgery, and narcotic analgesics.

Antipsychotic medications – these drugs may cause serotonin syndrome (rare)

(see section"Sideeffects").Thissyndromemayoccurmorefrequentlyifyou

areconcomitantlytakingmedicinesthataffectthecentral nervoussystem(see

above). Inform your doctor about any other medicine that you are taking.

Drug useand alcohol consumption:

Avoidconsumptionofalcoholicbeveragesduringtreatmentwiththisdrug,asit

may increase drowsiness.

Pregnancy and breastfeeding:

Consult a doctor or pharmacist before using medicines.

Consult a doctorif youare pregnantorplan tobecome pregnant.Newbornsmay

develop awithdrawal syndromeifthemothertookthemedicineduringthelast

trimester(lastthreemonths)ofpregnancy.Thewithdrawal syndromeincludesthe

following symptoms: tremor, muscle rigidity / weakness, drowsiness, irritability,

breathingdifficulty,andeatingdifficulties.Ifyourchilddevelopsoneormoreof

the above symptoms, contact your doctor.

Thismedicineshouldnotbetakenifyouarebreastfeeding.Asmall amountofthe

medicine may cross into the milk.

Driving and using machines:

Use of this medicine may impair alertness and therefore caution should be

exercised when driving a car, operating dangerous machinery and in any other

activity that requires alertness. Do not drive or operate machinery on the day of

the injection.

Smoking:

Ifyou are a smoker, inform your doctorbefore commencing treatment with this

medicine.

How to usethis medicine?

Always use according to the doctor's instructions. If you are unsure, check with

the doctor or pharmacist.

The dosage and manner of treatment will be determinedonly by the

doctor. The recommended dosageis usually:

AZypAdhera injection contains Olanzapine for prolonged release, so thatthe

frequencyofinjectionisonceintwoorfourweeks,accordingtothedoctor's

Directions for use:

ZypAdhera is to be administered only by a traineddoctor or nurse in an authorized

medical center with immediateaccess to emergency and resuscitation services.

The injection is administeredto the gluteal muscle.

Detailed instructions for preparation and injectionare included in the Prescribing

Information enclosed in the package.

After theinjection, youmust remain at the medicalcenter for3hours. Patients

must be accompanied when dischargedfrom the medical center.

Treatment should be continued as recommended by the doctor.

If you accidently received an overdose:

This medicine is administered by medical staff, so an overdose is unlikely.

Patientswhohavereceivedan overdosehaveexperiencedthefollowing

symptoms:

Rapid heart rate, irritability / aggressiveness, speech problems (involuntary

movements, especially of the face or tongue), and a decreased level of

consciousness. Other symptoms are:

Acute confusion, epileptic seizures, coma, slow breathing, aspiration, low or high

blood pressure, abnormal disturbances in heart rate.

Ifyou forget to come and get the injection of this medicineon the required

date, contact your doctor as soon as possible to schedule a new date.

Examinations and follow-up:

During treatment with this medicine, you must be under medical supervision and

monitor your blood pressure, especially if you are over the age of 65.

You should monitor blood glucose levels at the beginning and during treatment,

especially if you suffer from diabetes or borderline glucose levels (fasting glucose

levels of 100-126 mg/dl) and blood lipid levels, especially in patients suffering

fromdisturbancesinbloodlipidlevelsorwiththeriskfactorsofdevelopingsuch

disturbances.

Body weight should be monitored during treatment.

If you stop takingthis medicine

Even if there is an improvement in your health, do not stop taking this medicine

without consulting your doctor.

Ifyouhaveadditional questionsregardingtheuseofthismedicine,consultyour

doctor or pharmacist.

Side effects:

Like every medicine, the use of ZypAdheramay cause side effects in some

users. Do not bealarmed when you read the list of side effects.Youmay not

suffer from any of them.

Stop using thisdrug and notify the doctor or nurse immediately if:

After the injection you experience the following symptoms: High fever, muscle

rigidity, changes in mental state, unstable heart rate andblood pressure,

tachycardia,excessivesweating.These symptoms areexpressionsofa very rare

side effect of antipsychotic medicines, called NeurolepticMalignant Syndrome.

After the injection you experience the followingrare symptoms: involuntary

movements,especially ofthe face or tongue,oracombinationof fever,rapid

breathing, sweating, muscle rigidity,and drowsiness.These symptoms are

expressions of another side effectof antipsychotic medicines calledTardive

Dyskinesia.

Side effects relatedto treatment with ZypAdhera:

Pain at the injection site.

Averyrarebutserioussideeffectthatcanoccuraftereveryinjection:

IfZypAdhera enters the blood too quickly, the following serious side effects may

occur: excessive drowsiness, dizziness, confusion, disorientation, nervousness,

anxiety,aggression,increasedbloodpressure,difficultytalkingand/orwalking,

weakness, stiffness or muscle tremor, convulsions, unconsciousness.These

side effects, if they occurred, appeared in most cases about one hour after the

injection. Therefore, you must remain at the medical center for at least 3

hours from the time of the injection, in order to be able to obtain immediate

medical careor transfer totheemergencyroom.Inall cases, theseside

effects passed 24 to 72 hours following the injection. If one of the symptoms

appearswhileyouarenolongerunderthesupervisionofthemedicalstaff,you

must inform the doctor or nurse immediately.

Contact a doctor immediately if:

You experience nausea, weakness, frequent urination, binge eating, acetone

odourfromthebreath,difficultyinswallowing,seizures,decreasedorabsence

of menstruation, abnormal changes in the breast such as: secretion of milk or

enlargement of the breast.

You have peripheral edema (rare).

You have signs indicating venous thrombosis: swelling, pain and redness of

thelegs,whichmaybeaccompaniedbychestpainanddifficultybreathing.

activity or staying in hot places, signs of dehydration may appear, such as:

fever, excessive sweating or lack of sweating, dry mouth, excessive thirst, urinary

retention.

Side effects related to oral treatment with Olanzapinetablets, that can

also appear with ZypAdhera:

Appear frequently:drowsiness, weight gain, elevation of blood prolactin levels,

dry mouth, constipation, tremor, restlessness, increased appetite, dizziness,

muscle rigidity or cramps (including eye movement), speech disturbances,

involuntarymovements,exhaustion,fluidretention(thatcausesswellingofthe

hands,anklesorfeet),sexual dysfunctions,headache,increaseinlevelsofblood

cells and blood lipids, increase in blood and urine glucose levels, rash.

At the beginning of treatment, some patients experience dizziness, especially

when standing up from a sitting or lying position.This side effect usually

disappears spontaneously.You must sit or lie down until you feel improvement. If

there is no improvement, consult your doctor.

Uncommon side effects:

Slow heart rate, sensitivity to light, urine incontinence, urinary retention, hair loss,

irregular menstrual cycle including cessation, changes in the breasts of men as

well as women (e.g., lactation or abnormal enlargement).

Other side effects with unknown frequency:

Allergy, appearance of diabetes or exacerbation of existing diabetes, along

with the appearance of ketones in the blood or urine (ketoacidosis) or coma,

decrease in body temperature, seizures (usually in patients who suffered from

epilepsy),contractionsoftheeyemusclesthatcausetheeyestoroll,heartrate

disturbances, sudden death, pancreatitis that causes acute abdominal pain and

backache,feverandfeelingunwell,liverdisease(jaundiceoftheskinandsclera

of the eyes), muscle injury that causes unexplained muscle aches, prolonged/

painful erections.

If one of the side effects gets worse orif you suffer from a side effect not

mentioned inthe package insert, you must consult a doctor.

Howto store this medicine?

Avoidpoisoning!Toavoidpoisoning,thismedicineandall othermedicinesmust

be stored in asecure place out of the reach of children and/orinfants. Do not

induce vomiting unless explicitly instructed to doso by a doctor.

Do not use the medication afterthe expiry date on the package.The expiry date

isthe last day of that month.

Store at roomtemperature, below 30 ° C.

Do not refrigerate or freeze.

This medicine is recommended for use immediately after preparation.

Additional information

Apart from the active ingredient, this medication also contains:

The powder does not contain additional ingredients.

The solvent contains:

Carmellose sodium, mannitol,polysorbate 80,water for injections,hydrochloric

acid, sodium hydroxide.

How does this medicine appear and what the package contains:

Avial with dry powder, a vial with solvent, asyringe with an attached needleand

two separate needles.The needles are protected with a safety cap.

License holder:Eli Lilly Israel Ltd., P.O Box 2160, Herzliya Pituach 46120.

Manufacturer:LillyPharma, Giessen, Germany.

Drug registration numbers in the Ministry of Health's National Drug

Registry:

ZypAdhera 210 mg: 145013198701

ZypAdhera 300 mg: 145023198801

ZypAdhera 405 mg: 145033198901

This leaflet was reviewed and approved by the Ministry of Healthin March 2013.

Forsimplicityandeaseofreading,thisleafletwaswritteninthemasculine

gender.This medication is nonetheless intended for both genders.

ףיעס האר אנא ,םיליעפ יתלבה םירמוחה תמישרל

לעיתיצמתעדימליכמהזןולע .הפורתבשמתשתםרטבופוסדעןולעהתאןויעבארק

.חקורה לא וא אפורה לא הנפ ,תופסונ תולאש ךל שי םא .הפורתה

םאוליפאםהלקיזהלהלולעאיה.םירחאלהתואריבעתלא.ךתלחמבלופיטלהמשרנוזהפורת

.המוד םתלחמ יכ ךל הארנ

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.לבגומ וניה וז

?הפורתה תדעוימ המל

.הינרפוזיכס ילוחב לופיטל תכשוממתוליעפ תלעב הקירזב ןתינה יטוכיספיטנא רישכתוניה הרהדאפיז

:תיטיופרת הצובק

.תויפיט-א תויטוכיספ יטנאתופורת

:הפורתב שומישה ינפל

:םארישכתב שמתשהל ןיא

:םיללוכתיגרלאהבוגתלםינמיס.םירחאההפורתהיביכרממדחאלואןיפזנאלואלשיגרךניה

.ןושלב וא ןורגב ,םינפב ,םייתפשב תוחיפנ,המישנב וא העילבב תויעב ,החירפ

.הקינמ ךניה

.תיוז תרצ המוקואלג חתפל ןוכיס לעב וא לבוסךניה

.(היצנמד)ןויטישב תורושקה תוזוכיספמלבוס ךניה

.םירודכב הסקרפיז םע יוארכ טלשנךבצמ

:הפורתב שומישב תועגונה תודחוימ תורהזא

תרבגומתינפוגתוליעפןוגכ,תושבייתהוףוגהםוחברתיתיילעןכתיתםהבםיבצממענמיהלשי

.םימח תומוקמב הפוכתהייהש וא

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.תיחרכה יאופרה זכרמהמ רורחשה תעבהוולמ תוחכונ.הקרזהה

:םאאפורל רפס הרהדאפיזב לופיטה ינפל

.יהשלכ הפורתל וא והשלכ ןוזמל שיגר ךניה

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.ץבשמ רבעב תלבס וא לבוס ךניה

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,םצעהחמב,(ןוסניקרפ)םיבצעהתכרעמב,םדהתכרעמב,(םייעמבהמיסחןוגכ)לוכיעהתכרעמב

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תלחמלשםימוטפמיסבהרמחהלםורגללולעתינמזובןתמ-(הפודוול)ןוסניקרפלתופורת

.ןוסניקרפה

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הפורתלכלעאפורלחוודלשי.(ליעלהאר)תיזכרמהםיבצעהתכרעמלעתועיפשמהתופסונ

.לטונ ךניהש תפסונ

:לוהוכלא תכירצו הפורתב שומיש

.תוינונשיה תא ריבגהל םילולעה ,הפורתב לופיטה תפוקתב םיילוהוכלא תואקשמ תכירצמ ענמיהל שי

:הקנהו ןוירה

.תופורתב שומישה ינפל חקורב וא אפורב ץעוויהל שי

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.בלחל רובעל הלולע הפורתלש הנטק תומכ .הקינמ ךניה םא הפורתב שמתשהל ןיא

