DIFLUCAN 200 MG/5 ML

Israel - English - Ministry of Health

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Active ingredient:
FLUCONAZOLE 200 MG / 5 ML
Available from:
PFIZER PHARMACEUTICALS ISRAEL LTD
ATC code:
J02AC01
Pharmaceutical form:
POWDER FOR SUSPENSION
Administration route:
PER OS
Manufactured by:
PFIZER PGM, FRANCE
Therapeutic group:
FLUCONAZOLE
Therapeutic indications:
Cryptoccosis including cryptoccocal meningitis, systemic candidiasis including candidemia, mucosal candidiasis, vaginal candidiasis, dermatomycosis all as specified in leaflet.
Authorization number:
106752907100
Authorization date:
2012-07-01

Documents in other languages

Patient Information leaflet Patient Information leaflet - Arabic

23-01-2021

Patient Information leaflet Patient Information leaflet - Hebrew

23-01-2021

نونسملا كيدل تدجو اذإ لاإ رابكلل ةداع ىطع

ي يذلا كلذل هباشم يئاود رادقم .ةيولك لكاشم ةيولك لكاشم مهيدل نوجلاعتم يفيظولا ءادلأاب قلعتم رمأك ،يئاودلا كرادقم ريغي نأ كبيبط نأش نم .كيتيلكل !هب ىصوملا يئاودلا رادقملا زواجت زوجي لا .ماعطلاب ةقلاع نودب ،موي لك نم ةددحم ةعاس يف ءاودلا لامعتسإب ىصوي :ريضحتلا تاميلعت يف ةلصفم ريضحتلا تاميلعت .هفرص لبق قلعملا ريضحتب يلديصلا موقي ."يبطلا مقاطلل ةصصخم ةيلاتلا تامولعملا" ةرقف يف ،ةرشنلا هذه ةياهن لبق ةرم لك يف قلعملل ةقلغملا ةنينقلا ضخ بجي :لامعتسلإا ةقيرط .لامعتسلإا نم ةحيحصلا ةيمكلا سايقل ةصصخملا سايقلا ةقعلم لامعتسإ كيلع نإ .ءاودلا ةيمك سايق لجأ نم ةيتيب ةقعلم لامعتسإ زوجي لا .ءاودلا ةيمكلا ىقلتت لاأ زئاجلا نمو مجحلا ةيحان نم فلتخت ةيتيبلا قعلاملا .ءاودلا نم ةحيحصلا ربكأ

ً

ايئاود

ً

ارادقم أطخلاب تلمعتسإ اذإ نم أطخلاب لفط علب اذإ وأ

ً

اطرفم

ً

ايئاود

ً

ارادقم تلمعتسإ اذإ رضحأو ىفشتسملا يف ئراوطلا ةفرغل وأ بيبطلا ىلإ

لااح هجوت ،ءاودلا ىلإ طرفم يئاود رادقم لامعتسإ ببسي نأ زئاجلا نم .ءاودلا ةبلع كعم .ديج ريغ روعش ءايشأب روعشلا وأ ةيؤر ،عامس :لمشت دق يئاودلا رادقملا طرف ضارعأ تافرصتو نايذه( ةيعقاو ريغ راكفأ كلذ يف امب ،عقاولا يف ةدوجوم ريغ .تلااحلا هذه يف جلاع ىلإ جاتحت نأ زئاجلا نم .)ةيديوناراپ بولطملا دعوملا يف ءاودلا اذه لوانت تيسن اذإ يئاودلا رادقملا نع ضيوعتلل فعاضم يئاود رادقم لامعتسإ زوجي لا .كلذب كركذت لاح هلمعتسإف ،يئاود رادقم لامعتسإ تيسن اذإ .يسنملا يئاودلا رادقملا لمعتست لاف ،يلاتلا يئاودلا رادقملا دعوم

ابيرقت ناح اذإ .يسنملا .بيبطلا ةيصوت بسح جلاعلا ىلع ةبظاوملا بجي أرط ولو ىتح بيبطلا ةراشتسإ نودب ءاودلاب جلاعلا نع فقوتلا زوجي لا .ةيحصلا كتلاح ىلع نسحت ءاودلا عباط صيخشت بجي !ةمتعلا يف ةيودأ لامعتسإ زوجي لا .ءاود اهيف لمعتست ةرم لك يف يئاودلا رادقملا نم دكأتلاو .كلذ رملأا مزل اذإ ةيبطلا تاراظنلا عض بيبطلا رشتسإ ،ءاودلا لامعتسإ لوح ةيفاضإ ةلئسأ كيدل ترفوت اذإ .يلديصلا وأ ةيبناجلا ضارعلأا )4 دنع ةيبناج

اضارعأ ببسي دق

ناكولفيد لامعتسإ نإ ،ءاود لكب امك زئاجلا نم .ةيبناجلا ضارعلأا ةمئاق نم شهدنت لا .نيلمعتسملا ضعب .اهنم

ايأ يناعت لاأ دودر ثودح نكل ةيسسحت لعف دودر صاخشلأا ضعب ىدل روطتت يبناج ضرع يأ كيدل روطت اذإ .ردان رمأ وه ةريطخ ةيسسحت لعف مل يبناج ضرع يأ لمشي كلذ .كب صاخلا يلديصلل وأ بيبطلل هجوت .ةرشنلا هذه يف ركذي :ثودح ةلاح يف بيبطلل

ً

لااح هجوتلا بجي ردصلا يف طغض وأ ئجافم ريفص ،سفنتلا يف تابوعص نيتفشلا وأ هجولا ،نينفجلا خافتنإ

ةكاح ءارمح قطانم وأ دلجلا يف رارمحإ ،مسجلا ةفاك يف ةكح دلجلا يف حفط رثؤي دق( تلاصيوح ببسي يذلا حفط لثم ،ةريطخ ةيدلج لعف دودر )ناسللاو مفلا ىلع :لمشت دبكلا يف لكاشمل ضارعأ .كدبك ىلع ءاودلا رثؤي دق قاهرإ

ماعطلل ةيهشلا نادقف

ؤيقت

)ناقري( نينيعلا وأ دلجلا رارفصإ

هجوتو ءاودلا لامعتسإ نع فقوت ،ضارعلأا هذه نم دحاوب ترعش اذإ .كبيبطل

ً

لااح ةيفاضإ ةيبناج ضارعأ :لمشت )صاخشأ 10 نيب نم 1 ىتح ىدل رهظت( ةعئاش ةيبناج ضارعأ عادص

نايثغ ،ؤيقت ،لاهسإ ،نطبلا يف جاعزنإ

مدلا يف دبكلا تاميزنإ ةبسن يف عافترإ

حفط

:لمشت )صخش 100 نيب نم 1 ىتح ىدل رهظت( ةعئاش ريغ ةيبناج ضارعأ ،دلجلا بوحش ىلإ يدؤي دق يذلا ءارمحلا مدلا ايلاخ ددع يف ضافخنإ

سفنتلا يف تابوعص وأ فعض ماعطلل ةيهشلا ةلق مونلل ليمب روعشلا ،قرأ

تاريغت ،ردخ وأ زخن ،زخوب روعشلا ،ةخودب روعشلا ،راود ،تاجلاتخإ

قاذملا ةساح يف مفلا يف فافج ،ةخفن ،مضه رسع ،كاسمإ

ةيلضع ملاآ

)ناقري( نينيعلا وأ دلجلا رارفصإو دبكلا ررضت قرعتلا ديازت ،ةكح ،)ىرش( دلجلا يف تلاصيوح ،خافتنإ

ةنوخس ،ضرمب ماع روعش ،قاهرإ

:لمشت )صخش 1000 نيب نم 1 ىتح ىدل رهظت( ةردان ةيبناج ضارعأ تاثولتلا ةهجاوم ىلع دعاست يتلا ءاضيبلا مدلا ايلاخ ددع يف ضافخنإ

ةفزنلأا فاقيإ ىلع دعاست يتلا ىرخلأا مدلا ايلاخ نم ددع يفو ضافخنإ ةجيتن ثدحي دق ،يجسفنبلا وأ رمحلأا ىلإ دلجلا نول ريغت مدلا ايلاخ يف ىرخأ تاريغتو ةيومدلا تاحيفصلا ةيمك يف موحشلا ،لورتسلوكلا نم ةعفترم بسن( مدلا يف ةيئايميك تاريغت )مدلا مدلا يف مويساتوپلا بسن ضافخنإ

فاجترإ

مظن يف تاريغت ،)ECG( بلقلل يئابرهكلا طيطختلا ةملاس مدع

بلقلا دبكلا روصق عم عساو حفط روهظ لمشت ،)ةريطخ

انايحأ( ةيسسحت لعف دودر خافتنإ ،ةريطخ ةيدلج لعف دودر ،دلجلا رشقتو دلجلا يف تلاصيوح هجولا وأ نيتفشلا رعشلا طقاست :)دعب ددحي مل اهعويش ضارعأ( فورعم ريغ اهعويش ةيبناج ضارعأ عافترإ ،ددغلا خافتنإ ،ةنوخس ،يدلج حفط عم ةيساسح طرفل ضرع ءاضعأ باهتلإو )eosinophilia( ءاضيبلا مدلا ايلاخ نم عون يف .)DRESS( )ةظيلغلا ءاعملأاو ىلكلا ،بلقلا ،نيتئرلا ،دبكلا( ةيلخاد وأ ةيبناجلا ضارعلأا ىدحإ تمقافت اذإ ،يبناج ضرع رهظ اذإ كيلع ،ةرشنلا هذه يف ركذي مل يبناج ضرع نم يناعت امدنع . بيبطلا ةراشتسإ ىلع طغضلا ةطساوب ةحصلا ةرازول ةيبناج ضارعأ نع غيلبتلا ناكملإاب ةحفصلا ىلع دوجوملا »يئاود جلاع بقع ةيبناج ضارعأ نع غيلبت« طبارلا ىلإ كهجوي يذلا )

www.health.gov.il

( ةحصلا ةرازو عقومل ةيسيئرلا :طبارلا حفصت قيرط نع وأ ،ةيبناج ضارعأ نع غيلبتلل رشابملا جذومنلا

https://sideeffects.health.gov.il

؟ءاودلا نيزخت ةيفيك )5 قلغم ناكم يف رخآ ءاود لكو ءاودلا اذه ظفح بجي !ممستلا بنجت يدافتل كلذو ،عضرلا وأ/و لافطلأا ةيؤر لاجمو يديأ لوانتم نع

