Fluconazole 50mg 5ml Powder for Oral Suspension PL · PDF fileFluconazole 50mg/5ml Powder for...

UKPAR Fluconazole 50mg5ml Powder for Oral Suspension PL 068310220

1

FLUCONAZOLE 50MG5ML POWDER FOR ORAL SUSPENSION PL 068310220

UKPAR

TABLE OF CONTENTS Lay Summary

Page 2

Scientific discussion

Page 3

Steps taken for assessment

Page 12

Steps taken after authorisation ndash summary

Page 13

Summary of Product Characteristics Product Information Leaflet Labelling

Page 14

Page 25

Page 27


2

FLUCONAZOLE 50MG5ML POWDER FOR ORAL SUSPENSION

PL 068310220

LAY SUMMARY On 15th June 2011 the MHRA granted Genus Pharmaceuticals Limited a Marketing Authorisation (licence) for Fluconazole 50mg5ml Powder for Oral Suspension Fluconazole 50mg5ml Powder for Oral Suspension contains the active ingredient fluconazole Fluconazole belongs to a group of medicinal products called triazole antifungal drugs These medicinal products are used for the treatment of a wide variety of infections caused by fungi Fluconazole 50mg5ml Suspension is used in the treatment of the following in adults and children bull Fungal infections caused by fungi of the Candida genus (called candidiasis) (Thrush) This type of infection may occur in the mouth and throat may cause chest infections candidiasis in the urinary tract and infection associated with the use of dentures bull 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) bull 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 bull 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 bull Other generalised fungal infections (eg coccidiomycosis paracoccidiomycosis sporotrichosis and histoplasmosis) bull 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 50mg5ml Powder for Oral Suspension outweigh the risks hence a Marketing Authorisation has been granted


3


PL 068310220

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


4

INTRODUCTION

Based on the review of the data on quality safety and efficacy the UK granted a Marketing Authorisation for the medicinal product Fluconazole 50mg5ml Powder for Oral Suspension (PL 068310220) 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 bull 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

bull Systemic candidiasis (including disseminated deep infections and peritonitis) bull Acute cryptococcal meningitis in adults including patients with AIDS transplanted

patients or other patients with other causes of immunosuppression

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

bull Prevention of fungal infections in patients predisposed to such infections as a result of

chemotherapy or radiotherapy including bone transplant patients bull 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 50mg5ml Powder for Oral Suspension is submitted as an abridged application according to Article 103 of Directive 200183EC claiming to be a hybrid medicinal product to Diflucan 150mg Capsules first authorised to Pfizer Limited on 7th June 1998 (PL 000570290) 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


5

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


6

PHARMACEUTICAL ASSESSMENT

DRUG SUBSTANCE INN Fluconazole Chemical name 2-(24-difluorophenyl)-13-bis-(1H-124-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 3063 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


7

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 000570290) The reference product used in the bioequivalence study is Triflucan 50mg5ml 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 lsquodo not freeze the reconstituted suspensionrsquo and lsquodo not store above 30oCrsquo 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


8

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 200183EC 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 patientsusers 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


9

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


10

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 50mg5ml Oral Suspension (Test) versus Triflucan (fluconazole) 50mg5ml 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

(nghmL) AUC0-infin

(nghmL) Cmax

(ngml)

Test (T) 9025606 10058612 210414 Reference (R) 9019735

10007 10242048

9821 212850

9886 TR Ratio (90 CI)

(9730 ndash 10291) (9493 ndash 10160) (9517 ndash 10269)

The results for the primary variables indicated that the 90 confidence intervals testreference 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


11

OVERALL CONCLUSION AND RISK BENEFIT ASSESSMENT QUALITY The important quality characteristics of Fluconazole 50mg5ml 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 benefitrisk 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 applicantrsquos Fluconazole 50mg5ml Oral Suspension and the reference product Triflucan (fluconazole) 50mg5ml Oral Suspension (after reconstitution) Fluconazole 50mg5ml 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 applicantrsquos product and the reference product are interchangeable Extensive clinical experience with fluconazole is considered to have demonstrated the therapeutic value of the compound The benefitrisk is therefore considered to be positive


