Fluconazole 2 Mg/Ml Solution For Infusion
SUMMARY OF PRODUCT CHARACTERISTICS
1. NAME OF THE MEDICINAL PRODUCT
Fluconazole 2 mg/ml Solution for Infusion
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Fluconazole 2mg/ml.
Each 25 ml contains 50 mg of fluconazole Each 50 ml contains 100 mg of fluconazole Each 100 ml contains 200 mg of fluconazole Each 200 ml contains 400 mg fluconazole
3. PHARMACEUTICAL FORM
Solution for infusion.
Clear, colourless solution
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
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.
Fluconazole is indicated for the treatment of the following infections when caused by fungi that are known or are likely to be fluconazole-susceptible.
• Genital candidiasis. Vaginal candidiasis, acute or recurrent. Candidal balanitis. The treatment of partners who present with symptomatic genital candidiasis should be considered.
• Mucosal candidiasis. These include oropharyngeal, oesophageal, non-invasive bronchopulmonary infections, candiduria, mucocutaneous and chronic oral atrophic candidiasis (denture sore mouth). Normal hosts and patients with compromised immune function may be treated.
• Systemic candidiasis including candidaemia, disseminated candidiasis and other forms of invasive candidal infection. These include infections of the peritoneum, endocardium and pulmonary and urinary tracts. Candidal infections in patients with malignancy, in intensive care units or those receiving cytotoxic or immunosuppressive therapy may be treated.
• For the prevention of fungal infections in immunocompromised patients considered at risk as a consequence of neutropenia following cytotoxic chemotherapy or radiotherapy, including bone marrow transplant patients.
• Cryptococcosis, including cryptococcal meningitis and infections of other sites (e.g. pulmonary, cutaneous). Normal hosts and patients with AIDS, organ transplants or other causes of immunosuppression may be treated. Fluconazole Infusion can be used as maintenance therapy to prevent relapse of cryptococcal disease in patients with AIDS.
• Tinea pedis, tinea corporis, tinea cruris, tinea versicolor and dermal Candida infections. Fluconazole Infusion is not indicated for nail infections and tinea capitis.
Consideration should be given to official guidance on the appropriate use of antifungal
agents.
4.2 Posology and method of administration
For intravenous infusion use.
Fluconazole is administered by intravenous infusion at a rate of approximately 5-10ml/min, dependent on the clinical state of the patient. On transferring from the intravenous route to the oral route or vice versa, there is no need to change the daily dose. Fluconazole Solution for Infusion is formulated in 0.9% sodium chloride solution, each 200 mg (100 ml bottle) containing 15 mmol each of Na+ and Cl-.
The daily dose of fluconazole should be based on the nature and severity of the fungal infection. Most cases of vaginal candidiasis respond to single dose therapy. Therapy for those types of infections requiring multiple dose treatment 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
1. Vaginal candidiasis - 150 mg single oral dose. Balanitis
2. Mucosal Candidiasis- 50 mg once daily for 7 - 14 days. Treatment should not normally exceed 14 days except in severely immunocompromised patients. In severe or recurrent cases the dose may be increased to100 mg once daily. Duration of treatment: 1-2 weeks. In order to prevent relapse treatment may be given for longer periods (6-8 weeks)
For atrophic oral candidiasis associated with dentures - the usual dose is 50 mg once daily for 14 days administered concurrently with local antiseptic measures to the denture.
For other candidal infections of mucosa except genital candidiasis (see above), e.g. oesophagitis, non-invasive bronchopulmonary infections, candiduria, mucocutaneous candidiasis etc., the usual effective dose is 50 mg daily, given for 14 - 30 days. In difficult cases the dose may be increased to 100 mg daily. In order to prevent relapse, treatment may be given for longer periods (6-8 weeks)
3. For candidaemia, disseminated candidiasis and other invasive candidal infections the usual dose is 400mg on the first day followed by 200mg daily. Depending on the clinical response the dose may be increased to 400mg daily. Duration of treatment is based upon the clinical response.
4. For the prevention of fungal infections in immunocompromised patients considered at risk as a consequence of neutropenia following cytotoxic chemotherapy or radiotherapy, the dose should be 50 to 400mg once daily, based on the patient's risk for developing fungal infection. For patients at high risk of systemic infection, e.g. patients who are anticipated to have profound or prolonged neutropenia such as during bone marrow transplantation, the recommended dose is 400mg once daily. Fluconazole Infusion administration should start several days before the anticipated onset of neutropenia, and continue for 7 days after the neutrophil count rises above 1000 cells per mm3.
