Fluctobar for the treatment of conditions such as genital and Mucosal candidiasis and tinea corporis

Fluconazole 2 mg/ml

Composition :

Each 1 ml of Fluctobor intravenous infusion contains fluconazole 2.00 mg.
Excipients: Sodium chloride, sodium hydroxide/hydrochloric acid. water for Injection.

Pharmacodynamics :

Fluctobar. fluconazole, a member of the triazole class of antifungal agents, is a potint and selective inhibitor of fungal enzymes necessary for the synthesis of ergosterol.
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 bas also been shown to be active in animal models of endemic mycoses, including infections with Blastomyces dermatitidis; with Coccidioides immitis, including intracranial infection and with Histoplasma capsulatum in normal and inununosuppressed animals. There have been reports ofeases of superinfection with Candida species other than C. albicans, which are often inherently not susceptible to fluconazole Candida krusei}, Such cases may require alternative antifungal therapy.

Pharmacokinetics :

The plasma elimination half-life is approximately 30 hours, plasma
concentrations are proportional to dose. Ninety percent steady-state levels are reached by day 4 -5 with multiple once daily dosing.
Administration ofa loading dose (on day I) of twice the usual daily dose enables plasma levels to approximate to 9()01o steady-state levels by day 2. The apparent volume of distribution approximates to total body water. Plasma protein binding is low (11-12%).
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 inthe 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. Fluconazole accumulates in the stratum corneum. At a dose of 50 mg once daily, the concentration of fluconazole after 12 days was 13 microgramlg and 1 days after cessation of treatment the concentration was still 5.8 microgram/g. 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. 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 dosing for other indications.

Pbarmacokinetics in Children :

In children, the following pharmacokinetic data have been reported:
Age studied                   Dose (mg/kg)          Half-life           AUC            11 days-11months       single IV3 mg/kg         23                110.1

9 months-I 3 years      Single-Oral 2mg/kg    25               94.7
9 months-13 years       Single-Oral 8mg/kg   19.5            362.5
S years-IS years          Multiple IV 2mg/kg    17.4*           67.4
S years-IS years          Multiple IV 4mg/kg    I5.2*           139.1
S years-IS years          Multiple PI 8mg/kg    17.6*           196.7
Mean age 7 years         Multiple Oral 3mg/kg  I5.5            41.6
• Denotes final day
In premature newborns (gestational age around 28 weeks), intravenous administration of fluconazole of 6 mglkg was given every third day for a maximum of five doses while the premature newborns remained in the intensive care-unit, The mean half life (hours) was 1!l.(range 44-185) on day ! which. decreased with time to a mean of 53 (range 30-131) on day 7 and 47 (range 27-68) on day 13.

Indications :

Once the results of cultures and other laboratory studies become available, antiinfective therapy should be adjusted accordingly.
Fluctobor is indicated for the treatment of the following conditions in adults and children:
1- Genital candidiasis: Vaginal candidiasis, acute or recurrent, candidal balanitis. The treatment of partners who present with symptomatic genital candidiasis should be considered.
2- Mucosal candidiasis: These include Oropharyngeal, oesophageal, non invasive bronchopulmonary infections, candiduria, mucocutaneous and chronic oral atrophic candidiasis (denture sore mouth). Normal hosts and patients with compromised immune function may be treated
3- Tinea pedis, tinea corporis, tinea cruris, tinea versicolor and dermal Candida infections. Fluctobar is not indicated for nail infections and tinea capitis.
4- Systemic candidiasis including candidaemia, disseminated candidiasis and other fonns of invasive candidal infection. These include infections of the peritoneum, endocardium and pulmonary and urinary tracts. Candidal infections in patients with malignancy, in intensive care units or those receiving cytotoxic or immunosuppressive therapy may be treated.
5- Cryptococcosis, including cryptococcal meningitis and infections of other sites (e.g. pulmonary, cutaneous). Normal hosts and patients with AIDS, organ transplants or other causes of immunosuppression may be treated. Fluctobar can be used as maintenance therapy to prevent relapse of cryptococcal disease in patients with AIDS.
6- Prevention of fungal infections in immunocompromised patients considered at risk as a consequence of neutropenia following cytotoxic chemotherapy or radiotherapy, including bone marrow transplant patients.