12


PL 068310220

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 MHRArsquos 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


13


PL 068310220

STEPS TAKEN AFTER AUTHORISATION - SUMMARY

Date submitted

Application type

Scope Outcome

14

SUMMARY OF PRODUCT CHARACTERISTICS 1 NAME OF THE MEDICINAL PRODUCT

Fluconazole 50mg5ml 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 61

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 41 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


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 42 and 51) In some patients with severe crytococcoal meningitis the mycological response during fluconazole treatment may be slower that during other treatments (see section 44)

42 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 ndash 150mg single oral dose 2 Mucosal Candidiasis Oropharyngeal candidiasis ndash the usual dose is 50mg once daily for 7-14 days Treatment should not

normally exceed 14 days except in severely immunocompromised patients


15

For atopic oral condidiasis associated with dentures ndash 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) eg 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 ndash 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 patientrsquos risk for developing fungal infection For patients at high risk of systemic infection eg 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 lsquoUse in patients with impaired renal functionrsquo Children over four weeks of age The recommended dose of fluconazole for mucosal candidiasis is 3 mgkg daily A leading dose of 6mgkg 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 mgkg 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 mgkg 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 mgkg 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 mgkg 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 12mgkg 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 50mg5ml 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


16

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 mlmin) 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 (mlmin) Percentage of dose recommended gt 50 100 le 50 (no dialysis) 50 Regular dialysis 100 after each dialysis

43 CONTRAINDICATIONS

Hypersensitivity to fluconazole or any other azole 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 44 and 45

44 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 amphotericin B in combination with flucytosine 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 medications some known to be potentially hepatotoxic andor 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 invasivesystemic 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 azoles 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 bull Congenital or documented acquired QT prolongation bull Cardiomyopathy in particular where heart failure is present bull Sinus bradycardia


17

bull Existing symptomatic arrhythmias bull Concomitant medication known to prolong the QT interval bull Electrolye disturbances such as hypokalaemia hypomagnesaemia and hypocalcaemia See section 45 Interaction with other medicinal products and other forms of interaction Fluconazole 50 mg5 ml powder for oral suspension contains respectively 2881 mg5 ml of sucrose as an excipient Patients with rare hereditary problems to fructose intolerance glucosegalactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine This medicinal product contains less than 1 mmol sodium (23 mg) per 5ml ie essentially lsquosodium-freersquo

45 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 gkg 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 43 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 43 Contraindications


18

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 43 Contraindications) The concomitant administration of terfenadine and fluconazole at doses of less than 400 mg daily should be carefully controlled (see Section 44 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


19

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

46 PREGNANCY AND LACTATION Data from several hundred women treated with standard doses (lt200mgday) 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 53) 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

47 EFFECTS ON ABILITY TO DRIVE AND USE MACHINES Experience with fluconazole indicates that treatment with this drug is unlikely to affect the patients ability to drive or use machines

48 UNDESIRABLE EFFECTS Adverse reactions associated with fluconazole observed in clinical trials and post-marketing studies are listed below Frequencies are defined as Very common (ge110) Common (ge1100 to lt110) Uncommon (ge11000 to lt1100) Rare (ge110000 to lt11000) Very rare (lt110000) 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 (ge110) 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


20

49 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 8200 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

System organ class Common (ge1100 to lt110)

Uncommon (ge11000 to lt1100)

Rare (ge110000 to lt11000)

Very rare (lt110000)

Not known

Infections and infestations

infection due to resistance microorganisms

Blood and lymphatic system disorders

anaemia Agranulocytosis leucopenia neutropenia thrombocytopenia

Immune system disorders

Anaphylactic reactions angiodemia face oedema

Metabolism and nutrition disorders

hypercholesterolemia hypertriglyceridemia hypokalaemia

Psychiatric disorders

insomnia somnolence

Nervous system disorders

headache convulsions dizziness paraesthesia abnormal taste sensations tremor vertigo

Cardiac disorders ventricular arrhythmia (QT prolongation torsades de pointes) - see section 44