:תונוכמב שומישו הגיהנ

תונוכמתלעפהב,בכרבהגיהנבתוריהזבייחמןכ-לעותונריעבםוגפללולעוזהפורתבשומישה

.הקרזהה םויב תונוכמ ליעפהל וא גוהנל ןיא .תונריע תבייחמה תוליעפ לכבו תונכוסמ

:ןושיע

.וז הפורתב לופיטה תלחתה ינפל אפורל ךכ לע חוודל שי ,ןשעמ ךניה םא

?הפורתב שמתשת דציכ

.חוטב ךניא םא חקורה וא אפורה םע קודבל ךילע .אפורה תוארוה יפל שמתשהל שי דימת

:אוה ללכ ךרדב לבוקמה ןונימה .דבלב אפורה ידי לע ועבקי לופיטה ןפואו ןונימה

םייעובשלתחאהיהתהקרזההתורידתשךכ,ךשוממןפואבןיפזנאלואתררחשמהרהדאפיזתקירז

.אפורה תוארוהלםאתהב תועובש העברא וא

:שומישה ןפוא

תושיגנלעבהשרומיאופרזכרמבהרשכהורבעש,דבלבתוחאואאפורידילעתנתינהרהדאפיז

.האייחהו םוריח יתורישל תידיימ

.זוכעה רירשל תישענהקרזהה

.הזיראב לולכה ,אפורל ןולעב תוטרופמ הקרזההוהנכההתוארוה

זכרמהמרורחשהתעבהוולמלגואדלשי.תועש 3 ךשמליאופרהזכרמבתוהשלשיהקרזההרחאל

.יאופרה

.אפורה ידי לע ץלמוהש יפכ לופיטב דימתהל שי

:רתוי הובג ןונימ תלביק תועטב םא

.ריבס וניא רתי ןונימ לש בצמ ןכל ,יאופר תווצי”ע תנתינהפורתה

:םיאבה םינימסתה תא ווח ,ידמ הובג ןונימ ולביקש םילפוטמ

(ןושלהואםינפהלשרקיעב,תוינוצראלתועונת)רובידבתויעב,תונפקות/תונבצע,ריהמבלבצק

:םה םיפסונ םינימסת.הרכהה בצמב הדיריו

,הובגואךומנםדץחל,היצריפסא,תיטיאהמישנ,תמדרת,םייטפליפאםיפקתה,ףירחלובלב

.בלה בצקב תוגירח תוערפה

תנמלעםדקהבאפורלהנפ ,שורדהןמזבוזהפורתםעהקירזהתלבקלעיגהלתחכשםא

.שדח דעומ םאתל

:בקעמו תוקידב

ליג לעמ דחוימב ,םד ץחל תוקידב עצבלו יאופר בקעמ תחת תויהל שי וז הפורתב לופיטה תפוקתב

םילוחבדחוימב,םדבםינמושהתומררחאןכו(םוצב 100 - 126 mg/dL )תוילובגרכוסתומרמ

.הלא תוערפה חתפל ןוכיס ימרוגמ וא םדה ינמוש תומרב תוערפהמ םילבוסה

.לקשמה רחא בוקעל שי לופיטה תפוקתב

הפורתה תליטנ תאקיספמ התא םא

.אפורה םע תוצעייתה אלל הפורתב לופיטה תא קיספהל ןיא ,ךתואירב בצמב רופיש לח םא םג

.חקורב וא אפורב ץעוויה ,הפורתב שומישל עגונב תופסונתולאש ךל שי םא

:יאוול תועפות

להביתלא.םישמתשמהמקלחביאוולתועפותלםורגללולעהרהדאפיזבשומישה,הפורתלכלומכ

.ןהמ תחא ףאמ לובסת אלוןכתי.יאוולהתועפות תמישר ארקמל

:םאתוחאל ואאפורל דימ חוודלו הפורתב שומישה תאקיספהל שי

בצמבםייוניש,םירירשתושקונ,הובגםוח:םיאבהםינימסתבשחהתאהקרזההרחאל

לשיוטיבםניהולאםינימסת.רתיתעזה,ריהמקפוד,םיביציאלםדץחלובלבצק,ישפנה

הריאממתיטפלוריונתנומסתתארקנה,תויטוכיספיטנאתופורתלשרתויבהרידניאוולתעפות

.( Neuroleptic Malignant Syndrome )

ואםינפהלשרקיעב,תוינוצראלתועונת:םיאבהםירידנהםינימסתבשחה/תאהקרזההרחאל

םניהולאםינימסת.תוינונשיוםירירשתושקונ,העזה,הריהמ המישנ,םוחלשבולישוא,ןושלה

Tardive Dyskinesia תארקנה ,תויטוכיספ יטנא תופורתתנייפאמה תפסוניאוול תעפות לש יוטיב

:הרהדאפיזב לופיטל תורושקה יאוול תועפות

.הקרזהה רוזאב באכ

הדימב :הקרזהלכרחאלתורקלהלוכירשאהרומחךאדואמתורידנםיתיעלהעיפומההעפות

,תרבגומתוינונשי:תואבהתורומחהיאוולהתועפותונכתיידמרהמםדלהעיגמהרהדאפיזו

/ורובידבישוק,םדהץחלבהילע,תונפקות,הדרח,תונבצע,תואצמתה-רסוח,לובלב,תרוחרחס

,ועריאוהדימב,ולאתועפות.הרכהרסוח,תותיווע,םירירשדערואתושקונ,השלוח,הכילהבוא

תועש 3 תוחפליאופרהזכרמבראשיהלשי,ןכל.הקרזההרחאלהעשכםירקמהתיברמבועיפוה

יוניפואתיאופרהרזעידימןפואבלבקלרשפאהיהיךרוצהתדימבשתנמלע,הקרזההדעוממ

םינימסתהדחאוהדימב.הקרזההרחאלתועש 72 דע 24 תועפותהופלח,םירקמהלכב .ןוימרדחל

.דימ תוחאל וא אפורל חוודל ךילע ,יאופרה תווצה תחגשה תחת ךניא רשאכ עיפומ

:םאאפורל דימ תונפל שי

,העילבבםיישק,הפהמןוטצאלשחיר,הליכאסומלוב,הבורמהנתשה,השלוח,הליחבךלשי

הלידגואבלחתשרפה:אמגודלדשבםיגירחםייוניש,ישדוחרוזחמרדעהואהתחפה,םיסוכרפ

.דשה לש

.(רידנ)תיפקיה תקצב ךל שי

תויהלםילולעש,םיילגרבםדואובאכ,תוחיפנ:תידירותקקפלעםיעיבצמהםינימסתךלשי

.המישנב ישוקו הזחב באכב םיוולמ

הייהשואתרבגומתינפוגתוליעפןמזבןוגכ,ףוגהםוחברתיתיילעןכתיתםהבםיבצמב

שבוי,העזהרסוחוארתיתעזה,םוח :ןוגכתושבייתהינמיסעיפוהלםילולע,םימחתומוקמב

.ןתש תריצא ,רבגומ ןואמיצ,הפב

עיפוהלםילוכירשא,םירודכבןיפזנאלואלשימופןתמבלופיטלתורושקהיאוולתועפות

:הרהדאפיז םע םג

,הפבשבוי,םדבןיטקלורפתומרבהילע,לקשמבהילע,תוינונשי :תובורקםיתיעלתועיפומ

תעונתללוכ)םירירשתויוצווכתהואתושקונ,תורוחרחס,רבגומןובאת,החונמרסוח,דער,תוריצע

,םיידיבתוחיפנלתמרוגה)םילזונתריצא,תושישת,תוינוצראלתועונת,רובידבתוערפה,(םייניע

,םדבםינמושהוםדיאתתומרבםייוניש,שארבאכ,ינימהדוקפתבתוערפה,(םיילגרואםיילוסרק

.החירפ ,ןתשבוםדב רכוסה תומרב הילע

וזהעפות.הביכשואהבישימהמיקברקיעב,תרוחרחסםישחםילוחהמקלח,לופיטהתליחתב

רופיששגרומאלםא.רופישבשיגרתרשאדעבכשלואתבשלךילע.המצעמללכךרדבתפלוח

.אפורל תונפל שי

,רעישתרישנ,ןתשתריצא,ןתשתפילד,שמשלתושיגר,יטיאבלבצק :תוקוחרםיתיעלתועיפומ

ןהוםירבגבןהםיידשבםייוניש,ותומלעיהלדעישדוחהרוזחמהלשהעפוההתורידתבתוערפה

.(הגירח הלידג וא בלח רוצי ןוגכ)םישנב

תרכסלשהרמחהואתרכסלשהעפוה,היגרלא :העודיהניאןתוחיכששתופסוניאוולתועפות

,ףוגהםוחבהדירי,תמדרתוא(סיזודיצאוטק)ןתשבואםדבםינוטקלשהעפוהליבקמב,תמייק

לוגלגלתומרוגהםייניעהירירשלשתוצווכתה,(היספליפאמולבסשםילוחבללכךרדב)םיסוכרפ

םוח,בגבאכוףירחןטבבאכלםרוגהבלבללשתקלד,ימואתפתוומ,בלהבצקבתוערפה,םייניעה

םירירשיבאכלתמרוגהםירירשבהעיגפ,(םייניעהןבולורועהתבהצה)דבכתלחמ,ילוחתשוחתו

.תבאוכ/תכשוממ הפקז ,םירבסומ יתלב

ךילע,ןולעבהרכזוהאלשיאוולתעפותמלבוסהתארשאכוא,הרימחמיאוולהתועפותמתחאםא

.אפורה םעץעייתהל

?הפורתה תאןסחאל ךיא

וא/וםידלילשםדיגשיהלץוחמרוגסםוקמברומשלשיתרחאהפורתלכווזהפורת!הלערהענמ

.אפורהמ תשרופמ הארוה אלל האקהל םורגתלא .הלערה ענמתךכ ידי-לעו תוקונית

הגופתהךיראת.הזיראהיבגלעעיפומה( Exp. Date )הגופתהךיראתירחאהפורתבשמתשהלןיא

.שדוח ותוא לש ןורחאה םויל סחייתמ

-ל תחתמ ,רדחה תרוטרפמטב ןסחאל שי

.איפקהל וא ררקלןיא

.הנכהה רחאל דימ שמתשהל ץלמומ

ףסונ עדימ

:םגהליכמ הפורתה ,ליעפה רמוחה לע ףסונ

.םיפסונםיביכרמ הליכמ הניא הקבאה

:ליכמ סממה

.דיסכורדיה ןרתנ ,תירולכורדיה הצמוח ,הקרזהל םימ , 80 טאברוסילופ ,לוטינמ ,םוידוס זולמרק

:הזיראה ןכות המו הפורתה תיארנ דציכ

לע.תודרפנםיטחמיתשותרבוחמטחמםעקרזמ,סממםעןוקובקב,השביהקבאםעןוקובקב

.תוחיטב ןגמ םייק םיטחמה

46120 חותיפ הילצרה , 2160 .ד.ת,מ"עב לארשי יליל ילא :םושיר לעב

.הינמרג ,ןסיג ,המראפ יליל :ןרצי

:תואירבה דרשמב יתכלממה תופורתה סקנפב הפורתה םושיר ירפסמ

145013198701 :ג"מ 210 הרהדאפיז

145023198801 :ג"מ 300 הרהדאפיז

145033198901 :ג"מ 405 הרהדאפיז

2013 ץרמב תואירבה דרשמ ידי לע רשואו קדבנהז ןולע

ינבלתדעוימהפורתה,תאזףאלע.רכזןושלבחסונהזןולע,האירקהתלקהלותוטשפהםשל

.םינימה ינש

.6دنبلاكلضفنمرظنا،ةلاّعفلاريغداوملاةمئاقل

اذإ.ءاودلالوحتامولعمزجومىلعةرشنلاهذهيوتحت .ءاودللكلامعتسالبقاهتياهنىتحناعمإبةرشنلاأرقا

.ينلاديصلاوأبيبطلاىلإهجوت،ةيفاضإةلئسأكيدلتناك

نأكلودبيناكنإوىتحمهرضينأهنأشنم.نيرخلآاىلإهريرمتبمقتلا.كضرمجلاعلءاودلااذهفصومت

.هباشممهضرم

.ةعومجملاهذهعمةدودحمةبرجتلانلأاًرظن،ةنس18نسنودنيقهارملاودلاولألةداعاّدعمسيلاريهدأبيز

؟ءاودلاصصخمةياغةيلأ

.ماصفلابنيباصملاىضرملاجلاعلةلّوطمةيلاّعفتاذةنقحبهؤاطعإمتيناهُذللداضمرضحتسموه اريهدأبيز

:ةيجلاعلاةليصفلا

.ةيجذومنريغناهُذللةداضمةيودأ

:ءاودلامادختسالبق

:اذإرضحتسملامادختساعنمُي

لكاشم،ًاحفط:يسسحتلالعفلادرتاملاعلمشت.ىرخلأاءاودلاتابّكرمدحأوأنيبازنلاولأةيساسحكيدل

.ناسللاوأقلحلا،هجولا،نيتفشلامّروت،سفنتلايفوأعلاتبلاايف

.لافطنيعضرت

.ةيوازلاةقّيض(قرزلاءاملا)اموكولغريوطتلرطخكيدلوأنميناعت

.فَرخلابةطبترمناهُذتلااحنميناعت

.صارقأبايسكيربزةطساوبيغبنيامككتلاحىلعةرطيسلامتت

:ءاودلالامعتسابةلصتاذةصاختاريذحت

ءاقبلاوأطرفمينامسجطاشنلثم،فافجلاومسجلاةرارحةجردعافتراىلإيدؤتدقتلااحنععانتملاابجي

.ةراحنكامأيفرركتملا

دوجو.نقحلادعومنملقلأاىلعتاعاس3ةدمليبطلازكرملايفيبطلامقاطلاةبقارمتحتءاقبلانقحلاموييفبجي

.يمازلإوهيبطلازكرملانمحيرستلادنعقفارم

:اذإبيبطلاربخأنيبازنلاوأبجلاعلالبق

.ءاوديأوأماعطيلأةيساسحكيدلاذإ

ةحبذ،بلقلامظنذوذش،بلقضرم،ةيبلقةتكس،ًًلاثم)بلقلا:ءادأيفبارطضانميضاملايفتيناعوأيناعت

.(ةيومدتارثخنمكتلئاعءانبأوأتنأيناعت/تيناعاذإ،ًلاثم)ةيومدلاةيعولأاوأ/و(ةيردص

.ةتكسنميضاملايفتيناعوأيناعت

،ىلكلا،دبكلا،(narrow-angle)ةيوازلاقّيضتعوننمةصاخو،اموكولغ،ًلاثم)نينيعلايفلكاشمنميناعت

