FLUCONAZOLE 100 MG CAPSULES - summary of medicine characteristics

Fluconazole 100 mg Capsules

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 100, mg fluconazole.

Excipient with known effect: Each tablet contains 97.5 mg of lactose (as lactose monohydrate)

For the full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Hard gelatine capsule

Blue cap, white body with the imprint FC100, containing a white odourless powder,

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Treatment of mycoses caused by yeast fungi (Candida and cryptococci), in particular:

– systemic candidiasis including candidaemia, candiduria, disseminated and other invasive, especially in risk patients potentially life-threatening candidal infections, such as infections of peritoneum, lung and urinary tract.

Fluconazole may be used in patients with malignancies, in patients in intensive care units, on cytostatic or immunosuppressive therapy

– cryptococcal meningitis. Immunocompromised patients (e. g with AIDS or after organ transplantation) may also be treated.

superficial mucosal candidiasis such as

recurrent oropharyngeal and oesophageal candidiasis

chronic-atrophic oral candidiasis (infection of the oral cavity in patients with dentures, in whom dental hygiene or topical measures are not sufficient)

non-invasive bronchopulmonary candidiasis (infection of the mucosa of the upper respiratory tract)

– Fluconazole is also indicated as therapeutic trial to prevent cryptococcal meningitis (relapse prophylaxis) in AIDS patients.

– Prevention of candidiasis in patients with malignancies during chemotherapy or radiotherapy and in immunocompromised patients (e.g. in AIDS or chemotherapy).

– Fungal infections of the skin including dermatomycosis like tinea

corporis/cruris/pe­dis and Pityriasis versicolor identified by direct microscopy and/or

positive culture and where systemic therapy should be considered accordingly.

– Acute and recurrent vaginal candidiases which do not respond to local therapy.

Consideration should be given to official guidance on the appropriate use of antifungal agents. Not all indications are applicable for paediatric patients; see details in section 4.2.

Note:

Not all strengths are suitable for each indication (see section 4.2).

4.2 Posology and method of administration

The dosage of Fluconazole is determined by the type and severity of the infection, by the sensitivity of the causative pathogen(s) as well as by the patient's age, bodyweight and renal function. Depending on the condition, oral or parenteral treatment can be initiated. The duration of treatment depends on the severity and the clinical course of the disease.

Oral pharmaceutical forms and solutions for infusion are available for therapy. Conversion from intravenous to oral administration or vice versa does not require any alteration in the daily dosage.

Administration in adults:

Fluconazole 50 mg/- 100 mg/- 200 mg Capsules

Systemic candidiasis

Initiation of therapy usually with 400 mg fluconazole once daily on the first therapeutic day, afterwards continuation of therapy with 200 mg fluconazole once daily. As required, the dose may be increased to 400 mg fluconazole once daily over the entire duration of treatment.

The duration of administration depends on the clinical efficacy while monitoring laboratory values (see section 4.8). It is recommended to continue therapy until the laboratory studies exclude an identifiable fungal infection still present up to now. Insufficient duration of treatment may lead to a relapse of the infection.

Cryptococcal meningitis

Therapy of cryptococcal meningitis:

Initiation of therapy usually with 400 mg fluconazole once daily on the first therapeutic day, afterwards continuation of therapy with 200 mg fluconazole once daily. As required, the dose should be increased to 400 mg fluconazole once daily over the entire duration of treatment.

The duration of administration is generally 6–8 weeks.

Fluconazole 50/-100 mg Capsules.

Candiduria:

50 mg fluconazole once daily. In severe courses of the disease, the dose may be increased to 100 mg fluconazole once daily as required.

The duration of administration is 14–30 days.

Candidiasis of superficial mucosae

Recurrent oropharyngeal candidiasis:

50 mg fluconazole once daily. In severe, especially recurrent courses of the disease, the dose may be increased to 100 mg fluconazole once daily as required.

The duration of administration is 7–14 days. In case of severe immunocompromised patients the duration of therapy may be prolonged.

Recurrent oesophageal candidiasis:

50 mg fluconazole once daily. In severe, especially recurrent courses of the disease, the dose may be increased to 100 mg fluconazole once daily as required.

The duration of administration is 14–30 days.

Chronic-atrophic candidiasis in patients with dentures:

50 mg fluconazole once daily. In addition, dental hygiene should be carried out as well as locally disinfectant measures taken.

The duration of administration is 14 days.

Non-invasive bronchopulmonary candidiasis:

50 mg fluconazole once daily. In severe courses of the disease, the dose may be increased to 100 mg fluconazole once daily as required.

The duration of administration is 14–30 days.

