Super-bioavailable itraconazole (SB ITZ) overcomes the limitations of conventional itraconazole (CITZ) such as interindividual variability and reduced bioavailability. It has been approved for systemic mycoses in Australia and Europe as 50 mg and the USA as 65 mg and in India as 50 mg, 65 mg, 100 mg, and 130 mg. However, data on the ideal dose and duration of SB ITZ treatment in managing dermatophytosis are insufficient. This consensus discusses the suitability, dosage, duration of treatment, and relevance of using SB ITZ in managing dermatophytosis in different clinical scenarios. Sixteen dermatologists (>15 years of experience in the field and ≥2 years clinical experience with SB ITZ), formed the expert panel. A modified Delphi technique was employed, and a consensus was reached if the concordance in response was >75%. A total of 26 consensus statements were developed. The preferred dose of SB ITZ is 130 mg once daily and if not tolerated, 65 mg twice daily. The preferred duration for treating naïve dermatophytosis is 4–6 weeks and that for recalcitrant dermatophytosis is 6–8 weeks. Moreover, cure rates for dermatophytosis are a little better with SB ITZ than with CITZ with a similar safety profile as of CITZ. Better patient compliance and efficacy are associated with SB ITZ than with CITZ, even in patients with comorbidities and special needs such as patients with diabetes, extensive lesions, corticosteroid abuse, adolescents, and those on multiple drugs. Expert clinicians reported that the overall clinical experience with SB ITZ was better than that with CITZ.

The rising prevalence of dermatophytosis is an emerging global public health challenge [1‒3]. In India, the incidence of dermatophytosis ranges from 36.6% to 78.4% as reported in a hospital setting-based studies [4]. Cases of chronic, recalcitrant, and recurrent dermatophytosis are increasing rapidly in India attributed to increased urbanization, migration, clothing style, climate change, overcrowding, and host immunosuppression [5]. Trichophyton mentagrophytes internal transcribed spacer (ITS) genotype VIII is specifically considered to be responsible for this recent rise in the number of superficial dermatophytosis cases in India [6]. In 2019, Kano et al. [7] sequenced the ITS region of the ribosomal DNA from this pathogen and suggested it to be a new species, T. indotineae. We now know that T. indotineae is found in near-epidemic proportions in India and has spread to the United Arab Emirates, Australia, Europe, and the USA [7‒10]. It is imperative to note that T. mentagrophytes ITS genotype VIII and T. indotineae are identical at a molecular level and are associated with the same therapeutic challenges [11]. Studies indicate that T. indotineae is mostly resistant to terbinafine, and itraconazole (ITZ) is the most effective drug against it [8]. However, sporadic cases of increased minimum inhibitory concentration (MIC) to ITZ are also being observed, which is an alarm bell [12].

Dermatologists are treating recalcitrant tinea infections using a combination of methods including increasing drug dosages and duration of treatment with existing antifungal drugs, topical antifungal drugs, and occasionally, oral retinoids [5, 13]. In 2018, the Indian consensus statement (ECTODERM) on the diagnosis and management of tinea corporis, pedis, and cruris recommended the use of ITZ (100–200 mg/day) or terbinafine (250 mg/day) for 2–4 weeks in naïve cases and for >4 weeks in recalcitrant cases [14]. A 2020 consensus statement from the Indian Association of Dermatologists, Venereologists, and Leprologists Taskforce against Recalcitrant Tinea (ITART) on the management of glabrous tinea, mentioned ITZ and terbinafine as first-line drugs, followed by griseofulvin and fluconazole as alternative therapies in recalcitrant tinea [15]. However, now multiple studies conducted in India have shown that dermatophytes are generally resistant to treatment with griseofulvin, terbinafine, and fluconazole, due to high MICs [16]. ITZ is the most routinely prescribed antifungal agent in India as currently predominant Trichophyton spp. are highly sensitive to this drug [17]. However, the bioavailability of ITZ is inconsistent due to its weakly basic nature and pellet parameters [16]. Although lipophilicity ensures a higher level of ITZ in sebum and the increased dosages (of as much as 200 mg twice daily) prescribed by many physicians should ensure an effective response, poor clinical outcomes have often, been observed in India [16]. This could be due to inadequate serum levels of the drug caused by variations in the quality of the medication such as the number of layers of the active ingredient, the thickness of the ITZ coating, the use of dummy pellets, and the polymer used for enhancing dissolution. This results in the unpredictable bioavailability of ITZ, one of the main premises behind the introduction of super-bioavailable ITZ (SB ITZ) [16].