5. For cryptococcal meningitis and cryptococcal infections at other sites, the usual dose is 400mg on the first day followed by 200mg - 400mg once daily. Duration of treatment for cryptococcal infections will depend on the clinical and mycological response, but is usually at least 6-8 weeks for cryptococcal meningitis. For the prevention of relapse of cryptococcal meningitis in patients with AIDS, after the patient receives a full course of primary therapy, Fluconazole Infusion may be administered indefinitely at a daily dose of 100 - 200mg.
6. For tinea pedis, corporis, cruris, versicolor and dermal Candida infections the recommended dosage is 50mg once daily. Duration of treatment is normally 2 to 4 weeks but tinea pedis may require treatment for up to 6 weeks. Duration of treatment should not exceed 6 weeks.
Children
As with similar infections in adults, the duration of treatment is based on the clinical and mycological response. The maximum daily dose in children is 400 mg as a single dose and this dose should not be exceeded.
Children over 4 weeks of age:
1. Mucous membrane candidiasis : the recommended dose 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.
2. Systemic candidiasis and cryptococcal infections: 6-12 mg/kg daily, depending on the severity of the disease.
3. For the prevention of fungal infections in immunocompromised patients considered at risk as a consequence of neutropenia following cytotoxic chemotherapy or radiotherapy, the dose should be 3-12mg/kg daily, depending on the extent and duration of the induced neutropenia (see adult dosing).
Despite extensive data supporting the use of fluconazole in children there are limited data available on the use for genital candidiasis in children below 16 years. Use at present is not recommended unless antifungal treatment is imperative and no suitable alternative agent exists.
Children four weeks of age and younger:
Neonates excrete fluconazole slowly. In the first two weeks of life, the same mg/kg dosing as in older children should be used but administered every 72 hours. During weeks 3 and 4 of life, the same dose should be given every 48 hours.
A maximum dosage of 12 mg/kg every 72 hours should not be exceeded in children in the first two weeks of life. For children between 3 and 4 weeks of life, 12 mg/kg every 48 hours should not be exceeded.
To facilitate accurate measurement of doses less than 10 mg administered to children in hospital, the intravenous infusion should be administered depending on the clinical condition of the child.
Elderly
The normal adult dose should be given if there is no evidence of renal impairment. In patients with renal impairment (creatinine clearance less than 50ml/min) the dosage schedule should be adjusted as described below.
Use in patients with impaired renal function
Fluconazole is mainly excreted unchanged in the urine. No change in dose is needed if treatment consists of a single dose.
For patients with impaired renal function who require multiple doses, the normal recommended dose for the indication should be given on day 1, followed by a daily dose according to the following table:
|
Creatinine clearance (ml/min) |
Percent of recommended dose |
|
>50 |
100% |
|
< 50 (no dialysis) |
50% |
|
Regular dialysis |
100% after each dialysis |
For information regarding administration and incompatibilities, see sections 6.2 and 6.6.
Compatibility of intravenous infusion
Although further dilution is unnecessary Fluconazole Solution for Infusion is compatible with the following administration fluids:
a) Dextrose 20%
b) Ringer's solution
c) Hartmann's solution
d) Potassium chloride in dextrose
e) Sodium bicarbonate 4.2%
f) Normal saline (0.9%)
Fluconazole may be infused through an existing line with one of the above listed fluids. No specific incompatibilities have been noted, although mixing with any other drug prior to infusion is not recommended.
4.3. Contraindications
Fluconazole should not be used in patients with known sensitivity to the drug, any of the inert ingredients or to related azole compounds.
Coadministration of terfenadine is contraindicated in patients receiving fluconazole at multiple doses of 400 mg per day or higher based upon results of a multiple dose interaction study .Co-administration of other drugs known to prolong the QT interval and which are metabolised via the enzyme CYP3A4 such as cisapride, astemizole, pimozide and quinidine are contraindicated in patients receiving fluconazole (see sections 4.4 Special warnings and special precautions for use and 4.5 Interaction with other medicaments and other forms of interaction).
4.4 Special Warnings and Special Precautions for Use
Fluconazole should be administered with caution to patients with liver dysfunction (see also 4.2).