Gastrointestinal disorders

vomiting nausea abdominal pain diarrhoea

dyspepsia flatulence anorexia constipation dry mouth

Hepatobiliary disorders

increase in the serum activities of liver-derived enzymes such as ALP ALT and AST

cholestasis a clinically relevant rise in total bilirubin jaundice hepatotoxicity

hepatitis liver cell necrosis liver failure with isolated fatalities The appropriate laboratory values should be very closely monitored (see section 44)

Skin and subcutaneous tissue disorders

maculopapular erythema rash

urticaria pruritus increased sweating

exfoliative skin disorders (Stevens-Johnson syndrome) alopecia

exfoliative skin disorders (toxic epidermal necrolysis or Lyell syndrome)

acute generalised exanthematous pustulosis (fixed) drug eruption

Musculoskeletal connective tissue and bone disorders

myalgia

Renal and urinary disorders

changes in renal function tests

General disorders and administration site conditions

fatigue malaise asthenia fever


21

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 51 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 14prop demethylase in susceptible fungi which converts lanosterol into ergosterol 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 albicans

Candida glabrata

Candida krusei

Candida parapsilosis

Candida tropicalis

Fluconazole 24 IE - 24 24 24 Non species related breakpoints have been determined mainly on the basis of PKPD 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 ndash 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


22

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 Cpelliculosa 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 griseofulvin Fluconazole at 6mgkgday for 6 weeks was not superior to griseofulvin administered at 11mgkgday for 6 weeks The overall success rate at 6 weeks was low (fluconazole 6 weeks 183 fluconazole 3 weeks 147 griseofulvin 177) across all the treatment groups These findings are not inconsistent with the natural history of tinea capitis without therapy

52 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 05 and 15 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 gg and seven days after discontinuation of the treatment it was still 58 gg At a dose of 150 mg once a week the fluconazole concentration in the stratum corneum on day seven was 234 gg and seven days after the second dose it was still 71 μgg The concentration of fluconazole in the nails after four months of administration of 150 mg once a week was 405 gg in healthy nails and 18 μgg 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


23

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 ndash 8mgkg fluconazole to children between ages of 9 months to 15 years a AUC of about 38 μghml was found per 1 mgkg dose units The average fluconazole plasma elimination half-life varied between 15 and 18 hours and the distribution volume was approximately 880mlkg 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 mgkg iv to children of 11 days ndash 11 months old The distribution volume in this age group was about 950mlkg

53 PRECLINICAL SAFETY DATA Preclinical data for conventional studies on repeat-dosegeneral 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 61 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)

62 INCOMPATIBILITIES None known

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

64 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 30ordmC

65 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)

66 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 TA Genus Pharmaceuticals


24

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

8 MARKETING AUTHORISATION NUMBER(S)

PL 068310220 9 DATE OF FIRST AUTHORISATIONRENEWAL OF THE AUTHORISATION 15062011 10 DATE OF REVISION OF THE TEXT

15062011


25


26


27


28


2


PL 068310220

LAY SUMMARY On 15th June 2011 the MHRA granted Genus Pharmaceuticals Limited a Marketing Authorisation (licence) for Fluconazole 50mg5ml Powder for Oral Suspension Fluconazole 50mg5ml Powder for Oral Suspension contains the active ingredient fluconazole Fluconazole belongs to a group of medicinal products called triazole antifungal drugs These medicinal products are used for the treatment of a wide variety of infections caused by fungi Fluconazole 50mg5ml Suspension is used in the treatment of the following in adults and children bull Fungal infections caused by fungi of the Candida genus (called candidiasis) (Thrush) This type of infection may occur in the mouth and throat may cause chest infections candidiasis in the urinary tract and infection associated with the use of dentures bull 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) bull 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 bull 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 bull Other generalised fungal infections (eg coccidiomycosis paracoccidiomycosis sporotrichosis and histoplasmosis) bull 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 50mg5ml Powder for Oral Suspension outweigh the risks hence a Marketing Authorisation has been granted


3


PL 068310220



Page 4


Page 6


Page 9


Page 10



4

INTRODUCTION










5



6







7



8



9



10


(nghmL) AUC0-infin

(nghmL) Cmax

(ngml)