A new technology that enhances the bioavailability of poorly soluble agents by improving their dissolution has been used to develop super-bioavailable SUBA® ITZ [18]. The super-bioavailable formulation has a uniform structure with a hypromellose phthalate polymeric matrix which is pH dependent. The drug is released in the small intestine, is more soluble than conventional ITZ (CITZ), has a high bioavailability, and minimal interindividual differences in response [19].

The Food and Drug Administration (FDA) approved the use of SB ITZ in histoplasmosis, blastomycosis, and aspergillosis for adults in 2018 [20, 21]. Currently, SB ITZ is approved as 50 mg in Australia (2014) and Europe (2017) and 65 mg and 130 mg as a dose (2×65 mg) in the USA (2018) [20‒25].

In India, multiple strengths of SB ITZ have been approved by the Central Drugs Standard Control Organization (CDSCO) over the last 2 years for the management of systemic mycoses [26‒29]. Some recent studies have demonstrated that SB ITZ is more effective than CITZ in treating dermatophytosis [30‒32]. A randomized, double-arm, open-label clinical study comparing the use of 100 mg BD CITZ with 50 mg BD SB ITZ in naïve, chronic, and recurrent dermatophytosis observed that SB ITZ usage resulted in faster improvement and a higher cure rate than CITZ (65.38% vs. 33.33%, respectively) [32]. Retrospective data analysis comparing the use of 65 mg versus 50 mg SB ITZ twice daily in treating dermatophytosis showed that treatment outcome was significantly better in the 65 mg group than others [30]. However, there is a dearth of evidence regarding the ideal dose of SB ITZ to be used in managing dermatophytosis since several doses are now approved for use. Therefore, the purpose of this consensus was to bridge this gap in knowledge by using input from experts to recommend the desirable dose and duration of SB ITZ use in naïve and recalcitrant cases, the use of SB ITZ in individuals with comorbidities, and the safety of SB ITZ use in special populations such as children, adolescents, and pregnant women.

A modified Delphi method was employed to develop consensus statements from a group of 16 experts in the field of clinical dermatology. Dermatologists with more than 15 years of experience in their field and at least 2 years of experience with SB ITZ use in clinical practice were chosen as members of the expert panel. A questionnaire was sent via an MS Google doc link with questions on different topics like the strength of SB ITZ in naïve (first episode) and recalcitrant (lasting from 6 weeks to 6 months) dermatophytosis; use in special populations like pregnant women and pediatric patients; use in patients with comorbidities like diabetes or special patient populations such as those with corticosteroids misuse (steroid modified tinea); safety of SB ITZ; and overall experience of experts with SB ITZ.

The panellists were asked to answer open-ended questions regarding these topics within a week. Based on the answers received, consensus statements were framed and sent via email to the experts to aid them in arriving at a consensus. After two rounds of the Delphi method, a physical meeting was conducted to discuss the statements for which consensus had not been achieved, such as statements revolving around the use of SB ITZ in patients with diabetes (PwD) and adolescents. A total of three rounds of discussions using questionnaires with a focus on the different aspects of SB ITZ use were conducted. The panellists had to agree, disagree, and state their opinions on the questions, wherever applicable. A concordance rate of >75% was set to reach a consensus. The steps followed to develop the consensus statements are given in Figure 1.

Fig. 1.

Steps in the development of the consensus. Fig. 1 describes the various steps in developing consensus statements on super bioavailable itraconazole using the modified Delphi method. MS, Microsoft; SB ITZ, super-bioavailable itraconazole.

Fig. 1.

Steps in the development of the consensus. Fig. 1 describes the various steps in developing consensus statements on super bioavailable itraconazole using the modified Delphi method. MS, Microsoft; SB ITZ, super-bioavailable itraconazole.

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A total of 26 statements in the initial round with a discussion on 3 statements in the final round were developed. The statements addressed issues on the differing strengths and durations of SB ITZ use in various types of dermatophytosis, the safety profile of SB ITZ, and its use in individuals with comorbidities. The consensus statements are provided in Table 1.

Table 1.

