Candivast is indicated in the following fungal infections:

 

• Candivast 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.

 

• Candivast 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)).

 

• Candivast is indicated in term newborn infants, infants, toddlers, children, and adolescents aged from 0 to 17 years old:

Candivast  is  used  for  the  treatment  of  mucosal  candidiasis  (oropharyngeal, oesophageal), invasive candidiasis, cryptococcal meningitis and the prophylaxis of candidal infections in immunocompromised patients. Candivast 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.

(See Section 5.2 Pharmacokinetic properties-special patient population)

 

• 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 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 daily	Indefinitely at a daily dose of 200 mg
Coccidioidomycosis		200 mg to 400 mg	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 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 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 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 daily	7 to 21 days. Longer periods may be used in patients with severely compromised immune function.
	- Chronic atrophic candidiasis	50 mg daily	14 days
	- Chronic mucocutaneous candidiasis	50mg to 100 mg 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 daily or 200 mg 3 times per week	An indefinite period for patients with chronic immune suppression
	- Oesophageal candidiasis	100 mg to 200 mg 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	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 dialysis)	50%
Regular dialysis	100% after each dialysis

 

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. Diflucan 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 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 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 daily	Depending on the severity of the disease
- Prophylaxis of Candida in immunocompromised patients	Dose: 3 to 12 mg/kg 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

Diflucan 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 Lists of excipients). • Coadministration of terfenadine is contraindicated in patients receiving candivast 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 Special warning and precautions for use and 4.5 Interaction with other medicinal products and other forms of interaction).

• 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, candivast 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 and histoplasmosis is limited, which prevents specific dosing recommendations.

 

• Renal system

Candivast should be administered with caution to patients with renal dysfunction (See Section 4.2 Posology and method of administration).

 

• Hepatobiliary system

Candivast should be administered with caution to patients with liver dysfunction. Candivast  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 candivast. 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.

 

Candivast 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 Contraindications and Section 4.5 Interaction with other medicinal products and other forms of interaction).

 

• 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  Interaction  with  other  medicinal products and other forms of interaction).

 

• 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 Contraindications).

 

• Cytochrome P450

Fluconazole is a potent CYP2C9 inhibitor and a moderate CYP3A4 inhibitor. Fluconazole is  also  an  inhibitor  of  CYP2C19.  Candivast  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 Contraindications and Section 4.5 Interaction with other medicinal products and other forms of interaction).

 

• Excipients

Capsules contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, congenital galactosemia, glucose-galactose malabsorption should not take this medicine.

 

Concomitant use of the following other medicinal products are contraindicated:

• 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. Co-administration of cisapride is contra-indicated in patients receiving fluconazole (see section 4.3 Contraindications).

 

• 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 Contraindications). 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 de  pointes. Coadministration of fluconazole and astemizole is contraindicated (see section 4.3 Contraindications).

 

• 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 Contraindications).

 

• 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 Contraindications).

 

• 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 Contraindications).

 

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 Special warning and precautions for use).

 

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  has  resulted  in  a  25% decrease in the AVC and 20% shorter half-life of fluconazole. In patients receiving concomitant rifampicin, an increase in 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.

 

- 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. 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  co-administered  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 Contraindications).

 

• Alfentanil

During concomitant treatment with fluconazole (400 mg) and intravenous alfentanil (20 μg/kg) in healthy volunteers the alfentanil AUC₁₀ increased 2-fold, probably through inhibition of CYP3A4.Dose adjustment of alfentanil may be 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 coumarin- type 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 and felodipine) are metabolized by CYP3A4. Also verapamil is 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 C_max 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. The author judged that the patient died from fentanyl intoxication. ^FDA

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 C_max  and AUC of flurbiprofen was increased by 23% and 81%, respectively, when coadministered with fluconazole compared to administration of flurbiprofen alone. Similarly, the C_max 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 C_min 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_max 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 C_max and AUC_τ 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_max 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.

 

• Lactation

 

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 Special warning and precautions for use).

No studies have been performed on the effects of candivast on the ability to drive or use machines.

