Fluconazole 150mg Capsules
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Fluconazole 150mg Capsules
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains 150mg of fluconazole.
For excipients, see 6.1.
3 PHARMACEUTICAL FORM
Capsule, hard.
Fluconazole 150mg Capsules have a blue body and cap.
4. CLINICAL PARTICULARS
4.1 Therapeutic Indications
Fluconazole is indicated for the treatment of the following infections when caused by fungi that are known or likely to be fluconazole-susceptible:
acute or recurrent vaginal candidiasis.
4.2. Posology and method of administration
For oral administration.
Adults
Vaginal candidiasis or candidal balanitis - 150mg as a single oral dose.
Children
Not recommended in children aged under 16 years unless antifungal treatment is imperative, and no suitable alternative agent exists, due to insufficient safety and efficacy (see section 5.2).
Elderly
Not recommended in patients aged over 60 years.
Use in renal impairment
Fluconazole is excreted predominantly in the urine as unchanged drug. No adjustments in single dose therapy are required.
Use in patients with hepatic insufficiency
Fluconazole should only be administered with special care and under careful monitoring in patients with liver insufficiency (see section 4.4).
4.3. Contraindications
Known hypersensitivity to fluconazole or to related azole compounds or any other ingredient in the formulation.
Conditions such as hypokalaemia and hypomagnesaemia Congenital or acquired long QT syndromes
Clinically relevant bradycardia, cardiac arrhythmia or severe cardiac insufficiency.
Co-administration of the following medicines with fluconazole is contra-indicated: antihistamines such as terfenadine, antispasmodics such as cisapride astemizole, pimozide and quinidine.
Medicines that prolong the QT interval such as antiarrhythmics of Class IA (eg. Disopyramide) or Class III (eg. Sotalol)
4.4 Special Warnings and Precautions for Use
Fluconazole should be administered with caution to patients with liver dysfunction (see section 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. The benefits of the treatment should be evaluated against the risks of developing serious liver damage if therapy is repeated in patients whose liver enzyme values rise during fluconazole treatment.
The dose of fluconazole must be reduced when creatinine clearance is below 50 ml/min.
In some patients, particularly those with serious underlying diseases such as AIDS and cancer, abnormalities of hepatic, renal, haematological and other biochemical function tests have been observed during treatment with fluconazole but the clinical significance and relationship to treatment is uncertain.
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.
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. These reports included seriously ill patients with multiple confounding risk factors, such as structural heart disease, electrolyte abnormalities and concomitant medications that may have been contributory.
Even though a connection between fluconazole and prolonged QT-interval has not been formally confirmed, fluconazole should be administered with caution to patients with these potentially proarryhthmic conditions, such as:
• Congenital or documented acquired QT prolongation
• Cardiomyopathy, particularly in the presence of heart failure
• Clinically significant (including sinus) bradycardia
• Symptomatic arrhythmias
• Electrolyte disturbances
• Concomitant administration of medicinal products known to prolong the QT-interval (see section 4.5).
For single dose use in patients with renal dysfunction, no dose adjustment is required (see section 4.2).
Fluconazole is a potent CYP2C9 inhibitor and a moderate CYP3A4 inhibitor. Fluconazole-treated patients who are concomitantly treated with drugs which have a narrow therapeutic window (e.g. warfarin and phenytoin) and which are metabolised through CYP2C9 and CYP3A4 should be monitored (see sections 4.3 and 4.5).
The product intended for pharmacy availability without prescription will carry a leaflet which will advise the patient:
Do not use Fluconazole Capsules without first consulting your doctor:
If you are under 16 or over 60 years of age.
If you are allergic to any of the ingredients in Fluconazole Capsules or other antifungals and other vaginal thrush treatments.
If you are taking any medicine other than the pill.
If you are taking astemizole (for allergies) or the prescription medicine cisapride (used to treat heart burn and to lower stomach acid).
If you have had thrush more than twice in the last six months.
If you have any disease or illness affecting your liver or kidneys or you have had unexplained jaundice.
If you suffer from any other chronic disease or illness such as AIDS and cancer.
If you or your partner have had exposure to a sexually transmitted disease.
The product should never be used again if the patient experiences a rash or anaphylaxis follows the use of the drug.