،رمياهزلاوأ،مظعلاعاخن،(نوسنيكراب)يبصعلازاهجلا،ةيومدلاةرودلا،(ءاعملأادادسنا،ًلاثم)يمضهلازاهجلا

.ةيراحتناراكفأ،يدثلاناطرس

.تاتسوربلاةدغيفمخضتنميضاملايفتيناعوأيناعت

وألورتسلوكلاتايوتسمنم،ضفخنموأعفترممدطغضنم،يركسلانم،(طوقسلاضرم)عرصلانميناعت

.مدلايفةعفترملاتاديرسيلغلايثلاث

.كيدلمدلاطغضميقلةبقارمبيبطلايرجُيدق،ةنس65نعكرمعديزيناكاذإ

وأبيبطلاربخأ،ةيذغلأاتافاضإوةيبطةفصونودنمةيودأكلذيفامبىرخأةيودألوانتتتنكاذإ

:لوانتتتنكاذإصاخلكشبينلاديصلاوأبيبطلاغلابإبجي.كلذبينلاديصلا

نيبزامابراكوأ(يويحداضم)نيساسكولفوربيس،(بائتكلااجلاعل)نيماسكوفولفلثمCYP1A2ىلعرثؤتةيودأ

.اريهدأبيزةعرجرييغتىلإةجاحكلانهنوكتدق–(جازملانازتلاوعرصلاضرمجلاعل)

يدؤيدق–بائتكلااجلاعلوأمونلل،(مابيزايدلا،لثم)ةئدهملاةيودلأا:لثميزكرملايبصعلازاهجلاىلعرثؤتةيودأ

.ساعنلاىلإنمازتملاءاطعلإا

.اهتيلاعفةدايزىلإاريهدأبيزعمنمازتملالامعتسلاايدؤيدق–مدلاطغضضفخلةنّيعمةيودأ

.نوسنيكرابلاضرمضارعأمقافتىلإنمازتملالامعتسلاايدؤيدق–(ابودوفيل)نوسنيكرابلاضرملةيودأ

.ةرّدخملاملالآاتانّكسموةيحارجلاتايلمعللريدختداوم،عرصللةيودأ

يتلاةيبناجلاضارعلأا"دنبلارظنا)(اًردان)نينوترسلاةمزلاتمىلإةيودلأاهذهيدؤتدق–ناهُذللةداضمةيودأ

زاهجلاىلعرثؤتةيفاضإةيودأهتاذتقولايفلوانتتتنكاذإىلعأةريتوبةمزلاتملاثدحتدق.("اًصاخاًمامتهايضتقت

.هلوانتتيفاضإءاوديألوحبيبطلاغلابإبجي.(هلاعأرظنا)يزكرملايبصعلا

:لوحكلاكلاهتساوءاودلالامعتسا

.ساعنلانمديزتنأاهنأشنميتلا،ءاودلابجلاعلاةرتفءانثألوحكلاتابورشمكلاهتسانععانتملاابجي

:عاضرلإاولمحلا

.ةيودلأالامعتسالبقينلاديصلاوأبيبطلاةراشتسابجي

ملأاتناكلاحيفماطفلاةمزلاتماًثيدحنودولوملاروطيدق.لمحللنيططختوأًلاماحتنكاذإبيبطلاةراشتسابجي

،نافجر:ةيلاتلاضارعلأاماطفلاةمزلاتملمشت.لمحلانم(ةريخلأاةثلاثلارهشلأا)ريخلأاثلثلايفءاودلاتلوانتدق

اًدحاواًضراعكلفطرّوطاذإ.ماعطلإايفلكاشموسفنتلايفلكاشم،نزح،ةيبصع،ساعن،تلاضعلافعض/بلصت

.بيبطلابيلصتا،هلاعأضارعلأانمرثكأوأ

.بيلحلاىلإءاودلانمةريغصةيمكلقتنتدق.اًعضرمتنكاذإءاودلالامعتساعنمُي

:تلالآامادختساوةدايقلا

تلالآاليغشت،ةبكرملاةدايقدنعةطيحلاذاختابجوتسيكلذلوةظقيلاىلعءاودلااذهلامعتسارثؤينأنكمملانم

.نقحلاموييفتلاآليغشتوأةبكرملاةدايقعنمُي.ةظقيلابلطتيطاشنيأيفوةرطخلا

:نيخدتلا

.ءاودلااذهبجلاعلاءدبلبقكلذببيبطلاغلابإبجي،اًنخدمتنكاذإ

؟ءاودلالمعتستفيك

مللاحيفينلاديصلاوأبيبطلاعمصحفتنأكيلعنّيعتي.اًمئادبيبطلاتاميلعتبجومبلامعتسلاامتينأبجي

.اًدكأتمنكت

:يهًةداعةعبّتملاةعرجلا.طقفبيبطلالبقنمجلاعلاةقيرطوةعرجلاديدحتمتي

اًقفوعيباسأةعبرأوأنيعوبسألكةرمنقحلاةريتونوكتثيحب،رمتسملكشبنيبازنلاوأاريهدأبيزةنقحقلطت

.بيبطلاتاميلعتل

:لامعتسلااةقيرط

ةيناكمإبحمسيدمتعميبطزكرميف،ًلايهأتاوزاتجادقاوناكنيذلا،طقفةضرمموأبيبطلبقنماريهدأبيزءاطعإمتي

.شاعنلإاوئراوطلاتامدخىلإاًروفلوصولا

.ةرخؤملالضعلخادىلإنقحلاءاطعإمتي

.ةوبعلايفةنّمضملا،بيبطلاةرشنيفةلّصفمنقحلاوريضحتلاتاميلعت

.يبطلازكرملانمحيرستلاءانثأقفارمدوجوبمامتهلاابجي.تاعاس3ةدمليبطلازكرملايفنقحلادعبثوكملابجي

.بيبطلاةيصوتلاًقفوجلاعلاىلعةبظاوملابجي

:أطخلاقيرطنعةطرفمةعرجتلوانتاذإ

.لمتحمريغوهةطرفمةعرجءاطعإثودحنإفكلذل،يبطمقاطلبقنمءاودلاءاطعإمتي

:ةيلاتلاضارعلأانم،ةطرفمةعرجىلعاولصحنوجَلاعُمشياع

طوبهو(ناسللاوأهجولايفةصاخ،ةيدارإلاتاكرح)،ملاكلايفلكاشم،ةيموجه/ةيبصع،بلقلايفةعيرسةريتو

:يهةيفاضإضارعأ.يعولاةلاحيف

.بلقلاةريتويفةذاشتابارطضا،عفترموأضفخنممدطغض،طفش،ءيطبسفنت،ةبوبيغ،عرصتابون،داحكابترا

بيبطلاىلإهجوت ،بولطملاتقولايفءاودلااذهىلعيوتحتيتلاةنقحلاىلعلوصحللرضحتنأتيسنلاحيف

.ديدجدعومنييعتلتقوعرسأب

:ةعباتملاوصوحفلا

نيذلاصاخشلألةصاخو،مدلاطغضصوحفءارجإوةيبطةبقارمىلإعوضخلاءاودلااذهبجلاعلاةرتفللاخبجي

.ةنس65نعمهرامعأديزت

نيذلاىضرملاىدلةصاخو،مدلاتاينهدتايوتسمةعباتمكلذكو(موصلالاحيف100-126mg/dL)ةيدودح

.تابارطضلااهذهريوطتلرطخلماوعنموأمدلاتاينهدتايوتسميفتابارطضانمنوناعي

.جلاعلاةرتفللاخنزولاةعباتمبجي

ءاودلالوانتنعتفقوتاذإ

.بيبطلاةراشتسانودنمءاودلابجلاعلافقوعنمُي،ةيحصلاكتلاحىلعرييغتأرطاذإىتح

.ينلاديصلاوأبيبطلارشتسا،ءاودلالامعتسابقلعتياميفةيفاضإةلئسأكيدلتناكاذإ

:ةيبناجلاضارعلأا

ةءارقدنععزفتلا.نيمدختسملانمءزجىدلةيبناجضارعأىلإيدؤيدقاريهدأبيزلامعتسانإف،ءاوديأرارغىلع

.اهنميأنميناعتلانأنكمملانم.ةيبناجلاضارعلأاةمئاق

:اذإاًروفةضرمملاوأبيبطلاغلابإوءاودلالامعتسافقوبجي

ةريتو،ةيسفنلاةلاحلايفتارييغت،تلاضعلابلصت،ةعفترمةرارحةجرد:ةيلاتلاضارعلأابنقحلادعبترعش

ةيبناجضارعأنعريبعتيهضارعلأاهذه.طرفمقّرعت،بلقلاضبنةريتوعراست،نيتباثريغمدلاطغضوبلقلا

Neuroleptic Malignant)ناهُذللداضملاءاودللةثيبخلاةمزلاتملاىعدت،ناهُذللةداضملاةيودلألاًدجةردان

.(Syndrome

،ةرارحلانيبجمدلاوأ،ناسللاوأهجولايفةصاخو،ةيدارإلاتاكرح:ةيلاتلاةردانلاضارعلأابنقحلادعبترعش

ةيودلأازّيمُتىرخأةيبناجضارعأنعريبعتيهضارعلأاهذه.ساعنلاوتلاضعلابلصت،قّرعتلا،عيرسلاسفنتلا

.Tardive Dyskinesiىعدت،ناهُذللةداضملا

:اريهدأبيزبجلاعلابةلصلاتاذةيبناجلاضارعلأا

.نقحلاعقوميفملأ

عرسأمدلاىلإاريهدأبيزلوصولاحيف :نقحلادعبثدحيدقوداحهنكلاًدجةديعبتارتفىلعرهظييبناجضراع

،ةيموجه،قلق،ةيبصع،ناهوت،كابترا،نارود،دئازساعن:ةيلاتلاةداحلاةيبناجلاضارعلأارهظتدقف،بجيامم

.يعولانادقف،تاجنشت،تلاضعلانافجروأبلصت،فعض،ريسلاوأ/وملاكلايفةبوعص،مدلاطغضعافترا

زكرملايفءاقبلابجي،كلذل.اهروهظلاحيفكلذو،نقحلادعبةعاسوحنتلااحلامظعميفضارعلأاهذهترهظ

ةفرغىلإهجوتلاوأةيروفةيبطةدعاسمىلعلوصحلافدهب،نقحلادعومنملقلأاىلعتاعاس3ةدمليبطلا

دحأرهظلاحيف.نقحلادعومنمةعاس72ىتح24للاختلااحلاةفاكيفضارعلأاتفتخا .ةجاحلادنعئراوطلا

.اًروفةضرمملاوأبيبطلاغلابإكيلعنّيعتي،يبطلامقاطلالبقنمةبقارملعضاخريغتنأوضارعلأا

:اذإبيبطلاىلإهجوتلابجي

ثودحةلق،تاجنشت،علاتبلاايفتابوعص،مفلانمنوتيسأةحئار،يرهقلكأ،طرفملّوبت،فعض،ؤيقتكيدلثدح

.يدثلامجحةدايزوأبيلحزارفإ:لاثملاليبسىلعيدثلايفةذاشتارييغت،ةيرهشلاةرودلامادعناوأ

.(اًردان)ةيطيحمةمذوكيدل

يفملأبةبوحصمنوكتنأاهنأشنم،نيلجرلايفرارمحاوملأ،مروت:يديرودادسناىلإريشتضارعأكيدل

.سفنتلايفةبوعصوردصلا

طرفملاينامسجلاطاشنلاءانثأًلاثم،مسجلاةرارحتاجرديفدئازعافترااهيفثدحينألمتحملانميتلاتلااحلايف

،قّرعتلامادعناوأطرفمقّرعت،ةرارحلاةجردعافترا :ًلاثم،فافجضارعأرهظتدق،ةراحنكامأيفثوكملاوأ

.لوبلاسابتحا،شطعلاةرايز،مفلافافج

عماًضيأرهظتدقيتلا،مفلاقيرطنعنيبازنلاوأصارقأءاطعإجلاعبةلصلاتاذةيبناجلاضارعلأا

:اريهدأبيز

،نافجر،كاسمإ،مفلافافج،مدلايفنيتكلاوربلاتايوتسمعافترا،نزولاةرايز،ساعنلا :ةبراقتمتارتفىلعرهظت

،ملاكلايفتابارطضا،(نينيعلاةكرحىلعلمتشي)تلاضعلاصلقتوأبلصت،راود،ةيهشلاةدايز،ةحارمدع

ءادلأايفتابارطضا،(نيلجرلاوأنيلحاكلا،نيديلامروتىلإيدؤييذلا)لئاوسلاسابتحا،كاهنإ،ةيدارإلاتاكرح

.حفط،لوبلاومدلايفركسلاتايوتسميفعافترا،مدلاتاينهدومدلاايلاختايوتسميفتارييغت،عادص،يسنجلا

يفتخي.ءاقلتسلااوأسولجلاةيعضونمضوهنلالاحيفةصاخو،راودبجلاعلاءدبدنعىضرملانمءزجرعشي

رعشتمللاحيف.نسحتبرعشتىتحءاقلتسلااوأسولجلاكيلعنّيعتي.ةداعهسفنءاقلتنميبناجلاضراعلااذه

