UKPAR 50mg/5ml Powder for Oral Suspension PL 06831/0220

FLUCONAZOLE 50MG/5ML POWDER FOR ORAL SUSPENSION PL 06831/0220

UKPAR

TABLE OF CONTENTS

Lay Summary Page 2

Scientific discussion Page 3

Steps taken for assessment Page 12

Steps taken after authorisation – summary Page 13

Summary of Product Characteristics Page 14

Product Information Leaflet Page 25

Labelling Page 27

1 UKPAR Fluconazole 50mg/5ml Powder for Oral Suspension PL 06831/0220

FLUCONAZOLE 50MG/5ML POWDER FOR ORAL SUSPENSION PL 06831/0220

LAY SUMMARY

On 15th June 2011, the MHRA granted Genus Pharmaceuticals Limited a Marketing Authorisation (licence) for Fluconazole 50mg/5ml Powder for Oral Suspension.

Fluconazole 50mg/5ml Powder for Oral Suspension contains the active ingredient fluconazole.

Fluconazole belongs to a group of medicinal products called drugs. These medicinal products are used for the treatment of a wide variety of caused by fungi.

Fluconazole 50mg/5ml Suspension is used in the treatment of the following in adults and children:

• Fungal infections caused by fungi of the Candida genus (called candidiasis) ("Thrush"). This type of may occur in the mouth and throat, may cause chest infections, candidiasis in the urinary tract and infection associated with the use of dentures.

• Generalised infections located in the abdomen, heart and respiratory system may also occur. Fluconazole is also indicated in the prevention of relapse of oral candidiasis in patients with acquired immune deficiency syndrome (AIDS).

• Infections caused by the fungus Cryptococcus (called Cryptococcosis), including meningitis and infections in other locations (lungs, in the skin, etc.). Fluconazole may be used as a maintenance treatment to prevent cryptococcosis relapses in patients with AIDS.

• The prevention of infections caused by fungi in patients with cancer or transplanted organs who are predisposed to such infections as a result of the treatment they are receiving.

• Other generalised fungal infections (e.g. coccidiomycosis, paracoccidiomycosis, sporotrichosis and histoplasmosis).

• Infections of the skin such as the different types of ringworm.

Fluconazole is not indicated for nail infections or tinea capitis in adults and children.

No new or unexpected safety concerns arose from this application and it was, therefore, judged that the benefits of taking Fluconazole 50mg/5ml Powder for Oral Suspension outweigh the risks; hence a Marketing Authorisation has been granted.

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FLUCONAZOLE 50MG/5ML POWDER FOR ORAL SUSPENSION PL 06831/0220

SCIENTIFIC DISCUSSION

TABLE OF CONTENTS

Introduction Page 4

Pharmaceutical assessment Page 6

Non-clinical assessment Page 9

Clinical assessment (including statistical assessment) Page 10

Overall conclusions and risk benefit assessment Page 11

3 UKPAR Fluconazole 50mg/5ml Powder for Oral Suspension PL 06831/0220

INTRODUCTION

Based on the review of the data on quality, safety and efficacy, the UK granted a Marketing Authorisation for the medicinal product Fluconazole 50mg/5ml Powder for Oral Suspension (PL 06831/0220), to Genus Pharmaceuticals Limited on 15th June 2010. This medicine is available with a prescription only (POM) and is indicated for in the treatment of mycoses caused by Candida, Cryptococcus and other susceptible yeasts, in particular: • Mucosal candidiasis: These include oropharyngeal candidiasis, oesophageal, non-invasive bronchopulmonary infections, candiduria, mucocutaneous candidiasis and chronic atrophic oral candidiasis (denture sore mouth). Both normal hosts and immunocompromised patients may be treated.

• Systemic candidiasis (including disseminated deep infections and peritonitis).

• Acute cryptococcal meningitis in adults, including patients with AIDS, transplanted patients or other patients with other causes of immunosuppression.

• Genital candidiasis. Acute or recurrent vaginal candidiasis. Candida balanitis. The treatment of partners who present with symptomatic genital candidiasis should be considered.

• Prevention of fungal infections in patients predisposed to such infections as a result of chemotherapy or radiotherapy, including bone transplant patients.

• Dermatomycosis, including infections such as Tinea pedis, Tinea corporis, Tinea cruris, Tinea versicolor. Fluconazole is not indicated for nail infections and tinea capitis.

Fluconazole should not be used for tinea capitis in children.

This application for Fluconazole 50mg/5ml Powder for Oral Suspension is submitted as an abridged application according to Article 10.3 of Directive 2001/83/EC, claiming to be a hybrid medicinal product to Diflucan 150mg Capsules, first authorised to Pfizer Limited on 7th June 1998 (PL 00057/0290).

Fluconazole is a triazole agent that acts as a potent and specific inhibitor of the fungal synthesis of sterols. Fluconazole, given both orally and intravenously, has been shown to be active in a broad variety of fungal infection animal models. This activity has been demonstrated in opportunistic mycoses, such as infections by Candida spp, including systemic candidiases in immunocompromised animals; infections by Cryptococcus neoformans, including intracranial infections; infections by Microsporum spp and infections by Trichophyton spp. Fluconazole has also been shown to be active in endemic mycosis animal models, including infections by Blastomyces dermatitidis, infections by Coccidioides immitis, including intracranial infection; and infections by Histoplasma capsulatum in normal and immunocompromised animals.

