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
1 ml of solution for infusion contains 2 mg fluconazole.
Each 100 ml vial or Non-PVC bag contains 200 mg fluconazole.
Excipients: Each 100ml contains 15.4 mmol sodium.
For a full list of excipients, see section 6.1
3 PHARMACEUTICAL FORM
Solution for infusion.
Clear and colorless solution.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Treatment of fungal disorders caused by yeast and fungi (Candida and Cryptococci), in particular:
a) Systemic candidiasis, including candidaemia, candiduria, disseminated candidiasis and other forms of invasive candidal infection. These include infections of the peritoneum, endocardium and pulmonary and urinary tracts. Fluconazole 2mg/ml Infusion may be administered to patients with malignant disease, patients in intensive care units and patients undergoing treatment with cytotoxic agents or immunosuppressants.
b) Severe mucosal candidiasis such as:
- severe, oropharyngeal and oesophageal candidiasis
- severe, non-invasive bronchopulmonary candidiasis (upper respiratory tract mucosa).
c) Cryptococcal meningitis. Normal hosts and patients who are immunocompromised (e.g. owing to AIDS or following organ transplantation) may be treated. Oral fluconazole may be used as maintenance therapy to prevent relapse of cryptococcal disease 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 dosage of fluconazole depends upon the nature and severity of infection, the sensitivity of the causative pathogen(s) and the age, body weight and renal function of the patient. The duration of treatment depends upon the severity and clinical course of the disease.
Fluconazole is also available for oral therapy. The patient should be switched from dosing by the intravenous route to dosing by the oral route as soon as possible. It is not necessary to change the daily dose of fluconazole when changing the route of administration from intravenous to oral.
Fluconazole 2mg/ml Infusion is formulated in 0.9% sodium chloride solution, each 200mg (100ml bottle) containing 15.4 mmol each of Na+ and Cl-(see also section 4.4 Special warnings and special precautions for use).
Use in adults
1) Systemic candidiasis
The usual initial dose is 400 - 800 mg fluconazole once daily on the first day of treatment. Therapy is then continued at a dose of 200 mg fluconazole once daily. If required, the dose can be increased to 400 mg fluconazole once daily over the entire duration of treatment.
The duration of treatment depends upon the clinical response. Therapy should be continued until laboratory tests indicate that active fungal infection has subsided. An insufficient duration of treatment may lead to recurrence of infection.
Severe candiduria 100 mg fluconazole once daily.
The duration of administration is 14-30 days.
2) Severe mucosal candidiasis
- severe, oropharyngeal candidiasis:
100 mg fluconazole once daily.
The duration of administration is 7-14 days.
- severe, oesophageal candidiasis: 100 mg fluconazole once daily.
The duration of administration is 14-30 days.
- severe, non-invasive bronchopulmonary candidiasis:
100 mg fluconazole once daily.
The duration of administration is 14-30 days.
3) Cryptococcal meningitis
Therapy of cryptococcal meningitis
The usual initial dose is 400 mg fluconazole once daily on the first day of treatment. Therapy is then continued with 200 mg fluconazole once daily. If required, the dose can be increased to 400 mg fluconazole once daily over the entire duration of treatment.
Prophylaxis of cryptococcal meningitis
A daily dose of 100-200 mg is recommended in maintenance treatment to prevent relapse of cryptococcal meningitis in AIDS patients. Prophylaxis of cryptococcal meningitis may be carried out with oral fluconazole.
There has been experience to date with treatment periods of up to 25 months.
Use in elderly patients
In elderly patients with no signs of impaired renal function, the usual dosage recommendations should be followed. In patients with creatinine clearance below 50 ml/min, the dosage should be adjusted according to the guidelines for patients with impaired renal function.
Use in children
It is recommended that Fluconazole 2 mg/ml Infusion should not be used in children and adolescents under the age of 16 years because efficacy and safety have not been sufficiently demonstrated. If there is no therapeutic alternative, the recommendations below should be followed.
As with similar infections in adult, the duration of treatment is based on the clinical and mycological response. Fluconazole is administered as a single daily dose.
For children with impaired renal function the daily dose should be reduced in accordance with the guidelines given for adults, see dosing in “Use in patients with impaired renal function
Children over four weeks of age:
The recommended dose of fluconazole for severe mucosal candidiasis is 3mg/kg daily. A loading dose of 6mg.kg may be used on the first day to achieve steady state blood concentrations more rapidly.