Consensus statements

Serial numberStatementConsensusReframed statementConsensus
Positioning of SB ITZ in different types of dermatophytosis   
SB ITZ is prescribed in the management of dermatophytosis Consensus   
SB ITZ is preferred over CITZ in the management of dermatophytosis Consensus 
Among available strengths, the preferred strength of SB ITZ for treatment of naïve dermatophytosis is 130 mg OD Consensus 
The preferred duration of usage of SB ITZ for treatment of naïve dermatophytosis is 4–6 weeks Consensus 
A higher dose is preferred for treating recalcitrant dermatophytosis Negative consensus 
The preferred strength of SB ITZ for treating recalcitrant dermatophytosis is 130 mg OD Consensus 
The preferred duration of usage of SB ITZ for treating recalcitrant dermatophytosis is 6–8 weeks Consensus 
Use of SB ITZ in comorbidities 
The subsets of patients in which SB ITZ is preferred over CITZ are individuals on concomitant drugs like PPI previously treated with CITZ, with multiple sites of involvement, with extensive lesions, having a history of topical corticosteroid abuse, and obese individuals Consensus 
The maximum duration preferred for the administration of SB ITZ for individuals on concomitant drugs like PPI, previously treated with CITZ but experienced treatment failure, with multiple sites of involvement, extensive lesions, having a history of topical corticosteroid abuse, and obese individuals is 6–8 weeks Consensus 
10 In patients with comorbidities like diabetes, SB ITZ is preferred over CITZ Consensus 
11 In patients unable to tolerate a high dose of 130 mg OD, SB ITZ is given at a dose of 65 mg BD Consensus 
Use of SB ITZ in special populations 
12 SB ITZ is prescribed in the adolescent age group of 12–18 years No consensus In adolescents weighing >50 kg, an adult dose of SB ITZ is prescribed Consensus 
13 The strength preferred in adolescents is 65 mg BD No consensus In adolescents between 35 and 50 kg, 65 mg SB ITZ OD is the preferred dose No consensus 
The duration of therapy for SB ITZ in adolescent patients is 4–6 weeks No consensus 
14 SB ITZ is prescribed in the pediatric age group of 6–12 years Negative consensus   
15 Pregnant women are prescribed SB ITZ Negative consensus 
Use of SB ITZ in onychomycosis 
16 SB ITZ is prescribed to treat onychomycosis Consensus 
17 SB ITZ 130 mg BD, pulse therapy, is preferred in the management of onychomycosis Consensus 
Safety of SB ITZ   
18 Patients are more compliant with SB ITZ than with CITZ Consensus 
19 Routine laboratory monitoring is required in patients treated with SB ITZ No consensus 
20 The side effects of SB ITZ are the same as those of CITZ Consensus 
Experience of experts 
21 SB ITZ clears symptoms faster than CITZ Negative consensus 
22 SB ITZ usage reduces the duration of treatment as compared to CITZ usage Negative consensus 
23 SB ITZ has better clinical efficacy than CITZ Consensus 
24 In clinical practice, SB ITZ usage experience is better than that of CITZ Consensus 
25 SB ITZ is the first choice of drug in the treatment of dermatophytosis Consensus 
26 Relapse rates are similar in patients treated with SB ITZ and CITZ Consensus 
Serial numberStatementConsensusReframed statementConsensus
Positioning of SB ITZ in different types of dermatophytosis   
SB ITZ is prescribed in the management of dermatophytosis Consensus   
SB ITZ is preferred over CITZ in the management of dermatophytosis Consensus 
Among available strengths, the preferred strength of SB ITZ for treatment of naïve dermatophytosis is 130 mg OD Consensus 
The preferred duration of usage of SB ITZ for treatment of naïve dermatophytosis is 4–6 weeks Consensus 
A higher dose is preferred for treating recalcitrant dermatophytosis Negative consensus 
The preferred strength of SB ITZ for treating recalcitrant dermatophytosis is 130 mg OD Consensus 
The preferred duration of usage of SB ITZ for treating recalcitrant dermatophytosis is 6–8 weeks Consensus 
Use of SB ITZ in comorbidities 
The subsets of patients in which SB ITZ is preferred over CITZ are individuals on concomitant drugs like PPI previously treated with CITZ, with multiple sites of involvement, with extensive lesions, having a history of topical corticosteroid abuse, and obese individuals Consensus 
The maximum duration preferred for the administration of SB ITZ for individuals on concomitant drugs like PPI, previously treated with CITZ but experienced treatment failure, with multiple sites of involvement, extensive lesions, having a history of topical corticosteroid abuse, and obese individuals is 6–8 weeks Consensus 
10 In patients with comorbidities like diabetes, SB ITZ is preferred over CITZ Consensus 
11 In patients unable to tolerate a high dose of 130 mg OD, SB ITZ is given at a dose of 65 mg BD Consensus 
Use of SB ITZ in special populations 
12 SB ITZ is prescribed in the adolescent age group of 12–18 years No consensus In adolescents weighing >50 kg, an adult dose of SB ITZ is prescribed Consensus 
13 The strength preferred in adolescents is 65 mg BD No consensus In adolescents between 35 and 50 kg, 65 mg SB ITZ OD is the preferred dose No consensus 
The duration of therapy for SB ITZ in adolescent patients is 4–6 weeks No consensus 
14 SB ITZ is prescribed in the pediatric age group of 6–12 years Negative consensus   
15 Pregnant women are prescribed SB ITZ Negative consensus 
Use of SB ITZ in onychomycosis 
16 SB ITZ is prescribed to treat onychomycosis Consensus 
17 SB ITZ 130 mg BD, pulse therapy, is preferred in the management of onychomycosis Consensus 
Safety of SB ITZ   
18 Patients are more compliant with SB ITZ than with CITZ Consensus 
19 Routine laboratory monitoring is required in patients treated with SB ITZ No consensus 
20 The side effects of SB ITZ are the same as those of CITZ Consensus 
Experience of experts 
21 SB ITZ clears symptoms faster than CITZ Negative consensus 
22 SB ITZ usage reduces the duration of treatment as compared to CITZ usage Negative consensus 
23 SB ITZ has better clinical efficacy than CITZ Consensus 
24 In clinical practice, SB ITZ usage experience is better than that of CITZ Consensus 
25 SB ITZ is the first choice of drug in the treatment of dermatophytosis Consensus 
26 Relapse rates are similar in patients treated with SB ITZ and CITZ Consensus 

