Fluconazole 2mg/Ml Solution For Infusion
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Fluconazole 2mg/ml Solution for Infusion
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each ml of solution for infusion contains 2 mg Fluconazole.
Each 100 ml vial contains 200 mg Fluconazole.
For Excipients, see Section 6.1.
3 PHARMACEUTICAL FORM
Solution for infusion.
Transparent solution.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Treatment of mycoses caused by Candida, Cryptococci, and other related yeasts, in particular:
• Mucosal candida infections including oropharyngeal, eosophageal, mucocutaneous and noninvasive bronchopulmonial candidiasis and candiduria in patients with decreased immunological defence.
Systemic candida infections, including candidemia in non-neutropenic patients.
Prophylaxis against deep Candida- infections (especially Candida albicans) in connection with bone marrow transplantation.
• Acute cryptococcal meningitis in adults, including patients with AIDS, transplanted patients or patients with other causes of immunosuppresion.
• Maintenance treatment to prevent recurrence of cryptococcal meningitis in patients with AIDS.
Consideration should be given to official guidance on the appropriate use of antifungal agents.
4.2 Posology and method of administration
The dose is dependent on the type and severity of infection. Treatment of infections requiring multiple dose treatment should be continued until clinical or laboratory parameters show that the infection has subsided. An inadequate period of treatment may lead to recurrence of the infection.
Oral pharmaceutical forms and solutions for infusion are available for therapy. Patients should be switched from intravenous to oral administration as soon as possible. The daily dose need not be altered when changing from intravenous to oral administration or vice versa..
Dosage in adults:
Mucosal Candidia:
• Oropharyngeal candidiasis -
The normal dose is 50mg daily, also in patients with impaired immune function. Administered for 7-14 days. The dose may be increased to 100mg if necessary. In patients with severely impaired immune response, the treatment may be continued for a longer period.
• Oesophageal mucotaneous, non-invasive bronchopulmonial candidiasis and candiduria -
The normal dose is 50mg daily for 14-30 days. In severe cases, the dose may be increased to 100mg.
Systemic Candida infections:
The dose in candidaemia and other invasive Candida infections is 400-800 mg on the first day and 200-400 mg daily thereafter. The dose depends on the type and severity of the infection.
In most cases a loading dose of 800 mg on the first day followed by 400 mg daily thereafter may be preferable. The duration of treatment, often up to several weeks, is determined by the clinical response.
Prophylaxis against deep Candida infections in patients with neutropenia due to bone marrow transplantation:
400 mg once daily. Prophylaxis with fluconazole should be initiated several days before anticipated neutropenia and should continue for 7 days after neutrophilic values have increased to>1x109/l.
Cryptococcal meningitis:
The normal dose is 400 mg on the first day then 200 mg-400 mg daily thereafter. The duration of treatment for cryptococcal infections depends on the clinical response, but is usually at least 6-8 weeks for cryptoccal meningitis.
A daily dose of 100-200 mg is recommended in maintenance treatment to prevent relapse of cryptococcal meningitis in AIDS patients.
The duration of the maintenance treatment of AIDS-patients should be considered with regard to increased risk of resistance to fluconazole.
Dosage in children and adolescents:
As with similar infections in adults, the duration of treatment is based on the clinical response. The maximum daily dose of 400mg should not be exceeded in children.
Mucosal Candida infections:
3 mg/kg once daily. 6 mg/kg may be given on day 1 in order to reach steady-state concentration more rapidly.
Prophylaxis against deep Candida infections in patients with neutropenia due to bone marrow transplantation:
The recommended dose is 3-12 mg/kg once daily. The dosage is dependent on the extent and duration of the neutropenia
Prevention of relapse of cryptococcal meningitis:
The recommended dose is 3-12 mg/kg daily, depending on the degree of severity of the infection.
Systemic Candida infections:
The recommended dose is 6-12 mg/kg daily, depending on the degree of severity of the infection.
Children four weeks of age and younger:
Fluconazole is excreted more slowly in neonates than in older children. The same dose in mg/kg should be used, but the dose interval extended. For premature newborn infants and neonates up to 2 weeks of age, the dose should be administered every 3rd day (72 hour interval), for children 2-4 weeks old, on alternate days (48 hour interval).