4 UKPAR Fluconazole 50mg/5ml Powder for Oral Suspension PL 06831/0220

The pharmacovigilance system as described by the applicant fulfils the requirements. It also provides adequate evidence that the applicant has the services of a qualified person responsible for pharmacovigilance and has the necessary means for the notification of any adverse reaction suspected of occurring.

A satisfactory justification for the absence of a Risk Management Plan (RMP) has been provided.

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PHARMACEUTICAL ASSESSMENT

DRUG SUBSTANCE INN: Fluconazole Chemical name: 2-(2,4-difluorophenyl)-1,3-bis-(1H-1,2,4-triazol-1-yl)-2-propanol Structure:

Physical form: white to almost white crystalline powder. Solubility: slightly soluble in water, freely soluble in methanol and soluble in acetone. Molecular formula: C13H12N6OF2 Molecular weight: 306.3

Fluconazole is the subject of a European Pharmacopoeia monograph.

All aspects of the manufacture of the drug substance from its starting materials are controlled by a Certificate of Suitability.

Appropriate proof of structure data has been supplied for the drug substance. All potential known impurities have been identified and characterised.

An appropriate specification with suitable test methods and limits is provided for the drug substance fluconazole. The methods of testing and limits for residual solvents are in compliance with current guidelines. Suitable Certificates of Analysis have been provided for all reference standards used. Batch analysis data are provided and comply with the proposed specification.

Appropriate stability data have been generated showing the drug substance to be a physically and chemically stable drug, and supporting an appropriate retest period.

DRUG PRODUCT Other ingredients Other ingredients consist of the pharmaceutical excipients sucrose, colloidal silica, titanium dioxide, xanthan gum, sodium citrate anhydrous, citric acid monohydrate, sodium benzoate (E-211) and orange flavour (containing maltodextrin and arabic gum).

All the ingredients with the exception of sodium citrate anhydrous and orange flavour comply with their relevant European Pharmacopoeia monographs. Sodium citrate anhydrous has a United States Pharmacopoeia (USP) monograph. Orange flavour complies with in-house specifications.

None of the excipients used contain material of animal or human origin.

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Product development The objective of the development programme was to produce a product that could be considered a hybrid medicinal product of Diflucan 150mg Capsules (PL 00057/0290).

The reference product used in the bioequivalence study is Triflucan 50mg/5ml Suspension, authorised in France to Pfizer Limited.

The applicant has provided a suitable product development section. Justifications for the use and amounts of each excipient have been provided and are valid.

Manufacture A description and flow-chart of the manufacturing method has been provided. Satisfactory batch formulae have been provided for the manufacture of the product. The manufacturing process has been validated and has shown satisfactory results. In-process controls are satisfactory based on batch data and controls on the finished product. Satisfactory process validation data on commercial batches have been provided.

Finished product specification The finished product specification is satisfactory. Test methods have been described and have been adequately validated, as appropriate. Batch data have been provided and comply with the release specification. Certificates of Analysis for all working standards used have been provided and are satisfactory.

Container-Closure System The product is packaged in bottles composed of type III topaz glass with a polyethylene cap and polyethylene seal for 35 ml of suspension. A polypropylene dosing cup is included to measure 5 and 10ml. The product comes in pack sizes of 1 and 10 bottles (hospital use).

Specifications and Certificates of Analysis have been provided. All primary product packaging complies with EU legislation regarding contact with food.

Stability Finished product stability studies have been conducted in accordance with current guidelines. Based on the results, a shelf life of 2 years has been set for an unopened product with no special storage instructions. For the reconstituted suspension, a shelf-life of 14 days after reconstitution has been set with storage instructions ‘do not freeze the reconstituted suspension’ and ‘do not store above 30oC’. This is satisfactory.

ADMINISTRATIVE Expert Report A pharmaceutical expert report has been written by a suitably qualified person and is satisfactory.

Summary of Product Characteristics (SmPC) This is pharmaceutically satisfactory.

Labelling This is pharmaceutically satisfactory.

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Patient Information Leaflet (PIL) This is pharmaceutically satisfactory.

A package leaflet has been submitted to the MHRA along with results of consultations with target patient groups ("user testing"), in accordance with Article 59 of Council Directive 2001/83/EC, as amended. The results indicate that the package leaflet is well-structured and organised, easy to understand and written in a comprehensive manner. The test shows that the patients/users are able to act upon the information that it contains.

MAA Form This is pharmaceutically satisfactory.

Conclusion It is recommended that a Marketing Authorisation is granted for this application.

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NON-CLINICAL ASSESSMENT

No new non-clinical data have been supplied with this application and none are required for an application of this type.

A satisfactory justification for the absence of an Environmental Risk Assessment has been provided.

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CLINICAL ASSESSMENT

CLINICAL PHARMACOLOGY To support the application, the Marketing Authorisation Holder has included a bioequivalence study:

A randomised, single-dose, single centre, crossover, comparative bioequivalence study, comparing the pharmacokinetics of Fluconazole 50mg/5ml Oral Suspension (Test) versus Triflucan (fluconazole) 50mg/5ml Oral Suspension (Reference) in healthy volunteers under fasting conditions.