Fluconazole has been associated with rare cases of serious hepatic toxicity including fatalities, primarily in patients with serious underlying medical conditions. In cases of fluconazole-associated hepatotoxicity, no obvious relationship to total daily dose, duration of therapy, sex or age of patient has been observed. Fluconazole hepatotoxicity has usually been reversible on discontinuation of therapy.
Patients who develop abnormal liver function tests during fluconazole therapy should be monitored for the development of more serious hepatic injury. Fluconazole should be discontinued if clinical signs or symptoms consistent with liver disease develop that may be attributable to fluconazole.
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 drugs. If a rash, which is considered attributable to fluconazole, develops in a patient treated for a superficial fungal infection, further therapy with this agent 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.
The coadministration of fluconazole at doses lower than 400 mg per day with terfenadine should be carefully monitored (see sections 4.3 Contraindications and 4.5 Interaction with Other Medicaments and Other Forms of Interaction).
In rare cases, as with other azoles, anaphylaxis has been reported.
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 torsade de pointes in patients taking fluconazole. 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 arrythmias
• Concomitant medication not metabolized by CY34A but known to prolong QT interval
• Electrolyte disturbances such as hypokalaemia, hypomagnesaemia and hypocalaemia
Fluconazole should be administered with caution to patients with renal dysfunction (see also 4.2).
Fluconazole is a potent CYP2C9 inhibitor and a moderate CYP3A4 inhibitor. Fluconazole treated patients who are concomitantly treated with drugs with a narrow therapeutic window metabolised through CYP2C9 and CYP3A4, should be monitored (see section 4.5 Interaction with Other Medicaments and Other Forms of Interaction).
4.5. Interaction with other medicinal products and other forms of interaction
Concomitant use of the following other medicinal products is contraindicated
Cisapride There have been reports of cardiac events including torsades de pointes in patients to whom fluconazole and cisapride were co-administered. A controlled study found that concomitant fluconazole 200 mg once daily and cisapride 20 mg four times a day yielded a significant increase in cisapride plasma levels and prolongation of QTc interval. In most of these cases, the patients appear to have been predisposed to arrhythmias or had serious underlying illnesses, and the relationship of the reported events to a possible fluconazole-cisapride drug interaction is unclear. Because of the potential seriousness of such an interaction, coadministration of cisapride is contra-indicated in patients receiving fluconazole. (See “Contraindications”.)
Terfenadine Because of the occurrence of serious dysrhythmias secondary to prolongation of the QTc interval in patients receiving other azole antifungals in conjunction with terfenadine, interactions studies have been performed. One study at a 200mg daily dose of fluconazole failed to demonstrate a prolongation in QTc interval. Another study at a 400mg and 800mg daily dose of fluconazole demonstrated that fluconazole taken in multiple doses of 400mg per day or greater significantly increased plasma levels of terfenadine when taken concomitantly. There have been spontaneously reported cases of palpitations, tachycardia, dizziness, and chest pain in patients taking concomitant fluconazole and terfenadine where the relationship of the reported adverse
events to drug therapy or underlying medical conditions was not clear. Because of the potential seriousness of such an interaction, it is recommended that terfenadine not be taken in combination with fluconazole. (See “Contraindications”.)
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.
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.
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:
The effect of other medicinal products on fluconazole
Hydrochlorothiazide: In a pharmacokinetic interaction study with healthy volunteers who concomitantly received fluconazole and multiple doses of hydrochlorothiazide the plasma concentrations of fluconazole increased by 40%. An effect of this size should not necessitate a change in the fluconazole dose regimen in patients who are concomitantly treated with diuretics, although the prescriber should bear this in mind.
Rifampicin (CYP450 inducer): Concomitant intake of fluconazole and rifampicin resulted in a 25% reduction in the AUC and 20% reduction in the half-life of fluconazole. An increase in the dose of fluconazole should be considered in patients concomitantly receiving rifampicin.
Effects of fluconazole on the metabolism of other medicinal products
Fluconazole is potent inhibitor of cytochrome P450 (CYP) isoenzyme 2C9 and a moderate inhibitor of CYP3A4. Besides the following observed interactions there is a risk of increased plasma concentrations of other medicinal products metabolised by CYP2C9 or CYP3A4 (i.e. ergot-alkaloids, HMG-CoA reductase inhibitors, quinidine) when co-administered with fluconazole. Therefore, caution should always be exercised when using these combinations and the patients should be carefully monitored. The effect persists for 4-5 days after the discontinuation of fluconazole treatment due to the long fluconazole half-life (see section 4.3).
