Oramax

Oramax is indicated in the following fungal infections.

Oramax is indicated in adults for the treatment of:

- Cryptococcal meningitis.

- Coccidioidomycosis.

- Invasive candidiasis.

- Mucosal candidiasis including oropharyngeal, oesophageal candidiasis, candiduria and chronic mucocutaneous candidiasis.

- Chronic oral atrophic candidiasis (denture sore mouth) if dental hygiene or topical treatment are insufficient.

- Vaginal candidiasis, acute or recurrent; when local therapy is not appropriate.

- Candidal balanitis when local therapy is not appropriate.

- Dermatomycosis including tinea pedis, tinea corporis, tinea cruris, tinea versicolor and dermal candida infections when systemic therapy is indicated.

- Tinea unguinium (onychomycosis) when other agents are not considered appropriate

Oramax is indicated in adults for the prophylaxis of:

- Relapse of cryptococcal meningitis in patients with high risk of recurrence.

- Relapse of oropharyngeal or oesophageal candidiasis in patients infected with HIV who are at high risk of experiencing relapse.

- To reduce the incidence of recurrent vaginal candidiasis (4 or more episodes a year).

- Prophylaxis of candidal infections in patients with prolonged neutropenia (such as patients with haematological malignancies receiving chemotherapy or patients receiving Hematopoietic Stem Cell Transplantation.

Oramax is indicated in term newborn infants, infants, toddlers, children, and adolescents aged from 0 to 17 years old:

Oramax is used for the treatment of mucosal candidiasis (oropharyngeal, oesophageal), invasive candidiasis and cryptococcal meningitis and the prophylaxis of candidal infections in immunocompromised patients. Oramax can be used as maintenance therapy to prevent relapse of cryptococcal meningitis in children with high risk of reoccurrence.

Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, anti-infective therapy should be adjusted accordingly.

Consideration should be given to official guidance on the appropriate use of antifungals.

Oramax 150mg capsule is indicated for the treatment of the following conditions:

- Acute vaginal candidiasis when local therapy is not appropriate

- Candidal balanitis when local therapy is not appropriate.

Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, anti-infective therapy should be adjusted accordingly.

Consideration should be given to official guidance on the appropriate use of antifungals.

Posology

The dose should be based on the nature and severity of the fungal infection. Treatment of infections requiring multiple dosing should be continued until clinical parameters or laboratory tests indicate that active fungal infection has subsided. An inadequate period of treatment may lead to recurrence of active infection.

Adults

Special populations

Elderly

Dosage should be adjusted based on the renal function (see “Renal impairment”).

Renal impairment

Oramax is predominantly excreted in the urine as unchanged active substance. No adjustments in single dose therapy are necessary. In patients (including paediatric population) with impaired renal function who will receive multiple doses of fluconazole, an initial dose of 50 mg to 400 mg should be given, based on the recommended daily dose for the indication. After this initial loading dose, the daily dose (according to indication) should be based on the following table:

Patients on haemodialysis should receive 100% of the recommended dose after each haemodialysis; on non-dialysis days, patients should receive a reduced dose according to their creatinine clearance.

Hepatic impairment

Limited data are available in patients with hepatic impairment, therefore fluconazole should be administered with caution to patients with liver dysfunction.

Paediatric population

A maximum dose of 400 mg daily should not be exceeded in paediatric population.

As with similar infections in adults, the duration of treatment is based on the clinical and mycological response. Oramax is administered as a single daily dose.

For paediatric patients with impaired renal function, see dosing in “Renal impairment”. The pharmacokinetics of fluconazole has not been studied in paediatric population with renal insufficiency (for “Term newborn infants” who often exhibit primarily renal immaturity please see below).

Infants, toddlers and children (from 28 days to 11 years old):

Adolescents (from 12 to 17 years old):

Depending on the weight and pubertal development, the prescriber would need to assess which posology (adults or children) is the most appropriate. Clinical data indicate that children have a higher fluconazole clearance than observed for adults. A dose of 100, 200 and 400 mg in adults corresponds to a 3, 6 and 12 mg/kg dose in children to obtain a comparable systemic exposure.

Safety and efficacy for genital candidiasis indication in paediatric population has not been established. If treatment for genital candidiasis is imperative in adolescents (from 12 to 17 years old), the posology should be the same as adults posology.

Term newborn infants (0 to 27 days):

Neonates excrete fluconazole slowly.