.بيبطلاىلإهجوتلابجينسحتب

،رعشلاطقاست،لوبلاسابتحا،لوبلابرست،سمشللةيساسح،ةئيطبلابلقلاضبنةريتو :ةديعبتارتفىلعرهظت

ءاوسدحىلعءاسنلاولاجرلاىدلنييدثلايفتارييغت،اهئافتخاىتحةيرهشلاةرودلاروهظةريتويفتابارطضا

.(ذاشمخضتوأبيلحلاجاتنإ،ًلاثم)

روهظلباقملايفو،مئاقيركسمقافتوأيركسلاروهظ،ةيساسح :اهعويشفورعمريغةيفاضإةيبناجضارعأ

ىضرملاىدلةداع)تاجنشت،مسجلاةرارحةجرديفطوبه،ةبوبيغوأ(ينوتيكضامُح)لوبلاوأمدلايفتانوتيك

ةافو،بلقلاةريتويفتابارطضا،نينيعلاريودتىلإيدؤييذلانينيعلاتلاضعصلقت،(عرصلانماوناعنيذلا

،ضرملابروعشلاوةرارحلاعافترا،رهظلايفملأونطبلايفداحملأىلإيدؤييذلاسايركنبلاباهتلا،ةيئاجف

،تلاضعلايفةرّسفمريغملاآىلإيدؤيتلاضعلايفررض،(نينيعلاضايبودلجلارارفصا)دبكلايفضرم

.ملؤم/رمتسمباصتنا

ةراشتساكيلعنّيعتي،ةرشنلايفهركذمتيمليبناجضراعنميناعتامدنعوأ،ةيبناجلاضارعلأادحأمقافتلاحيف

.بيبطلا

؟ءاودلانيزختبجيفيك

كلذبوعضرلاوأ/ولافطلأايديألوانتمنعاًديعبقلغمناكميفرخآءاوديأوءاودلااذهظفحبجي!ممستلاعنمإ

.بيبطلالبقنمةحيرصتاميلعتنودنمؤيقتلاببستلا.ممستلاعنمت

خيراتريشي.ةوبعلانمةيفلخلاةهجلاىلعرهاظلا(Exp.Date)لوعفملانايرسءاهتناخيرأتدعبءاودلالامعتساعنمُي

.هتاذرهشلانمريخلأامويلاىلإلوعفملانايرسءاهتنا

C-نملقأيأ،ةفرغلاةرارحةجردبنيزختلابجي

.ديمجتلاوأديربتلاعنمُي

.ريضحتلادعبًاروفلامعتسلاابىصوي

ةيفاضإتامولعم

:ىلعاًضيأءاودلايوتحي،ةلاّعفلاةداملاىلإةفاضإ

.ةيفاضإتابّكرمىلعقوحسملايوتحيلا

:ىلعبيذملايوتحي

.مويدوصلاديسكورديه،كيرولكورديهلاضمح،نقحللءام،80تابروسيلوب،لوتينام،مويدوصلازوليمراك

:ةوبعلايوتحتاذامىلعوءاودلاودبيفيك

.ربلإاىلعنامأيقاودجوي.نيتدرفنمنيتربإوةلوصومةربإعمةنقح،بيذمعمةروراق،فاجقوحسمعمةروراق

.46120حاوتيبايلستره،2160.ب.ص،ض.مليئارسإيليليليإ :ليجستلابحاص

.ايناملأ،نسيج،امرافيليل :جتنملا

:ةحصلاةرازويفيمسرلاةيودلأالجسيفءاودلاليجستمقر

145013198701 :مغلم210اريهدأبيز

145023198801 :مغلم300اريهدأبيز

145033198901 :مغلم405اريهدأبيز

.2013راذآيفةحصلاةرازولبقنماهيلعةقداصملاوةرشنلاهذهةعجارمتمت

1986 – ו"משתה )םירישכת( םיחקורה תונקת יפל ןכרצל ןולע

דבלב אפור םשרמ יפ לע תקוושמ הפורתה

ג"מ 405 הרהדאפיז

ףיחרת תנכהל סממוהקבא

ךשוממ רורחשב הקרזהל

:ליכמ הקבא ןוקובקב לכ

טארדיהונומטאומאפ ןיפזנאלוא

ןיפזנאלוא ג"מ 405 -ל ךרע הווש

Olanzapine pamoate monohydrate equivalent

to 405mg olanzapine

:ליכמ ןכומה ףיחרתה

ל"מ/ג"מ 150 ןיפזנאלוא

ג"מ 300 הרהדאפיז

ףיחרת תנכהל סממו הקבא

ךשוממ רורחשב הקרזהל

:ליכמ הקבא ןוקובקב לכ

טארדיהונומ טאומאפ ןיפזנאלוא

ןיפזנאלוא ג"מ 300 -ל ךרע הווש

Olanzapine pamoate monohydrate equivalent

to 300 mg olanzapine

:ליכמ ןכומה ףיחרתה

ל"מ/ג"מ 150 ןיפזנאלוא

ג"מ 210 הרהדאפיז

ףיחרת תנכהל סממו הקבא

ךשוממ רורחשב הקרזהל

:ותומכו ליעפה רמוחה

:ליכמ הקבא ןוקובקב לכ

טארדיהונומ טאומאפ ןיפזנאלוא

ןיפזנאלוא ג"מ 210 -ל ךרע הווש

Olanzapinepamoate monohydrate equivalent

to 210 mg olanzapine

:ליכמ ןכומה ףיחרתה

ל"מ/ג"מ 150 ןיפזנאלוא

1986)تارضحتسم( ةلدايصلا ةمظنأ بجومب كلهتسملل ةيبط ةرشن

طقف ةيبط ةفصو بجومب ءاودلا اذه قيوست متي

مغلم405اريهدأبيز

نقحللقلعتسُمريضحتلبيذموقوحسم

لًوطُمريرحتب

:اهتيمكو ةلاّعفلا ةداملا

:ىلع قوحسم ةروراق لك يوتحت

تارديهونوم تاوماب نيبازنلاوأ

نيبازنلاوأ مغلم405ةميق لداعي

Olanzapine pamoate monohydrate

equivalent to 405 mg olanzapine

:ىلع زهاجلا قلعتسُملا يوتحي

للم /مغلم150نيبازنلاوأ

مغلم300اريهدأبيز

نقحللقلعتسُمريضحتلبيذموقوحسم

لًوطُمريرحتب

:اهتيمكو ةلاّعفلا ةداملا

:ىلع قوحسم ةروراق لك يوتحت

تارديهونوم تاوماب نيبازنلاوأ

نيبازنلاوأ مغلم300ةميق لداعي

Olanzapine pamoate monohydrate

equivalent to 300 mg olanzapine

:ىلع زهاجلا قلعتسُملا يوتحي

للم /مغلم150نيبازنلاوأ

مغلم210اريهدأبيز

نقحللقلعتسُمريضحتلبيذموقوحسم

لًوطُمريرحتب

:اهتيمكو ةلاّعفلا ةداملا

:ىلع قوحسم ةروراق لك يوتحت

تارديهونوم تاوماب نيبازنلاوأ

نيبازنلاوأ مغلم210ةميق لداعي

Olanzapine pamoate monohydrate

equivalent to 210 mg olanzapine

:ىلع زهاجلا قلعتسُملا يوتحي

للم /مغلم150نيبازنلاوأ

Olanzapine 150mg/ml

1. NAME OFTHEMEDICINALPRODUCT

ZYPADHERA210mgpowderandsolventforprolonged releasesuspensionforinjection

ZYPADHERA300mgpowderandsolventforprolonged releasesuspensionforinjection

ZYPADHERA405mgpowderandsolventforprolonged releasesuspensionforinjection

2. QUALITATIVEANDQUANTITATIVECOMPOSITION

Each ZYPADHERA210mgvialcontainsolanzapinepamoate monohydrate equivalentto 210mg

olanzapine. Afterreconstitutioneach mlofsuspensioncontains150mgolanzapine.

Each ZYPADHERA300mgvialcontainsolanzapinepamoate monohydrate equivalentto 300mg

olanzapine.Afterreconstitutioneach mlofsuspensioncontains150mgolanzapine.

EachZYPADHERA405mgvialcontainsolanzapinepamoate monohydrate equivalentto 405mg

olanzapine.Afterreconstitutioneach mlofsuspensioncontains150mgolanzapine.

For afulllistofexcipientssee section6.1.

3. PHARMACEUTICALFORM

Powderand solventforprolonged release suspensionforinjection.

Powder:Yellowsolid.

Solvent:Clear, colourlessto slightlyyellowsolution.

4. CLINICALPARTICULARS

4.1 Therapeuticindications

ZYPADHERAis indicatedforthetreatmentofschizophrenia.

TheuseofZYPADHERAis limited topatients who have been diagnosed as non-compliantregarding

takingprescribed medicines and as aconsequenceareproneto outbursts ofpsychotic episodes.

ZYPADHERAis NOTto be usedin patients whoseconditionisadequatelycontrolled with oral

ZYPREXA.

ZYPADHERAis availableonlythrough a restrictedprogramwhich willbeconductedaccordingto

ZYPADHERAEURiskManagementPlan.

For apatienttoreceivetreatment, theprescribers,injectionadministrators,pharmacistsand patients

mustallbe trainedon the appropriateelements oftheZYPADHERARiskManagementPlan

conductedbyLilly.The ZYPADHERARiskManagementplan hasbeen developed toenablethesafe

useofZYPADHERAin patients,includingthe managementofthosepatients who develop Post-

InjectionDeliriumand SedationSyndrome. In addition to mandatinglabellanguagearoundthis risk,

this plan includeseducationand trainingactivitiesbyLillyto the followingtargetaudienceas

appropriate: prescribers,administrators oftreatmentpatientsandpharmacists.Alltrainingwillbe

fullydocumented.

4.2 Posology andmethod ofadministration

FOR INTRAMUSCULARUSEONLY. DONOTADMINISTERINTRAVENOUSLYOR

SUBCUTANEOUSLY.(seesection 4.4)

ZYPADHERAshould onlybe administered bydeep intramuscularglutealinjection bya healthcare

professionaltrainedintheappropriateinjection technique andinanauthorized healthcare facility

where post-injection observation andimmediateaccesstoemergencyand resuscitationservicesinthe

caseofoverdosecan be assured.

Aftereach injection, patients should beobservedandmonitoredina healthcarefacilityby

appropriatelyqualified personnelforatleast3 hoursforsigns and symptoms consistentwith

olanzapine overdose. Themedicalstaffateachfacilitywillmaintain records oftime ofinjection,

patientresponseand time ofthe patientleavingthe center.Itshould be confirmed thatthe patientis

alert, oriented, and absentofanysigns andsymptoms ofoverdose. Ifan overdoseis suspected, close

medicalsupervisionand monitoringshouldcontinue untilexamination indicatesthatsigns and

symptoms have resolved (seesection 4.4.).

Patients shouldbe treated initiallywithoralolanzapine beforeadministeringZYPADHERA, to

establishtolerabilityand response.

For Instructions forUse, see section 6.6.

Do notconfuseZYPADHERA210mg,300mg,405mgpowderand solventforprolonged release

suspension forinjectionwith olanzapine10mgpowderforsolution forinjection.

In ordertoidentifythefirstZYPADHERAdoseforallpatients,the scheme inTable 1 should be

considered.

Table1 Recommended dosescheme betweenoralolanzapine andZYPADHERA

TargetoralolanzapinedoseRecommendedstartingdoseof

ZYPADHERA Maintenancedoseafter2monthsof

ZYPADHERAtreatment

10mg/day 210mg/2weeksor405mg/4weeks 150mg/2weeksor300mg/4weeks

15mg/day 300mg/2weeks 210mg/2weeksor405mg/4weeks

20mg/day 300mg/2weeks 300mg/2weeks

Doseadjustment

Patients shouldbe monitored carefullyforsigns ofrelapseduringthe firstone to two months

oftreatment. Duringantipsychotictreatment,improvementin the patient’s clinicalcondition

maytake severaldays to some weeks.Patients shouldbe closelymonitored duringthis period.

Duringtreatmentdosemaysubsequentlybe adjustedon the basis ofindividualclinicalstatus.

Afterclinicalreassessmentdosemaybe adjusted within therange 150 mgto 300mgevery2

weeks or300to 405 mgevery4 weeks. (Table 1)

Supplementation

Supplementation with oralolanzapine wasnotauthorised in double-blind clinicalstudies. If

oralolanzapine supplementation is clinicallyindicated,thenthecombinedtotaldoseof

olanzapinefromboth formulations shouldnotexceedthe correspondingmaximumoral

olanzapine doseof20 mg/day.

Switchingto other antipsychotic medicinalproducts

Thereareno systematicallycollected data tospecificallyaddressswitchingpatients from

ZYPADHERAto otherantipsychotic medicinalproducts. Duetotheslowdissolution ofthe

olanzapine pamoate saltwhich providesa slowcontinuous releaseofolanzapinethatis complete

approximatelysix toeightmonths afterthelastinjection, supervision bya clinician,especiallyduring

thefirst2 months afterdiscontinuationofZYPADHERA,is needed when switchingto another

antipsychotic productandis consideredmedicallyappropriate.