10007 10242048

9821 212850





11



12


PL 068310220



2008






13


PL 068310220


Date submitted

Application type

Scope Outcome

14





















15
















16







17




18



19






20

49 OVERDOSE




Rare (ge110000 to lt11000)


Not known










insomnia somnolence


















myalgia






21





related breakpoint

Candida albicans

Candida glabrata

Candida krusei


Candida tropicalis



22





23













24




15062011


25


26


27


28


3


PL 068310220



Page 4


Page 6


Page 9


Page 10



4

INTRODUCTION










5



6







7



8



9



10


(nghmL) AUC0-infin

(nghmL) Cmax

(ngml)


10007 10242048

9821 212850





11



12


PL 068310220



2008






13


PL 068310220


Date submitted

Application type

Scope Outcome

14





















15
















16







17




18



19






20

49 OVERDOSE




Rare (ge110000 to lt11000)


Not known










insomnia somnolence


















myalgia






21





related breakpoint

Candida albicans

Candida glabrata

Candida krusei


Candida tropicalis



22





23













24




15062011


25


26


27


28


4

INTRODUCTION










5



6







7



8



9



10


(nghmL) AUC0-infin

(nghmL) Cmax

(ngml)


10007 10242048

9821 212850





11



12


PL 068310220



2008






13


PL 068310220


Date submitted

Application type

Scope Outcome

14





















15
















16







17




18



19






20

49 OVERDOSE




Rare (ge110000 to lt11000)


Not known










insomnia somnolence


















myalgia






21





related breakpoint

Candida albicans

Candida glabrata

Candida krusei


Candida tropicalis



22





23













24




15062011


25


26


27


28


5



6







7



8



9



10


(nghmL) AUC0-infin

(nghmL) Cmax

(ngml)


10007 10242048

9821 212850





11



12


PL 068310220



2008






13


PL 068310220


Date submitted

Application type

Scope Outcome

14





















15
















16







17




18



19






20

49 OVERDOSE




Rare (ge110000 to lt11000)


Not known










insomnia somnolence


















myalgia






21





related breakpoint

Candida albicans

Candida glabrata

Candida krusei


Candida tropicalis



22





23













24




15062011


25


26


27


28


6







7



8



9



10


(nghmL) AUC0-infin

(nghmL) Cmax

(ngml)


10007 10242048

9821 212850





11



12


PL 068310220



2008






13


PL 068310220


Date submitted

Application type

Scope Outcome

14





















15
















16







17




18



19






20

49 OVERDOSE




Rare (ge110000 to lt11000)


Not known










insomnia somnolence


















myalgia






21





related breakpoint

Candida albicans

Candida glabrata

Candida krusei


Candida tropicalis



22





23













24




15062011


25


26


27


28


7



8



9



10


(nghmL) AUC0-infin

(nghmL) Cmax

(ngml)


10007 10242048

9821 212850





11



12


PL 068310220



2008






13


PL 068310220


Date submitted

Application type

Scope Outcome

14





















15
















16







17




18



19






20

49 OVERDOSE




Rare (ge110000 to lt11000)


Not known










insomnia somnolence


















myalgia






21





related breakpoint

Candida albicans

Candida glabrata

Candida krusei


Candida tropicalis



22





23













24




15062011


25


26


27


28


8



9



10


(nghmL) AUC0-infin

(nghmL) Cmax

(ngml)


10007 10242048

9821 212850





11



12


PL 068310220



2008






13


PL 068310220


Date submitted

Application type

Scope Outcome

14





















15
















16







17




18



19






20

49 OVERDOSE




Rare (ge110000 to lt11000)


Not known










insomnia somnolence


















myalgia






21





related breakpoint

Candida albicans

Candida glabrata

Candida krusei


Candida tropicalis



22





23













24




15062011


25


26


27


28


9



10


(nghmL) AUC0-infin

(nghmL) Cmax

(ngml)


10007 10242048

9821 212850





11



12


PL 068310220



2008






13


PL 068310220


Date submitted

Application type

Scope Outcome

14





















15
















16







17




18



19






20

49 OVERDOSE




Rare (ge110000 to lt11000)


