STABILANOL

Israel - English - Ministry of Health

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Active ingredient:
FLUCONAZOLE
Available from:
TRIMA ISRAEL PHARMACEUTICAL PRODUCTS MAABAROT LTD
ATC code:
J02AC01
Pharmaceutical form:
SOLUTION FOR INFUSION
Composition:
FLUCONAZOLE 2 MG/ML
Administration route:
I.V
Prescription type:
Required
Manufactured by:
PHARMATHEN S.A., GREECE
Therapeutic group:
FLUCONAZOLE
Therapeutic area:
FLUCONAZOLE
Therapeutic indications:
Stabilanol is indicated in the following fungal infections .Stabilanol is indicated in adults for the treatment of: • Cryptococcal meningitis .• Coccidioidomycosis. 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.Stabilanol is indicated in adults for the prophylaxis of: • Relapse of crytopcoccal 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.• Prophylaxis of candidal infections in patients with prolonged neutropenia (such as patients with haematological malignancies receiving chemotherapy or patients receiving Hematopoietic Stem Cell Transplantation ).Stabilanol is indicated in term newborn infants, infants, toddlers, children and adolescents aged from 0 to 17 years old: Sta
Authorization number:
134 81 31179 01
Authorization date:
2011-06-30

טסוגוא

2019

,ה/דבכנ ה/אפור

,ה/דבכנ ת/חקור

:ןודנה

ןוכדע

ולע

אפורל

רישכת

Solution for Infusion

ilanol

Stab

ליעפ ביכרמ

Fluconazole 2 mg/ml

:היוותה

Fluconazole is indicated in the following fungal infections.

Fluconazole is indicated in adults for the treatment of:

Cryptococcal meningitis.

Coccidioidomycosis.

Invasive candidiasis.

Mucosal candidiasis (including oropharyngeal candidiasis, oesophageal

candidiasis, candiduria and chronic mucocutaneous candidiasis).

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

topical treatment are insufficient.

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.

Prophylaxis of candidal infections in patients with prolonged neutropenia (such

as patients with haematological malignancies receiving chemotherapy or patients

receiving Haematopoetic 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.

וננוצרב עידוהל

ולעב ןוכדע לחש

אפורל

ןודנבש רישכתה לש

מוא

ולע

לש

.רוקמה רישכת

ןולעה םוסרפל חלשנ תואירבה דרשמ לש טנרטניאה רתאבש תופורתה רגאמב

www.health.gov.il

לבקל ןתינו

ספדומ

תרבח ,םושירה לעבל הינפ י"ע האופר ירצות ,המירת מ"עב תורבעמ םיילארשי תורבעמ ץוביק ,

4023000

:ןופלט ,

074-7141147

,הכרבב

מ"עב תורבעמ ,םיילארשי האופר ירצות ,המירת

STABILANOL

SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

STABILANOL

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml of Solution for Infusion contains 2 mg of Fluconazole.

50 ml Solution for Infusion contains 100 mg Fluconazole.

Excipient(s) with known effect:

Each ml contains 9 mg sodium chloride (equivalent to 0.154 mmol sodium) (see section 4.4).

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Solution for infusion.

A clear and colourless solution.

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

candidiasis,

oesophageal

candidiasis,

candiduria

chronic

mucocutaneous

candidiasis).

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

treatment

insufficient.

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.

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

patients with haematological malignancies receiving chemotherapy or patients receiving

Haematopoetic 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

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

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

Prophylaxis of

candidal infections

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 mm

Special populations

Elderly

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

Renal impairment

”).

Renal impairment

Fluconazole

predominantly

excreted

urine

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 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. Fluconazole is 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.

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 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, or

vice versa

, there is no need to change the daily dose.

Intravenous infusion should be administrated at a rate not exceeding 10 ml/minute. Stabilanol

is formulated in sodium chloride 9 mg/ml (0.9%) solution for infusion, each 200 mg (100 ml

bottle) containing 15 mmol each of Na+ and C1-. Because Stabilanol is available as a dilute

sodium chloride solution, in patients requiring sodium or fluid restriction, consideration

should be given to the rate of fluid administration.

For instruction on dilution of the medicinal product before administration, see section 6.6.

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 is 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, Stabilanol

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

limited, which prevents specific dosing recommendations.

Renal system

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

section 4.2).

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 with potentially proarrhythmic

conditions. Coadministration of other medicinal products known to prolong the QT interval

and which are metabolised via the cytochrome P450 (CYP) 3A4 is 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 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

This medicinal product contains 0.154 mmol sodium per ml. To be taken into consideration

by patients on a controlled sodium diet.

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

occurrence

serious

cardiac

dysrhythmias

secondary

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

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

torsades de pointe

s. Coadministration of fluconazole and pimozide is contraindicated

(see section 4.3).

Quinidine: Although

studied

in

vitro

in

vivo

concomitant

administration

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

increase

halofantrine

plasma

concentration

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).

Alfentanil: During concomitant treatment with fluconazole (400 mg) and intravenous

alfentanil (20 µg/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

effect

amitriptyline

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

immunosuppressed

mice

showed

following

results:

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.

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

rhabdomyolysis

creatine

kinase

should

monitored.

HMG-CoA

reductase

inhibitors should be discontinued if a marked increase in creatine kinase is observed or

myopathy/rhabdomyolysis is diagnosed or suspected.

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.