Elderly patients

ZYPADHERAhasnotbeen systematicallystudiedinelderlypatients(>65 years). ZYPADHERAis

notrecommended fortreatmentin the elderlypopulation unlessa well-tolerated and effective dose

regimen usingoralolanzapine hasbeenestablished.Alowerstartingdose(150 mg/4 weeks)is not

routinelyindicated, butshould beconsideredforthose65 and overwhen clinicalfactors warrant.

ZYPADHERAis notrecommended to be started inpatients>75 years(see section 4.4).

Patients with renaland/orhepaticimpairment

Unlessa well-tolerated andeffective doseregimen usingoralolanzapine has beenestablished insuch

patients, ZYPADHERAshould notbe used.Alowerstartingdose(150mgevery4 weeks)should be

considered forsuch patients. In cases ofmoderate hepatic insufficiency(cirrhosis, Child-Pugh Class A

orB),thestartingdoseshould be150mgevery4 weeks and onlyincreased withcaution.

Gender

Thestartingdose anddoserange neednotbe routinelyalteredforfemale patientsrelative to male

patients.

Smokers

Thestartingdose anddoserange neednotbe routinelyaltered fornon-smokers relative to smokers.

When more than one factoris presentwhich mightresultin slowermetabolism(female gender,

geriatric age, non-smokingstatus), consideration should be given to decreasingthe dose.When

indicated, doseescalation should be performed withcaution inthesepatients.

Paediatricpopulation

ZYPADHERAis notrecommended foruse inchildren and adolescentsbelow18years duetoa lack

ofdata onsafetyandefficacy.

4.3 Contraindications

Hypersensitivitytothe active substanceorto anyoftheexcipientslistedin section 6.1.

Patients with known riskofnarrow-angle glaucoma.

4.4 Specialwarningsandprecautionsfor use

Specialcare mustbetakento applyappropriate injection techniqueto avoidinadvertentintravascular

orsubcutaneous injection(see section6.6).

Usein patients whoareinan acutely agitatedor severely psychotic state

ZYPADHERAshould notbe used totreatpatientswith schizophrenia whoare inan acutelyagitated

orseverelypsychotic statesuchthatimmediate symptomcontrolis warranted.

Post-injection Delirium/Sedationsyndrome

Duringpre-marketingclinicalstudies, reactions thatpresented withsigns and symptoms consistent

with olanzapineoverdose were reported inpatientsfollowingan injection ofZYPADHERA. These

reactions occurred in<0.1%ofinjections and approximately2%ofpatients.Mostofthesepatients

have developedsymptoms ofsedation(rangingfrommild in severityupto coma)and/ordelirium

(includingconfusion, disorientation, agitation,anxietyand othercognitive impairment). Other

symptoms noted include extrapyramidalsymptoms, dysarthria,ataxia, aggression,dizziness,

weakness, hypertensionand convulsion.Inmostcases, initialsigns and symptoms relatedto this

reaction have appeared within 1 hourfollowinginjection, andin allcasesfullrecoverywasreportedto

have occurred within 24–72 hours afterinjection. Reactionsoccurred rarely(<1in 1,000 injections)

between 1 and 3 hours,andveryrarely(<1 in10,000injections)after3 hours. Patients shouldbe

advised aboutthis potentialriskandtheneedto be observed for3 hoursin ahealthcare facilityeach

time ZYPADHERAis administered.

Priortogivingthe injection, the healthcare professionalshould determine thatthepatientwillnot

travelalone to theirdestination.Aftereach injection, patients shouldbe observedandmonitoredina

healthcarefacilitybyappropriatelyqualifiedpersonnelforatleast3hours forsigns and symptoms

consistentwitholanzapineoverdose. The medicalstaffateachfacilitywillmaintain records oftime of

injection,patientresponseand time ofthepatientleavingthe center.

Itshould beconfirmed thatthe patientis alert, oriented,and absentofanysigns and symptoms of

overdose. Ifan overdoseissuspected, closemedicalsupervision and monitoringshouldcontinue until

examination indicatesthatsigns and symptoms have resolved.

For the remainderofthe dayafterinjection, patients should be advised tobe vigilantforsigns and

symptoms ofoverdosesecondaryto postinjection adversereactions,be ableto obtain assistance if

neededandshould notdrive oroperate machinery(seesection4.7).

Ifparenteralbenzodiazepinesare essentialformanagementofpostinjection adversereactions,careful

evaluation ofclinicalstatusforexcessive sedation andcardiorespiratorydepression isrecommended

(seesection 4.5).

Injectionsite relatedadverseevents

Themostcommonlyreported injection site relatedadversereaction was pain.Themajorityofthese

reactions was reportedto be of“mild” to“moderate”severity. In the eventofaninjection siterelated

adversereaction occuring, appropriate measures to manage these events should betaken(seesection

4.8).

Dementia-relatedpsychosisand/or behaviouraldisturbances

Olanzapine is notapproved forthetreatmentofdementia-relatedpsychosis and/orbehavioural

disturbances andisnotrecommended foruse inthis particulargroup ofpatients becauseofan increase

in mortalityand the riskofcerebrovascularaccident. In placebo-controlled clinicaltrials(6-12 weeks

duration)ofelderlypatients(mean age 78 years)with dementia-related psychosisand/ordisturbed

behaviours, there wasa 2-fold increase inthe incidence ofdeath inoralolanzapine-treatedpatients

compared topatientstreated withplacebo(3.5%vs. 1.5%, respectively).The higherincidence ofdeath

wasnotassociated with olanzapine dose(mean dailydose4.4mg)orduration oftreatment. Risk

factors thatmaypredisposethis patientpopulationtoincreased mortalityincludeage >65 years,

dysphagia, sedation, malnutritionand dehydration,pulmonaryconditions(e.g., pneumonia, with or

withoutaspiration), orconcomitantuse ofbenzodiazepines. However, the incidence ofdeath was

higherin oralolanzapine-treated than in placebo-treated patientsindependentofthese riskfactors.

In the same clinicaltrials, cerebrovascularadverse reactions (CVAEventse.g., stroke, transient

ischemic attack),includingfatalities,werereported.There was a3-foldincreaseinCVAE inpatients

treated with oralolanzapinecompared topatientstreated withplacebo(1.3%vs. 0.4%, respectively).

Alloralolanzapine-and placebo-treated patients whoexperienced acerebrovasculareventhad pre-

existingriskfactors. Age >75 years and vascular/mixed type dementia wereidentifiedasriskfactors

forCVAE inassociationwith olanzapine treatment.The efficacyofolanzapine was notestablishedin

these trials.

Parkinson's disease

Theuseofolanzapinein the treatmentofdopamine agonistassociated psychosis in patients with

Parkinson's diseaseisnotrecommended. In clinicaltrials, worseningofParkinsonian symptomatology

and hallucinationswerereported verycommonlyand more frequentlythan withplacebo (seesection

4.8), and oralolanzapine wasnotmore effective than placebo in the treatmentofpsychoticsymptoms.

Inthese trials, patients were initiallyrequired to bestable onthelowesteffectivedoseofanti-

Parkinsonian medicinalproducts(dopamine agonist)and toremain onthesame anti-Parkinsonian

medicinalproducts and dosagesthroughoutthe study.Oralolanzapine was startedat2.5mg/dayand

titratedtoa maximumof15mg/daybased oninvestigatorjudgement.

NeurolepticMalignantSyndrome (NMS)

NMS isa potentiallylife-threateningcondition associated with antipsychotic medicinalproducts. Rare

cases reportedasNMShave also been received inassociation with oralolanzapine. Clinical

manifestationsofNMSarehyperpyrexia,muscle rigidity, alteredmentalstatus,and evidence of

autonomicinstability(irregularpulseorblood pressure, tachycardia, diaphoresis,and cardiac

dysrhythmia). Additionalsignsmayincludeelevated creatine phosphokinase,myoglobinuria

(rhabdomyolysis), and acute renalfailure. Ifa patientdevelops signs andsymptoms indicative of

NMS, orpresents with unexplainedhigh feverwithoutadditionalclinicalmanifestations ofNMS,all

antipsychotic medicines, includingolanzapine,mustbe discontinued.

Hyperglycaemia and diabetes

Hyperglycaemia and/ordevelopmentorexacerbationofdiabetesoccasionallyassociated with

ketoacidosis orcoma has been reportedrarely, includingsome fatalcases (seesection4.8).In some

cases, apriorincrease in bodyweighthasbeen reported which maybe apredisposingfactor.

Appropriate clinicalmonitoringisadvisablein accordancewith utilised antipsychotic guidelines, e.g.

measuringofblood glucoseatbaseline, 12 weeks afterstartingolanzapinetreatmentandannually

thereafter.Patients treatedwith anyantipsychotic agents,includingZYPADHERA, shouldbe

observedforsigns and symptoms ofhyperglycaemia (such aspolydipsia, polyuria,polyphagia, and

weakness)and patients with diabetesmellitus orwithriskfactorsfordiabetesmellitus should be

monitoredregularlyforworseningofglucosecontrol.Weightshould be monitored regularly, e.g. at

baseline, 4, 8and 12weeks afterstartingolanzapinetreatmentand quarterlythereafter.

Lipidalterations

Undesirable alterationsinlipids have been observed inolanzapine-treated patientsin placebo-

controlledclinicaltrials(see section 4.8). Lipidalterations should be managed as clinically

appropriate,particularlyindyslipidemic patientsandin patients withriskfactorsforthe development

oflipids disorders.Patientstreated with anyantipsychoticagents,includingZYPADHERA, should be

monitoredregularlyforlipids inaccordancewithutilised antipsychotic guidelines,e.g. atbaseline,12

weeks afterstartingolanzapinetreatmentand every5years thereafter.

Anticholinergic activity

While olanzapine demonstratedanticholinergic activityin vitro, experienceduringthe clinicaltrials

revealed alowincidenceofrelated events. However, as clinicalexperience with olanzapine in patients

with concomitantillness islimited,caution is advisedwhen prescribingforpatients with prostatic

hypertrophy, orparalyticileusand relatedconditions.

Hepatic function

Transient, asymptomatic elevationsofhepaticaminotransferases, ALT, ASThave been seen

commonly, especiallyinearlytreatment. Caution should beexercisedand follow-up organisedin

patients with elevated ALTand/orAST, in patientswith signs andsymptoms ofhepatic impairment,

in patients with pre-existingconditionsassociated with limited hepatic functionalreserve, andin

patients who are beingtreated with potentiallyhepatotoxic medicines.In cases wherehepatitis

(includinghepatocellular,cholestatic ormixed liverinjury)hasbeen diagnosed, olanzapinetreatment

should be discontinued.

Neutropenia

Caution shouldbe exercised in patients withlowleukocyte and/orneutrophilcounts foranyreason, in

patients receivingmedicines known to causeneutropenia,in patients with a historyofdrug-induced

bone marrowdepression/toxicity, in patients with bonemarrowdepression causedbyconcomitant

illness, radiationtherapyorchemotherapyand inpatients with hypereosinophilicconditions orwith

myeloproliferative disease.Neutropenia has been reported commonlywhen olanzapineand valproate

are usedconcomitantly(seesection4.8).

Discontinuation oftreatment

Acutesymptoms such as sweating, insomnia,tremor,anxiety, nausea, orvomitinghave been reported

veryrarely(<0.01%)whenoralolanzapine isstoppedabruptly.

QT interval

In clinicaltrials with oralolanzapine,clinicallymeaningfulQTc prolongations(Fridericia QT

correction[QTcF]≥500 milliseconds[msec]atanytime postbaselinein patientswith baseline

QTcF<500msec)were uncommon (0.1%to 1%)inpatientstreated with olanzapine, with no

significantdifferencesin associated cardiacevents compared to placebo.In clinicaltrials with

olanzapine powderforsolutionforinjection orZYPADHERA, olanzapine wasnotassociated witha

persistentincreaseinabsolute QTorin QTc intervals.However, aswith otherantipsychotics, caution

should be exercised when olanzapine is prescribed with medicines known to increase QTcinterval,

especiallyintheelderly, inpatients with congenitallongQTsyndrome, congestiveheartfailure, heart

hypertrophy, hypokalaemia orhypomagnesaemia.

Thromboembolism

Temporalassociationofolanzapinetreatmentand venousthromboembolismhasbeen reported

uncommonly(≥0.1%and< 1%).Acausalrelationship between the occurrenceofvenous

thromboembolismand treatmentwith olanzapine has notbeen established. However, since patients

with schizophrenia often presentwith acquiredriskfactorsforvenousthromboembolismallpossible

riskfactors ofVTE e.g. immobilisation ofpatients,should be identifiedand preventive measures

undertaken.

GeneralCNS activity

Given the primaryCNS effectsofolanzapine,cautionshould be used when itis taken in combination

with othercentrallyactingmedicinesand alcohol. As itexhibitsin vitrodopamineantagonism,

olanzapine mayantagonize the effects ofdirectand indirectdopamine agonists.

Seizures

Olanzapineshould be usedcautiouslyin patients whohave ahistoryofseizuresorare subjectto

factors which maylowerthe seizure threshold. Seizures have beenreportedto occurrarelyin patients

when treated with olanzapine. Inmostofthese cases,ahistoryofseizuresorriskfactorsforseizures

were reported.