There are few pharmacokinetic data to support this posology in term newborn infants.

Method of administration

Oramax may be administered either orally (Capsules and Powder for Oral Suspension) or by intravenous infusion (Solution for Infusion), the route being dependent on the clinical state of the patient. On transferring from the intravenous to the oral route, or vice versa, there is no need to change the daily dose.

Oramax can be taken with or without food.

For adult patients, please calculate the dose in ml to administer according to the posology in mg recommended and the product strength.

In Adults aged 16 - 60 years

Vaginal candidiasis or candidal balanitis - 150mg single oral dose.

Special populations

Elderly

Where there is no evidence of renal impairment, normal dose recommendations should be adopted.

Renal Impairment

Oramax is predominantly excreted in the urine as unchanged active substance. No adjustments in single dose therapy are necessary.

Hepatic impairment

Limited data are available in patients with hepatic impairment, therefore Oramax should be administered with caution to patients with liver dysfunction.

In Children

Oramax is not recommended for use in children and adolescents under the age of 16 years, unless antifungal treatment is imperative, and no suitable alternative agent exists, due to insufficient safety and efficacy.

Method of administration

The capsules should be swallowed whole and independent of food intake.

Coadministration of terfenadine is contraindicated in patients receiving Oramax at multiple doses of 400 mg per day or higher based upon results of a multiple dose interaction study. Coadministration of other medicinal products known to prolong the QT interval and which are metabolised via the cytochrome P450 (CYP) 3A4 such as cisapride, astemizole, pimozide, quinidine, and erythromycin are contraindicated in patients receiving fluconazole.

Hypersensitivity to the active substance, to related azole substances, or to any of the excipients.

Coadministration of terfenadine is contraindicated in patients receiving Oramax 150mg capsule at multiple doses of 400 mg per day or higher based upon results of a multiple dose interaction study. Coadministration of other medicinal products known to prolong the QT interval and which are metabolised via the cytochrome P450 (CYP) 3A4 such as cisapride, astemizole, pimozide, quinidine and erythromycin are contraindicated in patients receiving Oramax.

Tinea capitis

Fluconazole has been studied for treatment of tinea capitis in children. It was shown not to be superior to griseofulvin and the overall success rate was less than 20%. Therefore, Oramax should not be used for tinea capitis.

Cryptococcosis

The evidence for efficacy of fluconazole in the treatment of cryptococcosis of other sites (e.g. pulmonary and cutaneous cryptococcosis) is limited, which prevents dosing recommendations.

Deep endemic mycoses

The evidence for efficacy of fluconazole in the treatment of other forms of endemic mycoses such as paracoccidioidomycosis, lymphocutaneous sporotrichosis and histoplasmosis is limited, which prevents specific dosing recommendations.

Renal system

Oramax should be administered with caution to patients with renal dysfunction.

Adrenal insufficiency

Ketoconazole is known to cause adrenal insufficiency, and this could also although rarely seen be applicable to fluconazole.'The effect of fluconazole on other medicinal products'.

Hepatobiliary system

Oramax should be administered with caution to patients with liver dysfunction.

Oramax has been associated with rare cases of serious hepatic toxicity including fatalities, primarily in patients with serious underlying medical conditions. In cases of fluconazole associated hepatotoxicity, no obvious relationship to total daily dose, duration of therapy, sex or age of patient has been observed. Fluconazole hepatotoxicity has usually been reversible on discontinuation of therapy.

Patients who develop abnormal liver function tests during fluconazole therapy must be monitored closely for the development of more serious hepatic injury.

The patient should be informed of suggestive symptoms of serious hepatic effect (important asthenia, anorexia, persistent nausea, vomiting and jaundice). Treatment of fluconazole should be immediately discontinued and the patient should consult a physician.

Cardiovascular system

Some azoles, including fluconazole, have been associated with prolongation of the QT interval on the electrocardiogram. Fluconazole causes QT prolongation via the inhibition of Rectifier Potassium Channel current (I_kr). The QT prolongation caused by other medicinal products (such as amiodarone) may be amplified via the inhibition of cytochrome P450 (CYP) 3A4. During post-marketing surveillance, there have been very rare cases of QT prolongation and torsades de pointes in patients taking Oramax. These reports included seriously ill patients with multiple confounding risk factors, such as structural heart disease, electrolyte abnormalities and concomitant treatment that may have been contributory. Patients with hypokalemia and advanced cardiac failure are at an increased risk for the occurrence of life threatening ventricular arrhythmias and torsades de pointes.