BD, bis in die (twice daily); CITZ, conventional itraconazole; OD, once daily; PPI, proton pump inhibitors; SB ITZ, super-bioavailable itraconazole.

Recalcitrant dermatophytosis is rampant in India. Recalcitrance is related to the species associated with the disease and its resistance to antifungal therapy, the serum concentration of the drug achieved, the MIC levels, and the levels of the antifungal drug in the skin. Increasing clinical resistance has been seen with fluconazole, griseofulvin, and terbinafine which also have a high MIC; therefore, oral ITZ is the most effective drug in the management of dermatophytosis [16].

Dermatophytosis responds well to systemically administered ITZ [31]. Over the last decade, ITZ has emerged as the mainstay of systemic treatment for recalcitrant dermatophytosis. However, ITZ usage has certain disadvantages, which affect its efficacy; such as dependency on gastric acid and fatty food for absorption, poor bioavailability, and high interindividual variations in absorption. The novel formulation, SB ITZ, was developed to overcome the challenges encountered with CITZ. However, clinical data on the usage of SB ITZ in Indian patients are scarce. Different dosage forms are currently being marketed in the USA, Europe, and India [30, 31]. This study aimed to reach a consensus on the suitability, dosage, duration of treatment, and advantages of SB ITZ in managing dermatophytosis in different clinical scenarios. A study comparing the usage of 65 mg BD SB ITZ with 50 mg BD SB ITZ found a statistically significant higher trough concentration with 65 mg SB ITZ than with 50 mg SB ITZ (p < 0.05) [33]. Sebum concentrations of SB ITZ at 7 and 14 days were also significantly higher in the 65 mg group than in the 50 mg group (p < 0.05). A larger percentage of patients in the 65 mg group achieved therapeutic concentrations as compared to the 50 mg group [33]. A randomized, open-label, four-arm study comparing different dosing and strengths of SB ITZ and CITZ, reported that patients who received the SB ITZ (130 mg OD) treatment had 1.28 times higher serum concentrations of ITZ on day 1 as compared to those who received the SB ITZ (100 mg OD) treatment. In addition, the serum concentrations of ITZ for the patients who received SB ITZ (130 mg OD) kept rising till day 28 and were always higher than those of the patients who received SB ITZ (100 mg OD). The ITZ concentrations in the sebum for the patients who received SB ITZ (130 mg OD) were 1.45, 1.38, and 1.07 times higher than those of patients who received CITZ (100 mg BD), SB ITZ (100 mg OD), and CITZ (200 mg OD), respectively, at day 28 [34].

