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Safety of fluconazole in paediatrics: a systematic review.
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PMID:  23325436     Owner:  NLM     Status:  Publisher    
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PURPOSE: To determine the safety of fluconazole in neonates and other paediatric age groups by identifying adverse events (AEs) and drug interactions associated with treatment. METHODS: A search of EMBASE (1950-January 2012), MEDLINE (1946-January 2012), the Cochrane database for systematic reviews and the Cumulative Index to Nursing and Allied Health Literature (1982-2012) for any clinical study about fluconazole use that involved at least one paediatric patient (≤17 years) was performed. Only articles with sufficient quality of safety reporting after patients' exposure to fluconazole were included. RESULTS: We identified 90 articles, reporting on 4,209 patients, which met our inclusion criteria. In total, 794 AEs from 35 studies were recorded, with hepatotoxicity accounting for 378 (47.6 %) of all AEs. When fluconazole was compared with placebo and other antifungals, the relative risk (RR) of hepatotoxicity was not statistically different [RR 1.36, 95 % confidence interval (CI) 0.87-2.14, P = 0.175 and RR 1.43, 95 % CI 0.67-3.03, P = 0.352, respectively]. Complete resolution of hepatoxicity was achieved by 84 % of patients with follow-up available. There was no statistical difference in the risk of gastrointestinal events of fluconazole compared with placebo and other antifungals (RR 0.81, 95 % CI 0.12-5.60, P = 0.831 and RR 1.23, 95 %CI 0.87-1.71, P = 0.235, respectively). There were 41 drug withdrawals, 17 (42 %) of which were due to elevated liver enzymes. Five reports of drug interactions occurred in children. CONCLUSION: Fluconazole is relatively safe for paediatric patients. Hepatotoxicity and gastrointestinal toxicity are the most common adverse events. It is important to be aware that drug interactions with fluconazole can result in significant toxicity.
Authors:
Oluwaseun Egunsola; Abiodun Adefurin; Apostolos Fakis; Evelyne Jacqz-Aigrain; Imti Choonara; Helen Sammons
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Type:  JOURNAL ARTICLE     Date:  2013-1-17
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Title:  European journal of clinical pharmacology     Volume:  -     ISSN:  1432-1041     ISO Abbreviation:  Eur. J. Clin. Pharmacol.     Publication Date:  2013 Jan 
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Created Date:  2013-1-17     Completed Date:  -     Revised Date:  -    
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Nlm Unique ID:  1256165     Medline TA:  Eur J Clin Pharmacol     Country:  -    
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Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Academic Division of Child Health, Derbyshire Children's Hospital, University of Nottingham, Derby, DE22 3DT, UK, oluwaseun.egunsola@nottingham.ac.uk.
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Journal ID (nlm-ta): Eur J Clin Pharmacol
Journal ID (iso-abbrev): Eur. J. Clin. Pharmacol
ISSN: 0031-6970
ISSN: 1432-1041
Publisher: Springer-Verlag, Berlin/Heidelberg
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Received Day: 9 Month: 7 Year: 2012
Accepted Day: 27 Month: 11 Year: 2012
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pmc-release publication date: Day: 17 Month: 1 Year: 2013
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PubMed Id: 23325436
ID: 3651820
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DOI: 10.1007/s00228-012-1468-2

Safety of fluconazole in paediatrics: a systematic review
Oluwaseun EgunsolaAff1 Address: +44-1332-724685 +44-1332-724697 oluwaseun.egunsola@nottingham.ac.uk
Abiodun AdefurinAff1
Apostolos FakisAff2
Evelyne Jacqz-AigrainAff3Aff4
Imti ChoonaraAff1
Helen SammonsAff1
Academic Division of Child Health, Derbyshire Children’s Hospital, University of Nottingham, Derby, DE22 3DT UK
Department of Research & Development, Royal Derby Hospital, Derby, UK
Department of Paediatric Pharmacolgy and Pharmacogenetics, University of Paris Diderot, Sorbonne Paris Cité, INSERM CIC 9202, Paris, France
Department of Paediatric Pharmacology and Pharmacogenetics, Hôpital Robert Debré, 75019 Paris, France

Background

Invasive candidiasis is associated with high morbidity and mortality in neonates and children, with the highest incidence in premature neonates. Studies in neonates have shown an incidence rate of 2–28 % depending on birth weight [1]. Amphotericin B is the drug of choice for the treatment of invasive candidiasis; however, nephrotoxicity has been associated with this drug [2]. Fluconazole remains a suitable alternative and has also been used routinely as prophylaxis for very low birth weight neonates and children with other risk factors. Risk factors in neonates include prematurity, broad spectrum antibiotics, central venous catheter, mechanical ventilation, use of H2 receptor antagonists and parenteral nutrition. Immunosuppression from endogenous or exogenous causes, such as cystic fibrosis, malignancy, drug therapy (cytotoxics, corticosteroids, immunosuppressives), haematological diseases, organ or bone marrow transplantation and prolonged intensive care, are factors in paediatric patients beyond the neonatal period [3, 4].

Fluconazole, a bis-triazole broad spectrum antifungal agent discovered by Richardson et al. during a programme initiated by Pfizer Central Research in 1978 [5], is a suitable alternative to amphotericin B. It is available as an oral tablet, oral suspension and intravenous formulation. Its antifungal activity is achieved by preventing fungal membrane sterol synthesis through the inhibition of cytochrome P450 (CYP)-dependent lanosterol C-14α-demethylase conversion of lanosterol to ergosterol, resulting in an impairment of fungal cell replication. Although CYP is also present in mammalian cells, fluconazole is highly selective for fungal CYP [6, 7].

Fluconazole is well absorbed orally with extensive bioavailability, and most of the drug is excreted unchanged in the urine; only 11 % is excreted as metabolites, while a small percentage is excreted in the faeces. The elimination half-life of the drug is about 30 h (range 20–50 h), with a faster rate of elimination in older children than adults. In neonates, however, the mean plasma elimination half-life is longer (55–90 h) [810].

Fluconazole is licensed in children for mucosal candidiasis, invasive candidiasis and prophylaxis against candidal infections in immunocompromised patients. Common adverse reactions ascribed to the drug from clinical trials include deranged liver enzymes, cholestasis, headache, skin rash and gastrointestinal symptoms [11].

Due to the increasing use of the drug as prophylaxis and for the treatment of fungal infections in paediatric and neonatal patients, as well the need to identify toxicity associated with treatment, we decided to undertake a systematic review of safety data published on fluconazole in these populations.