For the treatment of systemic candidiasis and cryptococcal infections, the recommended dosage is 6-12 mg/kg daily, depending on the severity of the disease.
A maximum dosage of 400 mg daily should not be exceeded in children.
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. There are few pharmacokinetic data to support this posology in term newborn babies (see section 5.2).
A maximum dose 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.
The pharmacokinetics of fluconazole has not been studied in children with renal insufficiency.
Use in patients with impaired renal function
Fluconazole is excreted predominantly in the urine as unchanged drug. In patients (including children) with impaired renal function who will receive multiple doses of Fluconazole 2mg/ml Infusion, the normal recommended dose (according to indication) should be given on day 1, followed by a daily dose based on the following table:
|
Creatinine clearance (ml/min) |
Dosing interval Daily dose |
|
>50 |
24 hours (normal |
|
dosage) | |
|
<= 50 |
48 hours or half the |
|
normal daily dose | |
|
Dialysis |
one dose after every |
Method of administration:
The rate of intravenous infusion should not exceed 10 ml/min. The solution for infusion is ready for use, dilution of the solution is not necessary. In children, the rate of intravenous infusion should not exceed 5ml/min.
Fluconazole 2mg/ml Infusion is compatible with the following solutions:
a) Glucose 20% solution
b) Ringer’s solution
c) Ringer’s lactate solution
d) Potassium chloride 1% in 5% glucose solution
e) Sodium bicarbonate solution 4.2%
f) Normal sodium chloride solution
Fluconazole 2mg/ml Infusion can be infused through an infusion system with one of the above solutions.
Although no specific incompatibilities are known, Fluconazole 2mg/ml Infusion should not be mixed with other medicines in a solution for infusion.
4.3 Contraindications
Fluconazole should not be used in patients with known hypersensitivity to fluconazole, other azole derivatives or any of the other ingredients. 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.
Fluconazole should not be co-administered with drugs both known to prolong the QT-interval and metabolized by CYP3A4 such as cisapride, astemizole, pimozide and quinidine. (See also section 4.4 and 4.5).
4.4 Special warnings and precautions for use
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. Laboratory tests should be monitored closely.
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 CYP34A but known to prolong QT interval
• Electrolyte disturbances such as hypokalaemia
Hepatotoxicity
Monitoring of hepatic function parameters
Patients who demonstrate deterioration in liver function test results during fluconazole therapy should be carefully monitored, in order to avoid more severe hepatic damage. Fluconazole should be immediately discontinued if clinical symptoms occur that indicate hepatic damage. Very 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 mediactions, some known to be potentially hepatotoxic, and/or had underlying diseases which could have caused hepatic necrosis.
In cases of hepatotoxicity, no obvious relationship to total daily dose of Fluconazole, duration of therapy, sex or age of the patient has been observed. The abnormalities have usually been reversible on discontinuation of Fluconazole therapy.
As a causal relationship with Fluconazole cannot be excluded, 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 during treatment with Fluconazole.
Skin reactions
Rarely, during fluconazole treatment, patients have developed exfoliative skin reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis. AIDS patients are more prone to develop severe cutaneous reactions to many drugs. If a rash develops in a patient treated for a superficial fungal infection and that rash is considered to be attributable to fluconazole then further therapy with this agent should be discontinued. If a patient with invasive / systemic fungal infection develops a rash whilst receiving fluconazole then the patient should be monitored closely and fluconazole should be discontinued if bullous lesions or erythema multiforme develop. In rare case, as with azoles anaphylaxis has been reported (see section 4.8)
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.
The medicinal product contains 15.4 mmol of sodium per 100ml dose. To be taken into consideration by patients on a controlled sodium diet.
4.5 Interaction with other medicinal products and other forms of interaction
Medicinal products, which are contra-indicated - Combinations of the following drugs are contraindicated:
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
Cisapride (CYP3A4 substrate)
There have been reports of cardiac events including Torsade de Pointes in patients to whom fluconazole and cisapride were coadministered. A controlled study found that concomitant fluconazole 200 mg once daily and cisapride 20 mg four times a day yielded a significant increase in cisapride plasma levels and prolongation of QT interval Administration of cisapride is contraindicated in patients receiving fluconazole.
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.