The expert panel unanimously agreed to prescribe SB ITZ for the management of dermatophytosis and preferred it to CITZ.

Naïve Dermatophytosis

The strength of SB ITZ preferred in naïve dermatophytosis is 130 mg OD. The experts preferred to not prescribe lower doses in naïve dermatophytosis as the lesions in such cases are of the same severity as recalcitrant cases. As ITZ follows nonlinear pharmacokinetics, an OD dose is preferred [34]. The other advantage of a higher strength is the increased effectiveness of the treatment in infections that affect the hair follicles (Tinea capitis) [35]. A study comparing the pharmacokinetics of SB ITZ and CITZ demonstrated that SB ITZ usage leads to higher sebum concentrations of ITZ [36].

Some of the experts noted that gastritis is sometimes observed with a 130 mg OD dose. In patients with such symptoms, a regimen of 65 mg BD is likely to be better tolerated. In noncompliant patients, 130 mg OD is preferred. The panel recommended administering SB ITZ for 4–6 weeks and suggested that the treatment be continued for another 2–3 weeks if complete clearance of lesions could not be achieved in 4–6 weeks. The duration of treatment will also depend upon the severity of the disease (localized or generalized). Furthermore, it has been observed that topical antifungal therapy alone was effective only when the disease was limited (<10% of the body surface area/localized tinea infection). Systemic therapy was indicated when topical agents failed, or when the lesions involved multiple anatomic sites, persisted chronically, were recalcitrant, or recurrent, involved vellus hair, manifested as Majocchi’s granuloma, or were extensive lesions (covering more >10% of the body surface area) [10, 37].

Recalcitrant Dermatophytosis

In recalcitrant dermatophytosis cases, the preferred dose and duration of SB ITZ treatment is 130 mg OD and 6–8 weeks, respectively. Experts feel that higher doses of >130 mg SB ITZ are not necessary for treating recalcitrant dermatophytosis as 130 mg OD is sufficient to maintain adequate serum concentrations of the drug. However, some experts recommended using ITZ on a body weight basis. This may be particularly applicable to obese patients as individualized drug regimens for dose optimization of antifungals for different body weights may help reduce the failure rate [38]. A comparative trial has demonstrated that administration of CITZ (200 mg BD) and SB ITZ (130 mg BD) achieve the same serum levels of ITZ; this indicates that a lower dose of SB ITZ is likely to be as effective as a standard dose of CITZ [25, 39]. A study by Lindsay et al. [40] has demonstrated that when steady trough concentrations of <2,000 ng/mL were maintained, therapeutic levels of SB ITZ were attained faster with lesser interpatient variability than CITZ. On the 10th day, 69% of the SB ITZ group showed therapeutic concentrations of the drug in serum as compared to only 21% in the CITZ group (p < 0.001).

The duration of treatment was decided by the experts to guide the treatment of naïve and recalcitrant dermatophytosis; however, they noted that ultimately the treating physician’s discretion is required to decide the total duration of the therapy. Recurrences may occur due to inadequate duration of therapy, thus, it is desirable to extend the therapy to 2 weeks after the complete cure [37]. A prospective study on 40 patients assessed the effects of ITZ 200 mg BD administered for 1 week each month for 3 months along with 20 mg isotretinoin given for the same duration. After 2 months, clinical cure was observed in 90% of the patients and mycological cure was observed in 95% of the patients. Additionally, no biochemical or hematologic adverse effects were observed in any of the patients [41]. These results were superior to those observed in a similar study where the same drug combination was prescribed for only 6 weeks (complete cure in 70% and mycological cure in 83.3% of patients) [42]. The difference in the results of these two studies could be attributed to the longer duration of therapy in the first study which demonstrated the safety and efficacy of treatment with ITZ when used for 3 months. When the skin appears completely normal, with no residual change, it is termed as a clinical cure, whereas a negative potassium hydroxide microscopy indicates a mycological cure [41]. The achievement of both mycological and clinical cure has been defined as a complete cure [42]. The criteria for determining cure (clinical or mycological) and the follow-up period influence the results of double-blind trials that compare the effectiveness of antifungal agents. Generally, patients are included in a study if test positive for the studied fungal agent both in culture and mycologically, and the study endpoint is determined by a negative result in culture and microscopy [43].