Alfentanil A study observed a reduction in clearance and distribution volume as well as prolongation of Ty2 of alfentanil following concomitant treatment with fluconazole. A possible mechanism of action is fluconazole’s inhibition of CYP3A4. Dosage adjustment of alfentanil may be necessary.
Amitriptyline, nortriptyline Several case reports have described the development of increased amitripyline concentrations and signs of tricyclic toxicity when amitriptyline was used in combination with fluconazole. Co-administration 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.
Amphotericine 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 drugs in systemic infection with A. fumigatus. The clinical significance of results obtained in these studies is unknown.
Anticoagulants (CYP2C9 substrate): In an interaction study, fluconazole increased the prothrombin time (12%) after warfarin administration in healthy males. In post-marketing experience, as with other azole antifungals, bleeding events (bruising, epistaxis, gastrointestinal bleeding, hematuria and melaema) have been reported in association with increases in prothrombin time in patients receiving fluconazole concurrently with warfarin. Prothrombin time in patients receiving coumarin-type anticoagulants should be carefully monitored. Dose adjustment of warfarin 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 (CYP3A4 substrate) Following oral administration of midazolam, fluconazole resulted in substantial increases 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. If concomitant benzodiazepine therapy is necessary in patients being treated with fluconazole, consideration should be given to decreasing the benzodiazepine dosage and the patients should be appropriately monitored.
Fluconazole increases the AUC of triazolam (single dose) by approximately 50%, Cmax with 20-32% and increases t/ by 25-50 % due to the inhibition of metabolism of triazolam. Dosage adjustments of triazolam may be necessary.
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. Dosage adjustment of carbamazepine may be necessary depending on concentration measurements/effect.
Calcium channel antagonists CYP3A4 is involved in the metabolism of some dihydropyridine calcium channel antagonists, including nifedipine, isradipine, nicardipine, amlodipine and felodipine. There have been published reports of marked peripheral oedema and/or elevated calcium antagonist serum concentrations during concurrent use of itraconazole and felodipine, isradipine or nifedipine. This interaction would be expected to occur with other triazole antifungal agents. Consideration should be given to reducing the dose of the calcium antagonist.
Celecoxib A clinical study with Celecoxib has demonstrated a two-fold increase in celecoxib plasma concentrations when given concurrently with fluconazole 200 mg. this interaction is believed to be due to inhibition of cytochrome P450 2C9-mediated metabolism of celecoxib. Celecoxib therapy should be commenced at the lowest recommended dose in patients who are also receiving fluconazole.
Ciclosporin Fluconazole significantly increases the concentration and AUC of ciclosporin. 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.
Halofantrine Fluconazole can increase halofantrine plasma concentration due to an inhibitory effect on CYP3A4.
HMG-CoA reductase inhibitors The risk of myopathy or rhabdomyolysis is increased when fluconazole are administered concurrently with HMG-CoA reductase inhibitors metabolised through CYP3A4, such as atorvastatin and simvastatin, or through CYP2C9, such as fluvastatin. If concurrent therapy is required patients should be monitored for signs and symptoms of myopathy or rhabdomyolysis (muscle pain, tenderness or weakness), and creatine kinase (CK) levels. HMG-CoA reductase inhibitors should be discontinued if CK levels show a marked increase, or if myopathy or rhabdomyolysis is diagnosed or suspected.
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. Dosage adjustment of methadone may be necessary.
Non-steroidal anti-inflammatory drugs The Cmax and AUC of flurbiprofen was 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 with combined oral contraceptives have been performed using multiple doses of fluconazole. There were no relevant effects on either hormone level in the 50mg fluconazole study, while at 200mg daily the AUCS of ethinyloestradiol and levonorgestrel were increased 40% and 24% respectively. Thus multiple dose use of fluconazole at these dosesis unlikely to have an effect on the efficacy of the combined oral contraceptive
Phenytoin Fluconazole inhibits the hepatic metabolism of phenytoin. 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 (CYP450 inducer) 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 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. Dosage adjustment of saquinavir may be necessary
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 dosage adjustment of sirolimus depending on the effect/concentration measurements.