اديعب .بيبطلا نم ةحيرص تاميلعت نودب ؤيقتلا ببست لا .ممستلاب مهتباصإ )exp.date( ةيحلاصلا خيرات ءاضقنإ دعب ءاودلا لامعتسإ زوجي لا ريخلأا مويلا ىلإ ةيحلاصلا خيرات ريشي .ةبلعلا رهظ ىلع رهظي يذلا .رهشلا سفن نم .ةيوئم ةجرد 30 نود نيزختلا بجي هلامعتسإو ةيوئم ةجرد 30 نود زهاجلا قلعملا ظفح بجي ،ريضحتلا دعب

اموي 14 للاخ ةيفاضإ تامولعم )6

اضيأ ةلاعفلا ةداملل ةفاضلإاب ءاودلا يوتحي

Sucrose, natural orange flavour, citric acid anhydrous,

sodium citrate hydrous, sodium benzoate, xanthan

gum, colloidal silicone dioxide, titanium dioxide.

.زوركس مارغ 2.88 ىلع للم 5 لك يوتحي ،تاوزنب مويدوص غلم 83 ىلع لمجملاب )للم 60 مجحب( ةنينق لك يوتحت .تاوزنب مويدوص غلم 2.37 ىلع يوتحي قلعم للم 1 .مويدوص غلم 1.13 ىلع يوتحي قلعملا نم للم 1 ،ةباذلإا دعب :ةبلعلا ىوتحم وه امو ءاودلا ودبي فيك .قوحسم مارغ 24.4 ىلع يوتحت ثيح ،للم 60 يه ءاودلا ةنينق ةعس .للم 35 وه قلعملا مجح نإف ،طلخلا دعب قوحسملل ءاملا ةفاضإ دعب .تياو فوأ ىتح ضيبأ نولب قوحسملا رفوتي

.لاقتربلا معطب تياو فوأ ىتح ضيبأ نولب قلعم ىلع لوصحلا متي ،.ض.م ليئارسإ اكيتڤسامراف يإ فإ يپ رزياف :هناونعو زايتملإا بحاص .46725 حاوتيپ ايلستره ،9 ركنش عراش .اسنرف ،Poce-sur-Cisse ،زاوبمأ اڤيراف :هناونعو جتنملا مسإ :ةحصلا ةرازو يف يموكحلا ةيودلأا لجس يف ءاودلا لجس مقر

106-79-29073

.ركذملا ةغيصب ةرشنلا هذه ةغايص تمت ،ةءارقلا نيوهتو ةلوهس لجأ نم .نيسنجلا لاكل صصخم ءاودلا نإف ،كلذ نم مغرلا ىلع .2020 زومت يف اهثيدحت مت :يبطلا مقاطلل ةصصخم ةيلاتلا تامولعملا :قلعملا ريضحت تاميلعت .قوحسملا ريرحتل ةنينقلا ىلع ت

بر

.ةوقب ضخو ءام للم 24 فضأ

قلعم ىلع لوصحلا لجأ نم ،نيتقيقد ىتح ةقيقد ةدمل

اديج ضخ

اديج طولخم لباق للم 35 هردق مجح ىلع لوصحلا متي فوس قلعملا ريضحت دعب

.لامعتسلإل ةدم( ةنينقلا ةقصلم ىلع زهاجلا قلعملا ةيحلاص ءاضقنإ خيرات لجس

اموي 14 يه زهاجلا قلعملا ةيحلاص

PATIENT PACKAGE INSERT IN ACCORDANCE WITH THE

PHARMACISTS’ REGULATIONS )PREPARATIONS) – 1986

The medicine is dispensed with a doctor’s prescription only

Diflucan

®

50 mg/5 ml

Powder for preparing 35 ml oral suspension

Each 5 ml contains: Fluconazole 50 mg

For a list of inactive and allergenic ingredients in the preparation,

please see section 6 ‘‘Further Information”.

Read the leaflet carefully in its entirety before using the

medicine. This leaflet contains concise information about the

medicine. If you have further questions, refer to the doctor or

pharmacist.

This medicine has been prescribed to treat you. Do not pass

it on to others. It may harm them, even if it seems to you that

their medical condition is similar to yours.

1. WHAT IS THE MEDICINE INTENDED FOR?

Adults

Diflucan

50 mg/5 ml is intended for treating the following types

of fungal infections:

- Cryptococcal meningitis – a fungal infection in the brain

- Coccidioidomycosis – a disease of the bronchopulmonary

system

- Infections caused by

Candida

and originating in the blood

stream, body organs )e.g., heart, lungs( or urinary tract

- Oral thrush – infection affecting the lining of the oral cavity,

throat and dentures

- Genital thrush – infection of the vagina or penis

Skin fungus, including athlete's foot, fungus in the groin area,

pityriasis versicolor, nail fungus and skin inflammations caused

Candida

The medicine is also intended for:

- Preventing cryptococcal meningitis from coming back

- Preventing oral thrush from coming back

- Reducing the recurrence of vaginal thrush

- Stopping you from getting an infection caused by

Candida

)if your immune system is weak and not working properly(

Children and adolescents )0 to 17 years old)

Diflucan

50 mg/5 ml is intended for treating the following types

of fungal infections:

- Oral thrush – infection affecting the lining of the oral cavity

and throat

- Infections caused by

Candida

and originating in the blood

stream, body organs )e.g., heart, lungs( or urinary tract

- Cryptococcal meningitis – a fungal infection in the brain

The medicine is also intended for:

- Stopping you from getting an infection caused by

Candida

)if your immune system is weak and not working properly(

- Preventing cryptococcal meningitis from coming back.

Therapeutic group:

Anti-fungal from the azole group.

Diflucan

50 mg/5 ml belongs to a group of medicines called

“anti-fungals”. The active substance is fluconazole.

Fluconazole is intended for use in infections caused by fungi

and also for the prevention of infections caused by

Candida

The most common cause of fungal infections is a type of yeast

called

Candida

2. BEFORE USING THE MEDICINE

Do not use the medicine if:

x You are sensitive )allergic( to fluconazole, to other

medicines you have taken to treat fungal infections or to

any of the ingredients of the medicine )listed in section 6(.

The symptoms may include itching, reddening of the skin

or difficulty in breathing.

x You are taking astemizole, terfenadine )antihistamines for

treating allergy(

x You are taking cisapride )for treating stomach upsets(

x You are taking pimozide )for treating mental illness(

x You are taking quinidine )for treating heart arrhythmias(

x You are taking erythromycin )an antibiotic for treating

infections(

Special warnings regarding use of the medicine

Before treatment with Diflucan

®

, tell the doctor if:

You have liver or kidney problems

You suffer from heart disease, including heart rhythm

problems

You have abnormal levels of potassium, calcium or

magnesium in the blood

You develop severe skin reactions )itching, reddening of the

skin or difficulty in breathing(

You develop symptoms of ‘adrenal insufficiency’. In this

condition, the adrenal glands do not produce adequate

amounts of hormones such as cortisol )chronic, or

long-lasting fatigue, muscle weakness, loss of appetite,

weight loss, abdominal pain(

Other medicines and Diflucan

®

If you are taking, or have recently taken, other medicines,

including non-prescription medicines and nutritional

supplements, tell the doctor or pharmacist.

Tell your doctor immediately if you are taking: astemizole,

terfenadine )an antihistamine for treating allergy( or cisapride

)for stomach upsets( or pimozide )for treating mental illness(

or quinidine )for treating arrhythmias( or erythromycin )an

antibiotic for treating infections(, as these medicines must not

be taken with Diflucan

)see section: “Do not use the medicine

if ”(.

There are certain medicines that could interact with Diflucan

Make sure your doctor knows if you are taking any of the

following medicines:

Rifampicin or rifabutin )antibiotics for treating infections(

Alfentanil, fentanyl )used as anesthetic(

Amitriptyline, nortriptyline )for treating depression(

Amphotericin B, voriconazole )anti-fungal(

Medicines that thin the blood to prevent blood clots )warfarin

or similar medicines(

Benzodiazepines )midazolam, triazolam or similar medicines(

used to help you sleep or for anxiety

Carbamazepine and phenytoin )for treating fits(

Nifedipine, isradipine, amlodipine, verapamil, felodipine and

losartan )for treating hypertension(

Olaparib )for treating ovarian cancer(

Ciclosporin, everolimus, sirolimus, tacrolimus )to prevent

organ transplant rejection(

Cyclophosphamide or vincristine, vinblastine or similar

medicines for treating cancer

Halofantrine )for treating malaria(

Statins )atorvastatin, simvastatin, fluvastatin or similar

medicines( for reducing high cholesterol levels

Methadone )for treating pain(

Celecoxib, flurbiprofen, naproxen, ibuprofen, lornoxicam,

meloxicam, diclofenac )nonsteroidal anti-inflammatory drugs

)NSAIDs((

Oral contraceptive pills

Prednisone )steroid(

Zidovudine, saquinavir )for treating HIV-infected patients(

Anti-diabetes medicines such as chlorpropamide,

glibenclamide, glipizide or tolbutamide

Theophylline )for treating asthma(

Tofacitinib )for treating rheumatoid arthritis(

Vitamin A )a nutritional supplement(

Ivacaftor )for treating cystic fibrosis(

Amiodarone )for treating heart arrhythmias(

Hydrochlorothiazide )a diuretic(

Use of the medicine and food

The medicine can be taken with or without food.