Summary

The expert panel unanimously agreed to prescribe SB ITZ for the management of dermatophytosis and preferred it to CITZ as SB ITZ achieved greater trough concentrations and better cure rates than CITZ. The preferred dose of SB ITZ is 130 mg OD in both naïve and recalcitrant dermatophytosis. For naïve dermatophytosis, a treatment duration of 4–6 weeks is preferred; however, for recalcitrant dermatophytosis, the preferred duration of treatment is 6–8 weeks. But physician’s discretion is recommended to decide the total duration of therapy.

The panel of experts felt that SB ITZ is beneficial for the following individuals.

  • 1.

    Those on concomitant drugs such as proton pump inhibitors (PPIs) who were previously being treated with CITZ and have had a failed treatment: the absorption of CITZ is lowered during fasting; it is therefore advised that the medication be taken with a fatty meal. Furthermore, as it is weakly basic, it requires an acidic environment for dissolution. Therefore, PPIs that lower gastric acidity also reduce the absorption and bioavailability of CITZ by 66% [32, 36]. In contrast, SB ITZ is available in a pH-dependent matrix with intestinal absorption, has better bioavailability, and is not influenced by gastric pH [32].

  • 2.

    In individuals with multiple sites of involvement or extensive lesions: currently, dermatologists are encountering large, extensive lesions of dermatophytosis involving multiple sites, which complicate diagnosis and management. The conventional treatment methods mentioned in the literature may not be effective in such patients. Although CITZ is the most potent antifungal treatment for dermatophytosis as of now, its main disadvantage is its unpredictable absorption rate. The novel SB ITZ solves this issue with its enhanced solubility and exhibits a higher cure rate than CITZ [32].

  • 3.

    In case of topical steroid abuse/modified dermatophytosis, difficult-to-treat lesions: a randomized clinical study that had an almost equal number of topical steroid users in the CITZ (24.2%) and SB ITZ (23.1%) groups found that SB CITZ was associated with a higher complete cure rate (65.38%) than CITZ (33.33%) [32]. In a retrospective study, 23.38% of the participants had a history of corticosteroid use, and half of these patients reported the efficacy of SB ITZ as being excellent [44]. In all the above subsets of patients, treatment for 6–8 weeks was recommended by the expert panel.

  • 4.

    All the experts agreed that SB ITZ was preferred over CITZ in PwD. In PwD, particularly with type 2 diabetes, a 20–50% incidence of skin infections associated with inadequate glycemic control is observed to occur [45]. Although dermatophytosis affects immunocompetent individuals as well, a higher incidence of dermatophytosis has been observed in PwD. The rise in these infections to epidemic levels in tropical countries such as India is worrisome, especially since India has the second-largest population of PwD in the world. Thus, there is a need for novel antifungal drugs with good safety profiles and enhanced action to meet this challenge [46]. In terbinafine-resistant T. rubrum, a high dose of CITZ (300–400 mg/day) has been recommended; also, SB ITZ is preferred over CITZ due to its superior bioavailability [47]. The added benefit of using SB ITZ is that, unlike the CITZ capsule, it neither requires a full meal for its absorption nor does it need to be taken on an empty stomach as required for CITZ solutions [48, 49]. This is particularly relevant in PwD, as fasting in these patients can lead to increased gluconeogenesis and glycogen breakdown [50].

Summary

The subsets of patients such as those on concomitant drugs like PPI previously on CITZ who experienced failure of treatment; those with multiple, extensive lesions; those with steroid modified lesions; and PwD stand to benefit from using SB ITZ.

A consensus was reached regarding the prescription of an adult dose of SB ITZ in adolescents (12–18 years of age) weighing >50 kg. No consensus was reached regarding the dose in adolescents weighing 35–50 kg; while 62.5% of the experts preferred a 65 mg OD dose, 25% preferred prescribing a 130 mg OD dose, and 12.5% preferred prescribing 65 mg and 130 mg OD on alternate days. Regarding the duration of therapy, the experts were split in their opinion. Half of the experts preferred a 6–8-week duration and the other half preferred a 4–6 week-long course for adolescents. A retrospective study on children and adolescents who were being given oral ITZ solution (2.5 mg/kg/dose) prophylactically to prevent invasive fungal disease after stem cell transplantation (hematopoietic) demonstrated that the drug was well-tolerated. The drug was not discontinued in any of the treatments due to adverse effects [51]. A prospective study on children and adolescents with cystic fibrosis and allergic bronchopulmonary aspergillosis found that only 12.5% (2/16) of patients (median age of 14 years) attained therapeutic levels of ITZ/voriconazole following a mean dose of 5.1 mg/kg/day. Even when the dose was doubled to 10 mg/kg/day and administered in two doses, only 50% of the patients achieved therapeutic levels [52]. Therefore, the novel SB ITZ is preferred over the CITZ as lower doses of the medication are required to reach therapeutic concentrations [33].