Side effects :

Fluconazole is generally well tolerated. The most common undesirable effects observed during clinical trials and associated with fluconazole are: Nervous System Disorders: Headache. Skin and Subcutaneous Tissue Disorders: Rash. Gastrointestinal Disorders: Abdominal pain, diarrhoea, flatulence, nausea. In some patients, particularly those with serious underlying diseases such as AIDS and cancer, cbanges in renal and haematological function test results and
hepatic abnormalities have been observed during treatment with fluconazole and comparative agents, but the clinical significance and relationship to treatment is uncertain (see warnings and precautions). Hepatobiliary Disorders: Hepatic toxicity including rare cases of fatalities. elevated alkaline phosphatase, elevated bilirubin, elevated SOOT, elevated SGPT. .
In addition, the following undesirable effects have occurred during post- marketing:
Nervous System Dlso.,rders: Dizziness,” seizures, taste perversion.
Skin and Subcutaneous Tissue Disorden: Alopecia, exfoliative skin disorders including Stevens-Johnson syndrome and toxic epidermal necrolysis. Gastrointestinal Disord~rs: dyspepsia, vomiting.Blood and Lymphatic System Disorders: Leukopenia iacluding neutropenia
and agranulocytosis, thrombocytopenia.
Allergic-reaction: Anaphylaxis (including angioedema, face oedema, pruritus). urticariaHepatobiliary Disorders: Hepatic failure, hepatitis, hepatocellular necrosis, jaundice. Metabolism and Nutrition Disorders: Hyperdholesterclaemia hyper1riglyceridaemia, hypokalaemia Cardiac Disorders: QT prolongation, torsade de pointes

Contraindications :

– 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 eo-administered with cisapride or terfenadine which are known to both prolong the QT interval and are metabolised by CYP3A4.

Warnings and Precautions for use :

In some patients , particularly those with serious underlying diseases such 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. .
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 medications, some known to be potentially hepatotoxic, and/or had underlying diseases which could have ’caused the 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 abnonnalliver function jests 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.
Patients have rarely developed exfoliative cutaneous reactions, such as Stevens Johnson syndrome and toxic epidermal necrolysis, during treatment with fluconazole. AIDS patients are moreprone to the development of severe cutaneous reactions tif many drugs. If a rash develops in a patient treated for a superficial fungal infection which is considered attributable to fluconazole, further therapy with this agent should be discontinued. If patients with invasive/systemic fungal infections develop rashes, they should be monitored closely and fluconazole discontinued if bullous lesions or erythema multifonne 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 etectrocardiogram. 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 pro-arrhythmic conditions such as:
– Congenital or documented acquired QT prolongation.
– Cardiomyopathy, in particular when heart failure is present.
– Sinus bradycardia.
– Existing symptomatic arrhythmias.
– Concomitant medication not metabolized by CY34A but known to prolong QT interval.
– Electrolyte disturbances such as hypokalaemia, hypomagnesaemia and hypocalaemia.

Pregnancy :

There are no and adequate and well controlled studies in pregnant women. 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. 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.

Drug-drug interactions :