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, think you are pregnant or

are planning to become pregnant, consult with a doctor before

taking this medicine.

Do not take Diflucan

during pregnancy unless your doctor

has instructed you otherwise.

You can continue breastfeeding after taking a single dose of

fluconazole at a dosage of up to 150 mg.

Do not breastfeed if you are taking a repeated dose of Diflucan

Driving and operating machinery

The use of this medicine can sometimes cause dizziness or

fits and therefore requires caution when driving a vehicle and

operating machinery.

Important information about some of the ingredients of

the medicine

The medicine contains sucrose, sodium benzoate and

sodium )salt)

If you suffer from an intolerance to certain sugars or if you are

diabetic, contact your doctor before taking this medicine.

When used for over two weeks, the medicine can damage

your teeth.

Sodium benzoate may increase the likelihood of jaundice

)yellowing of the skin and eyes( in newborn babies )up to 4

weeks old(.

3. HOW SHOULD YOU USE THE MEDICINE?

Always use the preparation according to the doctor’s

instructions.

Check with the doctor or pharmacist if you are unsure about

the dosage and treatment regimen of the preparation.

The dosage and treatment regimen will be determined by the

doctor only. The usual dose generally depends on the type of

infection that you have.

Elderly

A similar dose to that generally given to adults unless you have

kidney problems.

Patients with kidney problems

Your doctor may change your dose, depending on your kidney

function.

Do not exceed the recommended dosage!

It is recommended to take the medicine at a set time each day,

irrespective of food.

Preparation instructions:

The pharmacist will prepare the suspension before dispensing.

Preparation instructions are detailed at the end of this leaflet

in section “The following information is intended for healthcare

professionals”.

How to use: Shake the closed bottle of suspension each time,

before use.

Use the measuring spoon intended for measuring the correct

amount of the medicine. Do not use a household teaspoon

to measure the amount of medicine. Household teaspoons

vary in size, and you may not receive the correct amount of

medicine.

If you accidentally take a higher dosage

If you took an overdose, or if a child has accidentally

swallowed the medicine, refer immediately to a doctor or

proceed to a hospital emergency room, and bring the package

of the medicine with you. Taking an overdose may cause you

to feel unwell.

Symptoms of an overdose may include: hearing, seeing or

feeling things that do not exist in reality, including unrealistic

thoughts )hallucinations and paranoid behavior(. You may need

treatment in such situations.

If you forgot to take the medicine at the required time

Do not take a double dose to make up for the forgotten dose. If

you forget to take a dose, take it as soon as you remember. If it

is almost time for your next dose, do not take the forgotten dose.

Adhere to the treatment regimen as recommended by the

doctor.

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

treatment with the medicine without consulting a doctor.

Do not take medicines in the dark! Check the label and

the dose each time you take a medicine. Wear glasses

if you need them.

If you have further questions regarding use of the

medicine, consult the doctor or pharmacist.

4. SIDE EFFECTS

As with any medicine, use of Diflucan

may cause side effects

in some users. Do not be alarmed when reading the list of side

effects. You may not suffer from any of them.

Some people develop allergic reactions although serious

allergic reactions are rare. If you develop any side effect,

contact your doctor or pharmacist. This includes any side effect

not listed in this leaflet.

Contact a doctor immediately in case of:

Difficulty in breathing, sudden wheezing or tightness in the

chest

Swelling of the eyelids, face or lips

Itching all over the body, reddening of the skin or itchy red

areas

Skin rash

Severe skin reactions such as a rash that causes blistering

)this can affect the mouth and tongue(

The medicine may affect your liver. Symptoms of liver problems

include:

Tiredness

Loss of appetite

Vomiting

Yellowing of the skin or the eyes )jaundice(

If you experience any of these symptoms, stop using the

medicine and contact your doctor immediately.

Additional side effects

Common side effects )occur in up to 1 in 10 people( include:

Headache

Abdominal discomfort, diarrhea, vomiting, nausea

Increased level of liver enzymes in the blood

Rash

Uncommon side effects )occur in up to 1 in 100 people( include:

Reduction in the number of red blood cells, which could

cause pale skin, weakness or breathing difficulties

Decreased appetite

Insomnia, feeling drowsy

Fits, dizziness, sensation of spinning, sensation of tingling,

pricking or numbness, changes in sense of taste

Constipation, difficult digestion, wind, dry mouth

Muscle pain

Liver damage and yellowing of the skin or eyes )jaundice(

Wheals, blistering of the skin )hives(, itching, increased

sweating

Tiredness, general feeling of being unwell, fever

Rare side effects )occur in up to 1 in 1000 people( include:

Decreased number of white blood cells that help deal with

infections and in the number of other blood cells that help

stop bleeding

Red or purple discoloration of the skin which may be caused

by a low platelet count and other blood cell changes

Blood chemistry changes )high levels of cholesterol, fats in

the blood(

Low levels of potassium in the blood

Shaking

Abnormal ECG, changes in heart rhythm

Liver failure

Allergic reactions )sometimes severe(, including the

appearance of a widespread rash with skin blisters and skin

peeling, severe skin reactions, swelling of the lips or face

Hair loss

Side effects of unknown frequency )effects whose frequency

has not yet been determined(:

Hypersensitivity reaction with skin rash, fever, swollen glands,

an increase in a type of white blood cell )eosinophilia( and

inflammation of internal organs )liver, lungs, heart, kidneys

and large intestine( )DRESS(.

If a side effect occurs, if one of the side effects worsens

or if you suffer from a side effect not mentioned in the

leaflet, consult with the doctor.

Side effects can be reported to the Ministry of Health

by clicking on the link “Report Side Effects of Drug

Treatment” found on the Ministry of Health homepage

)www.health.gov.il( that directs you to the online form for

reporting side effects, or by entering the link:

https://sideeffects.health.gov.il

5. HOW SHOULD THE MEDICINE BE STORED?

Avoid poisoning! This medicine, and any other medicine,

should be kept in a safe place out of the reach and sight of

children and/or infants in order to avoid poisoning. Do not

induce vomiting unless explicitly instructed to do so by the

doctor.

Do not use the medicine after the expiry date )exp. date( that

appears on the package. The expiry date refers to the last

day of that month.

Store below 30°C.

After preparation, store the prepared suspension below 30°C

and use within 14 days.

6. FURTHER INFORMATION

In addition to the active ingredient, the medicine also contains:

Sucrose, natural orange flavor, citric acid anhydrous, sodium

citrate hydrous, sodium benzoate, xanthan gum, colloidal

silicone dioxide, titanium dioxide.

Each 5 ml contains 2.88 grams of sucrose.

Each bottle )60 ml volume( contains a total of 83 mg of sodium

benzoate; 1 ml of suspension contains 2.37 mg of sodium

benzoate.

After dilution, 1 ml of suspension contains 1.13 mg of sodium.

What the medicine looks like and the contents of the package:

The capacity of the medicine bottle is 60 ml, when containing

24.4 grams of powder. After dilution, the volume of the

suspension is 35 ml.

The powder comes in a white to off-white color. After adding

the water to the powder, a white to off-white, orange flavored

suspension is obtained.

Registration holder and address: Pfizer PFE Pharmaceuticals

Israel Ltd., 9 Shenkar St., Herzeliya Pituach 46725.

Manufacturer

address:

Fareva

Amboise,

Pocé-sur-Cisse, France.

Registration number of the medicine in the National Drug

Registry of the Ministry of Health: 106-79-29073

Revised in July 2020.

The following information is intended for healthcare

professionals:

Instructions to make up the suspension:

1. Tap the bottle to release the powder.

2. Add 24 ml of water and shake vigorously.

3. Shake well for 1 to 2 minutes to obtain a well-mixed

suspension.

4. After reconstitution, there will be a usable volume of 35 ml.

5. Write the date of expiration of the reconstituted suspension

on the bottle label )the shelf-life of the reconstituted

suspension is 14 days(.

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Trican

®

200 mg Capsules

SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

Trican

200 mg capsules

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each hard capsule contains fluconazole 200 mg

Excipient(s) with known effects: each hard capsule also contains

198.83 mg lactose monohydrate

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Hard capsule.

Trican 200 mg hard gelatin capsule has a white body and a purple cap overprinted with

“Pfizer” and the code “FLU-200” with black ink. The capsule size is no. 0.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Fluconazole is indicated in the following fungal infections (see section 5.1).

Fluconazole is indicated in adults for the treatment of:

Cryptococcal meningitis (see section 4.4).

Coccidioidomycosis (see section 4.4).

Invasive candidiasis.

Mucosal candidiasis including oropharyngeal, oesophageal candidiasis, candiduria and

chronic mucocutaneous candidiasis.

Chronic oral atrophic candidiasis (denture sore mouth) if dental hygiene or topical

treatment are insufficient.

Vaginal candidiasis, acute or recurrent; when local therapy is not appropriate.

Candidal balanitis when local therapy is not appropriate.

Dermatomycosis including

tinea pedis, tinea corporis, tinea cruris, tinea versicolor

dermal

candida

infections when systemic therapy is indicated.

Tinea unguinium (onychomycosis)

when other agents are not considered appropriate.

Fluconazole is indicated in adults for the prophylaxis of:

Relapse of cryptococcal meningitis in patients with high risk of recurrence.

Relapse of oropharyngeal or oesophageal candidiasis in patients infected with HIV who

are at high risk of experiencing relapse.

To reduce the incidence of recurrent vaginal candidiasis (4 or more episodes a year).

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Prophylaxis of candidal infections in patients with prolonged neutropenia (such as

patients with haematological malignancies receiving chemotherapy or patients receiving

Hematopoietic Stem Cell Transplantation (see section 5.1)).