 

Patients should be warned about the potential for dizziness or seizures (see section 4.8 Undesirable  effects) while taking candivast 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 categories were used for the classification of undesirable effects: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, ≤1/100), rare (≥1/10,000, ≤1/1000), very rare (≤1/10,000). Adverse event frequencies have been estimated from spontaneous reports from post-marketing data.

 

Blood and the lymphatic system disorders

Uncommon     Anaemia

Rare                 Agranulocytosis, leukopenia, thrombocytopenia, neutropenia

 

Immune system disorders

Rare                 Anaphylaxis

 

Metabolism and nutrition disorders

Uncommon     Decreased appetite

Rare                 Hypercholesterolaemia, hypertriglyceridaemia, hypokalemia

 

Psychiatric disorders

Uncommon     Somnolence, insomnia

 

Nervous system disorders

Common         Headache

Uncommon     Seizures, paraesthesia, dizziness, taste perversion

Rare                 Tremor

 

Ear and labyrinth disorders

Uncommon     Vertigo

 

Cardiac disorders

Rare                Torsade de pointes (See Section 4.4 Special warnings and precautions for use), QT prolongation (See Section 4.4 Special warnings and  precautions for use)

 

Gastrointestinal disorders

Uncommon     Abdominal pain, vomiting, diarrhea, nausea

Rare                 Constipation, flatulence, dyspepsia, dry mouth

 

Hepatobiliary disorders

Common     Alanine  aminotransferase increased,  aspartate  aminotransferase increased, blood alkaline phosphatase increased (See Section 4.4 Special warnings and precautions for use).

Uncommon     Cholestasis, jaundice, bilirubin increased (See Section 4.4 Special warnings and precautions for use).

Rare                 Hepatic failure, hepatocellular necrosis, hepatitis, hepatocellular damage (See Section 4.4 Special warnings and precautions for use).

 

Skin and subcutaneous tissue disorders

Common         Rash (See Section 4.4 Special warnings and precautions for use)

Uncommon         pruritus, Drug eruption, increased sweating, urticaria (See Section 4.4 Special warnings and precautions for use)

Rare                Toxic epidermal necrolysis, Stevens-Johnson syndrome, angioedema, face oedema, alopecia,  acute  generalised  exanthematous-pustulosis, dermatitis exfoliative (See Section 4.4 Special warnings and precautions for use).

Unknown        Painful skin or blistering

 

Musculoskeletal and connective tissue disorders

Uncommon     Myalgia

 

General disorders and administration site conditions

Uncommon     Fatigue, malaise, asthenia, fever

 

• Pediatric Population: The pattern and incidence of adverse reactions and laboratory abnormalities recorded during pediatric clinical trials are comparable to those seen in adults.

• Signs and symptoms

There have been reports of overdose with fluconazole accompanied by hallucination and paranoid behavior.

 

• Treatment

In the event of overdose, symptomatic treatment (with supportive measures and gastric lavage if clinically indicated) may be adequate.

 

Fluconazole is largely excreted in urine, forced volume diuresis would probably increase the elimination rate. A three-hour hemodialysis session decreases plasma levels by approximately 50%.

• ATC classification

Pharmacotherapeutic group: 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 super infection 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>
Fluconazole	Candida albicans	Candida glabrata	Candida krusei	Candida parapsilosis	Candida tropicalis
	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.

 

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 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.

 

• Special population

- 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.

 

- 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.

 

- 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_max  was 1.54 µg/ml and occurred at 1.3 hours post-dose. The mean AUC was 76.4 ± 20.3 µg•h/ml, and the mean terminal half-life was 46.2 hours. These pharmacokinetic parameter values are higher than analogous values reported for normal young male volunteers. Coadministation of diuretics did not significantly alter AUC or C_max.

 

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 reduce 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 2-7 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 parturation 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 Pharmacodynamic properties).

- Lactose monohydrate,

- Sodium starch glycolate,

- Colloidal silicon dioxide,

- Magnesium stearate.

None.

36 months.

Store in a dry place below 30°C.

Keep out of reach and sight of children.

Blisters.

Pack size: 1 capsules.

None.