Duracan is indicated in the following fungal infections (see section 5.1).
Duracan 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
and dermal candida infections when systemic therapy is indicated.
• Tinea unguinium (onychomycosis) when other agents are not considered appropriate

• Duracan 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).
• 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)).
Duracan is indicated in term newborn infants, infants, toddlers, children, and adolescents
aged from 0 to 17 years old:
Duracan is used for the treatment of mucosal candidiasis (oropharyngeal, oesophageal),
invasive candidiasis, cryptococcal meningitis and the prophylaxis of candidal infections in
immunocompromised patients. Duracan 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.

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.

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
Genital candidiasis	- Acute vaginal candidiasis - Candidal balanitis	150 mg	Single dose
	- 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 mm3.

Special populations
Elderly
Dosage should be adjusted based on the renal function (see “Renal impairment”).
Renal impairment
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)	50%
Haemodialysis	100% after each haemodialysis

Patients on regular dialysis should receive 100% of the recommended dose after each
dialysis; 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. Duracan 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 in 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.
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:
Duracan may be administered either orally or by intravenous 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.
The capsules should be swallowed whole and independent of food intake.

 

 

Hypersensitivity to the active substance, to related azole substances, or to any of the excipients (see section 6.1). Coadministration of terfenadine is contraindicated in patients receiving Duracan 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).

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, Duracan
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 mycosis
The evidence for efficacy of fluconazole in the treatment of other forms of endemic mycoses
such as paracoccidioidomycosis, lymphocutaneous sporotrichosis and histoplasmosis is
limited, which prevents specific dosing recommendations.
Renal system
Duracan should be administered with caution to patients with renal dysfunction (see section
4.2).

Hepatobiliary system
Duracan should be administered with caution to patients with liver dysfunction.
Duracan 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. During post-marketing surveillance, there have been very
rare cases of QT prolongation and torsades de pointes in patients taking Duracan. 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.
Duracan should be administered with caution to patients with these potentially 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 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 potent CYP2C9 inhibitor and a moderate CYP3A4 inhibitor.
Fluconazole is also an inhibitor of CYP2C19. Duracan 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.

 

Concomitant use of the following other medicinal products is contraindicate d:
Cisapride:There have been reports of cardiac events including Torsade de Pointes in
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 QT 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 torsade depointes.
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 torsade de pointes. Coadministration of fluconazole and pimozide is
contraindicated (see section 4.3).
Quinidine: Although not studied in vitro or 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 of the following other medicinal products lead to precautions and
dose adjustments:
The effect of other medicinal products on fluconazole
Rifampicin: Concomitant administration of Duracan and rifampicin resulted in a 25%
decrease in the AUC and 20% shorter half-life of fluconazole. In patients receiving
concomitant rifampicin, an increase in the Duracan 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.
The effect of fluconazole on other medicinal products
Fluconazole : is a potent inhibitor of cytochrome P450 (CYP) isoenzyme 2C9 and a
moderate inhibitor of CYP3A4. Fluconazole is also an 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 metabolized by
CYP2C9 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 10 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 A. 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 coumarintype
anticoagulants concurrently with fluconazole the prothrombin time should be
carefully monitored. Dose adjustment of warfarin 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 metabolized 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 Cmax 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 and rhabdomyolysis and creatinine kinase should be
monitored. HMG-CoA reductase inhibitors should be discontinued if a marked
increase in creatinine kinase is observed or myopathy/rhabdomyolysis is diagnosed or
suspected.
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 or 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 Il-receptor antagonism which
occurs during treatment with losartan. Patients should have their blood pressure
monitored continuously.
Methadone: Fluconazole may enhance the serum concentration of methadone. Dose
adjustment of methadone may be necessary.
Non-steroidal anti-inflammatory drugs: The Cmax and AUC of flurbiprofen were
increased by 23% and 81%, respectively, when coadministered with fluconazole
compared to administration of flurbiprofen alone. Similarly, the Cmax 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 metabolized 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 Cmin 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 Cmax 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 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 Cmax 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 Cmax 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.

Pregnancy
Data from several hundred pregnant women treated with standard doses (<200 mg/day) of
fluconazole, administered as a single or repeated dose in the first trimester, show no
undesirable effects in the foetus.
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 lower than those in plasma.
Breast-feeding may be maintained after a single use of a standard dose 200 mg fluconazole or
less. Breast-feeding is not recommended after repeated use or after high dose fluconazole.
Fertility
Fluconazole did not affect the fertility of male or female rats (see section 5.3)

No studies have been performed on the effects of Duracan 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 Duracan and should be advised not to drive or operate machines if
any of these symptoms occur.

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 Duracan 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, hypokalaemia
Psychiatric disorders		Somnolence, insomnia
Nervous system disorders	Headache	Silures, 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

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
• Saudi Arabia:
The National Pharmacovigilance and Drug Safety Centre (NPC)
Fax: +966-11-205-7662
Call NPC at +966-11-2038222,
Ext: 2317-2356-2340.
Toll free phone: 19999
E-mail: npc.drug@sfda.gov.sa
Website: www.sfda.gov.sa/npc
• Other GCC States:
− Please contact the relevant competent authority.

There have been reports of overdose with Duracan 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%.

Antimycotics for systemic use, triazole derivatives, ATC code: J02AC01.
Mode 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 and
Cryptococcus. gattii as well as the endemic moulds Blastomyces dermatiditis,
Coccidioides immitis, Histoplasma capsulatum and Paracoccidioides brasiliensis

PK/PD 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.
Mechanism(s) 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 breakpointsA S≤/R>
	Candida albicans	Candida glabrata	Candida krusei	Candida parapsilosis	Candida tropicalis
Fluconazole	2/4	IE	--	2/4	2/4	2/4

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

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.

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 selective inhibitor of the isozymes
CYP2C9 and CYP3A4 (see section 4.5). Fluconazole is also an inhibitor of the isozyme
CYP2C19.
Excretion
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 in chlidren
Pharmacokinetic data were assessed for 113 paediatric patients from 5 studies; 2 singledose
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 Cmax 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 Cmax. 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.

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.
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).

Lactose Anhydrous
• Crospovidone NF
• Magnesium Stearate
• Colloidal Silicon Dioxide (Aerosil 200)
• ECG- Duracan (1,Blue/Blue)

Not applicable.

2 years.

Do not store above 30°C.

Alu-PVC/PVDC Blister

Not applicable.