If you are unsure about the cause of your symptoms If you are taking pimozide (used in psychosis)
If you are taking quinidine (an antiarrhythmic, used to treat an irregular heartbeat). Women only:
If you are pregnant, suspect you might be pregnant or are breast feeding.
If you have any abnormal or irregular vaginal bleeding or a blood stained discharge.
If you have vulval or vaginal sores, ulcers or blisters.
If you are experiencing lower abdominal pain or burning on passing urine.
Men only:
If your sexual partner does not have thrush
If you have penile sores, ulcers or blisters
If you have an abnormal penile discharge (leakage)
If your penis has started to smell If you have pain on passing urine.”
The product should never be used again if the patient experiences a rash or anaphylaxis follows the use of the drug.
Recurrent use (men and women): patients should be advised to consult their physician if the symptoms have not been relieved within one week of taking fluconazole 150mg capsule. Fluconazole 150mg capsule can be used if the candidal infection returns after 7 days. However, if the candidal infection recurs more than twice within six months, patients should be advised to consult their physician.
This product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interactions With Other Medicinal Products and Other Forms of Interaction
The following drug interactions relate to the use of multiple-dose fluconazole. The relevance to single-dose 150mg fluconazole has not yet been established.
The following combinations are contra-indicated:
Concomitant administration of fluconazole with astemizole may decrease the clearance of astemizole. Resulting increased plasma concentrations of astemizole can lead to prolonged QT interval and severe ventricular arrhythmia, torsades de pointes and cardiac arrest. Concomitant administration of astemizole and fluconazole is contra-indicated due to potential for serious, potentially fatal, cardiac effects.
Cisapride (CYP3A4 substrate): There have been reports of cardiac events including torsades de pointes in patients to whom fluconazole and cisapride were coadministered. 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. Coadministration of cisapride is contraindicated in patients receiving fluconazole. (See section 4.3.)
A controlled study found that concomitant fluconazole 200mg once daily and cisapride 20mg four times a day yielded a significant increase in cisapride plasma levels and prolongation of QT interval.
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 kinetic interaction study, co-administration of multiple-dose hydrochlorothiazide to healthy volunteers receiving fluconazole increased plasma concentrations of fluconazole by 40%. An effect of this magnitude should not necessitate a change in the fluconazole dose regimen in subjects receiving concomitant diuretics, although the prescriber should bear it in mind.
Medicinal products affecting the metabolism and/or excretion of fluconazole Rifampicin(CYP450 inducer): Concomitant administration of fluconazole and rifampicin resulted in a 25% decrease in the AUC and 20% shorter half-life of fluconazole. In patients receiving concomitant rifampicin, an increase in the fluconazole dose should be considered.
The effect offluconazole on other medicinal products
Fluconazole is a 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 coadministered with fluconazole. Therefore, care should always be taken when using these combinations and the patients should be carefully monitored. The effect may persist for 4-5 days after the end of fluconazole treatment due to the long fluconazole half-life.
Alfentanil
A study observed a reduction in clearance and distribution volume as well as prolongation of T/ 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
Fluconazole increases the effect of amitriptyline and nortriptyline. 5- nortriptyline and/or S-amitnptyline may be measured at initiation of the combination therapy and after one week. Dosage of amitriptyline/nortriptyline should be adjusted, if 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 postmarketing 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 anti-coagulants should be carefully monitored.
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. If concomitant benzodiazepine therapy is necessary in patients being treated with fluconazole, consideration should be given to decreasing the benzodiazepine dosage and the patient 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.
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 calcium antagonist.
Frequent monitoring for adverse events is recommended.
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.
Celecoxib
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.
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. and can cause a prolongation of the QT interval. The concomitant use of fluconazole and halofantrine is not recommended.
HMG-CoA: The risk of myopathy or rhabdomyolysis is increased when azole antifungals are administered concurrently with HMG-CoA reductase inhibitors such as atorvastatin. If concurrent therapy is required, patients should be monitored for signs and symptoms of myopathy or rhabdomyolysis (muscle pain, tenderness or weakness), and creatinine kinase (CK) levels. HMG-CoA therapy should be discontinued if CK levels show a marked increase, or if myopathy or rhabdomyolysis is diagnosed or suspected.