Blood samples were taken pre- and up to 120 hours post dose. There was a washout period of 21 days between each treatment period. Pharmacokinetic parameters were measured from the plasma and statistically analysed.

Results for fluconazole are presented below as log-transformed values: Treatment AUC0-t AUC0-∞ Cmax (ng·h/mL) (ng·h/mL) (ng/ml)

Test (T) 90256.06 100586.12 2104.14 Reference (R) 90197.35 102420.48 2128.50 100.07 98.21 98.86 T/R Ratio (90% CI) (97.30 – 102.91) (94.93 – 101.60) (95.17 – 102.69)

The results for the primary variables indicated that the 90% confidence intervals test/reference ratio of geometric means for AUC0-t and Cmax for fluconazole lie within acceptable limits. Thus, bioequivalence has been shown between the test and reference products in this study.

EFFICACY No new efficacy data were submitted with this application and none were required.

SAFETY With the exception of the data submitted during the bioequivalence study, no new safety data were submitted with this application and none were required. No new or unexpected safety concerns were raised during the bioequivalence study.

SUMMARY OF PRODUCT CHARACTERISTICS (SmPC), PATIENT INFORMATION LEAFLET (PIL) AND LABELLING The SmPC, PIL and labelling are medically satisfactory and consistent with those for the reference product, where appropriate.

CLINICAL EXPERT REPORT The clinical expert report has been written by an appropriately qualified physician and is a suitable summary of the clinical aspects of the dossier.

MAA FORM The MAA Form is medically satisfactory.

CONCLUSIONS It is recommended that a Marketing Authorisation is granted for this application.

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OVERALL CONCLUSION AND RISK BENEFIT ASSESSMENT

QUALITY The important quality characteristics of Fluconazole 50mg/5ml Powder for Oral Suspension are well-defined and controlled. The specifications and batch analytical results indicate consistency from batch to batch. There are no outstanding quality issues that would have a negative impact on the benefit/risk balance.

NON-CLINICAL No new non-clinical data have been supplied with this application and none are required for an application of this type.

EFFICACY Bioequivalence has been demonstrated between the applicant’s Fluconazole 50mg/5ml Oral Suspension and the reference product Triflucan (fluconazole) 50mg/5ml Oral Suspension (after reconstitution).

Fluconazole 50mg/5ml Powder for Oral Suspension can be considered a hybrid medicinal product to Diflucan 150mg Capsules.

No new or unexpected safety concerns arise from this application.

The SmPC, PIL and labelling are satisfactory and consistent with those for the reference product.

RISK BENEFIT ASSESSMENT The quality of the product is acceptable and no new non-clinical or clinical safety concerns have been identified. The bioequivalence study supports the claim that the applicant’s product and the reference product are interchangeable. Extensive clinical experience with fluconazole is considered to have demonstrated the therapeutic value of the compound. The benefit/risk is, therefore, considered to be positive.

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FLUCONAZOLE 50MG/5ML POWDER FOR ORAL SUSPENSION PL 06831/0220

STEPS TAKEN FOR ASSESMENT

1 The MHRA received the Marketing Authorisation application on 29th December 2008.

2 Following standard checks and communication with the applicant the MHRA considered the application valid on 7th January 2009.

3 Following assessment of the applications, the MHRA requested further information on the quality section of the dossier on 10th September 2009, 9th December 2010 and 6th May 2011.

4 The applicant responded to the MHRA’s requests, providing further information on the quality section of the dossier on 10th August 2010, 14th March 2011 and 6th June 2011.

5 The application was approved on 15th June 2011.

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FLUCONAZOLE 50MG/5ML POWDER FOR ORAL SUSPENSION PL 06831/0220

STEPS TAKEN AFTER AUTHORISATION - SUMMARY

Date Application Scope Outcome submitted type

13 SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT Fluconazole 50mg/5ml Powder for Oral Suspension

2 QUALITATIVE AND QUANTITATIVE COMPOSITION Each 5ml of oral suspension contains 50mg of fluconazole

For a full list of excipients see section 6.1.

3 PHARMACEUTICAL FORM Powder for oral suspension. The powder is almost white. A whitish suspension is obtained after its reconstitution with water.

4 CLINICAL PARTICULARS 4.1 THERAPEUTIC INDICATIONS Fluconazole is indicated in the treatment of mycoses caused by Candida, Cryptococcus and other susceptible yeast, in particular:

1. Mucosal candidiasis: These include oropharyngeal candidiasis, oesophageal, non-invasive bronchopulmonary infections, candiduria, mucocutaneous candidiasis and chronic atrophic oral candidiasis (denture sore mouth). Both normal hosts and immunocompromised patients may be treated.

2 Systemic candidiasis (including disseminated deep infections and peritonitis).

3. Acute cryptococcal meningitis in adults, including patients with AIDS, transplanted patients or other patients with other causes of immunosuppression.

4. Genital candidiasis. Acute or recurrent vaginal candidiasis. Candida balanitis. The treatment of partners who present with symptomatic genital candidiasis should be considered.

5. Prevention of fungal infections in patients predisposed to such infections as a result of chemotherapy or radiotherapy, including bone transplant patients.

6. Dermatomycosis, including infections such as Tinea pedis, Tinea corporis, Tinea cruris, Tinea versicolor. Fluconazole is not indicated for nail infections and tinea capitis.