Ervthromycin:
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
Terfenadine (CYP3A4 substrate)
As severe cardiac arrhythmias occurred secondary to QTC prolongation in patients concurrently receiving azole anti-fungal agents and terfenadine, interaction studies were performed. One study with fluconazole administration at doses of 200 mg/day showed no prolongation of the QTC interval. Another study with fluconazole administration at doses of 400 mg/day and 800 mg/day showed significant increases in plasma terfenadine concentrations following concurrent administration of fluconazole at doses of 400 mg/day and above. Concomitant treatment with fluconazole 400 mg per day or higher dose is contraindicated (see section 4.3). With concomitant treatment with doses below 400 mg per day, the treatment should be closely monitored.
Hydrochlorothiazide
Concurrent multiple administration of hydrochlorothiazide can increase plasma fluconazole concentrations; however, no dose adjustment of fluconazole is required.
Rifampicin (CYP450 inducer)
Concurrent administration of fluconazole and rifampicin lowers the plasma concentration of fluconazole and shortens its half-life. In patients undergoing concurrent rifampicin therapy, a dose increase of fluconazole should therefore be considered.
- Effect of fluconazole on the metabolism of other drugs
Note:
Fluconazole is a potent inhibitor of the cytochrome P450 (CYP) isoenzyme 2C9 and a moderate inhibitor of CYP3A4. In addition to the listed interactions, there is also a risk of increased plasma concentrations for other drugs metabolized via CYP2C9 or CYP3A4 (e.g. ergot alkaloids, HMG-CoA reductase inhibitors, quinidine) following co-medication with fluconazole; patients receiving such drugs require close monitoring. Due to the long half-life of fluconazole, the effect may persist for 4-5 days after discontinuation of fluconazole.
Alfentanil (CYP3A4 substrate)
A study observed a reduction in clearance and distribution volume as well as prolongation of T1/2 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:
Concurrent administration of fluconazole and amitriptyline or the active metabolite, nortriptyline, causes a rise in serum amitriptyline and 5-nortriptyline, S-amitriptyline concentrations. This lead to an increased risk of amitriptyline toxicity (toxicity of tricyclic antidepressants). Monitoring of amitriptyline blood concentrations and a subsequent dose reduction may be necessary.
Anticoagulants (CYP2C9 substrate)
In an interaction study, following warfarin administration in male volunteers, a 12% prolongation of the prothrombin time was observed in healthy males.
In post-marketing experience, as with other azole antifungals, bleeding events (bruising, epistaxis, gastrointestinal bleeding, haematuria, and melaena) 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
Short-acting benzodiazepines (CYP3A4 substrates)
Following oral administration of midazolam, administration of fluconazole caused a marked increase in serum midazolam concentrations and an increase in the effects of the drug. These effects appeared to be more marked following oral administration of
fluconazole than following intravenous administration. If benzodiazepine administration is necessary in patients undergoing fluconazole therapy, a dose reduction of the benzodiazepines should be considered and patients monitored appropriately. Fluconazole increases the AUC of triazolam (single dose) by approximately 50%, Cmax with 20-32% and increases tVfe by 25-50 % due to the inhibition of metabolism of triazolam. Dosage adjustments of triazolam may be necessary.
Calcium-channel blockers (CYP3A4 substrate)
Triazole antifungal agents such as Fluconazole, inhibit the hepatic isoenzyme, CYP34A, an enzyme which is involved in the breakdown of some dihydropyridine calcium-channel blockers, including nifedipine, isradipine, nicardipine, amlodipine and felodipine. In the scientific literature, marked peripheral oedema and/or increased serum concentrations of calcium channel-blockers have been reported, following concurrent administration of itraconazole and felodipine, isradipine or nifedipine. This interaction is also likely to occur with other combinations. A dose reduction of the calcium-channel blocker or withdrawal of drug should be considered. The adverse events arising with the simultaneous intake of calcium channel antagonists are vertigo, hypotension, headache, redness of face.
Carbamazepine (CYP3A4 substrate)
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
Celecoxib (CYP2C9 substrate)
During concomitant treatment with fluconazole (200 mg daily) and celecoxib (200 mg) the celecoxib Cmax and AUC increased by 68% and 134%, respectively. Half of the celecoxib dose may be necessary when combined with fluconazole.
Halofantrine (CYP3A4 substrate)
Fluconazole can increase halofantrine plasma concentration due to an inhibitory effect on CYP3A4.