Oramax should be administered with caution to patients with potentially proarrhythmic conditions.

Coadministration of other medicinal products known to prolong the QT interval and which are metabolised via the cytochrome P450 (CYP) 3A4 are contraindicated.

Halofantrine

Halofantrine has been shown to prolong QTc interval at the recommended therapeutic dose and is a substrate of CYP3A4. The concomitant use of fluconazole and halofantrine is therefore not recommended.

Dermatological reactions

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 medicinal products. If a rash, which is considered attributable to fluconazole, develops in a patient treated for a superficial fungal infection, further therapy with this medicinal product 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.

Hypersensitivity

In rare cases anaphylaxis has been reported.

Cytochrome P450

Fluconazole is a moderate CYP2C9 and CYP3A4 inhibitor. Fluconazole is also a strong inhibitor of CYP2C19. Oramax treated patients who are concomitantly treated with medicinal products with a narrow therapeutic window metabolised through CYP2C9, CYP2C19 and CYP3A4, should be monitored.

Terfenadine

The coadministration of fluconazole at doses lower than 400 mg per day with terfenadine should be carefully monitored.

Excipients

Oramax powder for oral suspension contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose/galactose malabsorption and sucrase-isomaltase insufficiency should not take this medicine.

Renal system

Oramax 150mg capsule should be administered with caution to patients with renal dysfunction.

Hepatobiliary system

Oramax 150 mg capsule has been associated with rare cases of serious hepatic toxicity including fatalities, primarily in patients with serious underlying medical conditions. In cases of Oramax-associated hepatotoxicity, no obvious relationship to total daily dose, duration of therapy, sex or age of patient has been observed. Oramax hepatotoxicity has usually been reversible on discontinuation of therapy.

Patients who develop abnormal liver function tests during Oramax therapy must be monitored closely for the development of more serious hepatic injury.

The patient should be informed of suggestive symptoms of serious hepatic effect (important asthenia, anorexia, persistent nausea, vomiting and jaundice). Treatment of Oramax should be immediately discontinued and the patient should consult a physician.

Cardiovascular system

Some azoles, including Oramax, 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 torsades de pointes in patients taking Oramax 150mg capsule. These reports included seriously ill patients with multiple confounding risk factors, such as structural heart disease, electrolyte abnormalities and concomitant treatment that may have been contributory.

Oramax 150mg capsule should be administered with caution to patients with these potentially proarrhythmic conditions. Coadministration of other medicinal products known to prolong the QT interval and which are metabolised via the cytochrome P450 (CYP) 3A4 are contraindicated.

Halofantrine

Halofantrine has been shown to prolong QTc interval at the recommended therapeutic dose and is a substrate of CYP3A4. The concomitant use of Oramax and halofantrine is therefore not recommended.

Dermatological reactions

Patients have rarely developed exfoliative cutaneous reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, during treatment with Oramax. AIDS patients are more prone to the development of severe cutaneous reactions to many medicinal products. If a rash, which is considered attributable to Oramax, develops in a patient treated for a superficial fungal infection, further therapy with this medicinal product should be discontinued. If patients with invasive/systemic fungal infections develop rashes, they should be monitored closely and Oramax discontinued if bullous lesions or erythema multiforme develop.

Hypersensitivity

In rare cases anaphylaxis has been reported.

Cytochrome P450

Oramax is a potent CYP2C9 inhibitor and a moderate CYP3A4 inhibitor. Oramax is also an inhibitor of CYP2C19. Oramax 150mg capsule treated patients who are concomitantly treated with medicinal products with a narrow therapeutic window metabolised through CYP2C9, CYP2C19 and CYP3A4, should be monitored.

Terfenadine

The coadministration of Oramax at doses lower than 400 mg per day with terfenadine should be carefully monitored.

The product intended for pharmacy availability without prescription will carry a leaflet which will advise the patient:

“Do not use Oramax 150mg capsule 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 Oramax 150mg capsule or other antifungals, such as ketoconazole and itraconazole, or and other 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 heartburn 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 have had unexplained jaundice

If you suffer from any other chronic disease or illness

If you or your partner have had exposure to a sexually transmitted disease

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 having lower tummy 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 Oramax 150mg capsule. Oramax 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.

Patients should be advised to see their doctor if they experience any adverse effects such as redness, irritation or swelling associated with the treatment.