Method
Search strategy

We searched MEDLINE (1946–January 2012), EMBASE (1950–January 2012), the Cochrane database for systematic reviews, Cumulative Index to Nursing and Allied Health Literature (CINAHL1982–January 2012) and the Cochrane library (Cochrane Central Register of Controlled Trials, Cochrane database of systematic reviews, and Database of abstracts of reviews of effects) for any clinical study about fluconazole use that involved at least one paediatric patient (≤17 years). Any study with involvement of a paediatric age group participant taking at least a single dose of fluconazole was eligible. Only studies with a report of safety after exposure to fluconazole in the paediatric patients were included. There was no restriction on the language of publication of the articles as translations to extract relevant data were done; where translations were not possible, abstracts containing relevant data were used. Also included in this review were any clinical study, whether comparative or non-comparative, randomised controlled trials (RCTs) or case reports and also letters to the editors that documented exposure of a paediatric patient to fluconazole and reported on safety. Included articles and extracted data were validated by two reviewers. Search terms comprised free text words and subject headings. These included terms relating to azole or imidazole or fluconazole, adverse effects or adverse drug reactions or side effects, pharmacokinetics and drug interactions.

Data extraction

Data extracted from each study included the year of publication, type of study, number of paediatric patients exposed, age of paediatric patients exposed, doses of fluconazole used, route of administration and safety data. The safety data extracted were occurrence of any adverse event (AE), any drug interactions, any withdrawal due to AEs and any drug-related death.

Data quality assessment

To minimise the risk of bias, we assessed the quality of included RCTs using the CONSORT checklist for reporting of harm [12]. All RCTs with scores of ≥6 out of nine criteria were considered to provide good quality safety reporting. Cohort studies were scored using the STROBE checklist [13], where a score of >70 % is considered to be good. Case series were evaluated using the health technology assessment checklist [14], and all studies fulfilling the good or satisfactory criteria were included.

Data collection

The relevant data were extracted onto the data extraction form. Participants in the study were grouped into paediatric age groups of preterm neonates (<36 weeks gestation, 0–27 days), full-term neonates (0–27 days, >37 weeks gestation), infants and toddlers (28 days–23 months), children (2–11 years) and adolescents (12–17 years). All reported AEs were pooled together from the various studies. The duration of treatment was grouped into <21, 21–42 and >42 days; the treatment dose was grouped into <3, 3–6 and >6 mg/kg; the route of administration was recorded as intravenous (IV), oral or IV and oral.

Statistical analysis

Meta-analysis was performed using the Stata/IC v.11 statistical package (StataCorp LP, College Station, TX). Only those studies rated as good were included in the meta-analysis. Studies with zero frequency were included in the meta-analysis by entering 0.5 to zero cells so that all of the information could be used.

The relative risk (RR) was calculated for these binary outcomes (RR >1 indicates a positive effect of fluconazole). We calculated the pooled relative risks with fixed effect models using the Mantel and Haenszel method. The heterogeneity of the model was examined by calculating the DerSimonian and Laird’s Q statistic [15] and the I2-statistic [16]. Both were compared with a chi-square distribution with degrees of freedom (df) equal to the number of trials minus one. We used the Q statistic for testing the presence of heterogeneity and the I2-statistic for estimating the degree of heterogeneity. When heterogeneity was observed, we used the with random effect models as suggested by DerSimonian and Laird [15].

The forest plots have been created for presenting the pooled effects of fluconazole. The effects of indication, age groups, dose range, route of administration and duration of treatment on risk of AEs in the fluconazole groups against the active comparator were assessed using random effect models.

Poisson regression analysis was used to test the effect of indication, age groups, dose groups, route of administration and duration of treatment on incidence of AEs and hepatotoxicity in the fluconazole group. The incidence–rate ratios (IRR) are reported from the Poisson regression analysis. All results are reported with 95 % confidence intervals (CIs), and all P values are two-tailed.


Results

Our search revealed 1,702 articles, of which 117 met our inclusion criteria (Fig. 1). These were reduced to 90 following assessment of data quality. Two articles in foreign languages (Chinese and Hebrew) were excluded because the articles could not be translated. All 90 articles were published between 1986 and 2011, and the most frequent type of studies was the case report, followed by the case series and the RCT (Table 1). Thirty-one (34 %) of the studies involved neonates only.

The largest group of patients who received fluconazole were taking part in RCTs (1,793 patients). These studies compared fluconazole with griseofulvin, placebo, nystatin, amphotericin B and other azole antifungals. One study compared different routes of administration [17]. Seven of the 14 RCTs were exclusively conducted in neonates (term and preterm) [1723], while the remainder involved children across the paediatric age spectrum (birth–17 years) [2431]. Fluconazole was used as prophylaxis in six of the eight neonatal RCTs.

The second largest group of patients on fluconazole (1,564) were enrolled in cohort studies [3238]. All cohort study patients were preterm neonates, with fluconazole administered either prophylactically orally or intravenously. The other large group of patients (795) were in case series [3959]. Fifteen of these studies were conducted in term and preterm neonates, while the others cut across the paediatric age group. Seventy-seven patients were involved in eight pharmacokinetic studies [6067], three of which were performed exclusively in preterm and term neonates.

Dosage and administration

Fluconazole was either administered as prophylaxis or therapeutically. The median prophylactic dose was 3 mg/kg/day [interquartile range (IQR) 3–6 mg/kg/day] over a median period of 42 days (IQR 1.57–42 days). The median administered therapeutic dose was 6 mg/kg/day (IQR 5–6 mg/kg/day) over a median duration of 42 days (IQR 14–67 days). Therapeutic indications were invasive candidiasis, taenia capitis, fungal meningitis, urinary tract infection and other mycotic infections. The duration of treatment ranged between 1 day [4042] and 9 years [68]. The most common routes of administration were oral (30 %), IV (23 %) or both (28 %) (Table 1).