Use in the elderly:
The normal adult dose should be given if there is no evidence of renal impairment. Renal impairment in adults and children:
With repeated dosing, the normal dose is given on day 1; thereafter the dose interval or the daily dose is adjusted in relation to creatinine clearance as follows:
|
• Creatinine clearance (ml/min) |
• Daily dose |
|
• > 50 |
• Normal dose regime (100%) |
|
• 11-50 |
• Half normal daily dose (50%) |
|
• Patients receiving dialysis |
• One dose after every dialysis session |
Patients with liver insufficiency:
Fluconazole should only be administered with special care and under careful monitoring in patients with liver insufficiency (see section 4.4).
Administration:
For intravenous infusion only.
Fluconazole is dissolved in isotonic saline solution, with an electrolyte content of Na+ 150 mmol and Cl- 150 mmol per 1000ml, and may be administered directly as an infusion.
The infusion rate should not exceed 20mg (10ml)/minute for adults. For children, it is recommended that the infusion rate not exceed 10mg (5ml)/min. for premature infants, the infusion time should be no less than 15 minutes. In patients requiring sodium or fluid restriction, the rate of administration should be taken into consideration as Fluconazole consists of a salt solution. In such cases the infusion should be given over a longer period.
4.3 Contraindications
Fluconazole should not be used in patients with known hypersensitivity to fluconazole or to related azole compounds or any other ingredient in the formulation.
Fluconazole should not be co-administered with drugs both known to prolong QT-interval and metabolised by CYP3A4 such as cisapride, astemizole, terfenadine, pimozide and quinidine (see Section 4.5 Interactions with other medicinal products and other forms of interaction).
4.4 Special warnings and precautions for use
Severe liver toxicity, including death, has been reported in rare cases, most often in patients with serious underlying illnesses. No obvious connection, however, has been found between daily dose, duration of treatment, gender or age. Patients that develop abnormal liver function tests or significant increases from already abnormal levels during treatment should be carefully monitored.
Treatment should be discontinued if clinical signs of liver disease, with possible connection to fluconazole, develop. The liver toxicity has most often been reversible following withdrawal of the treatment. 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.
Certain azoles, including fluconazole, have been associated with prolongation of the QT interval. Rare cases of torsade de pointes have been reported during treatment with 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 known to prolong QT interval (see Section 4.5 “Interactions with other medicinal products and other forms of interaction”)
Electrolyte disturbances such as hypokalaemia, hypomagnesaemia and hypocalaemia should be corrected prior to initiation of fluconazole treatment.
In rare cases patients have developed exfoliative skin reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis in treatment with fluconazole. AIDS-patients have a higher tendency for the development of serious skin reactions from various drugs. Where patients with minor fungal infections that are being treated with fluconazole develop a skin rash, considered to be connected to treatment with fluconazole, the treatment should be stopped.
If patients who are being treated for invasive fungal infections or systemic infections develop a skin rash, they should be closely monitored and the treatment discontinued if bullous skin reactions or erythema multiforme develop.
Fluconazole is a potent inhibitor of cytochrome P450 (CYP) isoenzyme 2C9 and a moderate inhibitor of CYP3A4. Patients who receive concomitant treatment with fluconazole and drugs which have a narrow therapeutic interval (e.g. warfarin and phenytoin) and which are metabolised via CYP2C9 and/or CYP3A4 should be closely monitored (see sections 4.3 Contraindications and 4.5 Interactions with other medicinal products and other forms of interaction).
Fluconazole may lengthen the prothrombin time following administration of warfarin. Close monitoring of the prothrombin time is recommended.
Rare instances of anaphylactic reactions have been reported (see section 4.8 Undesirable effects).
For dosage in renal impairment, see section 4.2 Posology and method of administration.
Fertile women undergoing long-term treatment with fluconazole should use adequate methods of contraception (see section 4.6 Pregnancy and lactation).
Data regarding efficacy and safety of fluconazole in children and adolescents less than 16 years of age are still limited. Therefore the benefits of the treatment with fluconazole should be carefully evaluated against the risks.
Important information about some of the ingredients of Fluconazole
Your medicine contains 3.54 mg of sodium per ml. To be taken into consideration by patients on a controlled sodium diet.