Oramax capsules contain lactose and should not be given to patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose- galactose malabsorption.

No studies have been performed on the effects of Oramax on the ability to drive or use machines.

Patients should be warned about the potential for dizziness or seizures while taking Oramax and should be advised not to drive or operate machines if any of these symptoms occur.

No studies have been performed on the effects of Oramax 150mg capsule on the ability to drive or use machines. Patients should be warned about the potential for dizziness or seizures while taking Oramax 150mg capsule and should be advised not to drive or operate machines if any of these symptoms occur.

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 adverse reactions have been observed and reported during treatment with Oramax with the following frequencies: Very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).

* 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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

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 adverse reactions have been observed and reported during treatment with Oramax 150mg capsule with the following frequencies: Very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).

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

There have been reports of overdose with Oramax. Hallucination and paranoid behaviour have been concomitantly reported.

In the event of overdose, symptomatic treatment (with supportive measures and gastric lavage if necessary) may be adequate.

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%.

There have been reports of overdose with Oramax 150mg capsule and hallucination and paranoid behaviour have been concomitantly reported.

In the event of overdose, symptomatic treatment (with supportive measures and gastric lavage if necessary) may be adequate.

Oramax 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%.

Pharmacotherapeutic group: Antimycotics for systemic use, triazole derivatives, ATC code: J02AC01.

Mechanism of action

Fluconazole is a triazole antifungal agent. Its primary mode of action is the inhibition of fungal cytochrome P-450-mediated 14 alpha-lanosterol demethylation, an essential step in fungal ergosterol biosynthesis. The accumulation of 14 alpha-methyl sterols correlates with the subsequent loss of ergosterol in the fungal cell membrane and may be responsible for the antifungal activity of fluconazole. Fluconazole has been shown to be more selective for fungal cytochrome P-450 enzymes than for various mammalian cytochrome P-450 enzyme systems.

Fluconazole 50 mg daily given up to 28 days has been shown not to effect testosterone plasma concentrations in males or steroid concentration in females of child-bearing age. Fluconazole 200 mg to 400 mg daily has no clinically significant effect on endogenous steroid levels or on ACTH stimulated response in healthy male volunteers. Interaction studies with antipyrine indicate that single or multiple doses of fluconazole 50 mg do not affect its metabolism.

Susceptibility in vitro:

In vitro, fluconazole displays antifungal activity against most clinically common Candida species (including C. albicans, C. parapsilosis, C. tropicalis). C. glabrata shows a wide range of susceptibility while C. krusei is resistant to fluconazole.

Fluconazole also exhibits activity in vitro against Cryptococcus neoformans and Cryptococcus gattii as well as the endemic moulds Blastomyces dermatiditis, Coccidioides immitis, Histoplasma capsulatum and Paracoccidioides brasiliensis.

Pharmacokinetic/pharmacodynamic relationship

In animal studies, there is a correlation between MIC values and efficacy against experimental mycoses due to Candida spp. In clinical studies, there is an almost 1:1 linear relationship between the AUC and the dose of fluconazole. There is also a direct though imperfect relationship between the AUC or dose and a successful clinical response of oral candidosis and to a lesser extent candidaemia to treatment. Similarly cure is less likely for infections caused by strains with a higher fluconazole MIC.

Mechanisms of resistance

Candida spp have developed a number of resistance mechanisms to azole antifungal agents. Fungal strains which have developed one or more of these resistance mechanisms are known to exhibit high minimum inhibitory concentrations (MICs) to fluconazole which impacts adversely efficacy in vivo and clinically.

There have been reports 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.

Breakpoints (according to EUCAST)

Based on analyses of pharmacokinetic/pharmacodynamic (PK/PD) data, susceptibility in vitro and clinical response EUCAST-AFST (European Committee on Antimicrobial susceptibility Testing-subcommittee on Antifungal Susceptibility Testing) has determined breakpoints for fluconazole for Candida species (EUCAST Fluconazole rational document (2007)-version 2). These have been divided into non-species related breakpoints; which have been determined mainly on the basis of PK/PD data and are independent of MIC distributions of specific species, and species related breakpoints for those species most frequently associated with human infection. These breakpoints are given in the table below:

S = Susceptible, R = Resistant

A = Non-species related breakpoints have been determined mainly on the basis of PK/PD data and are independent of MIC distributions of specific species. They are for use only for organisms that do not have specific breakpoints.