HMG CoA reductase inhibitors (CYP2C9 substrate or CYP3A4 substrate)
The risk of myopathy and rhabdomyolysis increases when fluconazole is coadministered with HMG-CoA reductase inhibitors metabolised through CYP3A4, such as atorvastatin and simvastatin, or through CYP2C9, such as fluvastatin. If concomitant therapy is necessary, the patient should be observed for symptoms of myopathy and rhabdomyolysis and creatinine kinase should be monitored. HMG-CoA reductase inhibitors should be discontinued if a marked increase in creatinine kinase is observed or myopathy/rhabdomyolysis is diagnosed or suspected.
Oral contraceptives
Pharmacokinetic interaction studies with multiple administration of fluconazole and oral contraceptives produced the following results: 50 mg fluconazole daily have no effect on the endogenous serum steroid concentration or the kinetics of oral contraceptives in women; in contrast, 200 mg fluconazole daily increase the AUC of ethinylestradiol and levonorgestrel by 40% and 24%, respectively. Thus, multiple administration of fluconazole at these doses probably does not impair the efficacy of a 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.
Losartan (CYP2C9 substrate)
Via inhibition of CYP2C9, fluconazole reduces the conversion of losartan to its active metabolite (E-3174), which is responsible for the majority of the angiotensin-II-receptor-antagonistic effects that occur during losartan therapy. The patient’s blood pressure should be continuously monitored.
Methadone (CYP3A4 substrate)
Fluconazole may enhance the serum concentration of methodone.
Dosage adjustment of methadone may be necessary
Phenytoin (CYP2C9 substrate)
Concurrent, multiple administration of fluconazole and phenytoin may cause a clinically significant rise in serum phenytoin concentrations. In concurrent administration, therefore, serum phenytoin concentrations should be measured and the phenytoin dose should be adjusted to the therapeutic concentration.
Theophylline
In a placebo-controlled interaction study, concurrent administration of 200 mg fluconazole over a period of 14 days reduced the plasma clearance of theophylline by 18%. Patients who are receiving high dose theophylline or who are otherwise at increased risk for theophylline toxicity should be observed for signs of theophylline toxicity while receiving fluconazole. Therapy should be modified if signs of toxicity develop.
Chemotherapeutic agents Rifabutin (CYP3A4 substrate)
Concurrent administration of fluconazole and rifabutin can increase serum rifabutin concentrations and lead to uveitis.
Patients concurrently receiving fluconazole and rifabutin should thus be closely monitored.
Trimetrexate
Drugs which inhibit the P450 enzyme system, such as fluconazole, can cause a rise in plasma trimetrexate concentrations due to interactions. If clinically possible, concurrent administration of trimetrexate and fluconazole should be avoided. If these drugs are coadministered, serum trimetrexate concentrations and trimetrexate toxicity
(myelosuppression, renal and hepatic dysfunction and ulceration in the gastrointestinal tract) should be 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 200mg 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 200mg every eight hours either with or without fluconazole 400mg daily for seven days. The AUC of zidovudine significantly increased (74%) during co-administration with fluconazole. Patients receiving this combination should be monitored for the development of zidovudine-related adverse reactions.
Immunosuppressants
Ciclosporin (CYP3A4 substrate)
Fluconazole significantly increases the concentration and AUC of ciclosporin. This combination may be used by reducing the dosage of ciclosporin depending on ciclosporin concentration.
Prednisone (CYP3A4 substrate)
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.
Sirolimus (CYP3A4 substrate)
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.
Tacrolimus (CYP3A4 substrate)
There have been reports that an interaction exists when fluconazole is administered concomitantly with tacrolimus, leading to increased serum levels of tacrolimus. There have been reports of nephrotoxicity in patients to whom fluconazole and tacrolimus were co-administered.
Patients concurrently receiving fluconazole and tacrolimus should thus be closely monitored.
- Other interactions
Amphotericin B
Concurrent administration of fluconazole and amphotericin B in infected normal and immunosuppressed mice showed the following results: a small additive antifungal effect in systemic infection with C. albicans, no interaction in intracranial infection with Cryptococcus neoformans, and antagonism of the two drugs in systemic infection with A. fumigatus. The clinical significance of results obtained in these studies is unknown
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
Azithromvcin: 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.
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
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.
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.