Fluconazole is indicated in term newborn infants, infants, toddlers, children, and

adolescents aged from 0 to 17 years old:

Fluconazole is used for the treatment of mucosal candidiasis (oropharyngeal,

oesophageal), invasive candidiasis, cryptococcal meningitis and the prophylaxis of

candidal infections in immunocompromised patients. Fluconazole can be used as

maintenance therapy to prevent relapse of cryptococcal meningitis in children with high

risk of reoccurrence (see section 4.4).

Therapy may be instituted before the results of the cultures and other laboratory studies

are known; however, once these results become available, anti-infective therapy should

be adjusted accordingly.

Consideration should be given to official guidance on the appropriate use of antifungals.

4.2

Posology and method of administration

Posology

The dose should be based on the nature and severity of the fungal infection.

Treatment of infections requiring multiple dosing should be continued until clinical

parameters or laboratory tests indicate that active fungal infection has subsided. An

inadequate period of treatment may lead to recurrence of active infection.

Adults

Indications

Posology

Duration of treatment

Cryptococcosis

- Treatment of

cryptococcal

meningitis.

Loading dose:

400 mg on Day 1

Subsequent dose:

200 mg to

400 mg once

daily

Usually at least 6 to

8 weeks.

In life threatening

infections the daily dose

can be increased to

800 mg

- Maintenance

therapy to prevent

relapse of

cryptococcal

meningitis in patients

with high risk of

recurrence.

200 mg once

daily

Indefinitely at a daily

dose of 200 mg

Coccidioidomycosis

200 mg to

400 mg once

daily

11 months up to

24 months or longer

depending on the

patient. 800 mg daily

may be considered for

some infections and

especially for meningeal

disease

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Invasive candidiasis

Loading dose:

800 mg on Day 1

Subsequent dose:

400 mg once

daily

In general, the

recommended duration

of therapy for

candidemia is for

2 weeks after first

negative blood culture

result and resolution of

signs and symptoms

attributable to

candidemia.

Treatment of

mucosal candidiasis

- Oropharyngeal

candidiasis

Loading dose:

200 mg to

400 mg on Day 1

Subsequent dose:

100 mg to

200 mg once

daily

7 to 21 days (until

oropharyngeal

candidiasis is in

remission).

Longer periods may be

used in patients with

severely compromised

immune function

- Oesophageal

candidiasis

Loading dose:

200 mg to

400 mg on Day 1

Subsequent dose:

100 mg to

200 mg once

daily

14 to 30 days (until

oesophageal candidiasis

is in remission).

Longer periods may be

used in patients with

severely compromised

immune function

- Candiduria

200 mg to

400 mg once

daily

7 to 21 days. Longer

periods may be used in

patients with severely

compromised immune

function.

- Chronic atrophic

candidiasis

50 mg once daily

14 days

- Chronic

mucocutaneous

candidiasis

50 mg to 100 mg

once daily

Up to 28 days. Longer

periods depending on

both the severity of

infection or underlying

immune

compromisation and

infection

Prevention of

relapse of mucosal

candidiasis in

patients infected

with HIV who are at

high risk of

experiencing relapse

- Oropharyngeal

candidiasis

100 mg to

200 mg once

daily or 200 mg

3 times per week

An indefinite period for

patients with chronic

immune suppression

- Oesophageal

candidiasis

100 mg to

200 mg once

daily or 200 mg

3 times per week

An indefinite period for

patients with chronic

immune suppression

Genital candidiasis

- Acute vaginal

candidiasis

- Candidal balanitis

150 mg

Single dose

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- Treatment and

prophylaxis of

recurrent vaginal

candidiasis (4 or

more episodes a

year).

150 mg every

third day for a

total of 3 doses

(day 1, 4, and 7)

followed by

150 mg once

weekly

maintenance

dose

Maintenance dose:

6 months.

Dermatomycosis

- tinea pedis,

- tinea corporis,

- tinea cruris,

candida

infections

150 mg once

weekly or 50 mg

once daily

2 to 4 weeks,

tinea pedis

may require treatment

for up to 6 weeks

- tinea versicolor

300 mg to

400 mg once

weekly

1 to 3 weeks

50 mg once daily

2 to 4 weeks

- tinea unguium

onychomycosis

150 mg once

weekly

Treatment should be

continued until infected

nail is replaced

(uninfected nail grows

in). Regrowth of

fingernails and toenails

normally requires 3 to

6 months and 6 to

12 months, respectively.

However, growth rates

may vary widely in

individuals, and by age.

After successful

treatment of long-term

chronic infections, nails

occasionally remain

disfigured.

Prophylaxis of

candidal infections

in patients with

prolonged

neutropenia

200 mg to

400 mg once

daily

Treatment should start

several days before the

anticipated onset of

neutropenia and

continue for 7 days after

recovery from

neutropenia after the

neutrophil count rises

above 1000 cells per

Special populations

Elderly

Dosage should be adjusted based on the renal function (see “

Renal impairment

”).

Renal impairment

Fluconazole is predominantly excreted in the urine as unchanged active substance. No

adjustments in single dose therapy are necessary. In patients (including paediatric

population) with impaired renal function who will receive multiple doses of fluconazole,

an initial dose of 50 mg to 400 mg should be given, based on the recommended daily

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dose for the indication. After this initial loading dose, the daily dose (according to

indication) should be based on the following table:

Creatinine clearance (ml/min)

Percent of recommended dose

>50

100%

≤50 (no haemodialysis)

Haemodialysis

100% after each haemodialysis

Patients on haemodialysis should receive 100% of the recommended dose after each

haemodialysis; on non-dialysis days, patients should receive a reduced dose according to

their creatinine clearance.

Hepatic impairment

Limited data are available in patients with hepatic impairment, therefore fluconazole

should be administered with caution to patients with liver dysfunction (see sections 4.4

and 4.8).

Paediatric population

A maximum dose of 400 mg daily should not be exceeded in paediatric population.

As with similar infections in adults, the duration of treatment is based on the clinical and

mycological response. Fluconazoleis administered as a single daily dose.

For paediatric patients with impaired renal function, see dosing in “

Renal impairment

”.

The pharmacokinetics of fluconazole has not been studied in paediatric population with

renal insufficiency (for “Term newborn infants” who often exhibit primarily renal

immaturity please see below).

Infants, toddlers and children (from 28 days to 11 years old):

Indication

Posology

Recommendations

- Mucosal candidiasis

Initial dose: 6 mg/kg

Subsequent dose: 3 mg/kg once

daily

Initial dose may be used on the

first day to achieve steady state

levels more rapidly

- Invasive candidiasis

- Cryptococcal meningitis

Dose: 6 to 12 mg/kg once daily

Depending on the severity of

the disease

- Maintenance therapy to

prevent relapse of cryptococcal

meningitis in children with high

risk of recurrence

Dose: 6 mg/kg once daily

Depending on the severity of

the disease

- Prophylaxis of

Candida

immunocompromised patients

Dose: 3 to 12 mg/kg once daily

Depending on the extent and

duration of the induced

neutropenia (see Adults

posology)

Adolescents (from 12 to 17 years old):

Depending on the weight and pubertal development, the prescriber would need to assess

which posology (adults or children) is the most appropriate. Clinical data indicate that

children have a higher fluconazole clearance than observed for adults. A dose of 100, 200

and 400 mg in adults corresponds to a 3, 6 and 12 mg/kg dose in children to obtain a

comparable systemic exposure.

Safety and efficacy for genital candidiasis indication in paediatric population has not

been established. Current available safety data for other paediatric indications are

described in section 4.8. If treatment for genital candidiasis is imperative in adolescents

(from 12 to 17 years old), the posology should be the same as adults posology.

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Term newborn infants (0 to 27 days):

Neonates excrete fluconazole slowly. There are few pharmacokinetic data to support this

posology in term newborn infants (see section 5.2).

Age group

Posology

Recommendations

Term newborn infants (0 to

14 days)

The same mg/kg dose as for

infants, toddlers and children

should be given every 72 hours

A maximum dose of 12 mg/kg

every 72 hours should not be

exceeded

Term newborn infants (from 15

to 27 days)

The same mg/kg dose as for

infants, toddlers and children

should be given every 48 hours

A maximum dose of 12 mg/kg

every 48 hours should not be

exceeded

Method of administration

Fluconazole may be administered either orally (Capsules and Powder for Oral

Suspension) or by intravenous infusion (Solution for Infusion), the route being dependent

on the clinical state of the patient. On transferring from the intravenous to the oral route,

vice versa

, there is no need to change the daily dose.

The physician should prescribe the most appropriate pharmaceutical form and strength

according to age, weight and dose. The capsule formulation is not adapted for use in

infants and small children. Oral liquid formulations of fluconazole are available that are

more suitable in this population.

The capsules should be swallowed whole and independent of food intake.

4.3

Contraindications

Hypersensitivity to the active substance, to related azole substances, or to any of the

excipients listed in section 6.1.

Coadministration of terfenadine is contraindicated in patients receiving fluconazole at

multiple doses of 400 mg per day or higher based upon results of a multiple dose

interaction study. Coadministration of other medicinal products known to prolong the QT

interval and which are metabolised via the cytochrome P450 (CYP) 3A4 such as

cisapride, astemizole, pimozide, quinidine and erythromycin are contraindicated in

patients receiving fluconazole (see sections 4.4 and 4.5).

4.4

Special warnings and precautions for use

Tinea capitis

Fluconazole has been studied for treatment of

tinea capitis

in children. It was shown not

to be superior to griseofulvin and the overall success rate was less than 20%. Therefore,

fluconazole should not be used for

tinea capitis.

Cryptococcosis

The evidence for efficacy of fluconazole in the treatment of cryptococcosis of other sites

(e.g. pulmonary and cutaneous cryptococcosis) is limited, which prevents dosing

recommendations.