Tardivedyskinesia

In comparatorstudies ofone yearorlessduration, olanzapine wasassociated witha statistically

significantlowerincidenceoftreatmentemergentdyskinesia. However,the riskoftardive dyskinesia

increaseswithlongtermexposure, andtherefore ifsigns orsymptoms oftardivedyskinesia appearin

a patientonolanzapine,a dosereduction ordiscontinuation shouldbe considered.Thesesymptoms

can temporallydeteriorateoreven arise afterdiscontinuation oftreatment.

Posturalhypotension

Posturalhypotensionwasinfrequentlyobserved intheelderlyinolanzapineclinicaltrials. As with

otherantipsychotics,itisrecommended thatblood pressureis measured periodicallyin patientsover

65 years.

Suddencardiac death

In postmarketingreports with olanzapine, the eventofsuddencardiac deathhasbeen reportedin

patients with olanzapine. In a retrospective observationalcohortstudy, theriskofpresumed sudden

cardiacdeathin patients treated witholanzapinewasapproximatelytwice the riskin patients notusing

antipsychotics. In the study, theriskofolanzapinewascomparable totheriskofatypical

antipsychotics includedin apooled analysis.

Paediatric population

Olanzapineis notindicatedforusein the treatmentofchildrenand adolescents. Studiesinpatients

aged 13-17years showed various adversereactions,includingweightgain, changesin metabolic

parameters and increases inprolactinlevels. Long-termoutcomesassociated withtheseevents have

notbeen studiedand remain unknown (see sections4.8 and 5.1).

Useinelderly patients (>75 years)

No information on the useofZYPADHERAin patients>75 years is available. Dueto biochemical

and physiologicalmodification and reductionofmuscularmass,this formulationisnotrecommended

to bestarted in thissub-group ofpatients.

4.5 Interactionwith othermedicinalproducts and otherformsofinteraction

Paediatric population

Interaction studieshave onlybeen performed inadults.

Caution shouldbe exercised in patients whoreceive medicinalproductsthatcan inducehypotension or

sedation.

Potentialinteractions affecting olanzapine

Sinceolanzapineis metabolised byCYP1A2, substancesthatcanspecificallyinduceorinhibitthis

isoenzymemayaffectthe pharmacokineticsofolanzapine.

Induction ofCYP1A2

Themetabolismofolanzapine maybe induced bysmokingand carbamazepine, which maylead to

reduced olanzapine concentrations. Onlyslightto moderateincrease in olanzapineclearancehasbeen

observed.The clinicalconsequencesarelikelytobe limited, butclinicalmonitoringis recommended

and anincreaseofolanzapine dose maybe consideredifnecessary(seesection 4.2).

InhibitionofCYP1A2

Fluvoxamine, a specific CYP1A2 inhibitor,hasbeenshown tosignificantlyinhibitthe metabolismof

olanzapine.The mean increasein olanzapine C

followingfluvoxamine was 54%infemale non-

smokers and 77 %in malesmokers.The mean increase in olanzapine AUCwas52 %and 108%,

respectively. Alowerstartingdoseofolanzapineshould be considered inpatientswho areusing

fluvoxamine oranyotherCYP1A2 inhibitors, such asciprofloxacin. Adecreasein the doseof

olanzapine should be considerediftreatmentwithaninhibitorofCYP1A2 isinitiated.

Fluoxetine (a CYP2D6 inhibitor),single dosesofantacid (aluminium, magnesium)orcimetidine have

notbeen foundto significantlyaffectthe pharmacokineticsofolanzapine.

Potentialfor olanzapine toaffectothermedicinalproducts

Olanzapine mayantagonisethe effects ofdirectand indirectdopamine agonists.

Olanzapine does notinhibitthe main CYP450isoenzymesin vitro(e.g. 1A2, 2D6, 2C9, 2C19, 3A4).

Thus no particularinteraction isexpected asverifiedthroughin vivostudieswhere no inhibitionof

metabolismofthefollowingactive substances wasfound:tricyclic antidepressant(representingmostly

CYP2D6 pathway), warfarin (CYP2C9),theophylline (CYP1A2)ordiazepam(CYP3A4 and 2C19).

Olanzapine showed nointeractionwhen co-administered with lithiumorbiperiden.

Therapeutic monitoringofvalproate plasma levels didnotindicate thatvalproatedosage adjustmentis

required afterthe introduction ofconcomitantolanzapine.

GeneralCNS activity

Caution shouldbe exercised in patients who consume alcoholorreceive medicinalproductsthatcan

causecentralnervous systemdepression.

Theconcomitantuseofolanzapine with anti-Parkinsonian medicinalproductsinpatients with

Parkinson's diseaseand dementiaisnotrecommended (seesection 4.4).

QTc interval

Caution shouldbe usedifolanzapine is beingadministeredconcomitantlywith medicinalproducts

known to increaseQTcinterval(seesection4.4).

4.6 Fertility,pregnancy andlactation

Pregnancy

Thereareno adequateandwell-controlled studiesin pregnantwomen. Patientsshould be advised to

notifytheirphysician iftheybecome pregnantorintend to become pregnantduringtreatmentwith

olanzapine. Nevertheless, because human experienceislimited,olanzapineshouldbe used in

pregnancyonlyifthepotentialbenefitjustifiesthepotentialrisktothefoetus.

Neonatesexposed toantipsychotics(includingolanzapine)duringthethirdtrimesterofpregnancyare

atriskofadversereactionsincludingextrapyramidaland/orwithdrawalsymptoms thatmayvaryin

severityand durationfollowingdelivery.There havebeenreportsofagitation, hypertonia,hypotonia,

tremor, somnolence,respiratorydistress,orfeedingdisorder. Consequently, newbornsshould be

monitoredcarefully.

Breastfeeding

In a studyoforalolanzapine in breastfeeding, healthywomen, olanzapine was excretedin breast

milk. Mean infantexposure(mg/kg)atsteadystate wasestimated to be 1.8%ofthe maternal

olanzapine dose(mg/kg).Patients shouldbe advised nottobreastfeed an infantiftheyaretaking

olanzapine.

4.7 Effects onabilityto driveandusemachines

No studieson the effects onthe abilityto drive and usemachineshave been performed.As olanzapine

maycausesomnolence anddizziness, patients should be cautioned aboutoperatingmachinery,

includingmotorvehicles.

Patients shouldbe advisednottodrive oroperate machineryfortheremainderofthe dayaftereach

injection dueto the possibilityofapost-injectionDelirium/Sedationsyndrome eventleadingto

symptoms consistentwith olanzapine overdose(seesection4.4).

4.8 Undesirableeffects

Post-injectionDelirium/Sedationsyndromereactionshave occurred withZYPADHERAleadingto

symptoms consistentwith olanzapine overdose(seesections 4.2and 4.4). Clinicalsigns andsymptoms

includedsymptoms ofsedation(rangingfrommild in severityup to coma)and/ordelirium(including

confusion, disorientation, agitation, anxietyand othercognitive impairment). Othersymptoms noted

includeextrapyramidalsymptoms, dysarthria, ataxia, aggression, dizziness, weakness, hypertension

and convulsion.

Otheradversereactions observed in patientstreated with ZYPADHERAwere similartothose seen

with oralolanzapine. In clinicaltrials with ZYPADHERA, the onlyadversereaction reported ata

statisticallysignificantlyhigherrate in the ZYPADHERAgroup thanin the placebo group was

sedation(ZYPADHERA8.2%, placebo 2.0%). Among allZYPADHERAtreatedpatients, sedation

wasreported by4.7%ofpatients .

In clinicaltrials with ZYPADHERAthe incidenceofinjection siterelated adversereactions was

approximately8%.The mostcommonlyreportedinjectionsiterelated adversereaction waspain(5%);

some otherinjection siteadversereactions reportedwere (in decreasingfrequency):nodule type

reactions,erythema type reactions,non-specificinjection sitereactions,irritation,oedema type

reactions, bruising, haemorrhage, andanaesthesia. Theseevents occurredin about0.1 to 1.1%of

patients.

Theundesirable effects listed belowhave been observed followingadministrationoforalolanzapine

butmayoccurfollowingadministration ofZYPADHERA.

Adults

Themostfrequently(seenin ≥1%ofpatients)reported adversereactionsassociated with the use of

olanzapinein clinicaltrialswere somnolence, weightgain, eosinophilia,elevatedprolactin,

cholesterol, glucoseand triglyceridelevels(see section 4.4), glucosuria,increased appetite, dizziness,

akathisia, parkinsonism(see section 4.4), dyskinesia, orthostatic hypotension, anticholinergic effects,

transientasymptomaticelevations ofhepaticaminotransferases(see section 4.4),rash,asthenia,

fatigue and oedema.

Tabulatedlistofadversereactions

Thefollowingtableliststhe adversereactions andlaboratoryinvestigations observed from

spontaneous reportingand in clinicaltrials.Within each frequencygrouping, adversereactionsare

presented in orderofdecreasingseriousness.Thefrequencyterms listed are defined asfollows:Very

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

to <1/1,000),veryrare(<1/10,000), notknown (cannotbeestimatedfromthe dataavailable).

Very common Common Uncommon Notknown

Blood andthe lymphatic systemdisorders

Eosinophilia Leukopenia

Neutropenia Thrombocytopenia

Immune systemdisorders

Allergic reaction

Metabolismandnutritiondisorders

Weightgain 1 Elevatedcholesterol

levels 2,3

Elevated glucose

levels 4

Elevatedtriglyceride

levels 2,5

Glucosuria

Increased appetite

Developmentor

exacerbation of

diabetes occasionally

associated with

ketoacidosis orcoma,

includingsome fatal

cases (seesection4.4)

Hypothermia

Nervous systemdisorders

Somnolence Dizziness

Akathisia 6

Parkinsonism 6

Dyskinesia 6

Seizureswhere in most

cases ahistoryof

seizures orriskfactors

forseizureswere

reported

Neuroleptic malignant

syndrome (see section

4.4)

Dystonia(including

oculogyration)

Tardive dyskinesia

Discontinuation

symptoms 7

Cardiac disorders

Bradycardia

c prolongation (see

section4.4) Ventricular

tachycardia/fibrillation,

suddendeath (see

section4.4)

Vascular disorders

Orthostatic

hypotension Thromboembolism

(includingpulmonary

embolismand deep

vein thrombosis)(see

section4.4)

Gastrointestinaldisorders

Mild, transient

anticholinergiceffects

includingconstipation

and drymouth Pancreatitis

Hepato-biliary disorders

Transient,

asymptomatic

elevationsofhepatic Hepatitis(including

hepatocellular,

cholestatic ormixed

aminotransferases

(ALT, AST),

especiallyinearly

treatment(seesection

4.4) liverinjury)

Skin and subcutaneoustissue disorders

Rash Photosensitivity

reaction

Alopecia

Musculoskeletalandconnectivetissue disorders

Rhabdomyolysis

Renalandurinary disorders

Urinaryincontinence,

urinaryretention Urinaryhesitation

Pregnancy, puerperiumandperinatalconditions

Drugwithdrawal

syndrome neonatal(see

section4.6)

Reproductivesystemandbreastdisorders

Erectile dysfunctionin

males

Decreasedlibidoin

malesand females Amenorrhea

Breastenlargement

Galactorrhea in

females

Gynaecomastia/breast

enlargementin males Priapism

Generaldisorders and administrationsite conditions

Asthenia

Fatigue

Oedema

Investigations

Elevatedplasma

prolactinlevels 8 High creatine

phosphokinase

Increased total

bilirubin Increased alkaine

phosphatase

Clinicallysignificantweightgain wasobserved acrossallbaseline BodyMass Index (BMI)

categories.Followingshorttermtreatment(median duration 47 days),weightgain ≥7%ofbaseline

bodyweightwasverycommon(22.2 %),≥15 %wascommon (4.2 %)and≥25%wasuncommon

(0.8%).Patients gaining≥7 %,≥15%and≥25%oftheirbaseline bodyweightwithlong-term

exposure(atleast48 weeks)wereverycommon (64.4 %,31.7%and 12.3%,respectively) .

Meanincreasesinfastinglipid values (totalcholesterol, LDL cholesterol, andtriglycerides)were

greaterinpatients withoutevidence oflipid dysregulation atbaseline.

Observed forfastingnormallevels atbaseline (<5.17mmol/l)which increased to high

(≥6.2mmol/l).

Changesintotalfastingcholesterollevelsfromborderlineatbaseline(≥5.17-

<6.2mmol/l)tohigh (≥6.2mmol/l)were verycommon.

4

Observedforfastingnormallevels atbaseline (<5.56mmol/l)which increased to high (≥7mmol/l).

Changesinfastingglucosefromborderlineatbaseline(≥5.56-<7mmol/l)tohigh (≥7mmol/l)were

verycommon.

5

Observedforfastingnormallevels atbaseline (<1.69mmol/l)which increased to high

(≥2.26mmol/l). Changesin fastingtriglycerides fromborderlineatbaseline (≥1.69mmol/l-

<2.26mmol/l)tohigh (≥2.26mmol/l)were verycommon.

6 In clinicaltrials,theincidence ofParkinsonismand dystoniain olanzapine-treated patients was

numericallyhigher, butnotstatisticallysignificantlydifferentfromplacebo. Olanzapine-treated

patients had alowerincidenceofParkinsonism, akathisiaand dystoniacomparedwithtitrateddosesof

haloperidol. In the absenceofdetailed information onthe pre-existinghistoryofindividualacuteand

tardive extrapyramidalmovementdisorders,itcannotbe concluded atpresentthatolanzapine

producesless tardive dyskinesia and/orothertardive extrapyramidalsyndromes.