4.5 Interaction with other medicinal products and other forms of interaction
The following combinations are contraindicated:
• Astemizole (CYP3A4-substrate): Astemizole overdoses have led to prolonged QT interval a severe ventricular arrhythmia, torsade de pointes and cardiac arrest. Concomitant administration of astemizole and fluconazole is contraindicated due to the potential for serious, potentially fatal, cardiac effects.
• Cisapride (CYP3A4-substrate): Cardiovascular effects, including torsade de pointes, have been reported in patients having received concomitant treatment with fluconazole and cisapride. In one controlled study, where 200 mg fluconazole was administered once daily concomitantly with cisapride 20 mg four times daily, a significant increase in plasma levels of cisapride and prolongation of the QTc-interval where achieved. Concurrent treatment with cisapride and fluconazole is contraindicated (see 4.3 Contraindications).
• Terfenadine (400 mg fluconazole and higher; CYP3A4-substrate): Serious cardiac arrhythmias, secondary to prolonged QTc- interval, have occurred in patients treated with anti-fungal medications such as triazolic compounds and terfenadine. Concomitant treatment with 200 mg fluconazole daily showed no prolongation of the QTc-interval. With doses of 400 mg and 800 mg fluconazole daily, the plasma concentration of terfenadine increased significantly. Concomitant treatment with fluconazole 400 mg per day or higher dose is contraindicated. With concomitant treatment with doses below 400 mg per day, the treatment should be closely monitored.
The effects of fluconazole on other drugs:
• 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. A similar effect may occur with amphotericin B cholesteryl sulfate complex.
• Fluconazole is a potent inhibitor of cytochrome P450 (CYP) isoenzyme 2C9 and a moderate inhibitor of CYP3A4. In addition to the interactions given below, there is a risk that elevated serum concentrations of other drugs metabolised via CYP2C9 and CYP3A4 will not be secreted with concomitant administration of fluconazole.
Caution should therefore always be observed during combination therapy with medications such as these and the patient closely monitored. The effects may persist for several days due to the long half life of fluconazole.
Alfentanil (CYP3A4-substrate): In concomitant treatment with fluconazole (400 mg) and intravenous alfentanil (20 pg/kg) in healthy volunteers, AUC10 - increased twofold and clearance decreased by 55 % for alfentanil, probably through inhibition of CYP3A4. The combination may require dose adjustment.
• Amitriptyline (CYP2D6-substrate): Several case histories have described the
development of elevated amitriptylline concentrations and signs of tricyclic toxicity when amitriptylline is used in combination with fluconazole. Concomitant infusion of fluconazole and nortriptylline, the active metabolite of amitriptylline, have been reported to lead to increased nortriptylline levels. Due to the risk of amitriptylline toxicity, monitoring of amitriptylline levels should be considered with dose adjustment where indicated.
• Anticoagulants (CYP2C9-substrate): In concomitant treatment with fluconazole and warfarin, the prothrombin time increased up to twofold. This is probably due to an inhibition of the metabolism of warfarin via CYP2C9. The prothrombin time should be monitored closely in patients treated concomitantly with fluconazole and coumarintype anticoagulants.
• Benzodiazepines (CYP3A4-substrate): Fluconazole may inhibit the metabolism of benzodiazepines metabolised via CYP3A4, e.g. midazolam and triazolam. In concomitant oral single dose treatment with fluconazole (400 mg) and midazolam (7.5 mg) AUC increased 3.7 times and the half life of midazolam 2.2 times. The combination should be avoided. Where concomitant treatment is considered necessary, a reduction in the dose of midazolam should be considered and the patient monitored closely In concomitant treatment with fluconazole (100 mg daily for 4 days) and triazolam (0.25 mg) the AUC and half-life of triazolam increased respectively 2.5 and 1.8 times. Prolonged and enhanced effects from triazolam have been observed. The combination may require reduction in the dose of triazolam.
• Calcium channel antagonists (CYP3A4-substrates): Some dihydropyridine calcium channel antagonists, including nifedipine, isradipine, nicardipine, amlodipine, and felodipine, are metabolised via CYP3A4. 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 occur also with fluconazole.
• Celecoxib (CYP2C9-substrate): In concomitant treatment with fluconazole (200 mg daily) and celecoxib (200 mg), Cmax and AUC for celecoxib increased by 68 % and 134 % respectively.
Halving the dose of celecoxib is recommended in combination therapy with fluconazole.