Prophylaxis of cryptococcal meningitis:

After treatment of cryptococcal meningitis is terminated in AIDS patients (see above), a therapeutic trial for prevention (relapse prophylaxis) should be carried out with a dose of 100–200 mg fluconazole once daily while monitoring laboratory values (see also section 4.8). Experience to date results from therapeutic periods up to 25 months.

Fluconazole 50 mg Capsules:

Prevention of candidiases

In patients with malignancies during chemotherapy or radiotherapy and in immunocompromised patients (e.g. in AIDS or chemotherapy).

1. 50 mg fluconazole once daily to prevent candidiasis in immunocompromised patients (see also section 4.8).

2. In patients during cytotoxic chemotherapy or radiotherapy if systemic candidiasis is to be expected e. g. due to occurring potentiated or prolonged neutropenic phase, administration of 400 mg fluconazole once daily is advisable. Administration of fluconazole should be initiated 2–3 days prior to the anticipated onset of neutropenia and continued a further 7 days after the neutrophile number has increased to more than 1000 cells per mm3.

In patients with malignancies, yeast prophylaxis should be performed during the therapeutic duration of chemotherapy or radiotherapy.

Dermal infections:

Tinea corporis/cruris, Pityriasis versicolor:

50 mg once daily or 150 mg once weekly for 2–4 weeks.

Tinea pedis:

50 mg once daily for up to 6 weeks.

Fluconazole 50/- 150 mg Capsules:

Vaginal candidiasis

As far as not prescribed otherwise, 150 mg fluconazole is taken as a single dose.

Fluconazole is predominantly excreted with urine in unchanged form. As it is single dose therapy, no adjustment according to the degree of renal dysfunction is necessary.

Administration of Fluconazole 150 mg Capsules is usually limited to a single dose.

Administration in elderly patients

In elderly patients without any evidence of impaired renal function, the usual dose recommendations should be heeded. If creatinine clearance is below 50 ml/min, the dosage should be adjusted according to the guidelines for patients with impaired renal function.

Administration in children in missing therapeutic alternative

Especially the pharmaceutical forms solution for oral intake and powder/granules for oral suspension are advisable for oral use in children.

Fluconazole should not be used in children of less than 16 years except in case of no therapeutic alternative, as efficacy and safety has not been sufficiently shown. The subsequent daily dosages are recommended for children:

Mucous membrane candidiasis: The recommended dosage of fluconazole is 3 mg/kg daily. A loading dose of 6 mg/kg may be used on the first day to achieve steady state levels more rapidly.

Systemic candidal/cryp­tococcal infections: Recommended dose is 6–12 mg/kg daily, depending on the severity of infection.

Prevention of candida infections in neutropenic children: 3–12 mg/kg daily depending on the extent and duration of the neutopenia (see adult dosing).

In children with impaired renal function, the dose should be adjusted according to the guidelines for adults (see below), depending on the degree of renal function impairment.

Patients (adult and paediatric) with impaired renal function

Fluconazole is predominantly excreted with urine in unchanged form. No adjustments in single dose therapy are required. Patients with impaired renal function (creatinine clearance <50 ml/min) should receive – if several doses of Fluconazole are administered – an initial dose between 50 mg/day and 400 mg/day on therapeutic day 1. Afterwards, the dosage intervals or the daily dose for the relevant indication should be adjusted according to creatinine clearance as follows:

Creatinine clearance is calculated as follows:

Men:

bodyweight in kg x (140 – age in years)

72 x serum creatinine (mg/100 ml)

Women:

above value x 0.85

Mode of administration

The hard capsules are to be taken unchewed together with sufficient liquid. They may be taken prior to or with a meal.

4.3 Contraindications

Hypersensitivity to fluconazole, other azole derivatives or to any of the excipients listed in section 6.1.

Co-administration 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, amiodarone, and erythromycin are contraindicated in patients receiving fluconazole (see sections 4.4 and 4.5).

Co-administration of terfenadine is contraindicated in patients receiving fluconazole at multiple doses of 400 mg per day or higher based upon results of a multiple dose interaction study.

4.4 Special warnings and precautions for use

Tinea capitis

Fluconazole has been studied for treatment of tinea capitis in children. It was shown not to be superior to griseofulvin and the overall success rate was less than 20%.

Therefore, fluconazole should not be used for tinea capitis.

Cryptococcosis

The evidence for efficacy of fluconazole in the treatment of cryptococcosis of other sites (e.g. pulmonary and cutaneous cryptococcosis) is limited, which prevents dosing recommendations.

Deep endemic mycoses

The evidence for efficacy of fluconazole in the treatment of other forms of endemic mycoses such as paracoccidioi­domycosis, lymphocutaneous sporotrichosis and histoplasmosis is limited, which prevents specific dosing recommendations.