Deep endemic mycoses

The evidence for efficacy of fluconazole in the treatment of other forms of endemic

mycoses such as

paracoccidioidomycosis, lymphocutaneous sporotrichosis

histoplasmosis

is limited, which prevents specific dosing recommendations.

Renal system

Fluconazole should be administered with caution to patients with renal dysfunction (see

section 4.2).

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Adrenal insufficiency

Ketoconazole is known to cause adrenal insufficiency, and this could also although rarely

seen be applicable to fluconazole. Adrenal insufficiency relating to concomitant

treatment with prednisone, see section 4.5

'The effect of fluconazole on other

medicinal products'.

Hepatobiliary system

Fluconazole should be administered with caution to patients with liver dysfunction.

Fluconazole has been associated with rare cases of serious hepatic toxicity including

fatalities, primarily in patients with serious underlying medical conditions. In cases of

fluconazole associated hepatotoxicity, no obvious relationship to total daily dose,

duration of therapy, sex or age of patient has been observed. Fluconazole hepatotoxicity

has usually been reversible on discontinuation of therapy.

Patients who develop abnormal liver function tests during fluconazole therapy must be

monitored closely for the development of more serious hepatic injury.

The patient should be informed of suggestive symptoms of serious hepatic effect

(important asthenia, anorexia, persistent nausea, vomiting and jaundice). Treatment of

fluconazole should be immediately discontinued and the patient should consult a

physician.

Cardiovascular system

Some azoles, including fluconazole, have been associated with prolongation of the QT

interval on the electrocardiogram. Fluconazole causes QT prolongation via the inhibition

of Rectifier Potassium Channel current (I

). The QT prolongation caused by other

medicinal products (such as amiodarone) may be amplified via the inhibition of

cytochrome P450 (CYP) 3A4. During post-marketing surveillance, there have been very

rare cases of QT prolongation and

torsades de pointes

in patients taking fluconazole.

These reports included seriously ill patients with multiple confounding risk factors, such

as structural heart disease, electrolyte abnormalities and concomitant treatment that may

have been contributory. Patients with hypokalemia and advanced cardiac failure are at an

increased risk for the occurrence of life threatening ventricular arrhythmias and

torsades de pointes

Fluconazole should be administered with caution to patients withpotentially

proarrhythmic conditions.

Coadministration of other medicinal products known to prolong the QT interval and

which are metabolised via the cytochrome P450 (CYP) 3A4 are contraindicated (see

sections 4.3 and 4.5).

Halofantrine

Halofantrine has been shown to prolong QTc interval at the recommended therapeutic

dose and is a substrate of CYP3A4. The concomitant use of fluconazole and halofantrine

is therefore not recommended (see section 4.5).

Dermatological reactions

Patients have rarely developed exfoliative cutaneous reactions, such as Stevens-Johnson

syndrome and toxic epidermal necrolysis, during treatment with fluconazole. AIDS

patients are more prone to the development of severe cutaneous reactions to many

medicinal products. If a rash, which is considered attributable to fluconazole, develops in

a patient treated for a superficial fungal infection, further therapy with this medicinal

product should be discontinued. If patients with invasive/systemic fungal infections

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develop rashes, they should be monitored closely and fluconazole discontinued if

bullous

lesions or

erythema

multiforme develop.

Hypersensitivity

In rare cases anaphylaxis has been reported (see section 4.3).

Cytochrome P450

Fluconazole is a moderate CYP2C9 and CYP3A4 inhibitor. Fluconazole is also a strong

inhibitor of CYP2C19. Fluconazole treated patients who are concomitantly treated with

medicinal products with a narrow therapeutic window metabolised through CYP2C9,

CYP2C19 and CYP3A4, should be monitored (see section 4.5).

Terfenadine

The coadministration of fluconazole at doses lower than 400 mg per day with terfenadine

should be carefully monitored (see sections 4.3 and 4.5).

Excipients

Capsules contain lactose monohydrate. Patients with rare hereditary problems of

galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption

should not take this medicine.

Diflucan capsules contain less than 1 mmol sodium (23 mg) per capsule, that is to say

essentially ‘sodium-free’.

4.5

Interaction with other medicinal products and other forms of interaction

Concomitant use of the following other medicinal products is contraindicated:

Cisapride:

There have been reports of cardiac events including

torsades de pointes

patients to whom fluconazole and cisapride were coadministered. A controlled study

found that concomitant fluconazole 200 mg once daily and cisapride 20 mg four times a

day yielded a significant increase in cisapride plasma levels and prolongation of QTc

interval. Concomitant treatment with fluconazole and cisapride is contraindicated (see

section 4.3).

Terfenadine:

Because of the occurrence of serious cardiac dysrhythmias

secondary to prolongation of the QTc interval in patients receiving azole

antifungals in conjunction with terfenadine, interaction studies have been

performed. One study at a 200 mg daily dose of fluconazole failed to demonstrate a

prolongation in QTc interval. Another study at a 400 mg and 800 mg daily dose of

fluconazole demonstrated that fluconazole taken in doses of 400 mg per day or greater

significantly increases plasma levels of terfenadine when taken concomitantly. The

combined use of fluconazole at doses of 400 mg or greater with terfenadine is

contraindicated (see section 4.3). The coadministration of fluconazole at doses lower than

400 mg per day with terfenadine should be carefully monitored.

Astemizole:

Concomitant administration of fluconazole with astemizole may

decrease the clearance of astemizole. Resulting increased plasma concentrations

of astemizole can lead to QT prolongation and rare occurrences of

torsades de

pointes

. Coadministration of fluconazole and astemizole is contraindicated (see section

4.3).

Pimozide:

Although not studied in vitro or in vivo, concomitant administration

of fluconazole with pimozide may result in inhibition of pimozide metabolism.

Increased pimozide plasma concentrations can lead to QT prolongation and rare

occurrences of torsades de pointes. Coadministration of fluconazole and

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2019-0053188

pimozide is contraindicated (see section 4.3).

Quinidine: Although not studied

in vitro

in vivo

, concomitant administration of

fluconazole with quinidine may result in inhibition of quinidine metabolism. Use of

quinidine has been associated with QT prolongation and rare occurrences of

torsades de

pointes

. Coadministration of fluconazole and quinidine is contraindicated (see section 4.3).

Erythromycin:

Concomitant use of fluconazole and erythromycin has the

potential to increase the risk of cardiotoxicity (prolonged QT interval,

torsades de

pointes

) and consequently sudden heart death. Coadministration of fluconazole and

erythromycin is contraindicated (see section 4.3).

Concomitant use of the following other medicinal products cannot be recommended:

Halofantrine: Fluconazole can increase halofantrine plasma concentration due to an

inhibitory effect on CYP3A4. Concomitant use of fluconazole and halofantrine has the

potential to increase the risk of cardiotoxicity (prolonged QT interval,

torsades de pointes

and consequently sudden heart death. This combination should be avoided (see section

4.4).

Concomitant use that should be used with caution:

Amiodarone: Concomitant administration of fluconazole with amiodarone may increase QT

prolongation. Caution must be exercised if the concomitant use of fluconazole and

amiodarone is necessary, notably with high dose fluconazole (800 mg).

Concomitant use of the following other medicinal products lead to precautions and dose

adjustments:

The effect of other medicinal products on fluconazole

Rifampicin Concomitant administration of fluconazole and rifampicin resulted in a 25%

decrease in the AUC and a 20% shorter half-life of fluconazole. In patients receiving

concomitant rifampicin, an increase of

the fluconazole dose should be considered.

Interaction studies have shown that when oral fluconazole is coadministered with food,

cimetidine, antacids or following total body irradiation for bone marrow transplantation, no

clinically significant impairment of fluconazole absorption occurs

Hydrochlorothiazide: In a pharmacokinetic interaction study, coadministration of

multiple-dose hydrochlorothiazide to healthy volunteers receiving fluconazole increased

plasma concentration of fluconazole by 40%. An effect of this magnitude should not

necessitate a change in the fluconazole dose regimen in subjects receiving concomitant

diuretics.

The effect of fluconazole on other medicinal products

Fluconazole is a moderate inhibitor of cytochrome P450 (CYP) isoenzymes 2C9 and

3A4. Fluconazole is also a strong inhibitor of the isozyme CYP2C19. In addition to the

observed /documented interactions mentioned below, there is a risk of increased plasma

concentration of other compounds metabolised by CYP2C9, CYP2C19 and CYP3A4

coadministered with fluconazole. Therefore, caution should be exercised when using

these combinations and the patients should be carefully monitored. The enzyme

inhibiting effect of fluconazole persists 4- 5 days after discontinuation of fluconazole

treatment due to the long half-life of fluconazole (see section 4.3).

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Alfentanil:

During concomitant treatment with fluconazole (400 mg) and intravenous

alfentanil (20

g/kg) in healthy volunteers the alfentanil AUC

increased 2-fold,

probably through inhibition of CYP3A4. Dose adjustment of alfentanil may be necessary

Amitriptyline, nortriptyline:

Fluconazole increases the effect of amitriptyline

and nortriptyline. 5- nortriptyline and/or S-amitriptyline may be measured at

initiation of the combination therapy and after one week. Dose of

amitriptyline/nortriptyline should be adjusted, if necessary

Amphotericin B: Concurrent administration of fluconazole and amphotericin B in infected

normal and immunosuppressed mice showed the following results: a small additive

antifungal effect in systemic infection with

C. albicans

, no interaction in intracranial

infection with

Cryptococcus neoformans

, and antagonism of the two medicinal products in

systemic infection with

Aspergillus fumigatus

. The clinical significance of results obtained

in these studies is unknown.