The following drug interactions relate to the use of multiple-dose fluconazole, and the relevance to single-dose 150 mg fluconazole has not yet been established.
Rifampicin: Concomitant administration of fluconazole and rifampicin resulted in a 25% decrease in the AUC and 200/0 shorter half-life of fluconazole. In patients receiving concomitant rifampicin, an increase in the fluconazole dose should be considered.
Hydrochlorothiazide: Cc-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. Anticoagulants: Fluconazole increased the prothrombin time (12%) after warfarin administration in healthy males. In post-marketing experience, as with other azole antifungals, bleeding events (bruising, epistaxis, gastrointestinal
bleeding, hernaturia and melaena) have been reported in association with increases in prothrombin time in patients receiving fluconazole concurrently -with warfarin. Prothrombin time in patients receiving cownarin-type anticoagulants should be carefully monitored.
Benzodiazepines (Short-Acting): Following oral administration of midazolam, fluconazole resulted in substantial increases in midaiolani concentrations and psychomotor effects. This effect on midazolam appears to be more pronounced following oral administration of fluconazole than with fluconazole administered intravenously, If concomitant benzodiazepine therapy is necessary in patients
being treated with fluconazole, consideration should be given to decreasing the benzodiazepine dosage and the patients shoukl be appropriately monitored. Sulphonylureas: Fluconazole has been shown to prolong the serum half-life of concomitantly administered oral sulphcnylureas (chlorpropamide, glibenclamide, glipizide and tolbutamide) in healthy volunteers. Fluconazole and oral sulphonylureas may be eo-administered to diabetic patients; but the
possibility of a hypoglycaemic episode should be borne in mind.
Phenytoin: 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. 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 50 mg fluconazole study, while at 200mg
daily the AUCs of ethinyloestradiol and lesonorgestrel were increased 40% and 24% respectively. ThUtmultiple dose use of fluconazole at these doses is unlikely to have an effect on the efficacy of the combined oralcontraceptive. In a 300 mg once weekly fluconazole study, the AUCs of ethinyl estradicl and norethindrone were increased by 24% and 13%, respectively.
Endogenous steroid: Fluconazole 50 mg daily does not affect endogenous steroid levels in females:
200-400 mg daily has no clinically significant effect on endogenous steroid levels or on ACTH stimulated response in healthy male volunteers.
Ciclosporin: A kinetic study in renal transplant patients found fluconazole 200 mg daily slowly increase ciciosporin concentrations. However, in another multiple dose study with 100 mg daily, fluconazole did not affect ciclosporin levels in patients with bone marrow transplants. Ciclosporin plasma concentration monitoring in patients receiving fluconazole is recommended. Theophylline: In a placebo-controlled interaction study, the administration of
fluconazole 200 mg for 14 days resulted in an 18% decrease in the mean plasma clearance of theophylline. Patients who are receiving high doses oftheophyuine 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.
Terfenadine: Because of the occurrence of serious dysrbythmias 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 200 mg daily dose of fluconazole failed to demonstrate a prolongation
in QTc intervaL Another study at a 400 mg and 800 mg daily dose of fluconazole demonstrated that fluconazole taken in multiple doses of 400 mg per day or greater significantly increased plasma levels ofterfenadine when taken concomitantly. There have been spontaneously reported cases of palpitations, tachycardia, dizziness, and chest pain in patients taking concomitant fluconazole
and ferfenadine where the relationship of the reported adverse events to drug therapy or underlying medical conditions was not clear. Because of the potential seriousness of such an interaction, it is recommended that terfenadine not to be taken in combination with fluconazole.
Cisapride: There have been reports of cardiac events including torsades de peiatik in patieRts to • hom-f1ucon~S8pride-were-~tered. acontrolled study found that concomitant fluconazole
200 mg once daily and cisapride 20 mg four times a day yielded a significant increase i cisapride plasma levels and prolongation of QTc interval. In most of these cases, the patients appear to have been predisposed to arrhythmias or had serious underlying illnesses, and the relationship of the reported events to a possible fluconazole-cisapride drug interaction is unclear. Because of the potential seriousness of such an interaction, co-administration of cisapride is
contraindicated in patients receiving fluconazole. Zidovudine: Two kinetic studies resulted in increased levels of zidovudine most
likely caused by the decreased conversion of zidovudine to its major metabolite.
One study determined zidovudine levels in AIDS or ARC patients before and following fluconazole 200 mg daily for 15 days. There was a significant increase in zidovudine AUC (20010). Patients receiving this combination should be monitored for the development of zidovudine-related adverse reactions.
Rifabutin: 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 eo-administered, Patients receiving rifabutin and fluconazole
concomitantly should be carefully monitored.
Tacrolimus: There have been reports that an interaction exists when fluconazole is administered concomitantly with tacrotimus, leading to increased serum levels oftacrolimus. There have been reports of nephrotoxicity io..patients to whom fluconazole and tacrolirnus were eo-administered. Patients receiving tacrolimus
and fluconazole concomitantly should be carefully monitored.
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 eo-administering fluconazole. This is particularly important for drugs known to prolong QT interval. Patients should be carefully
– Physicnias should be aware that drug-drug interaction studies with other medications have not been conducted, but that such interactions may occur. Known symptoms of overdosage and Known

symptoms of overdosage and particulars of its treatment :

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 8200 mg of fluconazole, unverified by his physician. The patient was admitted to the hospital and his condition resolved within 48 hours. In the event of overdosage, supportive measures and symptomatic treatment, with gastric lavage if necessary, may be adequate. As fluconazole is largely excreted in the urine, forced volume diuresis would probably increase the elimination rate. A three hour haemodialysis session decreases plasma levels by approximately 50%

Dosage and administration :

Fluctobar is administered by intravenous infusion at a rate of approximately 5- 10 ml/min, the route being dependent on the clinical state of the patient. On transferring from the intravenous route to the oral route or vice versa, there is no need to change the daily dose. fluctobar intravenous infusion is formulated in
0.9% sodium chloride solution. The daily dose ofFlucfobar should be based on the nature and severity of the fungal infection. Most cases of vaginal candidiasis respond \0 single dose therapy. Therapy for those types of infections requiring multiple dose treatment should be continued until clinical parameters or laboratory tests indicate that
active fungal infection has subsided. An inadequate period of treatment may lead to recurrence of active infection. Patients with AIDS and cryptococcal meningitis usually require maintenance therapy to prevent relapse.