• Cyclosporin (CYP3A4-substrate): Clinically significant interactions between cyclosporin and fluconazole have been observed at doses of fluconazole of 200 mg and higher. In concomitant treatment with 200 mg fluconazole daily and cyclosporine (2.7 mg/kg/day), AUC for cyclosporin increased approximately 1.8 times and clearance was reduced by approximately 55 %. The plasma concentration of cyclosporin should be monitored in concomitant treatment with fluconazole.
• 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.
• Halofantrin (CYP3A4-substrate): Drugs which inhibit CYP3A4 lead to an inhibition of halofantrin metabolism.
• HMG-CoA-reductase-inhibitors (CYP2C9- or CYP3A4-substrate): The risk of myopathy increases when fluconazole is administered concomitantly with HMG-CoAreductase inhibitors that are metabolised via CYP3A4, e.g. atorvastatin and simvastatin, or via CYP2C9, such as fluvastatin. Caution should be observed where concomitant treatment with fluconazole and HMG-CoA-reductase-inhibitors is considered necessary.
The combination may require dose reduction of the HMG-CoA reductase inhibitors. The patient should be observed with regard to signs of myopathy or rhabdomyolysis. Where myopathy or rhabdomyolysis are suspected, the treatment with HMG-CoAreductase- inhibitors must be discontinued.
• Losartan (CYP2C9-substrate): Fluconazole inhibits the conversion of losartan to its active metabolite (E-3174), which is responsible for the most 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.
• Oral contraceptive agents (CYP3A4-substrate): In a kinetic study with combined oral contraceptives and 50 mg fluconazole daily, hormonal levels were not affected. With 200 mg fluconazole daily, AUC for ethynylestradiol increased by 40 % and levonorgestrel by 24 %. Fluconazole at these dosages probably has no effect on combined oral contraceptives.
• Phenytoin (CYP2C9-substrate): Concomitant, repeated treatment with 200 mg
fluconazole and 250 mg phenytoin intravenously increased AUC24 for phenytoin by 75 % and Cmin by 128 %. In combination treatment, plasma phenytoin concentrations should be monitored and the dose adjusted.
• 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 insufficiency when fluconazole is withdrawn.
Rifabutin (CYP3A4-substrate): In concomitant treatment with fluconazole and rifabutin, the serum concentrations of rifabutin increased. Uveitis has been reported. Patients undergoing concomitant treatment should be monitored closely.
• Sirolimus and tacrolimus (3A4-substrate): In concomitant oral treatment with
fluconazole and tacrolimus (0.15 mg/kg twice daily) the plasma concentration trough level of tacrolimus increased 1.4 and 3.1 times with a daily fluconazole dose of 100 mg and 200 mg respectively. Nephrotoxicity has been reported. Even though no interaction studies have been performed with fluconazole and sirolimus, a similar interaction can be anticipated. In concomitant treatment with fluconazole and tacrolimus or sirolimus, patients should be closely monitored and an adjustment in dose considered.
• Sulphonylureas (CYP2C9-substrate): Fluconazole has displayed prolonged half-life in serum for concomitantly administered sulphonylureas (glibencamide, glipizide, chlorpropamide and tolbutamide) in healthy volunteers. Fluconazole may be administered to diabetics together with sulphonylureas, but the risk of hypoglycemia should be considered.
• Theophylline: Fluconazole 200 mg reduces theophylline clearance by 18 %. In patients receiving high doses of theophylline and concomitant treatment with fluconazole, theophylline toxicity should be taken into consideration, and the dose must be adjusted as necessary.
• 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 (bone marrow suppression, renal and hepatic dysfunction, and gastro-intestinal ulceration) must be closely monitored.
• Zidovudine: In interaction studies, AUC of zidovudine increased significantly by approximately 20 % and 70 % in concomitant treatment with fluconazole 200 mg and 400 mg per day respectively, probably due to inhibited glucuronidation. Patients receiving the combination should be monitored closely with regard to zidovudine related adverse reactions.
The effects of other drugs on fluconazole:
• Hydrochlorthiazide: The plasma concentration of fluconazole increased by 40 % with concomitant administration of hydrochlorthiazide in healthy volunteers. An increase of this dimension does not necessitate adjustment in the dose of fluconazole capsules in patients undergoing treatment with diuretics, but the prescribing doctor should be aware of the fact.