Anticoagulants: In post-marketing experience, as with other azole antifungals, bleeding

events (bruising, epistaxis, gastrointestinal bleeding, hematuria, and melena) have been

reported, in association with increases in prothrombin time in patients receiving fluconazole

concurrently with warfarin. During concomitant treatment with fluconazole and warfarin the

prothrombin time was prolonged up to 2 fold, probably due to an inhibition of the warfarin

metabolism through CYP2C9. In patients receiving coumarin-type or indanedione

anticoagulants concurrently with fluconazole the prothrombin time should be carefully

monitored. Dose adjustment of the anticoagulant may be necessary.

Benzodiazepines (short acting), i.e. midazolam, triazolam: Following oral administration

of midazolam, fluconazole resulted in substantial increases in midazolam concentrations

and psychomotor effects. Concomitant intake of fluconazole 200 mg and midazolam

7.5 mg orally increased the midazolam AUC and half-life 3.7-fold and 2.2-fold,

respectively. Fluconazole 200 mg daily given concurrently with triazolam 0.25 mg

orally increased the triazolam AUC and half-life 4.4-fold and 2.3-fold, respectively.

Potentiated and prolonged effects of triazolam have been observed at concomitant

treatment with fluconazole. If concomitant benzodiazepine therapy is necessary in

patients being treated with fluconazole, consideration should be given to decreasing the

benzodiazepine dose, and the patients should be appropriately monitored.

Carbamazepine: Fluconazole inhibits the metabolism of carbamazepine and an increase

in serum carbamazepine of 30% has been observed. There is a risk of developing

carbamazepine toxicity. Dose adjustment of carbamazepine may be necessary depending

on concentration measurements/effect.

Calcium channel blockers: Certain calcium channel antagonists (nifedipine, isradipine,

amlodipine, verapamil and felodipine) are metabolised by CYP3A4. Fluconazole has the

potential to increase the systemic exposure of the calcium channel antagonists. Frequent

monitoring for adverse events is recommended.

Celecoxib: During concomitant treatment with fluconazole (200 mg daily) and celecoxib

(200 mg) the celecoxib C

and AUC increased by 68% and 134%, respectively. Half of

the celecoxib dose may be necessary when combined with fluconazole.

Cyclophosphamide: Combination therapy with cyclophosphamide and fluconazole

results in an increase in serum bilirubin and serum creatinine. The combination may be

used while taking increased consideration to the risk of increased serum bilirubin and

serum creatinine.

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Fentanyl: One fatal case of fentanyl intoxication due to possible fentanyl fluconazole

interaction was reported. Furthermore, it was shown in healthy volunteers that

fluconazole delayed the elimination of fentanyl significantly. Elevated fentanyl

concentration may lead to respiratory depression. Patients should be monitored closely

for the potential risk of respiratory depression. Dosage adjustment of fentanyl may be

necessary.

HMG CoA reductase inhibitors:

The risk of myopathy and rhabdomyolysis increases

when fluconazole is coadministered with HMG-CoA reductase inhibitors metabolised

through CYP3A4, such as atorvastatin and simvastatin, or through CYP2C9, such as

fluvastatin. If concomitant therapy is necessary, the patient should be observed for

symptoms of myopathy and rhabdomyolysis and creatine kinase should be monitored.

HMG-CoA reductase inhibitors should be discontinued if a marked increase in creatine

kinase is observed or myopathy/rhabdomyolysis is diagnosed or suspected.

Ibrutinib: Moderate inhibitors of CYP3A4 such as fluconazole increase plasma ibrutinib

concentrations and may increase risk of toxicity. If the combination cannot be avoided,

reduce the dose of ibrutinib to 280 mg once daily (two capsules) for the duration of the

inhibitor use and provide close clinical monitoring.

Ivacaftor: Co-administration with ivacaftor, a

cystic fibrosis transmembrane conductance

regulator (CFTR) potentiator, increased ivacaftor exposure by 3-fold and hydroxymethyl-

ivacaftor (M1) exposure by 1.9-fold. A reduction of the ivacaftor dose to 150 mg once

daily is recommended for patients taking concomitant moderate CYP3A inhibitors, such

as fluconazole and erythromycin.

Olaparib:

Moderate inhibitors of CYP3A4 such as fluconazole increase olaparib plasma

concentrations; concomitant use is not recommended. If the combination cannot be

avoided, limit the dose of olaparib to 200 mg twice daily.

Immunosuppresors (i.e. ciclosporin, everolimus, sirolimus and tacrolimus):

Ciclosporin: Fluconazole significantly increases the concentration and AUC of ciclosporin.

During concomitant treatment with fluconazole 200 mg daily and ciclosporin (2.7

mg/kg/day) there was a 1.8-fold increase in ciclosporin AUC. This combination may be

used by reducing the dose of ciclosporin depending on ciclosporin concentration.

Everolimus: Although not studied

in vivo

in vitro

, fluconazole may increase serum

concentrations of everolimus through inhibition of CYP3A4.

Sirolimus:

Fluconazole increases plasma concentrations of sirolimus presumably by

inhibiting the metabolism of sirolimus via CYP3A4 and P-glycoprotein. This

combination may be used with a dose adjustment of sirolimus depending on the

effect/concentration measurements.

Tacrolimus: Fluconazole may increase the serum concentrations of orally administered

tacrolimus up to 5 times due to inhibition of tacrolimus metabolism through CYP3A4 in the

intestines. No significant pharmacokinetic changes have been observed when tacrolimus is

given intravenously. Increased tacrolimus levels have been associated with nephrotoxicity.

Dose of orally administered tacrolimus should be decreased depending on tacrolimus

concentration.

Losartan:

Fluconazole inhibits the metabolism of losartan to its active metabolite

(E-31 74) which is responsible for most of the angiotensin II-receptor antagonism which

occurs during treatment with losartan. Patients should have their blood pressure

monitored continuously.

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Methadone: Fluconazole may enhance the serum concentration of methadone. Dose

adjustment of methadone may be necessary.

Non-steroidal anti-inflammatory drugs:

The C

and AUC of flurbiprofen was increased

by 23% and 81%, respectively, when coadministered with fluconazole compared to

administration of flurbiprofen alone. Similarly, the C

and AUC of the

pharmacologically active isomer [S-(+)-ibuprofen] was increased by 15% and 82%,

respectively, when fluconazole was coadministered with racemic ibuprofen (400 mg)

compared to administration of racemic ibuprofen alone.

Although not specifically studied, fluconazole has the potential to increase the systemic

exposure of other NSAIDs that are metabolised by CYP2C9 (e.g. naproxen, lornoxicam,

meloxicam, diclofenac). Frequent monitoring for adverse events and toxicity related to

NSAIDs is recommended. Adjustment of dose of NSAIDs may be needed.

Phenytoin: Fluconazole inhibits the hepatic metabolism of phenytoin. Concomitant repeated

administration of 200 mg fluconazole and 250 mg phenytoin intravenously, caused an

increase of the phenytoin AUC24 by 75% and C

by 128%. With coadministration, serum

phenytoin concentration levels should be monitored in order to avoid phenytoin toxicity.

Prednisone: There was a case report that a liver-transplanted patient treated with prednisone

developed acute adrenal cortex insufficiency when a three month therapy with fluconazole

was discontinued. The discontinuation of fluconazole presumably caused an enhanced

CYP3A4 activity which led to increased metabolism of prednisone. Patients on long-term

treatment with fluconazole and prednisone should be carefully monitored for adrenal cortex

insufficiency when fluconazole is discontinued.

Rifabutin: Fluconazole increases serum concentrations of rifabutin, leading to

increase in the AUC of rifabutin up to 80%. There have been reports of uveitis in

patients to whom fluconazole and rifabutin were coadministered. In combination

therapy, symptoms of rifabutin toxicity should be taken into consideration.

Saquinavir: Fluconazole increases the AUC and C

of saquinavir with approximately

50% and 55% respectively, due to inhibition of saquinavir’s hepatic metabolism by

CYP3A4 and inhibition of P-glycoprotein. Interaction with saquinavir/ritonavir has not

been studied and might be more marked. Dose adjustment of saquinavir may be

necessary.

Sulfonylureas: Fluconazole has been shown to prolong the serum half-life of concomitantly

administered oral sulfonylureas (e.g., chlorpropamide, glibenclamide, glipizide,

tolbutamide) in healthy volunteers. Frequent monitoring of blood glucose and appropriate

reduction of sulfonylurea dose is recommended during coadministration.

Theophylline: In a placebo-controlled interaction study, the administration of fluconazole

200 mg for 14 days resulted in an 18% decrease in the mean plasma clearance rate of

theophylline. Patients who are receiving high dose theophylline or who are otherwise at

increased risk for theophylline toxicity should be observed for signs of theophylline toxicity

while receiving fluconazole. Therapy should be modified if signs of toxicity develop.

Tofacitinib: Exposure of tofacitinib is increased when tofacitinib is co-administered with

medications that result in both moderate inhibition of CYP3A4 and strong inhibition of

CYP2C19 (e.g., fluconazole).

Therefore, it is recommended to reduce tofacitinib dose to

5 mg once daily when it is combined with these drugs.

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Vinca alkaloids: Although not studied, fluconazole may increase the plasma levels of the

vinca alkaloids (e.g. vincristine and vinblastine) and lead to neurotoxicity, which is possibly

due to an inhibitory effect on CYP3A4.

Vitamin A: Based on a case-report in one patient receiving combination therapy with

all-trans-retinoid acid (an acid form of vitamin A) and fluconazole, CNS related

undesirable effects have developed in the form of pseudotumour

cerebri

, which

disappeared after discontinuation of fluconazole treatment. This combination may be

used but the incidence of CNS related undesirable effects should be borne in mind.