-- = Susceptibility testing not recommended as the species is a poor target for therapy with the medicinal product.

IE = There is insufficient evidence that the species in question is a good target for therapy with the medicinal product.

ATC classification

Pharmacotherapeutic group: Antimycotics for systemic use, triazole derivatives, ATC code: J02AC01.

Mode of action

Oramax is a triazole antifungal agent. Its primary mode of action is the inhibition of fungal cytochrome P-450-mediated 14 alpha-lanosterol demethylation, an essential step in fungal ergosterol biosynthesis. The accumulation of 14 alpha-methyl sterols correlates with the subsequent loss of ergosterol in the fungal cell membrane and may be responsible for the antifungal activity of Oramax. Oramax has been shown to be more selective for fungal cytochrome P-450 enzymes than for various mammalian cytochrome P-450 enzyme systems.

Oramax 50 mg daily given up to 28 days has been shown not to effect testosterone plasma concentrations in males or steroid concentration in females of child-bearing age. Oramax 200 mg to 400 mg daily has no clinically significant effect on endogenous steroid levels or on ACTH stimulated response in healthy male volunteers. Interaction studies with antipyrine indicate that single or multiple doses of Oramax 50 mg do not affect its metabolism.

Susceptibility in vitro

In vitro, Oramax displays antifungal activity against most clinically common Candida species (including C. albicans, C. parapsilosis, C. tropicalis). C. glabrata shows a wide range of susceptibility while C. krusei is resistant to Oramax.

Oramax also exhibits activity in vitro against Cryptococcus neoformans and Cryptococcus gattii as well as the endemic moulds Blastomyces dermatiditis, Coccidioides immitis, Histoplasma capsulatum and Paracoccidioides brasiliensis.

PK/PD relationship

In animal studies, there is a correlation between MIC values and efficacy against experimental mycoses due to Candida spp. In clinical studies, there is an almost 1:1 linear relationship between the AUC and the dose of Oramax. There is also a direct though imperfect relationship between the AUC or dose and a successful clinical response of oral candidiasis and to a lesser extent candidaemia to treatment. Similarly cure is less likely for infections caused by strains with a higher Oramax MIC.

Mechanism(s) of resistance

Candida spp have developed a number of resistance mechanisms to azole antifungal agents. Fungal strains which have developed one or more of these resistance mechanisms are known to exhibit high minimum inhibitory concentrations (MICs) to Oramax which impacts adversely efficacy in vivo and clinically.

There have been reports of superinfection with Candida species other than C. albicans, which are often inherently not susceptible to Oramax (e.g. Candida krusei). Such cases may require alternative antifungal therapy.

Breakpoints (according to EUCAST)

Based on analyses of pharmacokinetic/pharmacodynamic (PK/PD) data, susceptibility in vitro and clinical response EUCAST-AFST (European Committee on Antimicrobial susceptibility Testing-subcommittee on Antifungal Susceptibility Testing) has determined breakpoints for Oramax for Candida species (EUCAST Oramax rational document (2007)-version 2). These have been divided into non-species related breakpoints; which have been determined mainly on the basis of PK/PD data and are independent of MIC distributions of specific species, and species related breakpoints for those species most frequently associated with human infection. These breakpoints are given in the table below:

S = Susceptible, R = Resistant

A = Non-species related breakpoints have been determined mainly on the basis of PK/PD data and are independent of MIC distributions of specific species. They are for use only for organisms that do not have specific breakpoints.

-- = Susceptibility testing not recommended as the species is a poor target for therapy with the medicinal product. IE = There is insufficient evidence that the species in question is a good target for therapy with the medicinal product.

The pharmacokinetic properties of fluconazole are similar following administration by the intravenous or oral route.

Absorption

After oral administration fluconazole is well absorbed, and plasma levels (and systemic bioavailability) are over 90% of the levels achieved after intravenous administration. Oral absorption is not affected by concomitant food intake. Peak plasma concentrations in the fasting state occur between 0.5 and 1.5 hours post-dose. Plasma concentrations are proportional to dose. Ninety percent steady state levels are reached by day 4-5 with multiple once daily dosing. Administration of a loading dose (on day 1) of twice the usual daily dose enables plasma levels to approximate to 90% steady-state levels by day 2.

Distribution

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 in the CSF are approximately 80% the corresponding plasma levels.