Sulfonylureas: Fluconazole has been shown to prolong the serum half-life of concomitantly administered oral sulfonylureas (e.g., chlorpropamide, glibenclamide, glipizide, tolbutamide) in healthy volunteers. Frequent monitoring of blood glucose and appropriate reduction of sulfonylurea dosage is recommended during co-administration. Fluconazole and oral sulphonylureas may be coadministered to diabetic patients, but the possibility of a hypoglycaemic episode should be borne in mind.
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.
The use of fluconazole in patients concurrently taking astemizole or other drugs metabolised by the cytochrome P450 system may be associated with elevations in serum levels of these drugs. In the absence of definitive information, caution should be used when co-administering fluconazole. This is particularly important for drugs known to prolong QT interval. Patients should be carefully monitored.
Interaction studies have shown that diet, cimetidine, antacids or whole-body radiation during bone marrow transplantation do not significantly influence the absorption of orally administered fluconazole into the blood.
Physicians should be aware that drug-drug interaction studies with other medications have not been conducted, but that such interactions may occur.
4.6 Pregnancy and lactation
Pregnancy
Data from several hundred pregnant women treated with standard doses (below 200 mg/day) of fluconazole, administered as a single or repeated dose during the first trimester, do 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 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.
Animal studies show teratogenic effects.
Accordingly, Fluconazole should not be used in pregnancy, or in women of childbearing potential unless adequate contraception is employed.
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
Fluconazole has little or no effect on the ability to drive a vehicle or operate machinery. When driving a vehicle or operating machinery, it should nevertheless be taken into account that lightheadedness or seizures are uncommon occurrences (see section 4.8).
4.8. Undesirable effects
The following frequency data are used in the evaluation of undesirable effects: Very common: (> 1/10)
Common: (> 1/100, < 1/10)
Uncommon: (> 1/1,000 < 1/100)
Rare (> 1/10,000 < 1/1,000)
Very rare (< 1/10,000, not known (cannot be estimated from the available data ) The following undesirable effects have been observed:
Blood and lymphatic system disorders Uncommon: anaemia
Rare: changes in the blood count, e.g. leukocytopenia (including neutropenia and agranulocytosis) and thrombocytopenia,. The appropriate laboratory values should be very closely monitored (see section 4.4).
Immune system disorders
Rare: severe hypersensitivity reactions (anaphylactic reactions including angioedema, facial oedema)
Metabolism and nutrition disorders
Rare: hypertriglyceridaemia, hyperchlolesterolaemia, hypokalaemia
Psychiatric disorders
Uncommon: insomnia, somnolence
Nervous system disorders
Common: headache
Uncommon: dizziness, peripheral nervous disorders, tremor, convulsions, impaired sense of taste, pareaesthesia,
Gastrointestinal disorders
Common: digestive disorders, such as nausea, vomiting, abdominal pain, diarrhoea
Uncommon: dry mouth, loss of appetite, constipation, dyspepsia, flatulence
Hepatobiliary disorders
Common: An increase in the serum activities of liver-derived enzymes such as alkaline phosphatase (ALP), alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
Uncommon: cholestasis, a clinically relevant rise in total bilirubin, jaundice, hepatocellular damage
Rare:hepatitis, liver cell necrosis, liver failure with isolated fatalities. The appropriate laboratory values should be very closely monitored (see section 4.4).
Skin and subcutaneous tissue disorders
Common: skin rashes
Uncommon: Pruritus, increased sweating,
Rare: hair loss (alopecia), severe skin disorders, with exfoliation, such as Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell syndrome), erythema exudativum multiforme (see section 4.4)
Musculoskeletal and connective tissue disorders
Uncomon: myalgia
Renal and urinary disorders
Changes in laboratory test results of kidney function have been observed. The appropriate laboratory values should be very closely monitored (see section 4.4).
Cardiac disorders:
QT prolongation, torsade de pointes (see section 4.4)
Ear and labyrinth disorders Uncommon : Vertigo
General disorders and administration site conditions
Uncommon: fatigue, malaise, asthenia, fever.
Undesirable effects have been observed more often in HIV-infected patients than in non- HIV-infected patients. However, the pattern of undesirable effects was similar in these patients.
4.9 Overdose
In the event of overdosage, supportive measures and symptomatic treatment, with gastric lavage if necessary, may be adequate.
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.