Voriconazole: (CYP2C9, CYP2C19 and CYP3A4 inhibitor): Coadministration of oral

voriconazole (400 mg Q12h for 1 day, then 200 mg Q12h for 2.5 days) and oral

fluconazole (400 mg on day 1, then 200 mg Q24h for 4 days) to 8 healthy male subjects

resulted in an increase in C

and AUC

of voriconazole by an average of 57% (90% CI:

20%, 107%) and 79% (90% CI: 40%, 128%), respectively. The reduced dose and/or

frequency of voriconazole and fluconazole that would eliminate this effect have not been

established. Monitoring for voriconazole associated adverse events is recommended if

voriconazole is used sequentially after fluconazole.

Zidovudine: Fluconazole increases C

and AUC of zidovudine by 84% and 74%,

respectively, due to an approx. 45% decrease in oral zidovudine clearance. The half-life

of zidovudine was likewise prolonged by approximately 128% following combination

therapy with fluconazole. Patients receiving this combination should be monitored for the

development of zidovudine-related adverse reactions. Dose reduction of zidovudine may

be considered.

Azithromycin: An open-label, randomized, three-way crossover study in 18 healthy

subjects assessed the effect of a single 1200 mg oral dose of azithromycin on the

pharmacokinetics of a single 800 mg oral dose of fluconazole as well as the effects of

fluconazole on the pharmacokinetics of azithromycin. There was no significant

pharmacokinetic interaction between fluconazole and azithromycin.

Oral contraceptives: Two pharmacokinetic studies with a combined oral contraceptive have

been performed using multiple doses of fluconazole. There were no relevant effects on

hormone level in the 50 mg fluconazole study, while at 200 mg daily, the AUCs of ethinyl

estradiol and levonorgestrel were increased 40% and 24%, respectively. Thus, multiple dose

use of fluconazole at these doses is unlikely to have an effect on the efficacy of the

combined oral contraceptive.

4.6

Fertility, pregnancy and lactation

Pregnancy

An observational study has suggested an increased risk of spontaneous abortion in women

treated with fluconazole during the first trimester.

There have been reports of multiple congenital abnormalities (including brachycephalia,

ears dysplasia, giant anterior fontanelle, femoral bowing and radio-humeral synostosis) in

infants whose mothers were treated for at least three or more months with high doses

(400-800 mg daily) of fluconazole for coccidioidomycosis. The relationship between

fluconazole use and these events is unclear.

Studies in animals have shown reproductive toxicity (see section 5.3).

Fluconazole in standard doses and short-term treatments should not be used in pregnancy

unless clearly necessary.

Fluconazole in high dose and/or in prolonged regimens should not be used during pregnancy

except for potentially life-threatening infections.

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Breast-feeding

Fluconazole passes into breast milk to reach concentrations similar to those in plasma (see

section 5.2). Breast-feeding may be maintained after a single dose of 150 mg fluconazole.

Breast-feeding is not recommended after repeated use or after high dose fluconazole. The

developmental and health benefits of breast-feeding should be considered along with the

mother’s clinical need for Fluconazole and any potential adverse effects on the breast-fed

child from Fluconazole or from the underlying maternal condition.

Fertility

Fluconazole did not affect the fertility of male or female rats (see section 5.3)

4.7

Effects on ability to drive and use machines

No studies have been performed on the effects of fluconazole on the ability to drive or use

machines.

Patients should be warned about the potential for dizziness or seizures (see section 4.8)

while taking fluconazole and should be advised not to drive or operate machines if any of

these symptoms occur.

4.8

Undesirable effects

The most frequently (≥1/100 to <1/10) reported adverse reactions are headache,

abdominal pain, diarrhoea, nausea, vomiting, alanine aminotransferase increased,

aspartate aminotransferase increased, blood alkaline phosphatase increased and rash.

The following adverse reactions have been observed and reported during treatment with

fluconazole with the following frequencies: Very common (≥1/10); common (≥1/100 to

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

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

System Organ

Class

Common

Uncommon

Rare

Not Known

Blood and the

lymphatic

system disorders

Anaemia

Agranulocytosis,

leukopenia,

thrombocytopenia,

neutropenia

Immune system

disorders

Anaphylaxis

Metabolism and

nutrition

disorders

Decreased

appetite

Hypercholesterolaemia,

hypertriglyceridaemia,

hypokalemia

Psychiatric

disorders

Somnolence,

insomnia

Nervous system

disorders

Headache

Seizures,

paraesthesia,

dizziness,

taste

perversion

Tremor

Ear and

labyrinth

disorders

Vertigo

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Cardiac

disorders

Torsade de pointes (see

section 4.4), QT

prolongation (see

section 4.4)

Gastrointestinal

disorders

Abdominal pain,

vomiting,

diarrhoea,

nausea

Constipation

dyspepsia,

flatulence, dry

mouth

Hepatobiliary

disorders

Alanine

aminotransferase

increased (see

section 4.4),

aspartate

aminotransferase

increased (see

section 4.4),

blood alkaline

phosphatase

increased (see

section 4.4)

Cholestasis

(see section

4.4), jaundice

(see section

4.4), bilirubin

increased (see

section 4.4)

Hepatic failure (see

section 4.4),

hepatocellular necrosis

(see section 4.4),

hepatitis (see section

4.4), hepatocellular

damage (see section

4.4)

Skin and

subcutaneous

tissue disorders

Rash (see

section 4.4)

Drug

eruption* (see

section 4.4),

urticaria (see

section 4.4),

pruritus,

increased

sweating

Toxic epidermal

necrolysis, (see section

4.4), Stevens-Johnson

syndrome (see section

4.4), acute generalised

exanthematous-

pustulosis (see section

4.4), dermatitis

exfoliative,

angioedema, face

oedema, alopecia

Drug reaction

with

eosinophilia

and systemic

symptoms

(DRESS)

Musculoskeletal

and connective

tissue disorders

Myalgia

General

disorders and

administration

site conditions

Fatigue,

malaise,

asthenia, fever

* including Fixed Drug Eruption

Paediatric population

The pattern and incidence of adverse reactions and laboratory abnormalities recorded

during paediatric clinical trials, excluding the genital candidiasis indication, are

comparable to those seen in adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is

important. It allows continued monitoring of the benefit/risk balance of the medicinal

product. Any suspected adverse event should be reported to the Ministry of Health

according to the National Regulation by using an online form

https://sideeffects.health.gov.il

4.9

Overdose

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There have been reports of overdose with fluconazole. Hallucination and paranoid

behaviour have been concomitantly reported.In the event of overdose, symptomatic

treatment (with supportive measures and gastric lavage if necessary) may be adequate.

Fluconazole is largely excreted in the urine; forced volume diuresis would probably increase

the elimination rate. A three-hour haemodialysis session decreases plasma levels by

approximately 50%.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Antimycotics for systemic use, triazole derivatives, ATC

code: J02AC01.

Mechanism of action

Fluconazole is a triazole antifungal agent. Its primary mode of action is the inhibition of

fungal cytochrome P-450-mediated 14 alpha-lanosterol demethylation, an essential step

in fungal ergosterol biosynthesis. The accumulation of 14 alpha-methyl sterols correlates

with the subsequent loss of ergosterol in the fungal cell membrane and may be

responsible for the antifungal activity of fluconazole. Fluconazole has been shown to be

more selective for fungal cytochrome P-450 enzymes than for various mammalian

cytochrome P-450 enzyme systems.

Fluconazole 50 mg daily given up to 28 days has been shown not to effect testosterone

plasma concentrations in males or steroid concentration in females of child-bearing age.

Fluconazole 200 mg to 400 mg daily has no clinically significant effect on endogenous

steroid levels or on ACTH stimulated response in healthy male volunteers. Interaction

studies with antipyrine indicate that single or multiple doses of fluconazole 50 mg do not

affect its metabolism.

Susceptibility

in vitro:

In vitro

, fluconazole displays antifungal activity against most clinically common

Candida

species (including

C. albicans, C. parapsilosis, C. tropicalis).

C. glabrata

shows a wide

range of susceptibility while

C. krusei

is resistant to fluconazole.

Fluconazole also exhibits activity

in vitro

against

Cryptococcus neoformans

Cryptococcus. gattii

as well as the endemic moulds

Blastomyces dermatiditis

Coccidioides immitis

Histoplasma capsulatum

Paracoccidioides brasiliensis

Pharmacokinetic/pharmacodynamic relationship

In animal studies, there is a correlation between MIC values and efficacy against

experimental mycoses due to

Candida

spp. In clinical studies, there is an almost 1:1

linear relationship between the AUC and the dose of fluconazole. There is also a direct

though imperfect relationship between the AUC or dose and a successful clinical

response of oral candidosis and to a lesser extent candidaemia to treatment. Similarly

cure is less likely for infections caused by strains with a higher fluconazole MIC.

Mechanisms of resistance

Candida

spp have developed a number of resistance mechanisms to azole antifungal

agents. Fungal strains which have developed one or more of these resistance

mechanisms are known to exhibit high minimum inhibitory concentrations (MICs) to

fluconazole which impacts adversely efficacy

in vivo

and clinically.

There have been reports of superinfection with

Candida

species other than

C. albicans

which are often inherently not susceptible to fluconazole (e.g.

Candida krusei

). Such

cases may require alternative antifungal therapy.

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Breakpoints (according to EUCAST)

Based on analyses of pharmacokinetic/pharmacodynamic (PK/PD) data, susceptibility

in

vitro

and clinical response EUCAST-AFST (European Committee on Antimicrobial

susceptibility Testing-subcommittee on Antifungal Susceptibility Testing) has

determined breakpoints for fluconazole for

Candida

species (EUCAST Fluconazole

rational document (2007)-version 2). These have been divided into non-species related

breakpoints; which have been determined mainly on the basis of PK/PD data and are

independent of MIC distributions of specific species, and species related breakpoints for

those species most frequently associated with human infection. These breakpoints are

given in the table below:

Antifungal

Species-related breakpoints (S</R>)

Non-species

related

breakpoints

S</R>

Candida

albicans

Candida

glabrata

Candida

krusei

Candida

parapsilosis

Candida

tropicalis

Fluconazole

S = Susceptible, R = Resistant

A = Non-species related breakpoints have been determined mainly on the basis of PK/PD

data and are independent of MIC distributions of specific species. They are for use only

for organisms that do not have specific breakpoints.