Sulphonylureas Fluconazole has been shown to prolong the serum half-life of concomitantly administered oral sulphonylureas (chlorpropamide, glibenclamide, glipizide and tolbutamide) in healthy volunteers. . Frequent monitoring of blood glucose and appropriate reduction of sulfonylurea dosage is recommended during coadministration.
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. Dosage of orally administered tacrolimus should be decreased depending on tacrolimus concentration.
Theophylline In a placebo controlled interaction study, intake of fluconazole 200mg for 14 days resulted in 18% decrease in the mean plasma clearance of theophylline. Patients on treatment with high doses of theophylline or with any other reason to be at increased risk of theophylline toxicity should be observed for signs of theophylline toxicity while receiving fluconazole. Therapy should be modified if signs of toxicity develop.
Trimetrexate medicinal products such as fluconazole that inhibit the P450 enzyme system may cause interactions that increase trimetrexate plasma concentrations. If it is not possible to avoid concomitant administration of trimetrexate and fluconazole, trimetrexate serum levels and trimetrexate toxicity (bone marrow suppression, renal and hepatic dysfunction and gastrointestinal ulceration) must be monitored carefully.
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.
Zidovudine Fluconazole increases Cmax and AUC of zidovudine by 85% and 75%, 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. Dosage reduction of zidovudine may 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.
Endogenous steroid Fluconazole 50mg daily does not affect endogenous steroid levels in females: 200-400mg daily has no clinically significant effect on endogenous steroid levels or on ACTH stimulated response in healthy male volunteers
Pregnancy and lactation
4.6.
Pregnancy
Data from several hundred pregnant women treated with standard doses (<200 mg/day) of fluconazole, administered as a single or repeated dosage in the first trimester, show no undesired effects in the foetus.
There have been reports of multiple congenital abnormalities 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.
Animal studies show teratogenic effects (see section 5.3).
Use in pregnancy should be avoided except in patients with severe or potentially life-threatening fungal infections in whom fluconazole may be used if the anticipated benefit outweighs the possible risk to the fetus.
Lactation
Fluconazole is found in human breast milk at concentrations similar to plasma, hence its use in nursing mothers is not recommended.
4.7. Effects on ability to drive and use machines
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 haematological function test results and hepatic abnormalities (see section 4.4 Special warnings and special precautions for use) have been observed during treatment with fluconazole and comparative agents, but the clinical significance and relationship to treatment is uncertain.
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 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).
|
System Organ Class |
Frequency |
Undesirable effects |
|
Blood and the lymphatic system disorders |
Uncommon |
Anaemia |
|
Rare |
Agranulocytosis, leukopenia, neutropenia, thrombocytopenia | |
|
Immune system disorders |
Rare |
Anaphylaxis |
|
Metabolism and nutrition disorders |
Uncommon |
Decreased appetite |
|
Rare |
Hypertriglyceredaemia, Hypercholesterolaemia Hypokalaemia | |
|
Psychiatric disorders |
Uncommon |
Insomnia, somnolence |
|
Nervous system disorders |
Common |
Headache |
|
Uncommon |
Seizures, dizziness, paraesthesia, taste perversion | |
|
Rare |
Tremor | |
|
Ear and labyrinth disorders |
Uncommon |
Vertigo |
|
Cardiac disorders |
Rare |
Torsade de pointes, QT prolongation (see section 4.4) |
|
Gastrointestinal disorders |
Common |
Abdominal pain, diarrhoea, nausea, vomiting |
|
Uncommon |
Dyspepsia, flatulence, dry mouth, constipation | |
|
Hepato-biliary disorders |
Common |
Alanine aminotransferase increased (see section 4.4), aspartate aminotransferase increased (see section 4.4), blood alkaline phosphatase increased (see section 4.4) |
|
Uncommon |
Cholestasis (see section 4.4), jaundice (see section 4.4), bilirubin increased (see section 4.4) | |
|
Rare |
Hepatic failure (see section 4.4), hepatocellular necrosis (see section 4.4), Hepatitis (see section 4.4), hepatocellular damage (see section 4.4) | |
|
Skin and subcutaneous tissue disorders |
Common |
Rash (see section 4.4) |
|
Uncommon |
Pruritus (see section 4.4), urticaria (see section 4.4), increased sweating , drug eruption *(see section 4.4) | |
|
Rare |
Toxic epidermal necrolysis (see section 4.4) , Stevens-Johnson syndrome (see section 4.4), acute generalised exanthematous-pustulosis (see section 4.4) , dermatitis exfoliative, angioedema, face oedema, alopecia | |
|
Musculoskeletal, connective tissue and bone disorders |
Uncommon |
Myalgia |
|
General disorders and administration site conditions |
Uncommon |
Fatigue, malaise, asthenia, fever |
*: Including fixed drug eruption.