Toxicity

A total of 4,209 patients from 90 studies were exposed to fluconazole, with 794 AEs recorded in 35 studies. Hepatotoxicity was the most common AE across all age groups. About one-third of the reviewed articles exclusively involved preterm and term neonates, accounting for 2,434 fluconazole exposed neonates. A total of 307 AEs (38.6 %) were recorded in neonates, of which 295 (96.1 %) were hepatotoxic effects. Gastrointestinal events were the second most common AE documented. One hundred cases of respiratory symptoms were recorded in one study, none of which was found to be drug-related. Other adverse events identified were renal dysfunction, haematological abnormalities and rash (Table 2). The relative risk of all AEs in the fluconazole group was not statistically different from those treated with placebo (RR 1.30, 95 % CI 0.84–2.03, P = 0.238). Compared to all other antifungal drugs there was again no significant increase in the risk (RR 1.05, 95 % CI 0.62–1.80, P = 0.85) (Fig. 2a). The overall relative risk of adverse events in the fluconazole group was not significantly different within the treatment group (RR 0.82, 95 % CI 0.49–1.36, P = 0.437) or the prophylaxis group (RR 1.68, 95 % CI 0.55–5.11, P = 0.364) compared to other antifungal drugs. There were 378 recorded cases of hepatotoxicity, accounting for just under half of all the AEs across all age groups. The majority of cases (295) occurred in neonates. The relative risk of hepatotoxicity with fluconazole was 1.36 (95 % CI 0.87–2.14) and 1.43 (95 % CI 0.67–3.03) when compared with placebo and other antifungals, respectively (Fig. 2a and 2b); these relationships were not statistically significant (P = 0.175 and 0.352, respectively). However, when compared against nystatin, the only comparator to have sufficient numbers of patients for analysis, there was a significant increase in risk of hepatotoxicity with fluconazole (RR 1.92, 95 % CI 1.13–3.26, P = 0.016) (Fig. 2c).

Poisson regression analysis of the effect of treatment, age group, dose, route of administration, indication and duration of treatment on the incidence of hepatotoxicity of fluconazole was performed. This showed that the incidence of hepatotoxicity with therapeutic fluconazole was significantly greater than that with prophylaxis (IRR 5.34 95 % CI 1.99–14.37, P = 0.001), while the duration of treatment had no effect. Although the incidence of hepatotoxicity in neonates on fluconazole was greater than that in children (IRR 1.33, 95 % CI 0.63–2.80), this effect was not statistically significant (P = 0.451). The incidence of hepatotoxicity appears to decrease with increasing dose (IRR 0.52, 95 % CI 0.37–0.74, P = 0.001). Patients on oral fluconazole were less likely to have hepatotoxicity than those on IV fluconazole (IRR 0.21, 95 % CI 0.92–0.47, P = 0.001).

Only three of the cohort studies reported any AE; one of which was a prophylactic study which recorded 127 cases of cholestasis in 409 fluconazole-exposed extremely low birth weight neonates. However, this study did not report the number of non-exposed neonates. Of these patients, 69 % recovered, while the others were discharged or transferred to other facilities [36]. Another prophylactic cohort study recorded 60 cases of cholestasis in 140 fluconazole-exposed extremely low birth weight neonates as against 12 in 137 non-exposed neonates (P < 0.001) [34].

Of all the 378 hepatotoxicity cases, resolution of symptoms was not determined in 113 (30 %) cases, while in 42 (11 %) cases, all involving neonates, there was no improvement at discharge or upon referral to another hospital (188 neonates and 35 children had completely recovered during treatment or shortly after). Therefore, 84 % of patients, for whom follow-up was complete, had resolution of symptoms. Hepatotoxicity was the most frequent reason for withdrawal of the drug. Of the 41 drug-related withdrawals,17 (42 %) were due to elevated liver enzymes [26, 27, 30, 36, 42, 66, 69].

Gastrointestinal (GI) symptoms including nausea, vomiting, abdominal pain, diarrhoea, dyspepsia, anorexia and gastritis accounted for 15.4 % of AEs (122 cases) (Table 2). There was only one recorded case of GI event in neonates. There was no statistical difference in the risk of GI events of fluconazole compared with placebo (RR 0.81, 95 %CI 0.12–5.60, P = 0.831). The risk of GI events increased, but not significantly, when fluconazole was compared with other comparator antifungal drugs (RR 1.23, 95 % CI 0.88–1.71, P = 0.235) and nystatin (RR 2.02, 95 % CI 0.66–6.23, P = 0.219). Poisson regression analysis showed that the incidence of GI AEs were lower in neonates than children (IRR 0.15, 95 % CI 0.03–0.66, p = 0.012), while dose (IRR 1.07, 95 % CI 0.85–1.39, P = 0.585) and duration of treatment (IRR 1.01, 95 % CI 0.99–1.03, P = 0.07) were unlikely to significantly affect the incidence of GI events. Although oral administration increased the incidence of GI AEs, this increase was not significant (IRR 3.22, 95 % CI 0.72–14.33, P = 0.125).

There was a decrease in mortality when fluconazole was compared with placebo, but this was not significant (RR 0.62, 95 % CI, 0.38–1.03, P = 0.067). The mortality rate between the fluconazole group and antifungal drugs was not different (RR 1.01, 95 % CI 0.72–1.41, P = 0.960) (Table 3). No cases of drug-related death were documented. There were ten reported cases of serious AEs, five of which were not treatment-related [30]. The other serious AEs were five drug interactions [7074]. Two interactions in children were with all-trans retinoic acid (ALTRA) and resulted in acute renal failure and pseudotumour cerebri [70, 71]. Another case of acute renal failure in a 9-year-old child was recorded following interaction with tacrolimus [73]. A 12-year-old child had syncope following co-administration with amitriptyline [72]. Co-administration of fluconazole with vincristine also caused severe constipation [74].


Discussion

Hepatotoxicity was the most frequent AE described in this systematic review of the safety of fluconazole. It usually manifested as conjugated hyperbilirubinaemia or deranged liver enzymes and was also the most frequent reason for withdrawal of fluconazole in both neonates and paediatric patients. Our review demonstrated that over 80 % of the cases with known outcomes had complete resolution during treatment or after completion of therapy. Hepatotoxicity risk was significantly greater in patients on fluconazole compared with nystatin (p = 0.016). The better safety of nystatin compared with fluconazole has also been described by previous authors [75]. There was an increased risk of hepatotoxicity with fluconazole than placebo, but this increase was not significant (p = 0.175). Prematurity, total parenteral nutrition, infection and congenital abnormalities are known risk factors for hepatotoxicity in neonates [76]. More neonates than children developed hepatotoxicity, even though this incidence was not significantly different. Although animal studies have demonstrated a dose-dependent histological evidence of hepatotoxicity [77], this review did not show any significant effect of increasing dose on liver toxicity, probably because most of the reviewed articles administered fluconazole within the therapeutic dose limit of ≤12 mg/kg.

Our review also showed that GI events were the second most common AE after hepatotoxicity; however, the relative risk of this event is not statistically different between patients on fluconazole and placebo or other antifungals. There was just one recorded case of a GI AE in neonates. This may be related to the fact that neonates are unable to self- report these events, and GI events are less likely to be identified by clinicians and parents. Nausea and abdominal pain, for example, are extremely difficult, if not impossible to detect in this age group.