In some patients, particularly those with serious underlying diseases such as AIDS and cancer, abnormalities in haematological, hepatic, renal and other biochemical function test results have been observed during treatment with Fluconazole but the clinical significance and relationship to treatment is uncertain.

Hepatobiliary system

Fluconazole should be administered with caution to patients with liver dysfunction. Fluconazole has been associated with rare cases of serious hepatic toxicity including fatalities, primarily in patients with serious underlying medical conditions. Rarely, patients who died with severe underlying disease and who had received multiple doses of Fluconazole had post-mortem findings which included hepatic necrosis. These patients were receiving multiple concomitant medications, some known to be potentially hepatotoxic, and/or had underlying diseases which could have caused the hepatic necrosis.

No obvious relationship between hepatotoxicity and total daily dose of fluconazole, duration of therapy, gender or age of the patient has been observed. As a causal relationship with Fluconazole cannot be excluded, patients who develop abnormal liver test values or significant increases of originally abnormal levels during treatment 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. Fluconazole should be discontinued if clinical signs or symptoms consistent with liver disease develop that may be attributable to fluconazole. The benefits of the treatment should be evaluated against the risks of developing serious liver damage if therapy is continued in patients whose liver enzyme values rise during fluconazole treatment. In most cases, liver toxicity has been reversible at discontinuation of the treatment.

Cardiovascular system

Some azoles, including fluconazole, have been associated with QT-interval prolongation on the electrocardiogram. During post-marketing surveillance, very rare cases of QT prolongation and torsade de pointes during treatment with fluconazole have been reported. 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. Although the association of fluconazole and QT-prolongation has not been fully established, fluconazole should be used with caution in patients with potentially proarrythmic conditions such as:

Congenital or documented acquired QT prolongation

Cardiomyopathy, in particular when heart failure is present

Sinus bradycardia

Existing symptomatic arrhythmias

Concomitant medication not metabolised by CYP3A4 but known to prolong

QT interval (see section 4.3 and 4.5).

Electrolyte disturbances such as hypokalaemia, hypomagnesaemia and hypocalcaemia (which should be corrected prior to initiation of fluconazole treatment).

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).

Halofantrine

Halofantrine has been shown to prolong QTc at the recommended therapeutic dose and is a substrate of CYP3A4. The concomitant use of fluconazole and halofantrine is 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 with many medicinal products. If a rash develops in a patient treated for a superficial fungal infection, which is considered attributable to fluconazole, further therapy with this agent should be discontinued. If patients with invasive/systemic fungal infections develop rashes, they should be monitored closely and fluconazole should be discontinued if bullous lesions or erythema multiforme develop.

Hypersensitivity

Anaphylactic reactions in rare cases have been reported (see section 4.3 and 4.8).

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine because it contains lactose.

Renal system

Fluconazole should be administered with caution in patients with renal dysfunction (see section 4.2).

The dose of fluconazole must be reduced when creatinine clearance is below 50 ml/min (see section 4.2).

In women of child-bearing potential, appropriate contraceptive measures should be considered in case long-term treatment is indicated (see section 4.6.).

In addition for Fluconazole 200 mg Capsules:

Ponceau 4R (E 124) may cause allergic reactions.

(Cytochrome P450

Fluconazole is a potent CYP2C9 inhibitor and a moderate CYP3A4 inhibitor.

Fluconazole is also an inhibitor of CYP2C19. Fluconazole treated patients who are concomitantly treated with drugs with a narrow therapeutic window metabolised through CYP2C9, CYP2C19 and CYP3A4, should be monitored see section 4.5).

Adrenal insufficiency

Ketoconazole is known to cause adrenal insufficiency, and this could also although rarely seen be applicable to fluconazole.

Adrenal insufficiency relating to concomitant treatment with Prednisone is described in section 4.5

4.5 Interaction with other medicinal products and other forms of interaction

Cisapride (CYP3A4 substrate): There have been reports about cardiac cases including torsades de pointes in patients receiving fluconazole concomitantly with cisapride. Concomitant treatment with fluconazole and cisapride is contra-indicated (see section 4.3). 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.

Terfenadine (with doses of 400 mg fluconazole or higher; CYP3A4 substrate): Due to the occurrence of serious cardiac dysrhythmias secondarily to prolongation of the QTc-interval in patients on treatment with azole antifungals products concomitantly with terfenadine, interaction studies have been performed. One study with 200 mg fluconazole daily did not show any prolongation of the QTc-interval. Another study with 400 mg and 800 mg fluconazole daily showed that fluconazole in doses of 400 mg or more daily significantly increases the plasma level of terfenadine, if the two medicinal products are taken concomitantly. Concomitant treatment with terfenadine and fluconazole doses of 400 mg or more is contra-indicated. At fluconazole doses below 400 mg, the patient should be closely monitored.