Paediatric Population
The pattern and incidence of adverse reactions and laboratory abnormalities recorded during paediatric clinical trials, excluding the genital candidiasis indication are comparable to those seen in adults.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. 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 overdosage with fluconazole and 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 the event of overdosage, supportive measures and symptomatic treatment, with gastric lavage if necessary, may be adequate.
As fluconazole is largely excreted in the urine, forced volume diuresis would probably increase the elimination rate. A three hour haemodialysis session decreases plasma levels by approximately 50%.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacodynamic Group: Antimycotics for systemic use ATC code: J02A C01
Fluconazole belongs to the group of triazole antimycotics, specifically inhibiting fungal ergosterol synthesis.
Fluconazole shows little pharmacological activity in a wide range of animal studies. Some prolongation of pentobarbital sleeping times in mice (p.o.), increased mean arterial and left ventricular blood pressure and increased heart rate in anaesthetised cats (i.v.) occurred. Inhibition of rat ovarian aromatase was observed at high concentrations.
Both orally and intravenously administered fluconazole was active in a variety of animal fungal infection models. Activity has been demonstrated against opportunistic mycoses, such as infections with Candida spp. including systemic candidiasis in immunocompromised animals; with Cryptococcus neoformans, including intracranial infections; with Microsporum spp. and with Trichophyton spp. Fluconazole has also been shown to be active in animal models of endemic mycoses, including infections with Blastomyces dermatitides; with Coccidoides immitis, including intracranial infection and with Histoplasma capsulatum in normal and immunosuppressed animals.
There have been reports of cases of superinfection with Candida species other than C. albicans, which are often inherently not susceptible to fluconazole (e.g. Candida krusei). Such cases may require alternative antifungal therapy.
Fluconazole is highly specific for fungal cytochrome P-450 dependent enzymes. Fluconazole 50mg daily given up to 28 days has been shown not to affect testosterone plasma concentrations in males or steroid concentrations in females of child-bearing age. Fluconazole 200-400mg 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 50mg do not affect its metabolism.
The efficacy of fluconazole in tinea capitis has been studied in 2 randomised controlled trials in a total of 878 patients comparing fluconazole with griseofulvin. Fluconazole at 6 mg/kg/day for 6 weeks was not superior to griseofulvin administered at 11 mg/kg/day for 6 weeks. The overall success rate at week 6 was low (fluconazole 6 weeks: 18.3%; fluconazole 3 weeks: 14.7%; griseofulvin: 17.7%) across all treatment groups. These findings are not inconsistent with the natural history of tinea capitis without therapy.
5.2 Pharmacokinetic properties
The pharmacokinetic properties of fluconazole are similar following administration by the intravenous or oral route.
Absorption
After administration of 200 mg fluconazole, Cmax is around 4.6 mg/l and plasma concentrations obtained 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 obtained at steady state after 15 days are around 18 mg/l The intake of a double dose on day 1 results in plasma concentrations that are approximately 90% of steady state on day 2
Distribution
The volume of distribution corresponds to total body water. The protein binding in plasma is low (11-12%).
Fluconazole is distributed over the total body water. The concentration in saliva is similar to plasma levels. In patients with fungal meningitis, the concentration of fluconazole in the cerebrospinal fluid is approximately 80% of the corresponding plasma levels.
In the stratum corneum, epidermis-dermis and eccrine sweat higher concentrations of fluconazole are reached compared to those in the serum. Fluconazole is accumulated in the stratum corneum. At a dose of 150 mg once weekly, the concentration of fluconazole in the stratum corneum after 2 doses was 23.4 microgram/g and 7 days after second dosing the concentration was still 7.1 microgram/g.
Elimination
Fluconazole is mainly renally excreted. Approximately 80% of the administered dose is excreted in the urine in the non metabolised form. Fluconazole clearance is proportional to creatinine clearance. Circulating metabolites have not been demonstrated.