Drug interactions with fluconazole have been documented. Fluconazole is a potent inhibitor of CYP enzymes and is known to inhibit both CYP3A and CYP1A2 enzymes [78]. Therefore, drug interactions with medicines such as tacrolimus, vincristine, ALTRA, midazolam, caffeine and amitriptyline are likely. Clinicians need to be aware of these interactions and monitor for AEs.

The relatively small number of patients in several of the groups for meta-analysis requires that these results be interpreted with caution. There were very few placebo controlled RCTs—a pool of which involved fewer than 500 patients. Such a small number may be insufficient to detect rare events. Additionally, the majority of the RCTs are primarily efficacy studies with poor and inconsistent reporting of safety outcomes. We excluded about 25 % of the identified RCTs because of their poor quality of safety reporting. Some of these limitations were also identified in several studies evaluating the quality of safety reporting in RCTs [79, 80]. Authors often fail to indicate the severity of the AEs and, in several cases, the relationship with medication was not determined. In addition, the duration of observation and outcome of AEs were often not established, with about 30 % of cases of hepatotoxicity not followed up to identify whether resolution had occurred. Comparison of fluconazole with other antifungal agents, except nystatin, was also impossible because of the paucity of good quality studies. Further research should include studies with extended follow-up to capture data regarding the resolution of hepatotoxicity, especially in the neonatal population.

In conclusion, fluconazole is relatively safe for paediatric patients. Hepatotoxicity and GI events are the most common AEs. It is important to be aware that drug interactions with fluconazole can result in significant toxicity [81111].


Acknowledgements

This work is part of the TINN network (Collaborative Project) supported by the European Commission under the Health Cooperation Work Programme of the 7th Framework Programme (grant agreement no. 223614).

Funding

This research was conducted within the framework of a TINN project, a FP7 project sponsored by the European Commission.