Immunosuppressors (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

increase

serum

concentrations

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.

Methadone:

Fluconazole

enhance

serum

concentration

methadone.

Dose

adjustment of methadone may be necessary.

Non-steroidal

anti-inflammatory

drugs:

flurbiprofen

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 AUC

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.

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.

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.

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.

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 (>1/10) 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

Hypercholestero-

laemia,

hypertriglyceri-

daemia,

hypokalemia

Psychiatric

disorders

Somnolence,

insomnia

Nervous system

disorders

Headache

Seizures,

paraesthesia,

dizziness, taste

perversion

Tremor

Ear and labyrinth

disorders

Vertigo

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 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 events should be reported to the Ministry of Health according to

the National Regulation by using an online form https://forms.gov.il/forms/Resources/

DowloadSetup/AGFormsDownloadToolbar.htm?formid=AdversEffectMedic@moh.gov.il

Side effects can also be reported to the following email: safety@trima.co.il

4.9

Overdose

There have been reports of overdose with fluconazole and 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

animal

studies,

there

correlation

between

values

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.

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

A

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.

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 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. Coadministration 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 hr, 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 2-7 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).

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Sodium chloride

Water for injection

6.2

Incompatibilities

This medicinal product must not be mixed with other medicinal products except those

mentioned in section 6.6.

6.3

Shelf life

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

product should be used immediately. Any unused infusion should be discarded.

6.4

Special precautions for storage

Store in a dry place, below 25˚C. Do not freeze.

6.5

Nature and contents of container

Clear Type I, 50 ml glass bottle, closed with bromobutyl rubber stoppers and aluminium

caps.

6.6

Special precautions for disposal and other handling

Fluconazole intravenous infusion is compatible with the following administration fluids:

Dextrose 20%

b) Ringer’s solution

Hartmann’s solution

d) Potassium chloride in dextrose

Sodium bicarbonate 4.2%

Sodium chloride 9 mg/ml (0.9%)

Fluconazole may be infused through an existing line with one of the above-listed fluids.

Although no specific incompatibilities have been noted, mixing with any other medicinal

products prior to infusion is not recommended.

The solution for infusion is for single use only.

The dilution is to be made under aseptic conditions. The solution is to be inspected visually

for particulate matter and discoloration prior to administration. The solution should only be

used if the solution is clear and free from particles.

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

local requirements.

7.

MANUFACTURER

Pharmathen S.A., 6 Dervenakion st., 15351 Pallini Attikis, Greece

8.

LICENSE HOLDER

Trima Trading (1961) Ltd, Maabarot 4023000, Israel

9.

LICENSE NUMBER

134.81.31179.00/01/02/03/04

The content of this leaflet was approved by the Ministry of Health in September 2011 and

updated according to the guidelines of the Ministry of Health in January 2019.

SPC-0319-04

100478010 0319D

העדוה העדוה

לע לע

הרמחה הרמחה

(

(

עדימ עדימ

)תוחיטב )תוחיטב

ךיראת

09.09.11

םש

רישכת

תילגנאב

Stabilanol Solution for Injection

רפסמ

םושיר

134.81.31179.00

םש

לעב

םושירה

Trima Trading (1961) Ltd

םייונישה

ןולעב

םינמוסמ

עקרב

בוהצ ןולע אפורל

םיטרפ

לע

םי/יונישה

םי/שקובמה קרפ

ןולעב טסקט

יחכונ טסקט

שדח

Pregnancy

and lactation

Use during pregnancy

There is little

experience of fluconazole

use in human pregnancy.

Adverse effects on the

embryo have been observed

on laboratory animals only

at high doses, which are

associated with toxic effects

on pregnant laboratory

animals. These findings are

not thought to be correlated

to fluconazole use at

therapeutic doses. However,

the use of fluconazole

during pregnancy should be

avoided, apart from in

patients with severe and life-

threatening fungal

infections, in which

fluconazole may be used if

the expected benefits from

treatment exceed the

potential risk of toxic effects

on the embryo

Use during pregnancy

The pregnancy category for

fluconazole use for indications

other than vaginal candidiasis is

category D. A few published case

reports describe a rare pattern of

distinct congenital anomalies in

infants exposed in utero to high-

dose maternal fluconazole (400-

800 mg/day) during most or all of

the first trimester

The features seen in these infants

include brachycephaly, abnormal

facies, abnormal calvarial

development, cleft palate, femoral

bowing, thin ribs and long bones,

arthrogryposis, and congenital

heart disease. These effects are

similar to those seen in animal

studies

If fluconazole is used during

pregnancy, or if a patient

becomes pregnant while taking

fluconazole, the patient should be

informed of the potential risk to

the fetus

Special

Precautions

Store in a cool and dry

place (temperature < 25º C)

Store in a cool and dry place

(temperature < 25º C). Do not

for Storage

of the

product

and keep out of the reach of

children

freeze. and Keep out of the reach

of children

Marketing

authorization

holder

Trima Marketing (1961) Ltd

Maabarot 40230

Trima Marketing Trading (1961)

Ltd, Maabarot 40230, Israel

Manufacturer

Pharmathen S.A. – Site:

Dervenakion 6, Pallini

15351 Attiki

Tel.: 210-6665067

Pharmathen S.A. – Site:

Dervenakion 6, Pallini 15351

Attiki, Greece

Tel.: 210-6665067

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