Fluconazole is mainly excreted in the urine. forced volume diuresis would probably increase the elimination rate. A three hour haemodialysis session reduces concentrations by approximately 50%
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antimycotics for systemic use, Triazole derivatives ATC code: J02AC01 Type of action
Fluconazole is a substance, which belongs to the triazole derivative class of drugs. The agent is particularly effective against Candida species and cryptococci.
Mechanism of action
Fluconazole has a highly specific effect on cytochrome-P450-dependent fungal enzymes and is a potent and specific inhibitor of fungal sterol synthesis.
Spectrum of activity
Fluconazole has a wide spectrum of antimycotic activity. In various in-vivo animal activity studies (p.o. and i.v.), fluconazole is active in superficial and systemic infections with Candida, Cryptococcus and various dermatophytes.
Candida krusei is resistant to fluconazole. The susceptibility of Candida glabrata is variable. Candida dubliniensis is not primarily resistant but shows a high tendency towards resistance, mainly during therapy. Fluconazole has little of no activity against Aspergillus, Mucor, Microsporum and Trichophyton species.
In animal experimental models of endemic mycosis, fluconazole was shown to be effective, including in infections with Blastomyces dermatitidis, Coccidioides immitis and Histoplasma capsulatum in normal and immunosuppressed animals. As with other azoles, due to the lack of a standardised procedure, the results of in-vitro tests are of lesser significance in terms of predicting
Clinical efficacy than the results of in-vivo studies.
In volunteers, 200-400 mg fluconazole daily have no clinically relevant effect on endogenous serum steroid concentrations or ACTH-stimulated cortisol release.
Absorption
The pharmacokinetics of fluconazole are similar following both intravenous and oral administration. Peak plasma concentrations in fasting patients are reached 0.5-1.5 hours after administration, the plasma elimination half-life is approximately 30 hours. Plasma concentrations are dose-proportional up to doses of 1600 mg/day.
Following multiple administration of fluconazole once daily, plasma concentrations of 90% of steady state are reached after 4-5 days. The volume of distribution corresponds approximately to total body water. Plasma protein binding is low (12%).
Distribution
Fluconazole penetrates well into all tissues and bodily fluids investigated to date. Fluconazole concentrations in saliva and sputum are comparable to plasma concentrations. In patients with fungal meningitis, fluconazole concentrations in the cerebrospinal fluid are approximately 80% of the corresponding plasma values.
In the stratum corneum, epidermis and perspiration, fluconazole reaches higher concentrations than in the serum, whereby it particularly accumulates in the stratum corneum. At a daily dose of 50 mg, the fluconazole concentration here was 73 pg/g, 12 days after the end of treatment and 5.8 pg/g, 7 days after the end of treatment.
Metabolism/elimination
There is no evidence of circulating metabolites. The major route of excretion is renal, with approximately 80% of the administered dose appearing in the urine as unchanged drug. Fluconazole clearance is proportional to creatinine clearance.
The plasma elimination half-life is approximately 30 hours in people with normal renal function, with a range observed from 20 to 50 hours. The plasma elimination half-life increases to 98 to 125 hours in renal function impairment (creatinine clearance <20ml / minute).
The long plasma elimination half-life allows once-daily dosing in the treatment of all fungal infections.
Pharmacokinetics in Children
Pharmacokinetic data were assessed for 113 paediatric patients from 5 studies; 2 single dose studies, 2 multiple dose studies and a study in premature neonates. Data from 1 study were not interpretable due to changes in formulation partway through the study. Additional data were available from a compassionate use study.
|
Age |
Dosage (mg/kg) |
Clearance (ml/min/kg) |
Half-life (hours) |
C '-max (pg/ml) |
Volume of distribution (steady state) Vdss (L/kg) |
|
9 months-13 years |
Single oral 2 mg/kg |
0.40 (38%) n = 14 |
25.0 |
2.9 (22%) n = 16 | |
|
9 months-13 years |
Single oral 8 mg/kg |
0.51 (60%) n = 15 |
19.5 |
9.8 (20%) n = 15 | |
|
5- |
Multiple i.v. |
0.49 |
17.4 |
5.5 |
0.722 |
|
15 years |
2 mg/kg |
(40%) n = 4 |
(25%) n = 5 |
(36%) n = 4 | |
|
5- |
Multiple i.v. |
0.59 |
15.2 |
11.4 |
0.729 |
|
15 years |
4 mg/kg |
(64%) n = 5 |
(44%) n = 6 |
(33%) n = 5 | |
|
5- |
Multiple i.v. |
0.66 |
17.6 |
14.1 |
1.069 |
|
15 years |
8 mg/kg |
(31%) n = 7 |
(22%) n = 8 |
(37%) n = 7 |
After administration of 2 - 8 mg/kg fluconazole to children between the ages of 9 months to 15 years, an AUC of about 38 pg.h/ml was found per 1 mg/kg dose units. The average fluconazole plasma elimination half-life varied between 15 and 18 hours and the distribution volume was approximately 880 ml/kg after multiple doses. A higher fluconazole plasma elimination half-life of approximately 24 hours was found after a single dose. This is comparable with the fluconazole plasma elimination half-life after a single administration of 3 mg/kg i.v. to children of 11 days-11 months old. The distribution volume in this age group was about 950 ml/kg.