References
Supplementary references
1.. Benjamin DK Jr,Stoll BJ,Gantz MG,Walsh MC,Sanchez PJ,Das A,et al. Neonatal candidiasis: epidemiology, risk factors, and clinical judgmentPediatricsYear: 2010126e865e87310.1542/peds.2009-341220876174
2.. Pappas PG,Kauffman CA,Andes D,Benjamin DK,Calandra TF,Edwards JE Jr,et al. Clinical practice guidelines for the management of candidiasis: update by the Infectious Diseases Society of AmericaClin Infect DisYear: 20094850353510.1086/59675719191635
3.. Roilides E. Invasive candidiasis in neonates and childrenEarly Hum DevYear: 201187Suppl 1S75S7610.1016/j.earlhumdev.2011.01.01721251769
4.. Festekjian A,Neely M. Incidence and predictors of invasive candidiasis associated with candidaemia in childrenMycosesYear: 20115414615310.1111/j.1439-0507.2009.01785.x19821906
5.. Richardson K,Cooper K,Marriot MS,Tarbit MH,Troke PF,Whittle PJ. Discovery of fluconazole:a novel antifungal agentRev Infect DisYear: 199012S267S27110.1093/clinids/12.Supplement_3.S2672184503
6.. Grant SM,Clissold SP. Fluconazole: a review of its pharmacodynamics and pharmacokinetic properties and therapeutic potential in superficial and systemic mycosesDrugsYear: 19903987791610.2165/00003495-199039060-000062196167
7.. Kelly SL,Lamb DC,Kelle DE. Y132H substitution in Candida albicans sterol 14α-demethylase confers fluconazole resistance by preventing binding to haemFEMS Microbiol LettYear: 199918017117510556708
8.. Pfizer Inc (2011) DIFLUCAN®. Available from http://labeling.pfizer.com. Accessed: 7 April 2012
9.. Brammer KW,Coates PE. Pharmacokinetics of fluconazole in paediatric patientsEur J Clin Microbiol Infect DisYear: 19941332532910.1007/BF019746138070441
10.. Saxen H,Hoppu K,Pohjavuori M. Pharmacokinetics of fluconazole in very low birth weight infants during the first two weeks of lifeClin Pharmacol TherYear: 19935426927710.1038/clpt.1993.1478375121
11.. Medicines and Healthcare products Regulatory Agency (MHRA) 2005. Fluconazole 2 mg/ml solution for infusion. Available at: http://www.mhra.gov.uk/home/groups/par/documents/websiteresources/con079044.pdf. Accessed: 7 Dec 2011
12.. de Vries TW,van Roon EN. Low quality of reporting adverse drug reactions in paediatric randomised controlled trialsArch Dis ChildYear: 2010951023102610.1136/adc.2009.17556220551194
13.. Potts JA,Rothman AL. Clinical and laboratory features that distinguish dengue from other febrile illnesses in endemic populationsTrop Med Int HealthYear: 20081311328134010.1111/j.1365-3156.2008.02151.x18298607
14.. Maund E,Craig D,Suekarran S,Neilson AR,Wright K,Brealey S,Dennis L,Goodchild L,Hanchard N,Rangan A,Richardson G,Robertson J,McDaid C. Management of frozen shoulder: a systematic review and cost-effectiveness analysisHealth Technol AssessYear: 20121611419
15.. DerSimonian R,Laird N. Meta-analysis in clinical trialsControl Clin TrialsYear: 1986717718810.1016/0197-2456(86)90046-23802833
16.. Higgins JP,Thompson SG,Deeks JJ,Altman DG. Measuring inconsistency in meta-analysesBr Med JYear: 200332755756010.1136/bmj.327.7414.55712958120
17.. Kicklighter SD,Springer SC,Cox T,Hulsey TC,Turner RB. Fluconazole for prophylaxis against candidal rectal colonization in the very low birth weight infantPediatricsYear: 200110729329810.1542/peds.107.2.29311158461
18.. Violaris K,Carbone T,Bateman D,Olawepo O,Doraiswamy B,Lacorte M. Comparison of fluconazole and nystatin oral suspensions for prophylaxis of systemic fungal infection in very low birthweight infantsAm J PerinatolYear: 201027737810.1055/s-0029-122487119504425
19.. Driessen M,Ellis JB,Cooper PA,Wainer S,Muwazi F,Hahn D,et al. Fluconazole vs. amphotericin B for the treatment of neonatal fungal septicemia: A prospective randomized trialPediatr Infect Dis JYear: 1996151107111210.1097/00006454-199612000-000118970221
20.. Kaufman D,Boyle R,Hazen KC,Patrie JT,Robinson M,Donowitz LG. Fluconazole prophylaxis against fungal colonization and infection in preterm infantsN Engl J MedYear: 200123451660166610.1056/NEJMoa01049411759644
21.. Manzoni P,Stolfi I,Pugni L,Decembrino L,Magnani C,Vetrano G,et al. A multicenter, randomized trial of prophylactic fluconazole in preterm neonatesN Engl J MedYear: 20073562483249510.1056/NEJMoa06573317568029
22.. Aydemir C,Oguz SS,Dizdar EA,Akar M,Sarikabadayi YU,Sibel S,et al. Randomised controlled trial of prophylactic fluconazole versus nystatin for the prevention of fungal colonisation and invasive fungal infection in very low birth weight infantsArch Dis Child Fetal Neonatal EdYear: 201196F164F16810.1136/adc.2009.17899620659937
23.. Kaufman DA,Cuff AL,Wamstad JB,Boyle R,Gurka MJ,Grossman LB,et al. Fluconazole prophylaxis in extremely low birth weight infants and neurodevelopmental outcomes and quality of life at 8 to 10 years of ageJ PediatrYear: 201115875965.e110.1016/j.jpeds.2010.11.00221168853
24.. Groll AH,Just-Nuebling G,Kurz M,Mueller C,Nowak-Goettl U,Schwabe D,et al. Fluconazole versus nystatin in the prevention of Candida infections in children and adolescents undergoing remission induction or consolidation chemotherapy for cancerJ Antimicrob ChemotherYear: 19974085586210.1093/jac/40.6.8559462438
25.. Gupta AK,Adam P,Dlova N,Lynde CW,Hofstader S,Morar N,et al. Therapeutic options for the treatment of tinea capitis caused by Trichophyton species: griseofulvin versus the new oral antifungal agents, terbinafine, itraconazole, and fluconazolePediatr DermatolYear: 20011843343810.1046/j.1525-1470.2001.01978.x11737692
26.. Flynn PM,Cunningham CK,Kerkering T,San Jorge AR,Peters VB,Pitel PA,et al. Oropharyngeal candidiasis in immunocompromised children: a randomized, multicenter study of orally administered fluconazole suspension versus nystatinJ PediatrYear: 199512732232810.1016/S0022-3476(95)70321-77636666
27.. Ninane J,Gluckman E,Gibson BS,Stevens RF,Darbyshire PJ,Ball LM,et al. A multicentre study of fluconazole versus oral polyenes in the prevention of fungal infection in children with hematological or oncological malignanciesEur J Clin Microbiol Infect DisYear: 19941333033710.1007/BF019746147794307
28.. Schaison GS,Decroly FC. Propylaxis, cost and effectiveness of therapy of infections caused by Gram-positive organisms in neutropenic childrenJ Antimicrob ChemotherYear: 199127Suppl B616710.1093/jac/27.suppl_B.611829078
29.. Hernandez-Sampelayo T,Roberts A,Tricoire J,Gibb DM,Holzel H,Novelli VM,et al. Fluconazole versus ketoconazole in the treatment of oropharyngeal candidiasis in HIV-infected childrenEJCMIDYear: 19941334034410.1007/BF01974616
30.. Foster KW,Friedlander SF,Panzer H,Ghannoum MA,Elewski BE. A randomized controlled trial assessing the efficacy of fluconazole in the treatment of pediatric tinea capitisJ Am Acad DermatolYear: 20055379880910.1016/j.jaad.2005.07.02816243128
31.. Mondal RK,Singhi SC,Chakrabarti A,Jayashree M. Randomized comparison between fluconazole and itraconazole for the treatment of candidemia in a pediatric intensive care unit: a preliminary studyPediatr Crit Care MedYear: 2004556156510.1097/01.PCC.0000144712.29127.8115530193
32.. Bertini G,Perugi S,Dani C,Filippi L,Pratesi S,Rubaltelli FF. Fluconazole prophylaxis prevents invasive fungal infection in high-risk, very low birth weight infantsJ PediatrYear: 200514716216510.1016/j.jpeds.2005.02.02016126042
33.. Manzoni P,Arisio R,Mostert M,Leonessa M,Farina D,Latino MA,et al. Prophylactic fluconazole is effective in preventing fungal colonization and fungal systemic infections in preterm neonates: a single-center, 6-year, retrospective cohort studyPediatricsYear: 20061171e22e3210.1542/peds.2004-222716326690
34.. Aghai ZH,Mudduluru M,Nakhla TA,Amendolia B,Longo D,Kemble N,et al. Fluconazole prophylaxis in extremely low birth weight infants: association with cholestasisJ PerinatolYear: 20062655055510.1038/sj.jp.721157016940972