High skin concentration 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 73 µg/g and 7 days after cessation of treatment the concentration was still 5.8 µg/g. At the 150 mg once-a-week dose, the concentration of fluconazole in stratum corneum on day 7 was 23.4 µg/g and 7 days after the second dose was still 7.1 µg/g.

Concentration of fluconazole in nails after 4 months of 150 mg once-a-week dosing was 4.05 µg/g in healthy and 1.8 µg/g in diseased nails; and, fluconazole was still measurable in nail samples 6 months after the end of therapy.

Biotransformation

Fluconazole is metabolised only to a minor extent. Of a radioactive dose, only 11% is excreted in a changed form in the urine. Fluconazole is a moderate inhibitor of the isozymes CYP2C9 and CYP3A4. Fluconazole is also a strong inhibitor of the isozyme CYP2C19.

Elimination

Plasma elimination half-life for fluconazole is approximately 30 hours. The major route of excretion is renal, with approximately 80% of the administered dose appearing in the urine as unchanged medicinal product. 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 vaginal candidiasis, once daily and once weekly dosing for other indications.

Pharmacokinetics in renal impairment

In patients with severe renal insufficiency, (GFR< 20 ml/min) half life increased from 30 to 98 hours. Consequently, reduction of the dose is needed. Fluconazole is removed by haemodialysis and to a lesser extent by peritoneal dialysis. After three hours of haemodialysis session, around 50% of fluconazole is eliminated from blood.

Pharmacokinetics during lactation

A pharmacokinetic study in ten lactating women, who had temporarily or permanently stopped breast-feeding their infants, evaluated fluconazole concentrations in plasma and breast milk for 48 hours following a single 150 mg dose of Oramax. Fluconazole was detected in breast milk at an average concentration of approximately 98% of those in maternal plasma. The mean peak breast milk concentration was 2.61 mg/L at 5.2 hours post-dose. The estimated daily infant dose of fluconazole from breast milk (assuming mean milk consumption of 150 ml/kg/day) based on the mean peak milk concentration is 0.39 mg/kg/day, which is approximately 40% of the recommended neonatal dose (<2 weeks of age) or 13% of the recommended infant dose for mucosal candidiasis.

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 one study were not interpretable due to changes in formulation pathway through the study. Additional data were available from a compassionate use study.

After administration of 2-8 mg/kg fluconazole to children between the ages of 9 months to 15 years, an AUC of about 38 µg·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.

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 6 mg/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 1040-1680) on day 13.

Pharmacokinetics in elderly

A pharmacokinetic study was conducted in 22 subjects, 65 years of age or older receiving a single 50 mg oral dose of fluconazole. Ten of these patients were concomitantly receiving diuretics. The C_max was 1.54 µg/ml and occurred at 1.3 hours post-dose. The mean AUC was 76.4 ± 20.3 µg·h/ml, and the mean terminal half-life was 46.2 hours. These pharmacokinetic parameter values are higher than analogous values reported for normal young male volunteers. Coadministration of diuretics did not significantly alter AUC or C_max. In addition, creatinine clearance (74 ml/min), the percent of medicinal product recovered unchanged in urine (0-24 hr, 22%) and the fluconazole renal clearance estimates (0.124 ml/min/kg) for the elderly were generally lower than those of younger volunteers. Thus, the alteration of fluconazole disposition in the elderly appears to be related to reduced renal function characteristics of this group.

The pharmacokinetic properties of Oramax are similar following administration by the intravenous or oral route.

Absorption

After oral administration Oramax is well absorbed, and plasma levels (and systemic bioavailability) are over 90% of the levels achieved after intravenous administration. Oral absorption is not affected by concomitant food intake. Peak plasma concentrations in the fasting state occur between 0.5 and 1.5 hours post-dose. Plasma concentrations are proportional to dose. Ninety percent steady state levels are reached by day 4-5 with multiple once daily dosing. Administration of a loading dose (on day 1) of twice the usual daily dose enables plasma levels to approximate to 90% steady-state levels by day 2.

Distribution

The apparent volume of distribution approximates to total body water. Plasma protein binding is low (11-12%).

Oramax achieves good penetration in all body fluids studied. The levels of Oramax in saliva and sputum are similar to plasma levels. In patients with fungal meningitis, Oramax levels in the CSF are approximately 80% the corresponding plasma levels.