Astemizole (CYP3A4 substrate): Concomitant administration of fluconazole with astemizole may decrease the clearance of astemizole. Astemizole overdoses have led to prolonged QT interval and severe ventricular arrhythmia, rare occurrences of torsades de pointes and cardiac arrest. Concomitant treatment with fluconazole and astemizole is contra-indicated due to the potential for serious, even fatal, cardiac effects.

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.

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).

Amiodarone: Concomitant administration of fluconazole with amiodarone may result in inhibition of amiodarone metabolism. Use of amiodarone has been associated with QT prolongation. Co-administration of fluconazole and amiodarone is contraindicated (see section 4.3).

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

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. This combination should be avoided.

Concomitant use of the following other medicinal products lead to precautions

and dose adjustments:

Medicinal products affecting the metabolism of fluconazole:

Hydrochlorothi­azide: In a pharmacokinetic interaction study, coadministration of multiple-dose hydrochlorothiazide to healthy volunteers receiving fluconazole increased plasma concentration of fluconazole by 40%. An effect of this magnitude should not necessitate a change in the fluconazole dose regimen in subjects receiving concomitant diuretics1.

1

Mesure R. Protocol 245. An open placebo-controlled crossover study to determine any effect of concomitant diuretic treatment on fluconazole pharmacokinetics in healthy volunteers.

Rifampicin (CYP450 inducer): Concomitant intake of fluconazole and rifampicin resulted in a 25 % reduction of AUC and 20 % shorter half-life of fluconazole. Increase of dosage should be considered in patients concomitantly receiving rifampicin.

Effect of fluconazole on the metabolism of other medicinal products: Fluconazole is a potent inhibitor of cytochrome P450 (CYP) isoenzyme 2C9 and a moderate inhibitor of CYP3A4. Fluconzole is also an inhibitor of the isozyme CYP2C19. Besides the observed/documented interactions listed below there is a risk of increased plasma concentrations of other medicinal products metabolised by CYP2C9 or CYP3A4 (e.g. ergot-alkaloids, quinidine) when co-administered with fluconazole. Therefore, care should always be taken when using these combinations and the patients should be carefully monitored. The enzyme-inhibiting effect of fluconazole may persist for 4–5 days after end of fluconazole treatment due to the long half-life of fluconazole (see section 4.3).

Alfentanil (CYP3A4 substrate): A study observed reduction in clearance and distribution volume as well as prolongation of T^ of alfentanil following concomitant treatment with fluconazole. Concomitant intake of fluconazole 400 mg and alfentanil 20 |ig/kg intravenously in healthy volunteers increased the alfentanil AUC10 by approximately 2-fold and decreased the clearance by 55 %, probably through inhibition of CYP3A4. When using these combinations a dose adjustment may be required.

Amitriptyline, nortriptyline: Fluconazole increases the effect of amitriptyline and nortriptyline. 5– nortriptyline and/or S -amitnptyline may be measured at initiation of the combination therapy and after one week. Several case reports have described the development of increased amitriptyline concentrations and signs of tricyclic toxicity when amitriptyline was used in combination with fluconazole. Coadministration of fluconazole with nortriptyline, the active metabolite of amitriptyline, has been reported to result in increased nortriptyline levels. Due to the risk of amitriptyline toxicity, consideration should be given to monitoring amitriptyline levels and making dose adjustments as may be necessary.

Anticoagulants (CYP2C9 substrate): In an interaction study, fluconazole increased the prothrombin time (12%) after warfarin administration in healthy males. Concomitant intake of fluconazole during warfarin treatment has been shown to prolong the prothrombin time up to 2-fold. In post-marketing experience, as with other azole antifungals, bleeding events (bruising, epistaxis, gastrointestinal bleeding, hematuria and melena) have been reported in association with increase 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 warfarin metabolism via CYP2C9. The prothrombin time must be closely monitored in patients on treatment with coumarin derivatives or indanedione. Dose adjustment of the anticoagulant may be necessary.

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.

Benzodiazepines (Short Acting) (CYP3A4 substrate): Following oral administration of midazolam, fluconazole resulted in substantial increase in midazolam concentrations and psychomotor effects. This effect on midazolam appears to be more pronounced following oral administration of fluconazole than with fluconazole administered intravenously. Concomitant intake of fluconazole 400 mg and midazolam 7.5 mg orally increased the midazolam AUC and half-life 3.7– fold and 2.2-fold, respectively. Fluconazole given concurrently with triazolam (single dose) increased the AUC by approximately 50%, Cmax with 20–32% and increased t^ by 25–50 % due to the inhibition of metabolism of triazolam. Dosage adjustments of triazolam may be necessary. Potentiated and prolonged effects of triazolam have been observed at concomitant treatment with fluconazole. If it is necessary to treat patients with a benzodiazepine concomitantly with fluconazole, a reduction of the benzodiazepine dose should be considered, and the patients should be closely monitored.