The half-life in plasma is approximately 30 hours, which allows for single dose treatment in vaginal candidiasis and once daily dosing and once weekly dosing in connection with other indications.
It has been demonstrated that fluconazole 50 mg daily given for up to 28 days does not influence plasma concentrations in women of childbearing age.
Fluconazole 200-400 mg daily has no clinically significant effect on endogenous steroid levels or on ACTH stimulated responses in healthy, male volunteers.
A study compared the saliva and plasma concentrations of a single fluconazole 100mg dose administration in a capsule or in an oral suspension by rinsing and retaining in mouth for 2 minutes and swallowing. The maximum concentration of fluconazole in saliva after the suspension was observed 5 minutes after ingestion, and was 182 times higher than the maximum saliva concentration after the capsule which occurred 4 hours after ingestion. After about 4 hours, the saliva concentrations of fluconazole were similar. The mean AUC (0-96) in saliva was significantly greater after the suspension compared to the capsule. There was no significant difference in the elimination rate from saliva or the plasma pharmacokinetic parameters for the two formulations.
Pharmacokinetics in Children
In children, the following pharmacokinetic data have been reported:
|
Age Studied |
Dose (mg/kg) |
Half-life (hours) |
AUC (microgram.h/ml) |
|
11 days-11 months |
Single-IV 3mg/kg |
23 |
110.1 |
|
9 months-13 years |
Single-Oral 2mg/kg |
25.0 |
94.7 |
|
9 months-13 years |
Single-Oral 8mg/kg |
19.5 |
362.5 |
|
5 years-15 years |
Multiple IV 2mg/kg |
17.4* |
67.4 |
|
5 years-15 years |
Multiple IV 4mg/kg |
15.2* |
139.1 |
|
5 years-15 years |
Multiple IV 8mg/kg |
17.6* |
196.7 |
|
Mean Age 7 Years |
Multiple Oral 3mg/kg |
15.5 |
41.6 |
*Denotes final day
In premature new-borns (gestational age around 28 weeks), intravenous administration of fluconazole of 6mg/kg was given every third day for a maximum of five doses while the premature new-borns remained in the intensive care unit. 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 2768) 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.
5.3. Preclinical safety data
Reproductive Toxicity Increases in fetal anatomical variants (supernumerary ribs, renal pelvis dilation) and delays in ossification were observed at 25 and 50mg/kg and higher doses. At doses ranging from 80mg/kg (approximately 20-60x the recommended human dose) to 320mg/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.
Carcinogenesis Fluconazole showed no evidence of carcinogenic potential in mice and rats treated orally for 24 months at doses of 2.5, 5 or 10mg/kg/day. Male rats treated with 5 and 10mg/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 20mg/kg or with parenteral doses of 5, 25 or 75mg/kg, although the onset of parturition was slightly delayed at 20mg/kg p.o. In an intravenous perinatal study in rats at 5, 20 and 40mg/kg, dystocia and prolongation of parturition were observed in a few dams at 20mg/kg and 40mg/kg, but not at 5mg/kg.
The disturbances in parturition were reflected by a slight increase in the number of stillborn 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. PHARMACEUTICAL PARTICULARS
6.1. List of excipients
Sodium chloride Water for Injection.
6.2. Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in Section 6.6.
6.3. Shelf life
3 years.
From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.
6.4. Special precautions for storage
Keep container in the outer carton.
6.5. Nature and contents of container
Glass vial with a rubber stopper and aluminium overseal. Pack sizes: 25 ml, 50 ml, 100 ml and 200 ml.
6.6. Instruction for use and handling (and disposal)
For single use only. Discard any remaining solution.
Although further dilution is unnecessary, Fluconazole Solution for Infusion is compatible with the following administration fluids:
Dextrose 20%
Ringers solution Hartmann’s solution Sodium bicarbonate 4.2%
Normal Saline 0.9%
Fluconazole intravenous infusion may be infused through an existing line with one of the above list of fluids. No specific incompatibilities have been noted, although mixing with any other drug prior to infusion is not recommended.
Relonchem Limited,
27 Old Gloucester Street, London WC1 3XX.
8. MARKETING AUTHORISATION NUMBER
PL 20395/0012
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
16/10/2006
10 DATE OF REVISION OF THE TEXT
01/12/2015