A retrospective cohort study demonstrated that the administration of 5 mg/kg/day CITZ led to poor therapeutic concentrations below 12 years of age; about 75% of these children needed doses higher than the recommended dose to achieve therapeutic levels of ITZ in plasma. These variations are due to slower drug accumulation curves, particularly in children below 2 years of age, due to an immature CYP3A4 enzyme system [53]. Another retrospective study observed that therapeutic levels of 1–2 mg/L were achieved rapidly in most children with allergic bronchopulmonary aspergillosis when they were treated with 10 mg/kg/day (to a maximum of 400 mg/day) SB ITZ [54]. However, there is a lack of data on per kg dosing regimen for SB ITZ in children aged 6–12 years. Therefore, a negative consensus was reached regarding the administration of SB ITZ in the pediatric population. Generally, ITZ is well-tolerated by children [55]. Since children find swallowing tablets to be difficult, liquid/syrup formulations of ITZ are preferred. A starting dose of 2.5 mg/kg/day followed by therapeutic monitoring and dose adjustments to maintain trough concentrations of at least 0.5 mg/L is recommended by experts [56]. If CITZ treatment does not achieve adequate therapeutic concentrations, SB ITZ may be considered a suitable alternative to CITZ [33, 51].

A negative consensus was reached regarding the administration of SB ITZ during pregnancy. The panel of experts felt that evidence for use in this special group was insufficient. The results of this consensus agree with that of the 2018 consensus [14] which mentions that although no studies have detected an increased risk of teratogenicity with ITZ usage in pregnancy, the azole family, in general, is known to be associated with teratogenic risks. Therefore, it is safer to avoid products with ITZ during pregnancy [14]. Exposure to CITZ in the first trimester is not associated with an increased risk of congenital anomalies but is associated with a high chance of spontaneous abortion [57]. The category for oral ITZ in pregnancy as per the FDA is C and it is preferably avoided [58]. A systematic review on the use of antifungals during pregnancy has reported that no significant differences in the risk of birth defects were detected in infants whose mothers were exposed to ITZ versus those whose mothers were not exposed to the drug. However, four studies have found that maternal exposure to ITZ during pregnancy is associated with an increased risk of limb and congenital heart defects, and eye defects in 0.82% of the cases [59]. In addition, an increased rate of early abortion was also associated with maternal exposure to ITZ [60].

Summary

Adolescents weighing >50 kg should be prescribed the adult dose of SB ITZ. Pregnant women and children (<12 years) should not be prescribed SB ITZ for dermatophytosis.

The experts recommend the use of SB ITZ in treating fingernail and toenail onychomycosis due to dermatophytes. They recommended a dosage of 130 mg BD as pulse therapy for 1 week every month for managing onychomycosis (2 months for fingernails and 3 months for toenails). A randomized clinical trial comparing the use of SB ITZ (50 mg BD for 12 weeks) and CITZ (200 mg OD for 12 weeks) with a placebo, in patients with onychomycosis, demonstrated that SB ITZ had a significantly superior cure rate (p = 0.001) than CITZ (200 mg OD for 12 weeks) (p = 0.08) when both are compared with the placebo group [61].

Summary

Patients with onychomycosis due to dermatophytes are administered 130 mg BD of SB ITZ as pulse therapy for one week a month, for a period of 2 months for onychomycosis of fingernails, and 3 months for onychomycosis of toenails. The algorithm for the management of dermatophytosis using SB ITZ is provided in Figure 2.

Fig. 2.

Management of dermatophytosis with SB ITZ. Fig. 2 provides an algorithm for the management of naïve and recalcitrant dermatophytosis and onychomycosis. It includes the management of dermatophytosis in the presence of comorbidities and in special populations. BD, bis in die; CS, corticosteroid; DM, diabetes mellitus; OD, once daily; PPI, proton pump inhibitor; SB ITZ, super-bioavailable itraconazole.

Fig. 2.