Calcium channel antagonists (CYP3A4 substrates): Some dihydropyridine calcium channel antagonists, including nifedipine, isradipine, nicardipine, amlodipine, verapamil and felodipine, are metabolised via CYP3A4.

Fluconazole has the potential to increase the systemic exposure of the calcium channel antagonists. Literature reports have documented substantial peripheral oedema and/or elevated calcium antagonist serum concentrations during concurrent use of itraconazole and felodipine, isradipine, or nifedipine. An interaction might also occur with fluconazole. Frequent monitoring for adverse events is recommended.

Carbamazepine (CYP3A4 substrate): Due to the CYP3A4-inhibiting effect of fluconazole concomitant treatment with carbamazepine may lead to increased plasma levels of carbamazepine by 30%. There is a risk of developing carbamazepine toxicity. The literature includes reports that document increased undesirable effects described for carbamazepine e. g. vertigo, unsteady gait and diplopia. For this reason, the carbamazepine plasma concentration should be checked if such symptoms occur and the dose be reduced if necessary.

Celecoxib (CYP2C9 substrate): In a clinical study, concomitant treatment with Fluconazole 200 mg daily and celecoxib 200 mg resulted in 68 % and 134 % increase in celecoxib Cmax and AUC, respectively. The interaction is believed to be due to the inhibition of cytochrome P450 2C9 metabolism of celecoxib. Halving the Celecoxib dose is recommended to patients concurrently treated with fluconazole.

Cyclosporin (CYP 3A4 substrate): Fluconazole significantly increases the concentration and AUC of ciclosporin. Clinically significant interactions with cyclosporin have been shown at fluconazole doses of 200 mg and higher. In a pharmacokinetic study with renal transplant patients receiving fluconazole200 mg daily and cyclosporin 2.7 mg/kg/day, there was a 1.8-fold increase in cyclosporin AUC and a 55 % decrease in clearance. It is recommended to follow the cyclosporin plasma concentrations in patients on treatment with fluconazole. This combination may be used by reducing the dosage of ciclosporin depending on ciclosporin concentration.

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 possible fentanyl fluconazole interaction was reported. The author judged that the patient died from fentanyl intoxication. Furthermore, in a randomized crossover study with twelve healthy volunteers it was shown that fluconazole delayed the elimination of fentanyl significantly. Elevated fentanyl concentration may lead to respiratory depression. Dosage adjustment of fentanyl may be necessary.

Didanosine: Coadministration of didanosine and fluconazole appears to be safe and has little effect on didanosine pharmacokinetics or efficacy. However, it is important to monitor fluconazole response. It may be advantageous to stagger fluconazole dosing to a time prior to didanosine administration.

Halofantrine (CYP3A4 substrate): Drugs that inhibit CYP3A4 lead to an inhibition of halofantrine metabolism and can cause in increase in plasma concentrations of halofantrine. 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.

HMG-CoA reductase inhibitors (CYP2C9 or CYP3A4 substrates): The risk of myopathy and rhabdomyolysis is increased when fluconazole is administered concurrently with HMG-CoA reductase inhibitors that are metabolised via CYP3A4, such as atorvastatin and simvastatin, or via CYP2C9, such as fluvastatin. Up to 200 % individual increases in the area under the curve (AUC) of fluvastatin may occur as a result of the interaction between fluvastatin and fluconazole. Caution is warranted if concurrent administration of fluconazole and HMG-CoA reductase inhibitors is deemed necessary. The combination may require a dose reduction of the HMG-CoA reductase inhibitors. If concomitant therapy is necessary, patients should be monitored for signs and symptoms of myopathy or rhabdomyolysis and creatine kinase (CK) levels. HMG-CoA therapy should be discontinued if CK levels show a marked increase, or if myopathy or rhabdomyolysis is diagnosed or suspected.

Losartan (CYP2C9 substrate): Fluconazole inhibits the conversion of losartan to its active metabolite (E-3174), which is responsible for a large part of the angiotensin II receptor antagonism that occurs with losartan therapy. Concomitant treatment with fluconazole might lead to increased concentrations of losartan and decreased concentrations of the active metabolite. It is recommended that patients receiving the combination be monitored for continued control of their hypertension.

Methadone: Fluconazole may enhance the serum concentration of methadone. Dosage 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 dosage of NSAIDs may be needed.