Rifampicin (CYP450-inducers): Concomitant treatment with fluconazole (200 mg) and rifampicin (600 mg daily) reduced AUC for fluconazole by 23 % in healthy volunteers.
An increase in the dose of fluconazole should be considered in combination treatment.
4.6 Fertility, pregnancy and lactation
Pregnancy
Data from several hundred pregnant women treated with standard doses of fluconazole (less than 200 mg/day) as a single repeated dose during the first trimester of pregnancy, does not indicate undesirable effects on the foetus.
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 being treated for 3 or more months with high dose (400-800 mg/day) fluconazole therapy for coccidioidomycosis. The relationship between fluconazole and these events is unclear.
Studies in animals have shown reproductive toxicity (see section 5.3 Preclinical safety data), but the potential risk in humans is unknown.
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 in concentrations lower than those in plasma. Breast-feeding may be maintained after a single dose of fluconazole of 200mg or less. Breast-feeding is not recommended after repeated use of high-dose fluconazole.
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
In clinical trials, up to 10% have experienced adverse reactions. Approximately 1% discontinued the treatment due to adverse reactions.
The following treatment-related undesirable effects were reported in 4,048 patients receiving fluconazole for 7 or more days in clinical trials:
|
Organ systems |
Very common > 1/10 |
Common > 1/100, < 1/10 |
Uncommon > 1/1,000, < 1/100 |
Rare >1/10,000, <1/1,000 |
|
Blood and lymphatic system |
Anaemia | |||
|
Immune system |
Anaphylaxis | |||
|
Psychiatric |
Insomnia, somnolence | |||
|
Central and peripheral nervous system |
Headache |
Convulsion, dizziness, paresthesia, tremor, vertigo | ||
|
Autonomic nervous system |
Dry mouth, increased sweating | |||
|
Special senses |
Taste perversion | |||
|
Gastrointestinal |
Nausea and vomiting, abdominal pain, diarrhoea |
Anorexia, constipation, dyspepsia, flatulence | ||
|
Hepato-biliary |
Clinically significant increase of AST, ALT and alkaline phosphatase |
Cholestasis, hepatocellular damage, jaundice, clinically significant increase of total bilirubin |
Hepatic Necrosis | |
|
Skin and appendages |
Skin rash |
Pruritis |
Exfoliative skin disorder | |
|
Musculoskeletal |
Myalgia | |||
|
General |
Fatigue, malaise, asthenia, fever |
Adverse clinical events were reported more frequently in HIV infected patients (21%) than in non-HIV infected patients (13%). However, the patterns of adverse events in HIV infected and non-HIV infected patients were similar.
The following additional adverse events possibly causally related to the use of fluconazole have been observed after the receipt of the marketing authorisation:
Blood and lymphatic system
Leucopenia, including neutropenia and agranulocytosis, thrombocytopenia
Immune system
Angiooedema, face oedema, itching, urticaria
Metabolism and nutrition
Hypercholesterolemia, hypertriglyceridemia, hypokalemia
Nervous system
Seizures
Cardiac
Prolonged-QT, torsades de pointes (see section 4.4)
Hepatobiliary
Hepatic failure, hepatitis
Skin and appendages
Alopecia, toxic epidermal necrolysis
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
Toxicity:
Experience of overdose is limited for fluconazole. 1000 mg administered to an adult did not result in symptoms. 8200 mg administered to an adult, caused hallucinations and paranoid reaction. The patient was hospitalised and within 48 hours the patient’s condition was normal.
Symptoms:
Increased adverse reactions (headache, gastrointestinal symptoms), possibly hallucinations.
Treatment:
Where justified, gastric lavage. Symptomatic treatment. Fluconazole is mainly excreted in the urine. Forced volume diuresis will probably increase the elimination rate. A 3-hour hemodialysis session reduced plasma levels by approximately 50 %.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antimycotics for systemic use, triazole derivatives ATC-code: J02AC01
Fluconazole is a triaozole derivative with fungistatic effect, which specifically inhibits synthesis of the fungi’s ergosterol, which leads to defects in the cell membrane. Fluconazole has a high degree of specificity for the fungal cytochrome P450 dependent enzymes. At a dose of 50 mg daily for 28 days, fluconazole has not been shown to influence serum levels of testosterone in men or the steroid concentration in fertile women.