--

= Susceptibility testing not recommended as the species is a poor target for therapy

with the medicinal product.

IE = There is insufficient evidence that the species in question is a good target for

therapy with the medicinal product

5.2

Pharmacokinetic properties

The pharmacokinetic properties of fluconazole are similar following administration by the

intravenous or oral route.

Absorption

After oral administration fluconazole is well absorbed, and plasma levels (and systemic

bioavailability) are over 90% of the levels achieved after intravenous administration. Oral

absorption is not affected by concomitant food intake. Peak plasma concentrations in the

fasting state occur between 0.5 and 1.5 hours post-dose. Plasma concentrations are

proportional to dose. Ninety percent steady state levels are reached by day 4-5 with multiple

once daily dosing. Administration of a loading dose (on day 1) of twice the usual daily dose

enables plasma levels to approximate to 90% steady-state levels by day 2.

Distribution

The apparent volume of distribution approximates to total body water. Plasma protein

binding is low (11-12%).

Fluconazole achieves good penetration in all body fluids studied. The levels of fluconazole

in saliva and sputum are similar to plasma levels. In patients with fungal meningitis,

fluconazole levels in the CSF are approximately 80% the corresponding plasma levels.

High skin concentration of fluconazole, above serum concentrations, are achieved in the

stratum corneum, epidermis-dermis and eccrine sweat. Fluconazole accumulates in the

stratum corneum. At a dose of 50 mg once daily, the concentration of fluconazole after

12 days was 73 µg/g and 7 days after cessation of treatment the concentration was still

5.8 µg/g. At the 150 mg once-a-week dose, the concentration of fluconazole in stratum

corneum on day 7 was 23.4 µg/g and 7 days after the second dose was still 7.1 µg/g.

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Concentration of fluconazole in nails after 4 months of 150 mg once-a-week dosing was

4.05 µg/g in healthy and 1.8 µg/g in diseased nails; and, fluconazole was still measurable in

nail samples 6 months after the end of therapy.

Biotransformation

Fluconazole is metabolised only to a minor extent. Of a radioactive dose, only 11% is

excreted in a changed form in the urine. Fluconazole is a moderate inhibitor of the isozymes

CYP2C9 and CYP3A4 (see section 4.5). Fluconazole is also a strong inhibitor of the

isozyme CYP2C19.

Elimination

Plasma elimination half-life for fluconazole is approximately 30 hours. The major route of

excretion is renal, with approximately 80% of the administered dose appearing in the urine

as unchanged medicinal product. Fluconazole clearance is proportional to creatinine

clearance. There is no evidence of circulating metabolites.

The long plasma elimination half-life provides the basis for single dose therapy for vaginal

candidiasis, once daily and once weekly dosing for other indications.

Pharmacokinetics in renal impairment

In patients with severe renal insufficiency, (GFR< 20 ml/min) half life increased from 30 to

98 hours. Consequently, reduction of the dose is needed. Fluconazole is removed by

haemodialysis and to a lesser extent by peritoneal dialysis. After three hours of

haemodialysis session, around 50% of fluconazole is eliminated from blood.

Pharmacokinetics during lactation

A pharmacokinetic study in ten lactating women, who had temporarily or permanently

stopped breast-feeding their infants, evaluated fluconazole concentrations in plasma and

breast milk for 48 hours following a single 150 mg dose of Fluconazole. Fluconazole was

detected in breast milk at an average concentration of approximately 98% of those in

maternal plasma. The mean peak breast milk concentration was 2.61 mg/L at 5.2 hours

post-dose. The estimated daily infant dose of fluconazole from breast milk (assuming

mean milk consumption of 150 ml/kg/day) based on the mean peak milk concentration is

0.39 mg/kg/day, which is approximately 40% of the recommended neonatal dose

(<2 weeks of age) or 13% of the recommended infant dose for mucosal candidiasis.

Pharmacokinetics in children

Pharmacokinetic data were assessed for 113 paediatric patients from 5 studies; 2 single-dose

studies, 2 multiple-dose studies, and a study in premature neonates. Data from one study

were not interpretable due to changes in formulation pathway through the study. Additional

data were available from a compassionate use study.

After administration of 2-8 mg/kg fluconazole to children between the ages of 9 months to

15 years, an AUC of about 38 µg

h/ml was found per 1 mg/kg dose units. The average

fluconazole plasma elimination half-life varied between 15 and 18 hours and the distribution

volume was approximately 880 ml/kg after multiple doses. A higher fluconazole plasma

elimination half-life of approximately 24 hours was found after a single dose. This is

comparable with the fluconazole plasma elimination half-life after a single administration of

3 mg/kg i.v. to children of 11 days-11 months old. The distribution volume in this age

group was about 950 ml/kg.

Experience with fluconazole in neonates is limited to pharmacokinetic studies in premature

newborns. The mean age at first dose was 24 hours (range 9-36 hours) and mean birth

weight was 0.9 kg (range 0.75-1.10 kg) for 12 pre-term neonates of average gestation

around 28 weeks. Seven patients completed the protocol; a maximum of five 6 mg/kg

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intravenous infusions of fluconazole were administered every 72 hours. The mean half-life

(hours) was 74 (range 44-185) on day 1 which decreased, with time to a mean of 53

(range 30-131) on day 7 and 47 (range 27-68) on day 13. The area under the curve

(microgram.h/ml) was 271 (range 173-385) on day 1 and increased with a mean of 490

(range 292-734) on day 7 and decreased with a mean of 360 (range 167-566) on day 13. The

volume of distribution (ml/kg) was 1183 (range 1070-1470) on day 1 and increased, with

time, to a mean of 1184 (range 510-2130) on day 7 and 1328 (range 1040-1680) on day 13.

Pharmacokinetics in elderly

A pharmacokinetic study was conducted in 22 subjects, 65 years of age or older receiving a

single 50 mg oral dose of fluconazole. Ten of these patients were concomitantly receiving

diuretics. The C

was 1.54 µg/ml and occurred at 1.3 hours post-dose. The mean AUC was

76.4 ± 20.3 µg

h/ml, and the mean terminal half-life was 46.2 hours. These pharmacokinetic

parameter values are higher than analogous values reported for normal young male

volunteers. Coadministation of diuretics did not significantly alter AUC or C

. In addition,

creatinine clearance (74 ml/min), the percent of medicinal product recovered unchanged in

urine (0-24 h, 22%) and the fluconazole renal clearance estimates (0.124 ml/min/kg) for the

elderly were generally lower than those of younger volunteers. Thus, the alteration of

fluconazole disposition in the elderly appears to be related to reduced renal function

characteristics of this group.

5.3

Preclinical safety data

Effects in non-clinical studies were observed only at exposures considered sufficiently in

excess of the human exposure indicating little relevance to clinical use.

Carcinogenesis

Fluconazole showed no evidence of carcinogenic potential in mice and rats treated orally for

24 months at doses of 2.5, 5, or 10 mg/kg/day (approximately 27 times the recommended

human dose). Male rats treated with 5 and 10 mg/kg/day had an increased incidence of

hepatocellular adenomas.

Mutagenesis

Fluconazole, with or without metabolic activation, was negative in tests for mutagenicity in

4 strains of Salmonella typhimurium, and in the mouse lymphoma L5178Y system.

Cytogenetic studies in vivo (murine bone marrow cells, following oral administration of

fluconazole) and in vitro (human lymphocytes exposed to fluconazole at 1000 μg/ml)

showed no evidence of chromosomal mutations.

Reproductive toxicity

Fluconazole did not affect the fertility of male or female rats treated orally with daily doses

of 5, 10, or 20 mg/kg or with parenteral doses of 5, 25, or 75 mg/kg.

There were no foetal effects at 5 or 10 mg/kg; increases in foetal anatomical variants

(supernumerary ribs, renal pelvis dilation) and delays in ossification were observed at 25

and 50 mg/kg and higher doses. At doses ranging from 80 mg/kg to 320 mg/kg

embryolethality in rats was increased and foetal abnormalities included wavy ribs, cleft

palate, and abnormal cranio-facial ossification.

The onset of parturition was slightly delayed at 20 mg/kg orally and dystocia and

prolongation of parturition were observed in a few dams at 20 mg/kg and 40 mg/kg

intravenously. The disturbances in parturition were reflected by a slight increase in the

number of still-born pups and decrease of neonatal survival at these dose levels. These

effects on parturition are consistent with the species-specific oestrogen-lowering property

produced by high doses of fluconazole. Such a hormone change has not been observed in

women treated with fluconazole (see section 5.1).

Trican 200 mg Capsules LPD CC 13 October 2020

Page 20 of 20

2019-0053188

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Capsule content:

Lactose monohydrate

Starch

Magnesium stearate

Anhydrous colloidal silica

Sodium lauryl sulfate

Capsule shell:

Gelatin,

Titanium dioxide (E171)

Erythrosin (E127)

Indigo carmine (E132)

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

The expiry date of the product is indicated on the packaging materials.

6.4

Special precautions for storage

Store below 30ºC.

6.5

Nature and contents of container

PVC/Aluminium blister packs containing 7 capsules.

6.6

Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance

with local requirements.

7. MANUFACTURER

Fareva Amboise, Poce-sur-Cisse, France.

8. LICENSE HOLDER

Pfizer PFE Pharmaceuticals Israel Ltd., 9 Shenkar St., Herzliya Pituach 46725

9. LICENSE NUMBER

118-50-29947

Revised in 10/2020

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