Oral contraceptives: Two pharmacokinetic studies have been performed with a combined oral contraceptive and multiple dosing of fluconazole. 50 mg fluconazole did not influence any of the hormone concentrations, but 200 mg daily increased AUC of ethinyloestradiol and levonorgestrel with 40 % and 24 %, respectively. Thus, it is hardly likely that multiple dosing of fluconazole at these doses has an influence on the effect of the combined oral contraceptive.

In a 300 mg once weekly fluconazole study, the AUCs of ethinyl estradiol and norethindrone were increased by 24% and 13%, respectively.

Endogenous steroid Fluconazole 50 mg daily does not affect endogenous steroid levels in females: 200–400 mg daily has no clinically significant effect on endogenous steroid levels or on ACTH stimulated response in healthy male volunteers.

Phenytoin (CYP2C9 substrate): Fluconazole inhibits the hepatic metabolism of phenytoin. Repeated concomitant administration of fluconazole and phenytoin may increase the levels of phenytoin to a clinically significant degree. Intake of fluconazole 200 mg concomitantly with phenytoin 250 mg intravenously increased the phenytoin AUC by 75 % and Cmin by 128 %. If it is necessary to administer both substances concomitantly, the phenytoin concentration must be controlled, and the phenytoin dose adjusted, in order to avoid toxic concentrations and maintain therapeutic levels.

Prednisone (CYP3A4 substrate): A liver transplant recipient receiving prednisone experienced an Addisonian crisis when a three-month course of fluconazole was discontinued. The withdrawal of fluconazole likely caused an increase in CYP3A4 activity, leading to an increase in the degradation of prednisone. Patients receiving long-term therapy with fluconazole and prednisone should be closely monitored for signs of adrenal cortex insufficiency when fluconazole is withdrawn.

Rifabutine (CYP3A4 substrate): Reports about interaction with administration of fluconazole concomitantly with rifabutine have appeared, leading to increased serum levels of rifabutine and increase in the AUC of rifabutin up to 80%. Uveitis in patients treated concomitantly with fluconazole and rifabutine has been reported. Patients who receive rifabutine and fluconazole concomitantly must be closely followed and symptoms of rifabutin toxicity should be taken into consideration.

Saquinavir: Fluconazole increases the AUC of saquinavir with approximately 50%, Cmax with approximately 55% and decreases clearance of saquinavir with approximately 50% 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. Dosage adjustment of saquinavir may be necessary.

Sulphonyl urea (CYP2C9 substrate): It has been demonstrated that fluconazole prolongs the plasma half-life of concomitantly administered sulphonyl urea (chlorpropamide, glibenclamide, glipizide and tolbutamide) in healthy

volunteers. Fluconazole and oral sulphonyl urea derivatives may be used concomitantly to diabetics, but the possibility of development of hypoglycaemia must be kept in mind and blood glucose levels closely monitored frequently. An appropriate reduction of sulfonylurea dosage is recommended during co-administration.

Everolimus: Although not studied in vivo or in vitro, fluconazole may increase serum

concentrations of everolimus through inhibition of CYP3A4.

Tacrolimus and sirolimus (CYP3A4 substrates): There have been reports that an interaction exists when fluconazole is administered concomitantly with tacrolimus, leading to increased serum levels of 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 and also increases plasma concentrations of sirolimus presumably by inhibiting the metabolism of sirolimus via CYP3A4 and P-glycoprotein. Dosage of orally administered tacrolimus should be decreased depending on tacrolimus concentration. No significant pharmacokinetic changes have been observed when tacrolimus is given intravenously. Increased tacrolimus levels have been associated with nephrotoxicity. Concomitant intake of fluconazole and tacrolimus 0.15 mg/kg b. i. d. increased tacrolimus Cmin 1.4 and 3.1-fold with fluconazole doses of 100 mg and 200 mg, respectively. Renal toxicity has been reported in patients concomitantly receiving fluconazole and tacrolimus. Although no interaction studies have been conducted with fluconazole and sirolimus, a similar interaction as with tacrolimus might be expected. Patients who receive tacrolimus or sirolimus and fluconazole concomitantly must be closely monitored for tacrolimus/si­rolimus plasma levels and toxicity. These combinations may be used with a dosage adjustment of sirolimus depending on the effect/concen­tration measurements.

Theophylline: In a placebo controlled interaction study, intake of fluconazole 200 mg for 14 days resulted in 18 % decrease in the mean plasma clearance of theophylline. Patients on treatment with high doses of theophylline or with other reason to be at increased risk of theophylline toxicity should be carefully observed for signs of theophylline toxicity during fluconazole therapy, and the theophylline dose should be adjusted as necessary 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 AUCt 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.