Use in children Fluconazole should not be used for tinea capitis.

Consideration should be given to official guidance on the appropriate use of antimycotic agents. Before initiating treatment, samples should be taken for microbiological analysis and the suitability of the therapy should be subsequently confirmed (see sections 4.2 and 5.1)

In some patients with severe crytococcoal meningitis, the mycological response during fluconazole treatment may be slower that during other treatments (see section 4.4)

4.2 POSOLOGY AND METHOD OF ADMINISTRATION The daily dose of fluconazole will depend on the nature and severity of the fungal infection. Most cases of vaginal candidiasis respond to a single dose treatment. The treatment of those types of infection requiring multiple doses of the drug should be continued until the clinical parameters or laboratory tests indicate that the active fungal infection has subsided.

An inadequate treatment period may cause relapses of the active infection. Patients with AIDS and cryptococcal meningitis or recurrent oral candidiasis usually require maintenance treatment to prevent relapses.

Adults 1. Candidal vaginitis or balantis – 150mg single oral dose

2. Mucosal Candidiasis. Oropharyngeal candidiasis – the usual dose is 50mg once daily for 7-14 days Treatment should not normally exceed 14 days except in severely immunocompromised patients.

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For atopic oral condidiasis associated with dentures – the usual dose is 50mg once daily for 14 days administered concomitantly with local antiseptic measures to the dentures. For other candidal infections for mucosa (except genital candidiasis see above) e.g. oesophagitis, non- invasive broncopulmonary infections, candiduria, mucocutaneous candidiasis etc., the usual effective dose is 50mg daily, given for 14-30 days. In unusually difficult cases of mucosal candial infections, the dose may be increased to 100mg daily.

3. For tinea pedis, corporis, crusis, versicolor and dermal Candida infections, the recommended dosage is 50mg 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 400mg on the first day followed by 200mg daily. Depending on the clinical response, the dose may be increased to 400mg daily. Duration of treatment is based upon the clinical response.

5a. For cryptococcal meningitis and cryptococcal infections at other sites, the usual dose is 400mg on the first day followed by 200mg – 400mg once daily. Duration of treatment for crytococcal infections will depend on the clinical and mycological response, but is usually at least 6-8 weeks for crytococcal meningitis.

5b. For the prevention of relapse of crytococcal meningitis in patients with AIDS, after the patient received a full course of primary therapy. Fluconazole may be administered indefinitely at a daily dose of 100-200 mg.

6. 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 50 to 400mg 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 400mg once daily. Fluconazole 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 mm3.

Use in children As with similar infections in adults, the duration of treatment is based on the clinical and mycological response. Fluconazole 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’

Children over four weeks of age The recommended dose of fluconazole for mucosal candidiasis is 3 mg/kg daily. A leading dose of 6mg/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 mg/kg daily, depending on the extent and duration of the induced neutopenia (see adult dosing). A maximum dosage of 400mg daily should not be exceeded in children

Despite extensive data supporting the use of fluconazole in children, there are limited data available on the use of fluconazole in 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 hours. 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, 12mg/kg every 48 hours should not be exceeded. The pharmacokinetics of fluconazole has not been studied in children with renal insufficiency. To facilitate accurate measurement of doses less than 10mg, fluconazole should only be administered to children in hospital using the 50mg/5ml suspension orally or the intraveneous injection, depending on the clinical condition of the child. A suitable measuring device should be used for administration of the suspension. Once reconstituted, the suspension should not be further diluted.

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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 ml/min) the dosage schedule should be adjusted as below.

Use in patients with impaired renal function Fluconazole is excreted primarily in the urine as unchanged drug. No adjustments in single dose therapy are required. In patients (including children) with impaired renal functions who will receive multiple doses of fluconazole, the normal recommended dose (according to indication) should be given on day 1, followed by a daily dose based in the following table:

Creatinine clearance (ml/min) Percentage of dose recommended > 50 100% ≤ 50 (no dialysis) 50% Regular dialysis 100% after each dialysis

4.3 CONTRAINDICATIONS Hypersensitivity to fluconazole or any other compound or any of the excipients. Fluconazole must not be co-administered with drugs known to prolong the QT interval and which are metabolised by CYP3A4 such as cispride, astimizole, terfenadine, pimozide and quinidine. See sections 4.4 and 4.5

4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE There is some evidence that in some patients with cryptococcal meningitis, the mycological response during fluconazole treatment may be slower compared with treatment with in combination with . This should be taken into account for the treatment choice of patients with severe cryptococcal meningitis.

In some patients, particularly those with serious underlying diseases such as AIDS and cancer, abnormalities in haematological, hepatic, renal and other biochemical function test results have been observed during treatment with fluconazole but the clinical significance and relationship to treatment is uncertain

Very rarely, patients who died with severe underlying diseases and who have received multiple does of fluconazole had post-mortem findings which included hepatic necrosis. There patients were receiving multiple concomitant , some known to be potentially hepatotoxic and/or had underlying diseases that could have caused hepatic necrosis. In cases of hepatotoxicity, no obvious relation to the total daily dose of fluconazole, duration of therapy, sex or age of patient has been observed; the abnormalities have usually been reversible on discontinuation of fluconazole therapy.