Acute symptoms such as sweating, insomnia,tremor,anxiety, nauseaand vomitinghave been

reported when olanzapineis stoppedabruptly.

In clinicaltrials ofup to 12 weeks, plasma prolactin concentrationsexceededtheupperlimitof

normalrange in approximately30%ofolanzapine treatedpatients with normalbaseline prolactin

value. In the majorityofthesepatients the elevations were generallymild, and remainedbelowtwo

timestheupperlimitofnormalrange.

Long-termexposure(atleast48 weeks)

Theproportion ofpatientswho hadadverse, clinicallysignificantchangesin weightgain, glucose,

total/LDL/HDL cholesterolortriglycerides increased overtime. In adultpatientswho completed9-12

months oftherapy, therateofincreasein mean blood glucose slowedafterapproximately6 months.

Additionalinformation onspecialpopulations

In clinicaltrials inelderlypatients with dementia, olanzapine treatmentwasassociated witha higher

incidence ofdeath and cerebrovascularadverse reactions comparedto placebo(see also section4.4).

Verycommon adversereactions associated withtheuse ofolanzapinein thispatientgroup were

abnormalgaitandfalls.Pneumonia, increasedbodytemperature, lethargy, erythema,visual

hallucinations andurinaryincontinencewere observed commonly.

In clinicaltrials inpatientswith drug-induced (dopamine agonist)psychosis associated with

Parkinson’s disease, worseningofParkinsoniansymptomatologyand hallucinations werereported

verycommonlyand more frequentlythan with placebo.

In one clinicaltrialin patients with bipolarmania, valproate combination therapywith olanzapine

resulted in anincidenceofneutropeniaof4.1%;a potentialcontributingfactorcould behigh plasma

valproatelevels.Olanzapine administered withlithiumorvalproate resulted inincreasedlevels

10%)oftremor, drymouth, increased appetite, andweightgain. Speech disorderwasalso reported

commonly. Duringtreatmentwith olanzapine in combination withlithiumordivalproex,anincrease

of

7%frombaseline bodyweightoccurredin 17.4%ofpatients duringacutetreatment(upto 6

weeks). Long-termolanzapinetreatment(up to 12 months)forrecurrenceprevention in patients with

bipolardisorderwas associated withanincrease of

7%frombaseline bodyweightin39.9%of

patients.

Paediatric population

Olanzapine is notindicatedforthetreatmentofchildren and adolescentpatients below18 years.

Although no clinicalstudies designed tocompare adolescentsto adults have beenconducted,data

fromthe adolescenttrials were compared to thoseofthe adulttrials.

Thefollowingtable summarisesthe adversereactionsreported witha greaterfrequencyin adolescent

patients (aged 13-17 years)thanin adultpatients oradversereactions onlyidentified duringshort-term

clinicaltrialsin adolescentpatients. Clinicallysignificantweightgain (≥7%)appearsto occurmore

frequentlyintheadolescentpopulation compared toadults with comparableexposures.The magnitude

ofweightgainandtheproportion ofadolescentpatients who hadclinicallysignificantweightgain

were greaterwith long-termexposure (atleast24 weeks)than withshort-termexposure.

Withineach frequencygrouping, adversereactions arepresented in orderofdecreasingseriousness.

Thefrequencyterms listedare definedasfollows:Verycommon (≥1/10),common (≥1/100to

<1/10).

Metabolismandnutritiondisorders

Verycommon:Weightgain 9 , elevated triglyceridelevels 10 , increased appetite.

Common:Elevated cholesterollevels 11

.

Nervous systemdisorders

Verycommon:Sedation(including:hypersomnia,lethargy, somnolence).

Gastrointestinaldisorders

Common:Drymouth.

Hepato-biliary disorders

Verycommon:Elevations ofhepaticaminotransferases(ALT/AST;seesection 4.4).

Investigations

Verycommon:Decreasedtotalbilirubin,increased GGT, elevated plasma prolactin levels 12 .

Followingshorttermtreatment(median duration 22days),weightgain≥7%ofbaselinebodyweight

(kg)wasverycommon(40.6 %),≥15%ofbaseline bodyweightwascommon(7.1 %)and≥25%

wascommon (2.5 %).Withlong-termexposure (atleast24 weeks),89.4%gained≥7%, 55.3%

gained≥15%and 29.1%gained≥25%oftheirbaseline bodyweight.

10 Observed forfastingnormallevels atbaseline(<1.016mmol/l)whichincreased to high

(≥1.467mmol/l)andchangesin fastingtriglyceridesfromborderline atbaseline(≥1.016mmol/l-

<1.467mmol/l)to high (≥1.467mmol/l).

11 Changesintotalfastingcholesterollevels fromnormalatbaseline(<4.39mmol/l)tohigh

(≥5.17mmol/l)wereobserved commonly. Changesintotalfastingcholesterollevelsfromborderline

atbaseline(≥4.39-<5.17mmol/l)tohigh (≥5.17mmol/l)were verycommon.

Elevated plasma prolactin levels werereportedin47.4%ofadolescentpatients.

4.9 Overdose

Ifsigns and symptoms ofoverdoseconsistentwithpostinjectionDelirium/Sedationsyndrome are

observed,appropriate supportive measuresshould betaken (seesection 4.4).

While overdoseisless likelywith parenteralthan oralmedicinalproducts,referenceinformation for

oralolanzapine overdose ispresented below:

Signsand symptoms

Verycommon symptoms in overdose(>10%incidence)include tachycardia,agitation/aggressiveness,

dysarthria, various extrapyramidalsymptoms, and reduced levelofconsciousnessrangingfrom

sedationtocoma.

Othermedicallysignificantsequelae ofoverdoseinclude delirium, convulsion, coma, possible

neuroleptic malignantsyndrome, respiratorydepression, aspiration, hypertensionorhypotension,

cardiacarrhythmias(<2%ofoverdose cases)and cardiopulmonaryarrest. Fataloutcomeshave been

reported foracuteoraloverdosesaslowas450mgbutsurvivalhas also beenreportedfollowingacute

overdoseofapproximately2goforalolanzapine.

Management

Thereis no specific antidote forolanzapine. Symptomatic treatmentand monitoringofvitalorgan

functionshould be instituted accordingto clinicalpresentation, includingtreatmentofhypotensionand

circulatorycollapse andsupportofrespiratoryfunction. Do notuseepinephrine,dopamine, orother

sympathomimeticagents with beta-agonistactivitysincebeta stimulation mayworsenhypotension.

Cardiovascularmonitoringis necessarytodetectpossible arrhythmias. Close medicalsupervision and

monitoringshouldcontinueuntilthe patientrecovers.

5. PHARMACOLOGICALPROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group:Diazepines,oxazepinesand thiazepines, ATCcode N05A_H03.

Pharmacodynamic effects

Olanzapine is an antipsychotic, antimanicand mood stabilisingagentthatdemonstratesa broad

pharmacologicprofile acrossa numberofreceptorsystems.

In preclinicalstudies,olanzapineexhibiteda range ofreceptoraffinities (K

;< 100nM)forserotonin

5-HT

2A/2C , 5-HT

, 5-HT

;dopamine D

;cholinergic muscarinicreceptorsM

; 

adrenergic;andhistamineH

receptors. Animalbehaviouralstudies with olanzapine indicated 5HT,

dopamine, andcholinergicantagonism, consistentwiththereceptor-bindingprofile. Olanzapine

demonstrateda greaterin vitroaffinityforserotonin5-HT

than dopamine D

receptors and greater5-

than D

activityin vivo, models. Electrophysiologicalstudies demonstrated thatolanzapine

selectivelyreducedthefiringofmesolimbic (A10)dopaminergic neurons, while havinglittleeffecton

the striatal(A9)pathways involved in motorfunction.Olanzapine reduced a conditioned avoidance

response,a testindicative ofantipsychotic activity, atdoses belowthose producingcatalepsy, an effect

indicative ofmotorside-effects. Unlike some otherantipsychoticagents, olanzapine increases

respondinginan “anxiolytic”test.

In a PositronEmissionTomography(PET)studyin patients treated with ZYPADHERA

(300mg/4weeks), mean D

receptoroccupancywas60%orhigherattheend ofa6 month period, a

levelconsistentwiththatfound duringtreatmentwithoralolanzapine.

Clinicalefficacy

TheeffectivenessofZYPADHERAin thetreatmentand maintenancetreatmentofschizophreniais

consistentwiththe established effectivenessofthe oralformulation ofolanzapine.

Atotalof1,469patients with schizophrenia were included in2 pivotaltrials:

Thefirst, an8-week, placebo controlled trialconductedin adultpatients(N=404)who were

experiencingacutepsychotic symptoms. Patients wererandomized toreceive injections of

ZYPADHERA405mgevery4 weeks, 300mgevery2weeks, 210mgevery2 weeks, orplacebo

every2 weeks. No oralantipsychotic supplementationwasallowed.TotalPositiveand Negative

SymptomScores(PANSS)showed significantimprovementfrombaseline(baseline mean Total

PANSSScore 101)to endpoint(mean changes-22.57,-26.32,-22.49,respectively)with each dose of

ZYPADHERA(405mgevery4 weeks, 300mgevery2 weeks, and 210mgevery 2 weeks)as

compared toplacebo(mean change-8.51). Visitwisemean change frombaselineto endpointin

PANSSTotalscoreindicated thatbyDay3, patientsin the 300mg/2weeks and 405mg/4weeks

treatmentgroupshadstatisticallysignificantlygreaterreductions inPANSSTotalscore comparedto

placebo(-8.6,-8.2, and-5.2, respectively). All3 ZYPADHERAtreatmentgroups showed statistically

significantlygreaterimprovementthanplacebobeginningbyend ofWeek1.These results support

efficacyforZYPADHERAover8 weeks oftreatmentand adrugeffectthatwas observed as earlyas

1weekafterstartingtreatmentwith ZYPADHERA.

Thesecond, alongtermstudyin clinicallystablepatients(N=1,065)(baseline meanTotalPANSS

Score54.33to 57.75)whowereinitiallytreatedwith oralolanzapinefor4 to 8 weeks and then

switchedto continueon oralolanzapine orto ZYPADHERAfor24 weeks. No oralantipsychotic

supplementation was allowed.ZYPADHERAtreatmentgroups of150mgand 300mggiven every2

weeks (doses pooledforanalysis)and405mggiven every4 weeks were non inferiortothecombined

dosesof10,15 and 20mgoforalolanzapine(dosespooledforanalysis)asmeasured byrates of

exacerbation ofsymptoms ofschizophrenia (respective exacerbationrates, 10%,10%7%).

Exacerbationwasmeasuredbyworseningofitems on the PANSSderived BPRS Positive scaleand

hospitalizationdueto worseningofpositive psychoticsymptoms. The combined150mgand

300mg/2 weektreatmentgroup wasnoninferiortothe405mg/4weektreatmentgroup (exacerbation

rates10%foreach group)at24 weeks afterrandomisation.

Paediatric population

ZYPADHERAhasnotbeen studiedinthepaediatric population . The experience in adolescents (ages

13 to 17 years)is limitedtoshorttermoralolanzapineefficacydatain schizophrenia(6 weeks)and

mania associated withbipolarIdisorder(3 weeks),involvinglessthan 200 adolescents. Oral

olanzapine wasused asa flexible dosestartingwith2.5 and rangingup to 20mg/day. During

treatmentwith oralolanzapine, adolescents gainedsignificantlymore weightcompared withadults.

Themagnitude ofchangesin fastingtotalcholesterol,LDL cholesterol, triglycerides, and prolactin

(seesections 4.4 and4.8)were greaterin adolescentsthan inadults.There are nodata on maintenance

ofeffectand limited data on longtermsafety(seesections 4.4 and4.8).

5.2 Pharmacokinetic properties

Absorption

Olanzapine is metabolised in theliverbyconjugative and oxidative pathways. Themajorcirculating

metaboliteisthe 10-N-glucuronide. CytochromesP450-CYP1A2 and P450-CYP2D6 contribute tothe

formationofthe N-desmethyland 2-hydroxymethylmetabolites;both exhibited significantlylessin

vivo pharmacologicalactivitythan olanzapinein animalstudies.The predominantpharmacologic

activityisfromthe parent,olanzapine.

Aftera single IM injectionwith ZYPADHERAthe slowdissolutionoftheolanzapine pamoate saltin

muscle tissue beginsimmediatelyandprovides aslowcontinuous releaseofolanzapineformore than

fourweeks. The release becomesdiminishinglysmallerwithin eighttotwelve weeks. Antipsychotic

supplementationis notrequiredattheinitiation ofZYPADHERAtreatment(seesection 4.2).

Thecombinationoftherelease profile andthedosage regimen (IM injection everytwo orfourweeks)

resultinsustained olanzapine plasma concentrations.Plasma concentrations remain measurable for

severalmonths aftereach ZYPADHERAinjection.The half-life ofolanzapine afterZYPADHERAis

30 days comparedto 30 hoursfollowingoraladministration.The absorption andeliminationare

complete approximatelysixto eightmonths afterthelastinjection.

Distribution

Oralolanzapineisrapidlydistributed.Theplasma protein bindingofolanzapine isabout93%overthe

concentrationrange of7 toabout1,000ng/mL.In plasma, olanzapineis boundtoalbumin and α1-acid

glycoprotein.