35.. Weitkamp JH,Ozdas A,LaFleur B,Potts AL. Fluconazole prophylaxis for prevention of invasive fungal infections in targeted highest risk preterm infants limits drug exposureJ PerinatolYear: 20082840541110.1038/sj.jp.721191418185518
36.. Healy CM,Campbell JR,Zaccaria E,Baker CJ. Fluconazole prophylaxis in extremely low birth weight neonates reduces invasive candidiasis mortality rates without emergence of fluconazole-resistant Candida speciesPediatricsYear: 200812170371010.1542/peds.2007-113018381534
37.. Uko S,Soghier LM,Vega M,Marsh J,Reinersman GT,Herring L,et al. Targeted short-term fluconazole prophylaxis among very low birth weight and extremely low birth weight infantsPediatricsYear: 20061171243125210.1542/peds.2005-196916585321
38.. Manzoni P,Leonessa M,Galletto P,Latino MA,Arisio R,Maule M,et al. Routine use of fluconazole prophylaxis in a neonatal intensive care unit does not select natively fluconazole-resistant Candida subspeciesPediatr Infect Dis JYear: 20082773173710.1097/INF.0b013e318170bb0c18600191
39.. Gupta AK,Dlova N,Taborda P,Morar N,Taborda V,Lynde CW,et al. Once weekly fluconazole is effective in children in the treatment of tinea capitis: a prospective, multicentre studyBr J DermatolYear: 200014296596810.1046/j.1365-2133.2000.03479.x10809856
40.. Huttova M,Hartmanova I,Kralinsky K,Filka J,Uher J,Kurak J,et al. Candida fungemia in neonates treated with fluconazole: report of forty cases, including eight with meningitisPediatr Infect Dis JYear: 1998171012101510.1097/00006454-199811000-000109849984
41.. Sesmero JMM,Sedano FJF,García TM,Brussi MM,Ferrández JSR,Fernández RD,et al. Fungal chemoprophylaxis with fluconazole in preterm infantsPharm World SciYear: 20052747547710.1007/s11096-005-7909-616341958
42.. Fasano C,O’Keeffe J,Gibbs D. Fluconazole treatment of children with severe fungalEur J Clin Infect DisYear: 19941334434710.1007/BF01974617
43.. Wainer S,Cooper PA,Gouws H,Akierman A. Prospective study of fluconazole therapy in systemic neonatal fungal infectionPediatr Infect Dis JYear: 19971676376710.1097/00006454-199708000-000079271038
44.. Viscoli C,Castagnola E,Fioredda F,Ciravegna B,Barigione G,Terragna A. Fluconazole in the treatment of candidiasis in immunocompromised childrenAntimicrob Agents ChemotherYear: 19913536536710.1128/AAC.35.2.3652024968
45.. Cap J,Mojzesova A,Kayserova E,Bubanska E,Hatiar K,Trupl J,et al. Fluconazole in children: first experience with prophylaxis in chemotherapy-induced neutropenia in pediatric patients with cancerChemotherapyYear: 19933943844210.1159/0002389908222873
46.. Ehninger G,Schuler HK,Sarnow E. Fluconazole in the prophylaxis of fungal infection after bone marrow transplantationMycosesYear: 1996397–825926310.1111/j.1439-0507.1996.tb00135.x9009642
47.. Ahmed I,Wahid Z,Nasreen S,Ansarif M. Fluconazole pulse therapy: effect on inflammatory tinea capitis (kerion and agminate folliculitis)J Pak Assoc DermatolYear: 2004147074
48.. Gürpinar AN,Balkan E,Kiliç N,Kiriştioǧlu I,Avşar I,Doǧruyol H. Fluconazole treatment of neonates and infants with severe fungal infectionsJ Int Med ResYear: 1997252142189283996
49.. Marchiso P,Principi N. Treatment of oropharyngeal candidiasis in HIV-infected children with oral fluconazoleEur J Clin Microbiol Infect DisYear: 19941369410.1007/BF01974007
50.. Presterl E,Graninger W,Brammer KW,Dopfer R,Schmitt HJ,Gadner H,et al. Efficacy and safety of fluconazole in the treatment of systemic fungal infections in pediatric patientsEur J Clin Microbiol Infect DisYear: 19941334735110.1007/BF019746188070445
51.. Fasano C,O’Keeffe J,Gibbs D. Fluconazole treatment of neonates and infants with severe fungal infections not treatable with conventional agentsEur J Clin Microbiol Infect DisYear: 19941335135410.1007/BF019746198070446
52.. Driessen M,Ellis JB,Muwazi F,De Villiers FPR. The treatment of systemic candidiasis in neonates with oral fluconazoleAnn Trop PaediatrYear: 1997172632719425383
53.. Bilgen H,Ozek E,Korten V,Ener B,Molbay D. Treatment of systemic neonatal candidiasis with fluconazole [1]InfectionYear: 19952339410.1007/BF017135798655216
54.. Kamiya H,Ihara T,Yasuda N,Sakurai M,Ito M,Azuma E,et al. Experience of fluconazole granules and injection in pediatric patientsJpn J AntibiotYear: 1994472802888182899
55.. Sugita K,Miyake M,Takitani K,Murata T,Nishimura T,Aoki S. Pharmacokinetic and clinical evaluations of fluconazole in pediatric patientsJpn J AntibiotYear: 1994472963038182901
56.. Groll A,Nowak-Gottl U,Wildfeuer A,Weise M,Schwabe D,Gerein V,et al. Fluconazole treatment of oropharyngeal candidosis in spediatric cancer patients with severe mucositis following antineoplastic chemotherapyMycosesYear: 199235Suppl35401406787
57.. Godula-Stuglik U. Endotracheal colonisation with Candida albicans in prolonged ventilated neonates—clinical manifestations and treatment with oral fluconazolePediatr Relat TopYear: 199735459465
58.. Caballero S, Jaraba Caballero MP, Fernández Gutiérrez F, Muriel Zafra I, Huertas Muñoz MD, Alvarez Marcos R et al (1998) Prospective study of Candidal sepsis in the neonate. Estudio prospectivo de sepsis por Candida en el recien nacido 48:639–643
59.. Saporito N,Tina LG,Betta P,Sciacca A. Fluconazole in the treatment of Candida albicans infection in premature infantsClin Pediatr ChirYear: 199416263267
60.. Byers M,Chapman S,Feldman S,Parent A. Fluconazole pharmacokinetics in the cerebrospinal fluid of a child with Candida tropicalis meningitisPediatr Infect Dis JYear: 19921118958961408497
61.. Krzeska L,Yeates RA,Pfaff G. Single dose intravenous pharmacokinetics of fluconazole infantsDrugs Exp Clin ResYear: 1993192672718013270
62.. Lee JW,Seibel NL,Amantea M,Whitcomb P,Pizzo PA,Walsh TJ. Safety and pharmacokinetics of fluconazole in children with neoplastic diseasesJ PediatrYear: 199212098799310.1016/S0022-3476(05)81975-41593362
63.. Piper L,Smith PB,et al. Fluconazole loading dose pharmacokinetics and safety in infantsPediatr Infect Dis JYear: 20113037537810.1097/INF.0b013e318202cbb321085048
64.. Reuman PD,Kondor PRRND. Intraperitoneal and intravenous fluconazole pharmacokinetics in a pediatric patient with end stage renal diseasePediatr Infect Dis JYear: 1992111321331741189
65.. Saxen H,Virtanen M,Carlson P,Hoppu K,Pohjavuori M,Vaara M,et al. Neonatal Candida parapsilosis outbreak with a high case fatality ratePediatr Infect DisYear: 19951477678110.1097/00006454-199509000-00009
66.. Wenzl TG,Schefels J,Hornchen H,Skopnik H. Pharmacokinetics of oral fluconazole in premature infantsEur J PediatrYear: 199815766166210.1007/s0043100509069727851
67.. Seay RE,Larson TA,Toscano JP,Bostrom BC,O’Leary MC,Uden DL. Pharmacokinetics of fluconazole in immune-compromised children with leukemia or other hematologic diseasePharmacotherapyYear: 19951552587739946
68.. Saitoh A,Homans J,Kovacs A. Fluconazole treatment of coccidioidal meningitis in children: two case reports and a review of the literaturePediatr Infect Dis JYear: 2000191204120810.1097/00006454-200012000-0001811144385
69.. Schwarze R,Penk A,Pittrow L. Treatment of candidal infections with fluconazole in neonates and infantsEur J Med ResYear: 20005520320810806122
70.. Yarali N,Tavil B,Kara A,Özkasap S,Tunç B. Acute renal failure during ALTRA treatmentPediatr Hematol OncolYear: 20082511511810.1080/0888001080188828718363177
71.. Vanier KL,Mattiussi AJ,Johnston DL. Interaction of all-trans-retinoic acid with fluconazole in acute promyelocytic leukemiaJ Pediatr Hematol OncolYear: 20032540340410.1097/00043426-200305000-0001012759628
72.. Robinson RF,Nahata MC,Olshefski RS. Syncope associated with concurrent amitriptyline and fluconazole therapyAnn PharmacotherYear: 2000341406140911144697