The combination may require dose reduction of the HMG-CoA reductase inhibitors.
Losartan: Due to inhibition of CYP2C9 by fluconazole, there is decreased conversion of losartan to its active metabolite (E-3174) which is responsible for most of the angiotensin II receptor antagonism that occurs with losartan therapy. The patient should be monitored for continued control of their hypertension. Chemotherapeutic agents.
Methadone
Fluconazole may enhance the serum concentration of methadone. Dosage adjustment of methadone may be necessary.
Non-steroidal anti-inflammatory drugs
The Cmax and AUC of flurbiprofen were increased by 23% and 81%, respectively, when coadministered with fluconazole compared to administration of flurbiprofen alone. Similarly, the Cmax and AUC of the pharmacologically active isomer [S-(+)-ibuprofen] was increased by 15% and 82%, respectively, when fluconazole was coadministered with racemic ibuprofen (400 mg) compared to administration of racemic ibuprofen alone.
Although not specifically studied, fluconazole has the potential to increase the systemic exposure of other NSAIDs that are metabolized by CYP2C9 (e.g. naproxen, lornoxicam, meloxicam, diclofenac). Frequent monitoring for adverse events and toxicity related to NSAIDs is recommended. Adjustment of dosage of NSAIDs may be needed.
Oral contraceptives: Two kinetic 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 200 mg daily the AUCs of ethinyloestradiol and levonorgestrel were increased 40% and 24% respectively. Thus multiple dose use of fluconazole at these doses is unlikely to have an effect on the efficacy of the combined oral contraceptive.
Phenytoin (CYP2C9 substrate and potent CYP450 inducer): Concomitant administration of fluconazole and phenytoin may increase the levels of phenytoin to a clinically significant degree. If it is necessary to administer both drugs concomitantly, phenytoin levels should be monitored and the phenytoin dose adjusted to maintain therapeutic levels.
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): There have been reports that an interaction exists when fluconazole is administered concomitantly with rifabutin, leading to increased serum levels of rifabutin. There have been reports of uveitis in patients to whom fluconazole and rifabutin were co-administered. In combination therapy, symptoms of rifabutin toxicity should be taken into consideration, and Patients receiving rifabutin and fluconazole concomitantly should be carefully monitored.
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 (CYP2C9 substrates): Fluconazole has been shown to prolong the serum half-life of concomitantly administered oral sulphonylureas (chlorpropamide, glibenclamide, glipizide and tolbutamide) in healthy volunteers.
Fluconazole and oral sulphonylureas may be co-administered to diabetic patients, but 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. Patients receiving tacrolimus and fluconazole concomitantly should be carefully monitored. Dosage of orally administered tacrolimus should be decreased depending on tacrolimus concentration.
Terfenadine (400mg or higher, CYP3A4 substrate): 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. The coadministration of fluconazole at doses lower than 400 mg per day with terfenadine should be carefully monitored.
Theophylline: In a placebo controlled interaction study, the administration of fluconazole 200mg for 14 days resulted in an 18% decrease in the mean plasma clearance of theophylline. Patients who are receiving high doses of theophylline or who are otherwise at increased risk for theophylline toxicity should be observed for signs of theophylline toxicity while receiving fluconazole, and the therapy modified appropriately if signs of toxicity develop.
Vinca Alkaloids
Although not studied, fluconazole may increase the plasma levels of the vinca alkaloids (e.g. vincristine and vinblastine) and lead to neurotoxicity, which is possibly due to an inhibitory effect on CYP3A4.
Vitamin A
Based on a case-report in one patient receiving combination therapy with all-transretinoid 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.
Fluvastatin: Up to 200% increases in the area under the curve (AUC) of fluvastatin may occur as a result of the interaction between fluconazole and fluvastatin. An individual patient using fluvastatin 80mg daily may be exposed to considerable fluvastatin concentrations if treated with high doses of fluconazole. Caution should be exercised when fluconazole or other potent cytochrome P450 2C9 (CYP2C9) inhibitors are prescribed to patients who are also taking fluvastatin. The clinical significance of increased plasma concentrations and prolonged elimination of fluvastatin remains unclear.