As a causal relationship with fluconazole cannot be excluded, patients who develop abnormal liver function tests during fluconazole therapy should be monitored for 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 more prone to the development of severe cutaneous reactions to 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 closely monitored and fluconazole discontinued if bullous lesions or erythema multiforme develop.

In rare cases, as with other , anaphylaxis has been reported.

Some azoles, including fluconazole, have been associated with the prolongation of the QT interval on the electrocardiogram. During post-marketing surveillance, there have been very rare cases of QT prolongation and torsade de pointes in patients taking fluconazole. Although the association of fluconazole and QT prolongation has not been fully established, fluconazole should be used with caution in the following patients with potentially proarrythmic conditions such as:

• Congenital or documented acquired QT prolongation • Cardiomyopathy in particular where heart failure is present • Sinus bradycardia

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• Existing symptomatic arrhythmias • Concomitant known to prolong the QT interval • Electrolye disturbances such as hypokalaemia, hypomagnesaemia and hypocalcaemia.

See section 4.5 Interaction with other medicinal products and other forms of interaction.

Fluconazole 50 mg/5 ml powder for oral suspension contains respectively 2881 mg/5 ml of sucrose as an excipient. Patients with rare hereditary problems to fructose intolerance, glucose/galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine. This medicinal product contains less than 1 mmol sodium (23 mg) per 5ml, i.e. essentially ‘sodium-free’.

4.5 INTERACTION WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF INTERACTION The following drug interactions relate to use of multiple-dose fluconazole and the relevance to single- dose 150mg fluconazole has not been established.

Fluconazole inhibits cytochrome p450 isoenzymes CYP3A4 and CYP2C9. The concurrent use with drugs that metabolise via this route may cause increases in the serum levels of these drugs.

Alfentanil: In a placebo-controlled and crossover interaction study on healthy volunteers, the administration of doses of 400 mg of oral or intravenous fluconazole prior to the intravenous administration of alfentanil 20 g/kg caused a 55% reduction in alfentanil clearance by inhibiting its metabolism, thus its effects may be extended. If concurrent treatment with alfentanil is necessary in patients who are being treated with fluconazole, decreasing the dose of alfentanil should be considered, and the patients must be appropriately monitored.

Anticoagulants: In an interaction study, fluconazole extended the prothrombin time (12%) after the administration of warfarin in healthy subjects. Following its commercialisation, as with other azole antifungal drugs, events with bleeding (haematoma, nosebleed, gastrointestinal haemorrhage, haematuria and melena) have been notified, associated to increases in prothrombin time in patients receiving fluconazole concurrently with warfarin. Prothrombin time in patients receiving coumarin anticoagulant drugs should be carefully monitored.

Oral birth control drugs: Two pharmacokinetic studies with oral birth control drugs and fluconazole at multiple doses have been carried out. In the study using 50 mg of fluconazole there were no relevant effects on hormonal levels. However, using 200 mg daily of fluconazole, the area under the curve (AUC) of ethinyl-estradiol and levonorgestrel increased by 40% and 24% respectively. Therefore, the use of multiple doses of fluconazole at the doses mentioned above is unlikely to affect the efficacy of combined oral contraceptives.

Astemizole: Fluconazole inhibits cytochrome p450 isoenzyme 3A4, which may increase the serum levels of astemizole and therefore the risk of potentially fatal arrhythmias, and therefore its concurrent use is contraindicated (see section 4.3: Contraindications)

Benzodiazepines (midazolam, lorazepam, oxazepam, temazepam, lormetazepam, etc.): after the oral administration of midazolam, fluconazole caused substantial increases in midazolam concentrations and psychomotor effects. This effect on midazolam seems greater following oral administration of fluconazole than with intravenous administration. If concurrent treatment with benzodiazepines is necessary in treatment with fluconazole, decreasing the dose of benzodiazepine must be considered, and patients must be appropriately monitored.

Ciclosporin: In a pharmacokinetic study performed in renal transplant patients, a 200 mg daily dose of fluconazole was verified to slightly increase ciclosporin concentrations. However, in another multiple dose study using 100 mg daily of fluconazole, ciclosporin levels were not affected in bone marrow transplant patients. Therefore, monitoring the plasma concentration of ciclosporin is recommended in patients receiving fluconazole.

Cisapride: Cardiological alterations including torsade de pointes have been described in patients who were administered fluconazole together with cisapride. The co-administration of cisapride is contraindicated in patients receiving fluconazole (see section 4.3: Contraindications

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Phenytoin: The concomitant administration of fluconazole and phenytoin may increase phenytoin levels to a clinically significant degree. If it is necessary to administer both drugs concomitantly, phenytoin levels must be monitored and the phenytoin dose adjusted to maintain therapeutic levels.

Hydrochlorothiazide: In a pharmacokinetic interaction study, the co-administration of multiple doses of hydrochlorothiazide to healthy volunteers receiving fluconazole increased the plasma concentrations of fluconazole up to 40%. An effect of this type will not require a change in the dosage regimen of fluconazole in patients simultaneously receiving diuretics, although the prescriber will have to take this into account.

Rifabutin: An interaction has been described when fluconazole is administered concurrently with rifabutin, causing an increase in rifabutin serum levels. Uveitis episodes have been described in patients who were administered fluconazole together with rifabutin. Patients receiving rifabutin and fluconazole concurrently must be carefully monitored.