High skin concentration of Oramax, above serum concentrations, are achieved in the stratum corneum, epidermis-dermis and eccrine sweat. Oramax accumulates in the stratum corneum. At a dose of 50 mg once daily, the concentration of Oramax after 12 days was 73 μg/g and 7 days after cessation of treatment the concentration was still 5.8 μg/g. At the 150 mg once-a-week dose, the concentration of Oramax in stratum corneum on day 7 was 23.4 μg/g and 7 days after the second dose was still 7.1 μg/g.

Concentration of Oramax in nails after 4 months of 150 mg once-a-week dosing was 4.05 μg/g in healthy and 1.8 μg/g in diseased nails; and, Oramax was still measurable in nail samples 6 months after the end of therapy.

Biotransformation

Oramax is metabolised only to a minor extent. Of a radioactive dose, only 11% is excreted in a changed form in the urine. Oramax is a selective inhibitor of the isozymes CYP2C9 and CYP3A4. Oramax is also an inhibitor of the isozyme CYP2C19.

Excretion

Plasma elimination half-life for Oramax is approximately 30 hours. The major route of excretion is renal, with approximately 80% of the administered dose appearing in the urine as unchanged medicinal product. Oramax 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 vaginal candidiasis, once daily and once weekly dosing for other indications.

Pharmacokinetics in renal impairment

In patients with severe renal insufficiency, (GFR< 20 ml/min) half life increased from 30 to 98 hours. Consequently, reduction of the dose is needed. Oramax is removed by haemodialysis and to a lesser extent by peritoneal dialysis. After three hours of haemodialysis session, around 50% of Oramax is eliminated from blood.

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 one study were not interpretable due to changes in formulation pathway through the study. Additional data were available from a compassionate use study.

After administration of 2-8 mg/kg Oramax to children between the ages of 9 months to 15 years, an AUC of about 38 μg·h/ml was found per 1 mg/kg dose units. The average Oramax plasma elimination half-life varied between 15 and 18 hours and the distribution volume was approximately 880 ml/kg after multiple doses. A higher Oramax plasma elimination half-life of approximately 24 hours was found after a single dose. This is comparable with the Oramax 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.

Experience with Oramax 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 6 mg/kg intravenous infusions of Oramax 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 1040-1680) on day 13.

Pharmacokinetics in elderly

A pharmacokinetic study was conducted in 22 subjects, 65 years of age or older receiving a single 50 mg oral dose of Oramax. Ten of these patients were concomitantly receiving diuretics. The Cmax was 1.54 μg/ml and occurred at 1.3 hours post-dose. The mean AUC was 76.4 ± 20.3 μg·h/ml, and the mean terminal half-life was 46.2 hours. These pharmacokinetic parameter values are higher than analogous values reported for normal young male volunteers. Coadministation of diuretics did not significantly alter AUC or Cmax. In addition, creatinine clearance (74 ml/min), the percent of medicinal product recovered unchanged in urine (0-24 h, 22%) and the Oramax renal clearance estimates (0.124 ml/min/kg) for the elderly were generally lower than those of younger volunteers. Thus, the alteration of Oramax disposition in the elderly appears to be related to reduced renal function characteristics of this group.

Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the human exposure indicating little relevance to clinical use.

Carcinogenesis

Fluconazole showed no evidence of carcinogenic potential in mice and rats treated orally for 24 months at doses of 2.5, 5, or 10 mg/kg/day (approximately 2-7 times the recommended human dose). Male rats treated with 5 and 10 mg/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 Salmonella 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 μg/ml) showed no evidence of chromosomal mutations.

Reproductive toxicity

Fluconazole did not affect the fertility of male or female rats treated orally with daily doses of 5, 10, or 20 mg/kg or with parenteral doses of 5, 25, or 75 mg/kg.

There were no foetal effects at 5 or 10 mg/kg; increases in foetal anatomical variants (supernumerary ribs, renal pelvis dilation) and delays in ossification were observed at 25 and 50 mg/kg and higher doses. At doses ranging from 80 mg/kg to 320 mg/kg embryolethality in rats was increased and foetal abnormalities included wavy ribs, cleft palate, and abnormal cranio-facial ossification.

The onset of parturition was slightly delayed at 20 mg/kg orally and dystocia and prolongation of parturition were observed in a few dams at 20 mg/kg and 40 mg/kg intravenously. 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. These effects on parturition 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.

Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the human exposure indicating little relevance to clinical use.