Didanosine: Although co-administration of didanosine and fluconazole appears to have little effect on the pharmacokinetics or efficacy of didanosine, the response to fluconazole should be monitored. It may be advantageous to administer fluconazole at some time prior to didanosine.
Trimetrexate: Medicaments 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, trimetrexate serum levels and toxicity (bone marrow suppression, renal and hepatic dysfunction and gastrointestinal ulceration) must be monitored carefully.
Zidovudine
Fluconazole increases Cmax of zidovudine by 85%, 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.
Other types of interaction
Interaction studies have shown that when oral fluconazole is co-administered with food, cimetidine, antacids or following total body irradiation for bone marrow transplantation, no clinically significant impairment of fluconazole absorption occurs. Physicians should be aware that drug-drug interaction studies with other medications have not been conducted, but that such interactions may occur.
4.6 Fertility, pregnancy and lactation
Pregnancy:
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 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.
Animal studies show teratogenic effects (see section 5.3) but the potential risk to humans is unknown.
Accordingly, fluconazole capsules should not be used in pregnancy, or in women of childbearing potential unless adequate contraception is employed.
Use during lactation
Fluconazole is secreted in human breast milk at concentrations lower than those in plasma. Breast feeding may be continued after a single dose of Fluconazole 150 mg Capsules. Breastfeeding is not recommended after repeated use, or after high-dose fluconazole.
4.7 Effects on Ability to Drive and Use Machines
Experience with Fluconazole capsules indicates that therapy is unlikely to impair a patient's ability to drive or use machinery. However, when driving vehicles or operating machinery 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 |
Hyp ertri gl yceredaemi a, Hypercholesterol aemi a 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 |
Common |
Rash (see section 4.4) |
|
tissue disorders |
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
In most patients overdose results in gastrointestinal complaints and skin reactions (itch, rash, etc.). There has been a report of an overdose with fluconazole where 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 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
Pharmacotherapeutic Group Antimycotics for Systemic Use ATC Code: J 02 AC 01
Fluconazole, a member of the triazole class of antifungal agents, is a potent and selective inhibitor of fungal enzymes necessary for the synthesis of ergosterol which leads to defects in the cell membrane. Fluconazole is very specific for fungal cytochrome P450 enzymes.
Fluconazole shows little pharmacological activity in a wide range of animal studies. Some prolongation of pentobarbitone 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 is 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.
Mechanism of resistance
Depending on the yeast species involved, the principal mechanisms of resistance to fluconazole, in common with other azole antifungal agents, involve impairing the accumulation of the drug in the cell by
(i) altering the amino acid composition of lanosterol 14a-demethylase,
(ii) increasing drug efflux, and
(iii) altering the ergosterol biosynthetic pathways.
In Candida albicans, blockage of the ergosterol synthetic pathways is thought to primarily arise from blockage of sterol C5,6-desaturase which is encoded by ERG3,
In the more resistant species, Candida glabrata, the predominant pathway has not been fully elucidated but is thought to arise from upregulation of CDR genes (CDR1, CDR2 and MMDR1) responsible for efflux of the drug substance from the cells.
Resistance to fluconazole therefore usually confers resistance to other azole antifungal agents. In Cryptococcus neoformans the studies have demonstrated that the same principle mechanisms of resistance exist in this species, and that these may be affected by prior exposure to azole antifungal agents. Similar careful consideration of the benefits of the proposed dose versus the risk of development of resistance much therefore be applied with fluconazole as for any other antimicrobial chemotherapy.
Breakpoints
According to EUCAST, the following clinical breakpoints apply for fluconazole:
|
Organism |
EUCAST Breakpoints ( g/ml) | |
|
S < |
R> | |
|
Candida albicans, Candida parapsilosis, Candida tropicalis Non-species related breakpoints |
2 |
4 |
|
2 |
4 | |
The antimycotic spectrum of fluconazole includes a number of pathogens including the species Candida albicans, non-Candida albicans, Cryptococcus and dermatophytes.
The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advise should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.
Commonly susceptible species
C.albicans
C.kefyr
C.lusitaniae
C.parapsilosis
Species for which acquired resistance may be a problem
C.dubliniensis
C.famata C.guillermondii C.pelliculosa C. tropicalis
Inherently resistant organisms
C.glabrata
C.krusei
Resistant isolates of Candida albicans have been found in AIDS patients who have undergone long-term treatment with fluconazole.