Rifampin: The simultaneous administration of fluconazole and rifampin caused a 25% decrease of the AUC and a 20% decrease in the half-life of fluconazole. Therefore, in patients concurrently receiving rifampin, an increase in the dose of fluconazole should be considered.

Sulphonylureas: Fluconazole has been demonstrated to extend the serum half-life of sulphonylureas (chlorpropamide, glibenclamide, glipizide and tolbutamide) administered concurrently in healthy volunteers. Fluconazole and sulphonylureas may be concurrently administered to diabetic patients, but the possibility of occurrence of a hypoglycaemic episode must be considered.

Tacrolimus: Cases of interaction have been described when administering fluconazole concurrently with tacrolimus, causing an increase in tacrolimus serum levels. Cases of nephrotoxicity have been described in patients who were administered fluconazole together with tacrolimus. Patients receiving tacrolimus and fluconazole concurrently should be carefully monitored.

Theophylline: In a placebo-controlled interaction study, the administration of 200 mg daily of fluconazole for 14 days caused an 18% decrease of average theophylline plasma clearance. Therefore, patients who are receiving high doses of theophylline, or patients with a high risk of toxicity by theophylline should be observed whilst receiving fluconazole, in case there are any signs of toxicity by theophylline, in which case the treatment should be modified accordingly.

Terfenadine: Interaction studies have been performed given the occurrence of serious cardiac dysrhythmias secondary to QTc interval prolongation in patients who were receiving azole antifungal drugs together with terfenadine. A study performed with daily doses of 200 mg of fluconazole did not demonstrate QTc interval prolongation. Another study using daily doses of 400 and 800 mg of fluconazole demonstrated that fluconazole at doses of 400 mg daily or greater significantly increases terfenadine plasma levels when received concurrently. The combined use of fluconazole at doses of 400 mg or higher together with terfenadine is contraindicated. (See section 4.3. Contraindications) The concomitant administration of terfenadine and fluconazole at doses of less than 400 mg daily should be carefully controlled (see Section 4.4: Special warnings and precautions for use

Zidovudine: Two pharmacokinetic studies have exhibited increases in zidovudine levels, probably caused by the decrease in zidovudine conversion into its main metabolite. One study determined zidovudine levels in patients with AIDS or ARC before and after the administration of 200 mg of fluconazole daily for 15 days. A significant increase of the AUC for zidovudine was observed (20%). A second randomised, two periods, crossover, two treatment study studied the zidovudine levels in patients infected with HIV. In two occasions, with an interval of 21 days, the patients received 200 mg of zidovudine every 8 hours with or without 400 mg of fluconazole daily for 7 days. The AUC of zidovudine increased significantly (74%) during the combined administration with fluconazole. Those patients receiving this association must be monitored regarding the occurrence of zidovudine-related undesirable effects.

The use of fluconazole in patients who are concomitantly receiving HMG-CoA reductase inhibitors (such as lovastatin and simvastatin), HIV protease inhibitors (such as ritonavir and indinavir) or other drugs metabolised by isoenzyme CYP3A4 from the cytochrome P-450 system may be associated with increases in the serum levels of said drugs. Due to the lack of definitive information, caution is advised when administered concurrently with fluconazole.

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Interaction studies have demonstrated that, when administering oral fluconazole together with food, cimetidine, antacids or in patients subjected to bone marrow transplant radiotherapy, no clinically significant condition occurs in fluconazole absorption. Although no interaction studies have been performed with other drugs, the possible occurrence of other similar pharmacological interactions is not rejected.

4.6 PREGNANCY AND LACTATION Data from several hundred women treated with standard doses (<200mg/day) of fluconazole, administered as single or repeated dosage in the first trimester, show no undesired effect in the foetus.

There are reports of multiple congenital abnormalities (including brachycephalia, ears dysplasia, giant anterior fontanelle, femoral bowing and radiohumeral syntosis) in infants whose mothers were treated for at least three or more months with high doses (400-800mg daily) of fluconazole for coccidioidomycosis. The relationship between fluconazole and these incidents is unclear.

Animal studies show teratogenic effects (see section 5.3)

Accordingly, fluconazole at standard doses and short tem treatment should not be used in pregnancy unless clearly necessary. Fluconazole in high doses or in prolonged regimens should not be used in pregnancy except for life threatening infections

4.7 EFFECTS ON ABILITY TO DRIVE AND USE MACHINES Experience with fluconazole indicates that treatment with this drug is unlikely to affect the patient's ability to drive or use machines.

4.8 UNDESIRABLE EFFECTS Adverse reactions associated with fluconazole observed in clinical trials and post-marketing studies are listed below: Frequencies are defined as: Very common (≥1/10) Common (≥1/100 to <1/10) Uncommon (≥1/1000 to <1/100) Rare (≥1/10,000 to <1/1000) Very rare (<1/10,000) Not known (cannot be estimated from the available data)

Within each frequency group, undesirable effects are presented in order of decreasing seriousness. Adverse events with very common frequency (≥1/10) until now have not been recognised.

Paediatric population The pattern and incidence of side-effects and laboratory abnormalities recorded during paediatric use are comparable to those seen in adults.