73.. Dhawan A,Tredger JM,North-Lewis PJ,Gonde CE,Mowat AP,Heaton NJ. Tacrolimus (FK506) malabsorption: management with fluconazole coadministrationTranspl IntYear: 19971033133410.1111/j.1432-2277.1997.tb00713.x9249946
74.. van Schie RM,Bruggemann RJM,Hoogerbrugge PM,te Loo DMWM. Effect of azole antifungal therapy on vincristine toxicity in childhood acute lymphoblastic leukaemiaJ Antimicrob ChemotherYear: 20116681853185610.1093/jac/dkr22321652620
75.. Dhondt F,Ninane J,De Beule K,Dhondt A,Cauwenbergh G. Oral candidosis: treatment with absorbable and non-absorbable antifungal agents in childrenMycosesYear: 1992351–2181406784
76.. Klein CJ,Revenis M,Kusenda C,Scavo L. Parenteral nutrition-associated conjugated hyperbilirubinemia in hospitalized infantsJ Am Diet AssocYear: 20101101684169510.1016/j.jada.2010.08.01221034882
77.. Somchit N,Norshahida AR,Hasiah AH,Zuraini A,Sulaiman MR,Noordin MM. Hepatotoxicity induced by antifungal drugs itraconazole and fluconazole in rats: a comparative in vivo studyHum Exp ToxicolYear: 20042351952510.1191/0960327104ht479oa15625777
78.. Yamazaki H,Nakamoto M,Shimizu M,Murayama N,Niwa T. Potential impact of cytochrome P450 3A5 in human liver on drug interactions with triazolesBr J Clin PharmacolYear: 20106959359710.1111/j.1365-2125.2010.03656.x20565450
79.. Anderson M,Choonara I. A systematic review of safety monitoring and drug toxicity in published randomized controlled trials of antiepileptic drugs in children over a 10-year periodArch Dis ChildYear: 20119573173810.1136/adc.2009.16590220522477
80.. de Vries TW,van Roon EN. Low quality of reporting adverse drug reactions in paediatric randomised controlled trialsArch Dis ChildYear: 201095121023102610.1136/adc.2009.17556220551194
81.. Aihara Y,Mori M,Yokota S. Successful treatment of onychomycosis with fluconazole in two patients with hyperimmunoglobulin E syndromePediatr DermatolYear: 19961349349510.1111/j.1525-1470.1996.tb00732.x8987061
82.. Assaf RR,Elewski BE. Intermittent fluconazole dosing in patients with onychomycosis: results of a pilot studyJ Am Acad DermatolYear: 1996352 Part I21621910.1016/S0190-9622(96)90327-88708024
83.. Bode S,Pedersen-Bjergaard L,Hjelt K. Candida albicans septicemia in a premature infant successfully treated with oral fluconazoleScand J Infect DisYear: 19922467367510.3109/003655492090546561465588
84.. Bergman KA,Meis JF,Horrevorts AM,Monnens L. Acute renal failure in a neonate due to pelviureteric candidal bezoars successfully treated with long-term systemic fluconazoleActa Paediatr Int J PaediatrYear: 199281970971110.1111/j.1651-2227.1992.tb12342.x
85.. Bunin N. Oral fluconazole for treatment of disseminated fungal infectionPediatr Infect Dis JYear: 198981622537947
86.. Bonnet E,Massip P,Bauriad LA,Auvergant J. Fluconazole monotherapy for Candida meningitis in premature infantClin Infect DisYear: 19962364564610.1093/clinids/23.3.6448879800
87.. Cap J,Sejnova V,Soltes L,Krcmery V Jr. Fluconazole in the treatment of mycotic infection in childrenInt J Exp Clin ChemotherYear: 199144219223
88.. Cruciani M,Di Perri G,Molesini M,Vento S,Concia E,Bassetti D. Use of fluconazole in the treatment of Candida albicans hydrocephalus shunt infectionEur J Clin Microbiol Infect DisYear: 1992111095710.1007/BF019623871486898
89.. Guillén Fiel G,Gonzalez-Granado LI,Mosqueda R,Negreira S,Giangaspro E. Arthritis caused by Candida in an immunocompetent infant with a history of systemic candidiasis in the neonatal periodAnn Pediatr (Barc)Year: 200970438338510.1016/j.anpedi.2008.12.001
90.. Filipowicz J,Kozłowski M,Irga N,Szalewska M,Zurowska A,Slusarczyk M. Acute renal insufficiency during Candida albicans candidiasis in a 2-month old infant (in Polish)Przegl LekYear: 199754173759190641
91.. Hsieh WB,Leung C. Candidal arthritis after complete treatment of systemic candidiasisJ Chin Med AssocYear: 20056819119410.1016/S1726-4901(09)70248-515850071
92.. Kamitsuka MD,Nugent NA,Conrad PD,Swanson TN. Candida albicans brain abscesses in a premature infant treated with amphotericin B, flucytosine and fluconazolePediatr Infect Dis JYear: 199514432933110.1097/00006454-199504000-000207603822
93.. Kawamori J,Tsuruta S,Yoshida T. Effect of fluconazole on Aspergillus infection associated with chronic granulomatous disease (in Japanese)Kansenshogaku zasshi (J Jpn Assoc Infect Dis)Year: 199165912001204
94.. Maruta A,Matsuzaki M,Fukawa H,Kodama F. Clinical evaluation of fluconazole in the case of deep mycosis associated with leukemiaJpn J AntibiotYear: 19894211171262540357
95.. Zia-ul-Miraj M,Mirza I. Fluconazole for treatment of fungal infections of the urinary tract in childrenPediatr Surg IntYear: 1997125–641441610.1007/BF010769539244113
96.. Mercurio MG,Silverman RA,Elewski BE. Tinea capitis: fluconazole in Trichophyton tonsurans infectionPediatr DermatolYear: 199815322923210.1046/j.1525-1470.1998.1998015229.x9655323
97.. Morris SA,Bailey CJ,Cartledge JM. Neonatal renal candidiasisJ Paediatr Child HealthYear: 199430218618810.1111/j.1440-1754.1994.tb00608.x8198857
98.. Oka S,Tokitsu M,Mori H,Nakata H,Goto M,Shimida K. Clinical evaluation of fluconazoleJpn J AntibiotYear: 198942131392540365
99.. Oleinik EM,Della-Latta P,Rinaldi MG,Saiman L. Candida lusitaniae osteomyelitis in a premature infantAm J PerinatolYear: 199310431331510.1055/s-2007-9947498397571
100.. Neal DE Jr,Rodriguez G,Hanson JA,Harmon E. Fluconazole treatment of fungal UTIs in pediatric patientsInfect MedYear: 199613316970+77
101.. Aguilera Olmos R, Mezquita Edo C, Escorihuela Centelles A, Moreno Palanques MA, Rosales Marza A, Alos Alminana M, et al (1995) Systemic neonatal candidiasis. Treatment with fluconazole (in Spanish). Rev Esp Pediatr 51(306):572–574
102.. Pernica JM,Dayneka N,Hui CPS. Rectal fluconazole for tinea capitisPaediatr Child HealthYear: 20091457357421037831
103.. Ratajczak B, Wierzba J, Irga N, Czarniak P, Kosiak W, Samet A, et al (1996) The clinical course of fungal urinary tract infection in neonates (in Polish). Ped Pol 71:331–337
104.. Ramdas K,Minamoto GY. Candidal sepsis and meningitis in a very-low-birth weight infant successfully treated with fluconazole and flucytosineClin Infect DisYear: 19941979579610.1093/clinids/19.4.7937803656
105.. Stocker M,Caduff JH,Spalinger J,Berger TM. Successful treatment of bilateral renal fungal balls with liposomal amphotericin B and fluconazole in an extremely low birth weight infantEur J PediatrYear: 2000159967667810.1007/PL0000840511014467
106.. Tucker RM,Galgiani JN,Denning DW,Hanson LH,Graybill JR,Sharkey K,et al. Treatment of coccidioidal meningitis with fluconazoleRev Infect DisYear: 199012Suppl 3S380S38910.1093/clinids/12.Supplement_3.S3802330490
107.. Van’t Wout JW,De Graeff-Meeder ER,Paul LC,Kuis W,Van Furth R. Treatment of two cases of cryptococcal meningitis with fluconazoleScand J Infect DisYear: 198820219319810.3109/003655488090324372840732
108.. Viscoli C,Castagnola E,Corsini M,Gastaldi R,Soliani M,Terragna A. Fluconazole therapy in an underweight infantEur J Clin Microbiol Infect DisYear: 198981092592610.1007/BF019637852556276
109.. Wakiguchi H,Hisakawa H,Sinohara M,Watanabe S,Okada T,Misaki Y,et al. Fluconazole therapy for pediatric patients with severe candidal infectionsJpn J AntibiotYear: 19944733043088182902
110.. Weintrub PS,Chapman A,Piecuch R. Renal fungus ball in a premature infant successfully treated with fluconazolePediatr Infect Dis JYear: 199413121152115410.1097/00006454-199412000-000197892091
111.. Yagi S,Watanabe M,Nakajima M,Tsukiyama K,Moriya O,Hino J,et al. A clinical evaluation of fluconazole in the treatment of deep mycosisJpn J AntibiotYear: 19894211441522540360