Infections resulting from Aspergillus species, Zygomycetes including Mucor and Rhizopus, Microsporum and Trychophyton species should not be treated with fluconazole since fluconazole has little or no activity against these fungi.
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 6mg/kg/day for 6 weeks was not superior to griseofulvin administered at 11mg/kg/day for 6 weeks. The overall success rate at 6 weeks was low (fluconazole 6 weeks : 18.3%; fluconazole 3 weeks : 14.7%; griseofulvin : 17.7%) across all the 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 identical after intravenous and oral administration.
Absorption: After oral administration Fluconazole is well absorbed and plasma levels (and systemic bioavailability) are over 90%. Oral absorption is not affected by concomitant food intake. Peak plasma concentrations in the fasting state occur between 0.5 and 1.5 hours postdose with a plasma elimination half-life of approximately 30 hours. Ninety percent steady-state levels are reached by day 4-5 with multiple once daily dosing.
Plasma concentration is proportional to dose.
- after administration of 200mg of 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 400mg of fluconazole, Cmax is around 9 mg/l and plasma concentrations obtained at steady state after 15 days are around 18 mg/l.
Intake of a double dose on day 1 results in plasma concentrations that are approximately 90% of steady state on day 2.
Distribution: Administration of loading dose (on day 1) of twice the usual daily dose enables plasma levels to approximate to 90% steady- state levels by day 2.
Fluconazole achieves good penetration in all body fluids studied. The levels of fluconazole in saliva and sputum are similar to plasma levels. In patients with fungal meningitis, fluconazole levels in the CSF are approximately 80% of the corresponding plasma levels.
High skin concentrations of fluconazole, above serum concentrations, are achieved in the stratum corneum, epidermis-dermis and eccrine sweat. At a dose of 50mg once daily, the concentration of Fluconazole in the stratum corneum after 12 days was 78 pg/g and 7 days after cessation of treatment the concentration was still 5.8 pg/g.
Biotransformation
Fluconazole is broken down to a modest extent. Only 11% of a radioactive dose is excreted in the form of metabolites in the urine.
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 creatine clearance. There is no evidence of circulating metabolites.
The long plasma elimination half-life provides the basis for single dose therapy for genital candidiasis and once daily and once weekly dosing for other indications.
The mean half life in the plasma is approximately 30 hours.
Children metabolise fluconazole more rapidly. Accordingly the half life in children of 5-15 years is between 15.2 - 17.6 hours, about half that of adults.
It has been demonstrated that fluconazole 50mg daily given for upto 28 days does not influence plasma concentrations of testosterone in men or steroidal hormone concentrations of women of childbearing age.
Fluconazole 200mg - 400mg daily has no clinically significant effect on endogenous steroid levels or on ACTH stimulated responses in healthy male volunteers.
5.3. Preclinical safety data
Reproductive toxicity Increases in foetal anatomical variants 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 foetal 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 and in vitro 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 still-born pups and decrease of neonatal survival at these dose levels. The effects on parturition in rats are consistent with the species specific oestrogen-lowering property produced by high doses of fluconazole. Such a hormone change has not been observed in women treated with fluconazole.
6. PHARMACEUTICAL PARTICULARS
6.1 List of Excipients
Fluconazole Capsules contain:
Lactose monohydrate Maize starch Colloidal Silicon Dioxide Magnesium stearate Sodium lauryl sulphate Gelatin
Titanium dioxide (E171)
Patent Blue V (E131)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
36 months
6.4 Special Precautions for Storage
The product does not require any special storage requirements within Europe.
6.5
Nature and contents of container
Fluconazole capsules are packed in opaque PVC blister packs with aluminium foil backing.
Fluconazole 150mg Capsules are supplied in packs of 1 capsule.
6.6 Instruction for Use and Handling
Not applicable.
7. MARKETING AUTHORISATION HOLDER
Relonchem Limited Cheshire House, Gorsey Lane,
Widnes, Cheshire,
WA8 0RP United Kingdom
8. MARKETING AUTHORISATION NUMBER
PL 20395/0042
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
20/05/2010
10 DATE OF REVISION OF THE TEXT
01/12/2015