Trimetrexate: Fluconazole may inhibit the metabolism of trimetrexate, leading to increased trimetrexate plasma concentrations. If the combination cannot be avoided, trimetrexate serum levels and toxicity should be closely monitored.

Zidovudine: Two kinetic studies resulted in increased levels of zidovudine most likely caused by the decreased conversion of zidovudine to its major metabolite. One study determined zidovudine levels in AIDS or ARC patients before and following fluconazole 200 mg daily for 15 days. There was a significant increase in zidovudine AUC (20%). A second randomised, two-period, two-treatment cross-over study examined zidovudine levels in HIV infected patients. On two occasions, 21 days apart, patients received zidovudine 200 mg every eight hours either with or without fluconazole 400 mg daily for seven days. Fluconazole increases Cmax and AUC of zidovudine by 85% and 75%, respectively, due to an approx. 45% decrease in oral zidovudine clearance. The increase in AUC is, probably due to inhibition of the glucuronidation. The half life of zidovudine was likewise prolonged by approximately 128% following combination therapy with fluconazole. Dosage reduction of zidovudine may be considered. Patients receiving this combination must be controlled for zidovudine related side-effects.

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.

Pharmacodynamic interactions

Medicinal products that prolong QT interval: Case reports indicate that fluconazole might have the potential to induce QT prolongation leading to serious cardiac arrhythmia. Patients treated concomitantly with fluconazole and other drugs that prolong QT interval should be carefully monitored, since an additive effect cannot be excluded.

Amphotericin B: In vitro and in vivo animal studies have found antagonism between amphotericin B and azole derivatives. The mechanism of action of imidazoles is to inhibit ergosterol synthesis in fungal cell membranes. Amphotericin B acts by binding to sterols in the cell membrane and changing membrane permeability. Clinical effects of this antagonism are to date unknown, and a similar effect may occur with amphotericin B cholesteryl sulfate complex. 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 drugs in systemic infection with A. fumigatus. The clinical significance of results obtained in these studies is unknown.

Interaction studies have shown that no clinically significant change in absorption of fluconazole occurs with oral use together with food, cimetidine, antacids or after radiation therapy of the whole body in connection with bone marrow transplantation.

Physicians should be aware that drug-drug interaction studies with other medications have not been conducted, but that such interactions may occur.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are reports on multiple congenital abnormalities (including brachycephalia, ears dysplasia, giant anterior fontanelle, femoral bowing and radio-humeral synostosis) in children whose mothers were treated for 3 months or longer with high doses (400–800 mg/day) of fluconazole for coccidioidal mycosis. The relationship between these effects and fluconazole is unclear.

Studies in animals have shown teratogenic effects and reproductive toxicity (see section 5.3), but the potential risk in humans is unknown.

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 increased risk of undesirable effects in the foetus.

Fluconazole in standard doses and short-term treatment should not be used during pregnancy unless clearly necessary.

Fluconazole in high doses or in prolonged regimens should not be used during pregnancy except for 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.

4.7 Effects on ability to drive and use machines

Fluconazole has no or negligible influence on the ability to drive and use machines

However when driving vehicles or operating machines it should be taken into account that occasionally dizziness or seizures may occur.

4.8 Undesirable effects

Fluconazole is generally well tolerated.

In some patients, particularly those with serious underlying diseases such as AIDS and cancer, changes in renal and hematological function test results and hepatic abnormalities (see section 4.4) have been observed during treatment with fluconazole and comparative agents, but the clinical significance and relationship to treatment is uncertain

The following undesirable effects have been observed and reported during treatment with fluconazole with the following frequencies: Very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1000, <1/100), rare (> 1/10000, <1/1000) and very rare (>1/10000), not known (cannot be estimated from the available data).

The pattern and incidence of side effects and laboratory abnormalities recorded during paediatric clinical trials are comparable to those seen in adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the yellow card scheme at www.mhra.gov.uk/yellowcard

4.9 Overdose

There have been reports of overdose with Fluconazole and hallucination and paranoid behaviur have been concomitantly reported.

In one case, a 42 year-old patient infected with human immunodeficiency virus developed hallucinations and exhibited paranoid behaviour after reportedly ingesting 8200mg of fluconazole, unverified by his physician. The patient was admitted to the hospital and his condition resolved within 48 hours.

In case of overdosing the treatment is symptomatic with supporting measures and gastric lavage, if necessary. Fluconazole is mainly excreted in the urine. Forced volume diuresis will probably increase the elimination rate.