Fluconazole 200-400 mg daily has no clinically significant effect on endogenous steroid levels or on ACTH stimulated response in healthy male volunteers. Interaction studies with antipyrine indicate that single or multiple doses of fluconazole 50 mg do not affect its metabolism.
The spectrum activity includes a number of pathogens including Candida albicans and other candida-species, Cryptococcus species and dermatophytes. Candida krusei is resistant to fluconazole. Candida glabrata has a naturally reduced sensitivity to fluconazole, approximately 40 % of the isolates are resistant to fluconazole. Infections resulting from aspergillus-species should not be treated with fluconazole.
5.2 Pharmacokinetic properties
Absorption
The pharmacokinetic properties are similar following oral and intravenous administration. The bioavailability of fluconazole following oral administration is in excess of 90%. The degree of absorption is not affected by concomitant food intake. Maximum serum concentration is generally reached after 0.5 to 1.5 hours.
Distribution
The serum concentration is proportional to the dose. Binding to plasma proteins is approximately 12 %. The volume of distribution approximates total body water 0.7 l/kg. Clearance is 0.253 ml/min/kg. The half-life is approximately 30 hours, at which steady-state levels are achieved after 4-5 days of repeated dosing.
Where the dose is doubled on the first day of treatment, a steady-state level of approximately
90 % is reached on day 2.
Fluconazole has demonstrated good penetration to various body fluids. The concentration in saliva and sputum is equal to that in plasma. The concentration in cerebrospinal fluid is 80 % of the plasma level in patients with meningitis resulting from fungal infection.
High skin concentrations of fluconazole, well above serum concentrations, have been achieved in the stratum corneum, epidermis-dermis and in eccrine sweat. Fluconazole accumulates in the stratum corneum. At a dose of 150 mg once weekly, and after two doses of
fluconazole, the concentration was 23.4 pg/g and 7.1 pg/g a week later.
Metabolism
Fluconazole is metabolised only to a small degree. Only 11% of a radioactively labelled dose is excreted in urine in changed form.
Elimination
Fluconazole is primarily excreted via the kidneys. 80% of the dose appears, unchanged in the urine. In addition to renal excretion, approximately 10 of the dose is excreted in the form of metabolites.
Fluconazole clearance is proportional to creatinine clearance.
• Pharmacokinetics in Children
The plasma elimination half-life of fluconazole is approximately 20 hours in children after the neonatal period, and the distribution volume is approx. 1 l/kg.
Prematures, have a longer fluconazole plasma elimination half-life (approximately 70 hours) and a larger distribution volume (1.2-2.3 l/kg) compared with children born at the calculated date of delivery.
During the first weeks after birth the plasma clearance of fluconazole increases and the plasma elimination half-life decreases.
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.
In reproduction toxicity studies in rat an increased incidence of hydronephrosis and extension of renal pelvis was reported and embryonal lethality was increased. An increase in anatomical variations and delayed ossification was noted as well as prolonged delivery and dystocia. In reproduction toxicity studies in rabbits, abortions were recorded.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Sodium chloride Water for Injections.
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
4 years.
6.4 Special precautions for storage
Do not freeze
6.5 Nature and contents of container
Solution for infusion in 100ml clear Type 1 transparent glass vials, with bromobutyl stopper and aluminium/polypropylene flip-off cap.
Pack Sizes: One 100ml vial per pack.
6.6 Special precautions for disposal and other handling
The solution should be visually inspected prior to use and only clear solutions, without particles, should be used.
The infusion contains no preservatives. For single use only. Any remaining solution should be disposed of, in accordance with local requirements.
The infusion is compatible with the following infusion solutions:
- Dextrose 20% solution
- Ringer’s solution
- Ringer’s-lactate solution
- Potassium chloride 1% in 5% dextrose solution
- Sodium bicarbonate 4.2% solution
- Sodium chloride 9 mg/ml (0.9%) solution
7 MARKETING AUTHORISATION HOLDER
Laboratorio Reig Jofre S.A.
C/Gran Capitan, 10
08970 Sant Joan Despi (Barcelona)
Spain
8 MARKETING AUTHORISATION NUMBER(S)
PL 25174/0012
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION 24/02/2010
10 DATE OF REVISION OF THE TEXT
21/07/2015