These studies showed that clearance based on body weight was not affected by age. Mean clearance in adults was 0.23 (17%) ml/min/kg. The results in children aged from 5-13 years show that fluconazole may be more rapidly eliminated than in adults. Higher doses may thus be required in the treatment of severe, life-threatening infections.
Experience with fluconazole in neonates is limited to pharmacokinetic studies in premature newborns. The mean age at first dose was 24 hours (range 9-36 hours) and mean birth weight was 0.9 Kg (range 0.75-1.10 Kg) for 12 pre-term neonates of average gestation around 28 weeks. Seven patients completed the protocol; a maximum of five 6mg/Kg intravenous infusions of fluconazole were administered every 72 hours. The mean half-life (hours) was 74 (range 44-185) on day 1 which decreased with time to a mean of 53 (range 30-131) on day 7 and 47 (range 27-68) on day 13. The area under the curve (microgram.h/ml) was 271 (range 173-385) on day 1 and increased with a mean of 490 (range 292-734) on day 7 and decreased with a mean of 360 (range 167-566) on day 13. The volume of distribution (ml/kg) was 1183 (range 1070-1470) on day 1 and increased with time to a mean of 1184 (range 510-2130) on day 7 and 1328 (range 10401680) on day 13.
In premature infants (gestational age: 26th-29th week of pregnancy) the mean (%CV) clearance within the first 36 hours was 0.180 (35%, n = 7) ml/min/kg and reached a mean value of 0.218 (31%, n = 9) after 6 days and a mean value of 0.333 (56%, n = 4) after 12 days.
Correspondingly, the half-life fell from 73.6 hours to 53.2 hours after 6 days and to 46.6 hours after 12 days.
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.
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 1000 (ig/ml) showed no evidence of chromosomal mutations.
Impairment of fertility
Fluconazole did not affect the fertility of male or female rats treated with parenteral doses of 5, 25 or 75 mg/kg, although the onset of parturition was slightly delayed at 20 mg/kg. 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 estrogen-lowering property produced by high doses of Fluconazole. Such a hormone change has not been observed in women treated with Fluconazole.
6.1 List of excipients
Sodium chloride Water for injections
6.2 Incompatibilities
Although no specific incompatibilities have been reported, mixing Fluconazole 2mg/ml Solution for Infusion with solutions other than those mentioned in section 4.2: “Posology and method of administration” is not recommended.
6.3 Shelf life
For Glass vials: 36 Months For Non-PVC bags: 24 Months
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
Do not store above 25 °C. Do not freeze.
Keep vial in the outer carton in order to protect from light.
Do not store above 25 °C. Do not freeze.
Keep Non-PVC bag in over wrap pouch in order to protect from light.
6.5 Nature and contents of container
Clear glass vial (type I) sealed with butylated rubber closures on crimping with aluminium over-caps and protected by plastic flip-off seals.
Non PVC bag containing Ciprofloxacin solution packed in overwrap label .
Pack size: 100ml X 1
6.6 Special precautions for disposal
The infusion does not contain any preservative. It is for single use only.
Discard any remaining solution according to guidelines of the local authorities.
Do not use if container is found leaking or solution is not clear.
Solutions containing visible solid particles must not be used.
7 MARKETING AUTHORISATION HOLDER
Claris Lifesciences UK Limited
Crewe hall
Crewe
Cheshire
CW1 6UL
UNITED KINGDOM
8 MARKETING AUTHORISATION NUMBER(S)
PL20568/0002
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
28/10/2010
10 DATE OF REVISION OF THE TEXT
28/10/2010