Afterrepeated IM injections with150to 300mgZYPADHERAeverytwo weeks, the 10 th

to 90 th

percentile ofsteady-state plasma concentrations ofolanzapine were between 4.2 and73.2ng/ml. The

plasma concentrations ofolanzapineobserved acrossthe dose range of150 mgevery4 weeks to 300

mgevery2 weeks illustrateincreased systemic olanzapine exposure withincreasedZYPADHERA

doses. Duringthe initialthreemonths oftreatmentwith ZYPADHERA, accumulationofolanzapine

wasobserved butthere wasno additionalaccumulationduringlong-termuse(12months)inpatients

who wereinjected with up to 300mgeverytwo weeks.

Elimination

Olanzapine plasma clearanceafteroralolanzapineislowerin females (18.9l/hr)versusmales

(27.3l/hr),andin non-smokers (18.6l/hr)versussmokers (27.7l/hr). Similarpharmacokinetic

differencesbetween malesand femalesandsmokers and nonsmokers wereobserved in ZYPADHERA

clinicaltrials. However,themagnitude oftheimpactofgender, orsmokingon olanzapine clearanceis

smallincomparison totheoverallvariabilitybetweenindividuals.

Elderly

No specificinvestigations have been conductedinthe elderlywith ZYPADHERA.ZYPADHERAis

notrecommended fortreatmentin the elderlypopulation (65 years and over)unlessa well-tolerated

and effective dosage regimen usingoralolanzapinehasbeenestablished. In healthyelderly(65 and

over)versusnon-elderlysubjects,the mean elimination half-life was prolonged (51.8 versus

33.8hours)andtheclearancewasreduced(17.5 versus 18.2l/hr).The pharmacokinetic variability

observedin the elderlyiswithintherange forthe non-elderly. In 44 patients withschizophrenia >65

years ofage, dosingfrom5 to 20mg/daywasnotassociated withanydistinguishingprofile ofadverse

events.

Renalimpairment

In renallyimpairedpatients(creatinineclearance<10ml/min)versushealthysubjects, therewasno

significantdifference in mean elimination half-life (37.7 versus32.4hours)orclearance (21.2 versus

25.0l/hr). Amass balance studyshowedthatapproximately57%ofradiolabelledolanzapine appeared

in urine,principallyasmetabolites. Although patientswithrenalimpairmentwerenotstudied with

ZYPADHERA, itisrecommended thata well-tolerated and effective dosage regimen usingoral

olanzapineis established inpatients withrenalimpairmentbefore treatmentwithZYPADHERAis

initiated (seesection 4.2).

Smokers

In smokingsubjects with mildhepatic dysfunction, mean elimination half-life (39.3hours)oforally

administered olanzapine was prolonged andclearance (18.0l/hr)wasreducedanalogous to non-

smokinghealthysubjects(48.8hours and 14.1l/hr,respectively). Although patients with hepatic

impairmentwerenotstudied with ZYPADHERA, itisrecommended thata well-tolerated and

effective dosage regimen usingoralolanzapine is establishedin patients with hepatic impairment

beforetreatmentwith ZYPADHERAis initiated (seesection 4.2).

In a studyoforalolanzapine given to Caucasians,Japanese,and Chinese subjects,there were no

differencesin the pharmacokinetic parameters amongthe threepopulations.

5.3 Preclinicalsafety data

Preclinicalsafetystudieswereperformedusingolanzapinepamoatemonohydrate.Themainfindings

foundinrepeat-dosetoxicitystudies(rat,dog),ina2-yearratcarcinogenicitystudy,andintoxicityto

reproduction studies (rat, rabbit)werelimited to injection site reactionsforwhich no NOAELcould be

determined.Nonewtoxiceffectresultingfromsystemicexposuretoolanzapinecouldbeidentified.

However,systemicconcentrationsinthesestudiesweregenerallylessthanthatseenateffectlevelsin

the oralstudies;thus the information onoralolanzapine is providedbelowforreference.

Acute (single-dose)toxicity

Signs oforaltoxicityinrodents werecharacteristic ofpotentantipsychoticcompounds:hypoactivity,

coma, tremors, clonic convulsions,salivation, and depressed weightgain.The medianlethaldoses

were approximately210mg/kg(mice)and 175mg/kg(rats). Dogs tolerated singleoraldosesupto

100mg/kgwithoutmortality. Clinicalsigns included sedation,ataxia, tremors, increased heartrate,

labouredrespiration, miosis, and anorexia. In monkeys,single oraldosesupto 100mg/kgresulted in

prostration and, athigherdoses,semi-consciousness.

Repeated-dosetoxicity

In studiesupto 3months durationin miceand upto 1yearinrats anddogs, the predominanteffects

were CNS depression, anticholinergiceffects,and peripheralhaematologicaldisorders.Tolerance

developedtothe CNS depression. Growth parameterswere decreased athigh doses. Reversible effects

consistentwithelevated prolactin inratsincludeddecreasedweightsofovariesand uterusand

morphologic changesin vaginalepitheliumand in mammarygland.

Haematologic toxicity:Effects on haematologyparameters were found in each species, including

dose-relatedreductionsin circulatingleukocytesin miceand non-specificreductions ofcirculating

leukocytesin rats;however, no evidenceofbonemarrowcytotoxicitywasfound.Reversible

neutropenia,thrombocytopenia,oranaemia developedin afew dogs treatedwith8 or10mg/kg/day

(totalolanzapine exposure [AUC]is 12-to 15-fold greaterthan thatofa man given a12mgdose). In

cytopenic dogs, therewereno undesirable effects on progenitorand proliferatingcells inthe bone

marrow.

Reproductivetoxicity

Olanzapine hadno teratogenic effects. Sedationaffected matingperformance ofmalerats. Oestrous

cycleswere affected atdosesof1.1mg/kg(3 timesthe maximumhuman dose)and reproduction

parameters were influencedin ratsgiven 3mg/kg(9 timesthe maximumhuman dose). In the offspring

ofrats given olanzapine, delays infoetaldevelopmentand transientdecreasesin offspringactivity

levels wereseen.

Mutagenicity

Olanzapine was notmutagenic orclastogenicina fullrange ofstandardtests, which included bacterial

mutationtestsandin vitroand oralin vivomammalian tests.

Carcinogenicity

Based ontheresults oforalstudiesin miceand rats, itwasconcluded thatolanzapineis not

carcinogenic.

6. PHARMACEUTICALPARTICULARS

6.1 Listofexcipients

Powder

No excipients.

Solvent

Carmellosesodium

Mannitol

Polysorbate 80

Waterforinjections

Hydrochloricacid (forpHadjustment)

Sodiumhydroxide(forpHadjustment)

6.2 Incompatibilities

This medicinalproductmustnotbe mixed withothermedicinalproducts exceptthosementionedin

section6.6.

6.3 Shelflife

2 years.

Chemicalandphysicalstabilityofthe suspension in the vials hasbeen demonstrated for24 hoursat

20°C-25°C. Fromamicrobiologicalpointofview, theproductshould be usedimmediately.

6.4 Specialprecautionsfor storage

Do notrefrigerateorfreeze.Before reconstitution do notstore above 30°C.

6.5 Nature andcontents ofcontainer

210mgpowder:Type Iglassvial. Bromobutylstopperwithrustcolourseal.

300mgpowder:Type Iglassvial.Bromobutylstopperwith olive colourseal.

405mgpowder:Type Iglassvial.Bromobutylstopperwithsteelbluecolourseal.

3mlsolvent:Type Iglass vial.Butylstopperwith purple seal.

One cartoncontains one vialofpowderand one vialofsolvent,one Hypodermic Needle-Pro 3ml

syringe with pre-attached19-gauge, 38mmsafetyneedle, one 19-gauge, 38mmHypodermic Needle-

Pro safetyneedle andone 19-gauge, 50mmHypodermic Needle-Pro safetyneedle.

6.6 Specialprecautionsfor disposalandother handling

FOR DEEPINTRAMUSCULARGLUTEALINJECTIONONLY. DONOTADMINISTER

INTRAVENOUSLYORSUBCUTANEOUSLY.

Anyunused productorwaste materialshould be disposed ofin accordancewithlocalrequirements.

Reconstitution

STEP1:Preparingmaterials

Itis recommended thatglovesare used as ZYPADHERAmayirritate the skin.

Reconstitute ZYPADHERApowderforprolonged releasesuspensionforinjection onlywiththe

solventprovidedinthe packusingstandard aseptic techniques forreconstitution ofparenteral

products.

STEP2:Determining solventvolumefor reconstitution

Thistable providestheamountofsolventrequired toreconstitute ZYPADHERApowderfor

prolonged releasesuspension forinjection.

ZYPADHERA

vialstrength(mg) Volume ofsolventtoadd

(ml)

210 1.3

300 1.8

405 2.3

Itis importanttonote thatthereis more solventinthevialthan is neededtoreconstitute.

STEP3:Reconstituting ZYPADHERA

1.Loosenthe powderbylightlytappingthe vial.

2.Open the pre-packaged HypodermicNeedle-Pro syringe and needle with needleprotection device.

Peelblisterpouchand remove device. Insure needleisfirmlyseatedon the Needle-Pro device

with apushand aclockwise twist,thenpullthe needlecap straightawayfromtheneedle.Failure

to followtheseinstructionsmayresultina needlestickinjury.

3.Withdraw the pre-determined solventvolume (Step2)intothesyringe.

4.Injectthesolventvolume into the powdervial.

5.Withdraw airto equalize the pressurein the vial.

6.Removethe needle, holdingthevialuprightto preventanylossofsolvent.

7.Engage the needle safetydevice. Pressthe needle intothe sheathusinga one-handed technique.

Performa one-handed techniquebyGENTLYpressingthe sheathagainsta flatsurface. ASTHE

SHEATHIS PRESSED, THE NEEDLEIS FIRMLYENGAGEDINTOTHE SHEATH(Figure 1

and 2).

8.Visuallyconfirmthatthe needle is fullyengaged into the needleprotection sheath(Figure 3).Only

remove the Needle-Pro devicewiththeengaged needlefromthe syringe when required bya

specific medicalprocedure.Remove bygraspingtheLuerhub oftheneedle protection device with

thumb and forefinger, keepingthe freefingers clearofthe end ofthe devicecontainingthe needle

point.

Figure 1 Figure 2 Figure3

9.Tapthe vialfirmlyand repeatedlyon a hardsurface untilno powderis visible. Protectthe surface

to cushion impact(See Figure A).

Figure A:Tap firmlyto mix

10.Visuallycheckthe vialforclumps. Unsuspendedpowderappears as yellow, dryclumps clinging

to the vial.Additionaltappingmaybe required ifclumps remain(See Figure B).

Unsuspended:visibleclumps Suspended:no clumps

Figure B: Checkforunsuspended powderandrepeattappingifneeded .

11.Shakethe vialvigorouslyuntilthe suspension appearssmooth andis consistentincolorand

texture.Thesuspendedproductwillbe yellowandopaque (SeeFigure C).

Figure C:Vigorouslyshake vial

Iffoamforms, letvialstandto allowfoamto dissipate.Ifthe productis notusedimmediately, it

should be shaken vigorouslyto re-suspend. Reconstituted ZYPADHERAremainsstableforup to

24 hours inthe vial.

Administration

STEP1:Injecting ZYPADHERA

Thistable confirms thefinalZYPADHERAsuspension volume to inject.Suspensionconcentrationis

150mg/mlolanzapine.

Dose

(mg) Finalvolume to inject

(ml)

150 1.0

210 1.4

300 2.0

405 2.7

1.Determine which needle willbe used toadministertheinjectiontothe patient. Forobesepatients,

the 50 mmneedle is recommended forinjection:

Ifthe 50mmneedle is tobe usedforinjection, attachthe 38mmsafetyneedletothe syringe to

withdraw the required suspension volume.

Ifthe 38mmneedle is tobe usedforthe injection, attach the 50mmsafetyneedleto withdraw

therequired suspension volume.

2.Slowlywithdrawthe desired amount. Some excessproductwillremaininthe vial.

3.Engage the needle safetydeviceandremove needlefromsyringe.

4.Attach the remainingsafetyneedle to the syringe priorto injection. Once thesuspensionhasbeen

removed fromthe vial,itshould be injected immediately.

5.Selectand prepareasiteforinjectioninthe glutealarea. DONOTINJECTINTRAVENOUSLY

ORSUBCUTANEOUSLY.

6.Afterinsertion ofthe needle,aspirateforseveralseconds toensurenoblood appears. Ifanyblood

is drawn intothesyringe, discardthesyringe andthe doseand begin reconstitution and

administrationprocedure again. The injectionshouldbe performed with steady, continuous

pressure.

DONOTMASSAGE THEINJECTIONSITE.

7.Engage the needle safetydevice(Figures1 and 2).

8.Discardthe vials, syringe, needlesand anyunused solventin accordance with appropriateclinical

procedures.Thevialisforsingle use only.

7.Manufacturer

Lilly Pharma, Giessen, Germany

8. Licenceholder

EliLillyIsraelLtd., POB2160 Herzliya Pituach 46120,Israel

XZYPAVLG04

Theformatofthis leaflethasbeen defined bytheMoH, itscontents has been checked andapproved

onMarch2013.

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