Haemodialysis for 3 hours decreases the plasma levels with approx. 50%.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic Group

Antimycotics for systemic use, triazole derivatives

ATC code: J02AC01

Fluconazole is a triazole derivative with fungistatic effect, which specifically inhibits the synthesis of the fungi’s ergosterol, which is believed to lead to defects in the cell membrane. Fluconazole is highly specific for fungal cytochrome P-450 enzymes. Doses of fluconazole 50 mg daily for 28 days have not been shown to influence serum levels of testosterone in men or the steroid concentration in fertile women.

The spectrum of application includes a number of pathogens including Candida albicans and non-Candida albicans species, Cryptococcus spp and dermatophytes. Candida krusei is resistant to fluconazole. Forty percent of

Candida glabrata are primarily resistant to fluconazole. Infections caused by Aspergillus-species should not be treated with fluconazole.

5.2 Pharmacokinetic properties

Absorption: Fluconazole is well absorbed after oral intake. The absolute bioavailability is above 90 %. The oral absorption is not affected by concomitant food intake. The maximum fasting plasma concentration is reached 0.5–1.5 hours after dose intake. 90 % of the steady-state level is reached 4–5 days after dosing once daily.

Plasma concentration is proportional to the dose. After administration of 200 mg of fluconazole, Cmax is around 4.6 mg/l and plasma concentrations at steady-state after 15 days are around 10 mg/l. After administration of 400 mg of fluconazole, Cmax is around 9 mg/l and plasma concentrations at steadystate after 15 days are around 18 mg/l.

Intake of a double dose on day 1 results in plasma concentrations of approx. 90 % of steady-state on day 2.

Distribution: The volume of distribution corresponds to the total body water. The protein binding in plasma is low (11–12 %).

The concentration in saliva corresponds to the plasma concentration. In patients with fungal meningitis the concentration of fluconazole in the cerebrospinal fluid is approx. 80 % of the corresponding plasma concentration.

In stratum corneum, epidermis-dermis and in exocrine sweat higher concentrations of fluconazole are reached compared to those in serum.

Fluconazole is accumulated in stratum corneum. At a dose of 150 mg once weekly the concentration of fluconazole in stratum corneum was after 2 doses 23.4 gg/g and 7 days after the second dosing it was still 7.1 gg/g.

Elimination: Fluconazole is mainly renally excreted. Approx. 80 % of the taken dose is excreted in the urine in non-metabolized form. Fluconazole clearance is proportional to the creatinine clearance. Circulating metabolites have not been demonstrated.

The half-life in plasma is approximately 30 hours.

Children eliminate fluconazole more rapidly than adults do. The half-life in children and adolescents of 5–15 years is between 15.2–17.6 hours.

5.3 Preclinical safety data

Preclinical data from conventional studies on repeat-dose/general toxicity, genotoxicity or carcinogenicity indicate no special hazard for humans not already considered in other sections of the SPC.

Reproductive toxicity: In reproduction toxicity studies in rat, an increased incidence of hydronephrosis was observed. Increases in fetal 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 (approximately 20–60× the recommended human dose) to 320 mg/kg embryolethality in rats was increased and fetal abnormalities included wavy ribs, cleft palate and abnormal cranio-facial ossification. These effects are consistent with the inhibition of oestrogen synthesis in rats and may be a result of known effects of lowered oestrogen on pregnancy, organogenesis and parturition. In reproduction toxicity studies in rabbits abortions were recorded.

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. Male rats treated with 5 and 10 mg/ kg/day had an increased incidence of hepatocellular adenomas.

Mutagenesis Fluconazole, with or without metabolic activation, was negative in tests for mutagenicity in 4 strains of S. typhimurium and in the mouse lymphoma L5178Y system. Cytogenetic studies in vivo (murine bone marrow cells, following oral administration of fluconazole) and in vitro (human lymphocytes exposed to fluconazole at 1000pg/ml) showed no evidence of chromosomal mutations.

Impairment of fertility 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, although the onset of parturition was slightly delayed at 20 mg/kg p. o. In an intravenous perinatal study in rats at 5, 20 and 40 mg/kg, dystocia and prolongation of parturition were observed in a few dams at 20 mg/kg and 40 mg/kg, but not at 5 mg/kg. 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. The effects on parturition in rats 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.

6.1

Lactose monohydrate, Gelatin,

Maize starch, Magnesium stearate, Sodium lauril sulfate, Colloidal silicon dioxide,

Titanium dioxide (E 171)

printing ink:

Shellac,

Black iron oxide (E 172),

Propylene glycol

Indigo carmine (E 132)

6.2 Incompatibilities

No incompatibilities are known to date.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Do not store above 25 °C.

6.5 Nature and contents of container

The hard capsules are packed in PVC white, opaque/aluminium blisters and inserted into a carton.

Pack sizes: 1, 7, 10, 14, 20, 30, 50 or 100 capsules.

Not all pack sizes may be marketed.