Not known










insomnia somnolence


















myalgia






21





related breakpoint

Candida albicans

Candida glabrata

Candida krusei


Candida tropicalis



22





23













24




15062011


25


26


27


28


10


(nghmL) AUC0-infin

(nghmL) Cmax

(ngml)


10007 10242048

9821 212850





11



12


PL 068310220



2008






13


PL 068310220


Date submitted

Application type

Scope Outcome

14





















15
















16







17




18



19






20

49 OVERDOSE




Rare (ge110000 to lt11000)


Not known










insomnia somnolence


















myalgia






21





related breakpoint

Candida albicans

Candida glabrata

Candida krusei


Candida tropicalis



22





23













24




15062011


25


26


27


28


11



12


PL 068310220



2008






13


PL 068310220


Date submitted

Application type

Scope Outcome

14





















15
















16







17




18



19






20

49 OVERDOSE




Rare (ge110000 to lt11000)


Not known










insomnia somnolence


















myalgia






21





related breakpoint

Candida albicans

Candida glabrata

Candida krusei


Candida tropicalis



22





23













24




15062011


25


26


27


28


12


PL 068310220



2008






13


PL 068310220


Date submitted

Application type

Scope Outcome

14





















15
















16







17




18



19






20

49 OVERDOSE




Rare (ge110000 to lt11000)


Not known










insomnia somnolence


















myalgia






21





related breakpoint

Candida albicans

Candida glabrata

Candida krusei


Candida tropicalis



22





23













24




15062011


25


26


27


28


13


PL 068310220


Date submitted

Application type

Scope Outcome

14





















15
















16







17




18



19






20

49 OVERDOSE




Rare (ge110000 to lt11000)


Not known










insomnia somnolence


















myalgia






21





related breakpoint

Candida albicans

Candida glabrata

Candida krusei


Candida tropicalis



22





23













24




15062011


25


26


27


28

14





















15
















16







17




18



19






20

49 OVERDOSE




Rare (ge110000 to lt11000)


Not known










insomnia somnolence


















myalgia






21





related breakpoint

Candida albicans

Candida glabrata

Candida krusei


Candida tropicalis



22





23













24




15062011


25


26


27


28


15
















16







17




18



19






20

49 OVERDOSE




Rare (ge110000 to lt11000)


Not known










insomnia somnolence


















myalgia






21





related breakpoint

Candida albicans

Candida glabrata

Candida krusei


Candida tropicalis



22





23













24




15062011


25


26


27


28


16







17




18



19






20

49 OVERDOSE




Rare (ge110000 to lt11000)


Not known










insomnia somnolence


















myalgia






21





related breakpoint

Candida albicans

Candida glabrata

Candida krusei


Candida tropicalis



22





23













24




15062011


25


26


27


28


17




18



19






20

49 OVERDOSE




Rare (ge110000 to lt11000)


Not known










insomnia somnolence


















myalgia






21





related breakpoint

Candida albicans

Candida glabrata

Candida krusei


Candida tropicalis



22





23













24




15062011


25


26


27


28


18



19






20

49 OVERDOSE




Rare (ge110000 to lt11000)


Not known










insomnia somnolence


















myalgia






21





related breakpoint

Candida albicans

Candida glabrata

Candida krusei


Candida tropicalis



22





23













24




15062011


25


26


27


28


19






20

49 OVERDOSE




Rare (ge110000 to lt11000)


Not known










insomnia somnolence


















myalgia






21





related breakpoint

Candida albicans

Candida glabrata

Candida krusei


Candida tropicalis



22





23













24




15062011


25


26


27


28


20

49 OVERDOSE




Rare (ge110000 to lt11000)


Not known










insomnia somnolence


















myalgia






21





related breakpoint

Candida albicans

Candida glabrata

Candida krusei


Candida tropicalis



22





23













24




15062011


25


26


27


28


21





related breakpoint

Candida albicans

Candida glabrata

Candida krusei


Candida tropicalis



22





23













24




15062011


25


26


27


28


22





23













24




15062011


25


26


27


28


23













24




15062011


25


26


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15062011


25


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25


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