Figures

[Figure ID: Fig1]
Fig. 1 

Flow chart for articles included in the systematic review. CINAIL Cumulative Index to Nursing and Allied Health Literature, RCTs randomised controlled trials



[Figure ID: Fig2]
Fig. 2 

a Fluconazole adverse effects (AEs) compared to those of other antifungals. b Fluconazole hepatotoxicity compared with that of placebo. c Fluconazole hepatotoxicity compared with that of nystatin



Tables
[TableWrap ID: Tab1] Table 1 

Summary of the 90 studies that reported on the safety of fluconazole in paediatric populations included in this review


Characteristics of studies Number of studies Number of patients
Type of study n = 90 n = 4,209
  Case series 23 795
  Case reports 38 65
  RCT 14 1,793
  Cohort studies 7 1,564
  Pharmacokinetics studies 8 77
Route of Administration n = 90 n = 4,209
  Oral 27 1,465
  Intravenous and oral 26 1,602
  Intravenous 21 971
  Not reported 13 170
  Intraperitoneal/rectal 3 15
Age groups n = 90 n = 4,209
  Preterm neonates 20 2,354
  Term neonates 7 43
  Term and preterm neonates 4 37
  Other paediatric age groupsa 59 1,775

RCT, Randomised controlled trial

aIncluding studies involving infants up to adolescence (some of which included some neonates) and paediatric studies for which the age group was not stated


[TableWrap ID: Tab2] Table 2 

Reported adverse events from 35 studies


Adverse events Preterm neonates only Term and preterm neonates Infancy–adolescence Othersa Total
Conjugated bilirubin 231 4 1 236
↑Liver enzymes 55 13 47 16 131
Respiratory infectionb 100 100
GIT symptomsc 55 55
Headache 24 24
Vomiting 1 20 1 22
Abdominal pain 18 18
Other skin conditions 21 21
Rash/urticarial 19 19
Diarrhoea 16 1 17
Nausea 10 10
Eosinophilia 6 1 1 8
Altered renal function 3 4 7
Electrolyte derangement 2 2
Pruritus 6 6
Thrombocytopenia 5 5
Anaemia 2 2
Others 109 2 111
Total 293 29 451 21 794

GIT, Gastrointestinal tract

aNumber of adverse events (AEs) cut across age categories

bObtained from a single study

cPatients with anorexia, gastritis, dyspepsia, GI upset or a combination of any of nausea, vomiting, diarrhoea and abdominal pain


[TableWrap ID: Tab3] Table 3 

Effect of fluconazole compared with placebo, nystatin and active comparator


Relative risk 95 % confidence interval P value
Placebo
  Hepatotoxicity 1.37 0.87–2.14 0.175
  GI events 0.81 0.12–5.59 0.831
  Mortality 0.62 0.37–1.03 0.067
  Withdrawal due to AE 0.78 0.08–7.24 0.828
Other antifungals
  Hepatotoxicity 1.43 0.67–3.03 0.352
  GI events 1.23 0.88–1.71 0.235
  Mortality 1.01 0.72–1.41 0.960
  Withdrawal due to AE 1.25 0.62–2.53 0.534
Nystatin
  Hepatotoxicity 1.92 1.13–3.26 0.016*
  GI events 2.02 0.66–6.23 0.219
  Mortality 1.01 0.02–50.41 0.825
  Withdrawal due to AE 1.01 1.11–9.59 0.992

* (<0.05) statistically significant



Article Categories:
  • Review Article

Keywords: Keywords Fluconazole, Safety, Neonates, Paediatrics, Hepatotoxicity.

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