19 UKPAR Fluconazole 50mg/5ml Powder for Oral Suspension PL 06831/0220 System organ class Common Uncommon Rare (≥1/10,000 to <1/1000) Very rare Not known (≥1/100 to (≥1/1000 to (<1/10,000) <1/10) <1/100) Infections and infection due to infestations resistance microorganisms Blood and anaemia Agranulocytosis, leucopenia, lymphatic system neutropenia, disorders thrombocytopenia Immune system Anaphylactic reactions angiodemia, disorders face oedema Metabolism and hypercholesterolemia, nutrition disorders hypertriglyceridemia, hypokalaemia Psychiatric insomnia, disorders somnolence Nervous system headache convulsions, disorders dizziness, paraesthesia, abnormal taste sensations, tremor, vertigo Cardiac disorders ventricular arrhythmia (QT prolongation, torsades de pointes) - see section 4.4 Gastrointestinal vomiting, dyspepsia, disorders nausea, flatulence, abdominal pain, anorexia, diarrhoea constipation, dry mouth Hepatobiliary increase in the cholestasis, a hepatitis, liver cell necrosis, disorders serum activities clinically liver failure with isolated of liver-derived relevant rise in fatalities. The appropriate enzymes such as total bilirubin, laboratory values should be ALP, ALT and jaundice, very closely monitored (see AST hepatotoxicity section 4.4) Skin and maculopapular urticaria, exfoliative skin disorders exfoliative acute generalised subcutaneous erythema, rash pruritus, (Stevens-Johnson syndrome), skin disorders exanthematous tissue disorders increased alopecia (toxic pustulosis (fixed) sweating epidermal drug eruption necrolysis or Lyell syndrome) Musculoskeletal, myalgia connective tissue and bone disorders Renal and urinary changes in renal disorders function tests General disorders fatigue, malaise, and asthenia, fever administration site conditions

4.9 OVERDOSE Cases of overdose with fluconazole have been reported and one case of a 42-year old patient infected with the human immunodeficiency virus who exhibited hallucinations and paranoid behaviour after reporting that he had taken 8,200 mg of fluconazole. The patient was hospitalised and the symptoms resolved in 48 hours.

Symptomatic treatment may be suitable in the event of an overdose, with maintenance of vital signs and gastric lavage if necessary.

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Fluconazole is eliminated mainly through urine; therefore, forced diuresis will very probably increase the elimination rate. A three-hour haemodialysis session reduces plasma levels to approximately 50%.

5 PHARMACOLOGICAL PROPERTIES 5.1 PHARMACODYNAMIC PROPERTIES Pharmacotherapeutic group: antimycotic (triazole derivatives) ATC code: J02 AC 01

General properties Fluconazole is a bis-triazole antifungal drug that belongs to the new class of triazole antifungal drugs.

Mode of action Fluconazole is a powerful and specific inhibitor of the fungal synthesis of sterols. It acts by inhibiting cytochrome P450 14∝ demethylase in susceptible fungi which converts lanosterol into , an essential lipid component of the fungal membrane.

Fluconazole is highly specific for cytochrome P-450-dependent fungal enzymes. A daily dose of 50 mg of fluconazole, administered for a maximum period of up to 28 days, has demonstrated not to affect plasma concentrations of testosterone in males or steroid concentrations in women of child-bearing age. A daily dose of 200-400 mg of fluconazole does not have a clinically significant effect upon the levels of endogenous steroids or on their response to ACTH stimulation in healthy volunteers. Interaction studies with antipyrine indicate that fluconazole, at single or multiple doses of 50 mg, does not affect its metabolism.

Most fungi show in vivo a clear sensitivity to fluconazole greater than the sensitivity they show in vitro. This is a common problem to all azole antifungal drugs Fluconazole, both orally and intravenously, has demonstrated to be active in a wide variety of animal fungal infection models. Said activity has been demonstrated in opportunist mycoses, such as infections by Candida spp., including systemic candidiasis in immunocompromised animals; infections by Cryptococcus neoformans , including intracranial infections; infections by Microsporum spp., and infections by Trichophyton spp.

Fluconazole has demonstrated to be active in endemic mycosis animal models, including infections by Blastomyces dermatitidis; infections by Coccidioides immitis, including intracranial infection; and infections by Histoplasma capsulatum in normal and immunocompromised animals.

Mechanism of resistance Occasional isolates of fluconazole-resistant Candida albicans have been reported in patients receiving prolonged AIDS treatments. As with amphotericin B and any other antiinfectious drug, isolates that are resistant to a specific treatment may occur especially in immunocompromised patients receiving treatment with that drug.

Breakpoints Species related breakpoints Non-species related breakpoint* Candida Candida Candida Candida Candida albicans glabrata krusei parapsilosis tropicalis Fluconazole 2/4 IE - 2/4 2/4 2/4 * 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 with organisms that do not have specific breakpoints - Susceptibility testing not recommended as specires is a poor target for therapy with the drug. IE – there is insufficient evidence that the species in question is a good target for therapy with the drug

Susceptibility The prelevance 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 advice should be sought when local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable

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Commonly susceptible species C albicans C kefyr C lusitaniae C parapsilosis Species for which acquired resistance may be a problem C dublinien C famata C guillermondii C,pelliculosa C tropicalis Inherently resistant organisms C glabrata C krusei

The efficacy of fluconazole in tinea capitis has been studied in 2 randomised controlled trials in a total of 878 patients, comparing fluconazole with . 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 Absorption The pharmacokinetic properties of fluconazole are similar following its oral or intravenous administration. Fluconazole is well absorbed orally, with plasma levels (and systemic bioavailability) of more than 90% with respect to the levels reached following intravenous administration. Oral absorption is not affected by the combined administration of food. Peak plasma concentrations are obtained between 0.5 and 1.5 hours post-dose, with an elimination half-life of approximately 30 hours.