Carcinogenesis

Oramax showed no evidence of carcinogenic potential in mice and rats treated orally for 24 months at doses of 2.5, 5, or 10 mg/kg/day (approximately 2-7 times the recommended human dose). Male rats treated with 5 and 10 mg/kg/day had an increased incidence of hepatocellular adenomas.

Reproductive toxicity

Oramax did not affect the fertility of male or female rats treated orally with daily doses of 5, 10, or 20 mg/kg or with parenteral doses of 5, 25, or 75 mg/kg.

There were no foetal effects at 5 or 10 mg/kg; increases in foetal anatomical variants (supernumerary ribs, renal pelvis dilation) and delays in ossification were observed at 25 and 50 mg/kg and higher doses. At doses ranging from 80 mg/kg to 320 mg/kg embryolethality in rats was increased and foetal abnormalities included wavy ribs, cleft palate, and abnormal cranio-facial ossification.

The onset of parturition was slightly delayed at 20 mg/kg orally and dystocia and prolongation of parturition were observed in a few dams at 20 mg/kg and 40 mg/kg intravenously. 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. These effects on parturition are consistent with the species specific oestrogen-lowering property produced by high doses of Oramax. Such a hormone change has not been observed in women treated with Oramax.

Reconstitution instructions:

The reconstituted suspension will provide a white to off-white orange-flavoured suspension after reconstitution.

Powder for oral suspension 10 mg/ml in 60 ml capacity bottle: 35 ml suspension after reconstitution:

1. Tap the bottle to release the powder.

2. Add a small quantity of still water and shake it vigorously. Add water up to the level marked () on the bottle (this corresponds in total to adding the required 24 ml of water).

3. Shake well for 1 to 2 minutes to obtain a homogenous suspension.

4. After reconstitution there will be a usable volume of 35 ml.

5. Write the date of expiration of the reconstituted suspension on the bottle label (the shelf life of the reconstituted suspension is 28 days).

Powder for oral suspension 10 mg/ml in 175 ml capacity bottle: 100 ml suspension after reconstitution:

1. Tap the bottle to release the powder.

2. Add a small quantity of still water and shake it vigorously. Add water up to the level marked () on the bottle (this corresponds in total to adding the required 66 ml of water).

3. Shake well for 1 to 2 minutes to obtain a homogenous suspension.

4. After reconstitution there will be a usable volume of 100 ml.

5. Write the date of expiration of the reconstituted suspension on the bottle label (the shelf life of the reconstituted suspension is 28 days).

Instructions for use:

Shake the closed bottle of the reconstituted suspension before each use.

Instructions to use the oral syringe: Shake the prepared suspension well.

1. Open the bottle (safety cap).

2. Insert the adapter fitted onto the oral syringe into the bottle neck (Figure 1).

3. Turn the bottle with the oral syringe upside down and withdraw the quantity of suspension prescribed by the doctor (Figure 2). The graduations on the oral syringe are shown in ml. A maximum dose of 400 mg daily should not be exceeded in paediatric population.

4. Remove the oral syringe from the bottle.

5. The medicinal product may be given directly into the mouth from the oral syringe. The patient should remain upright during administration. Point the oral syringe at the inside of the cheek; release the suspension slowly into the patient's mouth (Figure 3).

6. Rinse the oral syringe.

7. Close the bottle with the safety cap; the adapter will remain on the bottle neck.

Dose conversion of the powder for oral suspension from mg/ml to ml/kg body weight (BW) for paediatric patients:

Oramax 10 mg/ml powder for oral suspension:

In children Oramax powder for oral suspension should be measured as closely as possible according to the following equation:

The graduations of the oral syringe are in increments of 0.2 ml. Therefore for intermediate weights and dosages, the dose to be given in ml should be calculated then rounded up or down to the nearest graduation of the oral syringe.

For example, a child weighing 11 kg prescribed Oramax 3 mg/kg/day should receive 33 mg/day, equivalent to 3.3 ml of the 10 mg/ml oral suspension. The dose may be rounded up to 3.4 ml, the nearest graduation on the oral syringe to provide the full dose.

A maximum dose of 400 mg daily should not be exceeded in the paediatric population (see table *).

The use of Oramax 10mg/ml powder for oral suspension is not recommended for doses > 15.0 ml (see table for doses highlighted in grey). When doses exceed 15.0 ml, it is recommended to use Oramax 40mg/ml powder for oral suspension.

Table Dosage examples:

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Any remaining suspension should be discarded 28 days after reconstitution.

There are no special instructions for use and handling.