Use in adults :

1- For the prevention of fungal infections in imrnunocompromised patients considered at risk as a consequence of neutropenia following cytotoxic chemotherapy 0< radiotherapy, the dose should be 50 to 400 mg once daily, based on the patient’s risk for developing fungal infection. For patients at high risk of systemic infection, e.g. patients who are anticipated to have profound or prolonged neutropenia such as during bone marrow transplantation, the recommended dose is 400 mg once daily. fluctobar administration should start several days before the anticipated onset of neutropenia, and continue for 7 days after the neutrophil count rises above 1000 cells per mm’,
2- Mucosal Candidiasis:
Oropharyngeal candidiasis – the usual dose is 50 mg once daily for 7-14 days Treatment should not normally exceed 14 days except in severely immunocompromised patients. For atrophic oral candidiasis associated with dentures – the usual dose is 50 mg once daily for 14 days administered concurrently with local antiseptic measures to the denture.
For other candidal infections of mucosa ei’cept genital candidiasis, e.g. oesophagitis, non-invasive bronchopulmonary infections, candiduria, mucocutaneous candidiasis etc., the usual effective dose is 50 mg daily, given for 14-30 days. In unusually difficult cases of mucosal candidal infections the dose may be increased to 100 mg daily.
3- For tinea pedis, corporis, cruris, versicolor and dermal candida infections the recommended dosage is.50 mg once daily. Duration of treatment is normally 2 to 4 weeks but tinea pedis may require treatment for up to 6 weeks. Duration of treatment should not exceed 6 weeks.
4- For candidaemia, disseminated candidiasis and other invasive candidal infections the usual dose is 400 mg on the first day followed by 200 mg daily. Depending on the clinical response the dose may be increased to 400 mg daily. Duration of treatment is based upon the clinical response 5a For cryptococcal meningitis and cryptococcal infections at other sites, the usual dose is 400 mg on the first day followed by 200 mg-400 mg once daily. Duration of treatment for cryptococcal infections will depend on the clinical and mycological response, but is usually at least 6-8 weeks for cryptococcal
meningitis 5b For the prevention of relapse of cryptococcal meningitis in patients with AIDS, after the patient receives a full course of primary therapy, Fluctobar may be administered indefmitely at a daily dose of 100-200 mg.
Use in children :
As with similar infections in adults, the duration of treatment is based on the clinical and mycological response. Fluctobar is administered as a single daily dose each day.
For children with impaired renal function, see dosing in “Use in patients with impaired renal function
Cbildren over four weeks of age: The recommended dose of Fluctobar for mucosal candidiasis is 3 mg/kg daily. A loading dose of 6 mg/kg may be used on the first day to achieve steady state levels more rapidly. 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.
For the prevention of fungal infections in immunocompromised patients considered at risk as a consequence of neutropenia following cytotoxic chemotherapy or radiotherapy, the dose should be 3-12 mglkg daily, depending On the exient and duratimrOftheiffiIITCea
A maximum dosage of 400 mg daily should not be exceeded in children. Despite extensive data supporting the use of Fluctobar in children there are limited data available on the use of Fluctobar for genital candidiasis in children below 16 years. Use at present is not recommended unless antifungal treatment is imperative and no suitable alternative agent exists. Children four weeks of age and younger: Neonates excrete fluconazole slowly. In the first two weeks of life, the same mg/kg dosing as in older children should be used but administered every 72 bours. During weeks 3 and 4 of life,
the same dose should be given every 48 hours. A maximum dosage of 12 mg/kg every 72 hours should not be exceeded in children in the first two weeks of life. For children between 3 and 4 weeks of
life, 12 rng/kg every 48 hours should not be exceeded. To facilitate accurate measurement of doses less than 10 mg, Fluctobar should
only be administered to children in hospital using the intravenous infusion, depending on the clinical condition of the child.
Use in the elderly :
The normal dose should be used if there is no evidence of renal impairment. In patients with renal impairment (creatinine clearance less than 50 mUmin) the dosage schedule should be adjusted as described below.

Use in patients with impaired renal function :
Fluconazole is excreted predominantly in the urine as unchanged drug. No adjustments in single dose therapy are required. In patients (including children) with impaired renal function who will receive multiple doses ofFluctobar, 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 Percent of recommended s 50 (no dialysis) 50%
Regular dialysis 100% after each dialysis

Compatibility of intravenous infusion :

Although further dilution is unnecessary, Fluctobar Intravenous Infusion is compatible with the following administration fluids:
– Dextrose 20%
– Ringer’s solution
– Hartmann’s solution
– Potassium chloride in dextrose
– Sodium bicarbonate 4.2%
– Normal saline (0.9%)
– Fluctobar may be infused through an existing line with one of the above listed fluids. No specific incompatibilities have been noted, although mixing with any
orther drug prior to infusion is not recommended.

Patient’s instructions :

– Experience with Flucfobar indicates that therapy is unlikely to impair a patient’s ability to drive or use machinery.
– Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.
– Do not use if the solution is cloudy or precipitated or if the seal is not intact.
– Fluctobar intravenous infusion: Do not freeze. The infusion does not contain any preservative. It is for single use only. Discard any remaining solution.

Presentation :

Fluctobar for intravenous infusion is supplied in a carton box containing 1 transparent glass vial of 50 ml.

Storage :

Store at a temperature not exceeding 30°C.

Manufactured by :

Global P1uumaceuticaJ Industries
6″ of October City – Egypt