Distribution Plasma concentrations are proportional to the doses. 90% of the equilibrium state levels are reached 4 or 5 days following multiple doses once daily. The administration of a higher dose on the first day, double the usual daily dose, increases plasma levels to 90% of the equilibrium state levels on the second day. The apparent distribution volume is close to the total body water. Binding to plasma proteins is low (11-12%). Fluconazole penetration in all the body fluids studied is high. Fluconazole levels in saliva and sputum are similar to plasma levels. In patients with fungal meningitis, the fluconazole concentration in cerebrospinal fluid is approximately 80% of the plasma concentration.

High concentrations of fluconazole are reached in the stratum corneum, dermis and epidermis and in eccrine sweat, higher than serum concentrations. Fluconazole accumulates in the stratum corneum. At a dose of 50 mg once daily, the fluconazole concentration after twelve days was 73 g/g, and seven days after discontinuation of the treatment, it was still 5.8 g/g. At a dose of 150 mg once a week, the fluconazole concentration in the stratum corneum on day seven was 23.4 g/g and seven days after the second dose it was still 7.1 μg/g.

The concentration of fluconazole in the nails after four months of administration of 150 mg once a week, was 4.05 g/g in healthy nails and 1.8 μg/g in affected nails. Fluconazole could still be measured in nail samples taken six months after treatment completion.

Metabolism-Elimination Its elimination is preferably renal, 80% of the dose appearing in urine without modification. Fluconazole clearance is proportional to creatinine clearance. There is no evidence of circulating metabolites. Its long elimination half-life allows administration of a single dose in the treatment of genital candidiasis and of a daily dose or a weekly dose in the treatment of any other mycoses it is indicated for. One study compared the plasma and saliva concentrations after a single dose of 100 mg of fluconazole administered in oral suspension (by rinsing and keeping in the mouth for two minutes and swallowing) or in a capsule. The maximum concentration of fluconazole in saliva with the suspension was observed five minutes after swallowing, and was 182 times greater than the maximum concentration in saliva after capsule administration, reached four hours after swallowing. After approximately four hours, fluconazole concentrations in saliva were similar. The mean AUC (0-96) in saliva was significantly higher following

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administration of the suspension compared to the capsule. There were no significant differences in the elimination rate from saliva or in the pharmacokinetic parameters for both formulations.

Pharmacokinetics in children Pharmacokinetic data were assessed for 113 paediatric patients from 5 studies; 2 single dose studies, 2 multiple dose studies and a study in premature neonates. Data from 1 study were not interpretable due to changes in formulation partway through the study. Additional data were available from a compassionate use study.

After administration of 2 – 8mg/kg fluconazole to children between ages of 9 months to 15 years, a 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 880ml/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 950ml/kg.

5.3 PRECLINICAL SAFETY DATA Preclinical data for conventional studies on repeat-dose/general toxicity, genotoxicity or carcinogenicity indicate no special hazard for humans not already considered in other sections of the SPC. In reproduction toxicity studies in rats, an increased incidence of hydronephrosis and extension of renal pelvis was reported and embryonal lethality was increased. An increase in anatomical variations and delayed ossification was noted as prolonged delivery and dystocia. In reproduction toxicity studies in rabbits, abortions were recorded.

6 PHARMACEUTICAL PARTICULARS 6.1 LIST OF EXCIPIENTS Sucrose colloidal silica titanium dioxide xanthan gum sodium citrate anhydrous citric acid monohydrate sodium benzoate (E-211) orange flavour (containing maltodextrin and arabic gum)

6.2 INCOMPATIBILITIES None known.

6.3 SHELF LIFE Unopened bottle: 2 years Reconstituted suspension: The reconstituted oral suspension has a shelf life of 14 days after reconstitution.

6.4 SPECIAL PRECAUTIONS FOR STORAGE Unopened bottle: No special storage conditions for the unopened medicinal product. Reconstituted suspension: Do not freeze the reconstituted suspension. Do not store above 30ºC.

6.5 NATURE AND CONTENTS OF CONTAINER Topaz type III glass bottle with polyethylene cap and polyethylene seal for 35 ml of suspension. A polypropylene dosing cup is included to measure 5 and 10ml. Pack sizes of 1 and 10 bottles (hospital use).

6.6 SPECIAL PRECAUTIONS FOR DISPOSAL INSTRUCTIONS FOR RECONSTITUTION Turn the bottle upside down and tap it gently until all the powder moves freely. Add 23ml of potable water and shake vigorously. Shake again before use. A whitish suspension is obtained after its reconstitution with water. Dilution is not appropriate. Any unused product should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER Genus Pharmaceuticals Limited T/A Genus Pharmaceuticals

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Park View House 65 London Road Newbury Berkshire RG14 1JN, UK

8 MARKETING AUTHORISATION NUMBER(S) PL 06831/0220

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 15/06/2011

10 DATE OF REVISION OF THE TEXT 15/06/2011

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