Management of dermatophytosis with SB ITZ. Fig. 2 provides an algorithm for the management of naïve and recalcitrant dermatophytosis and onychomycosis. It includes the management of dermatophytosis in the presence of comorbidities and in special populations. BD, bis in die; CS, corticosteroid; DM, diabetes mellitus; OD, once daily; PPI, proton pump inhibitor; SB ITZ, super-bioavailable itraconazole.

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The side effects encountered with SB ITZ are the same as those with CITZ. Routine laboratory monitoring is not necessary for patients being treated with SB ITZ. The results of a study comparing the use of SB ITZ (50 mg BD) with that of CITZ (100 mg BD) showed that SB ITZ treatment achieved better symptom control than CITZ treatment and that patients had similar tolerances to both, SB ITZ and CITZ [23]. An open-label, randomized trial showed that SB ITZ (130 mg BD) is well tolerated and safe as 200 mg BD of CITZ [25]. A four-arm, open-label, randomized study that compared the efficacy and safety of CITZ (100 mg BD/200 mg OD) and SB ITZ (130 mg OD/100 mg OD) found that both formulations were well-tolerated with no participant discontinuing the treatment. No changes in the serum levels of liver enzymes were observed, indicating safety of both the formulations [34]. A trial comparing the pharmacokinetics and adverse effects of SB ITZ (130 mg BD) with CITZ (200 mg BD) found that SB ITZ is slightly better tolerated than CITZ, although SB ITZ consistently achieved similar serum levels to CITZ at lower daily doses [38].

Summary

The safety profile of SB ITZ is similar to that of CITZ.

The expert panel felt that patients in their clinical practice showed higher compliance when treated with SB ITZ than with CITZ. The reason for this could be that SB ITZ can be taken with or without food, with gastric acid-lowering agents, and with OD dosing; it reduces the pill burden. However, a negative consensus was reached regarding the faster clearance of symptoms and decreased treatment duration with SB ITZ use when compared to CITZ. Overall, the experts agreed that SB ITZ had greater efficacy and that the experience with SB ITZ was better than with CITZ. There was also consensus about SB ITZ being the first choice for the treatment of dermatophytosis. A consensus was reached regarding similar relapse rates of SB ITZ and CITZ. A failure to respond to ITZ treatment may also be related to variations in the quality of the medication, which depends upon the size, number, layering, and type of pellets used in which SB ITZ shall be preferred. The consistent serum levels of ITZ achieved with SB ITZ as compared to CITZ translate into enhanced efficacy, particularly in recalcitrant cases.

Summary

Patient compliance, efficacy, and experience of experts in the clinics are better with SB ITZ than with CITZ in the management of dermatophytosis.

The rise in recalcitrant dermatophytosis in India and its spread globally necessitates appropriate treatment. Conventional management with CITZ has limitations, such as reduced bioavailability and interindividual variations. The new formulation, SB ITZ, uses a novel technology that helps in overcoming these challenges. This consensus on SB ITZ addresses the unanswered questions on the off-label use of SB ITZ in dermatophytosis. The experts agreed that SB ITZ usage was more effective and had greater patient compliance than CITZ usage in the management of naïve and recalcitrant dermatophytosis.

We acknowledge our sincere gratitude to the team of the Global Medical Affairs, Glenmark Pharmaceuticals Limited and BioQuest Solutions for their assistance with data collation, analysis and preparation of the manuscript of this expert consensus.

As per Indian Council for Medical Research (ICMR), any research on “educational practices such as instructional strategies or effectiveness of or the comparison among instructional techniques, curricula, or classroom management methods” can be exempted from Ethics Committee review. As per this statement, there is no need for Ethics Committee approval in case of our manuscript.

ICMR also states that “voluntary informed consent can be waived if it is justified that the research involves not more than minimal risk or when the participant and the researcher do not come into contact or when it is necessitated in emergency situations.” As per this statement, there is no need for informed consent in case of our manuscript. The work was conducted in accordance with the Declaration of the Helsinki Principles. Adherence to these guidelines will not ensure successful treatment in every situation. Further, these guidelines should not be deemed inclusive of all proper methods of care or exclusive of other methods of care reasonably directed to obtaining the same results. The ultimate judgment regarding the propriety of any specific procedure must be made by the physician in light of all the circumstances presented by the individual patient.

Dr. Dhiraj Dhoot and Dr. Hanmant Barkate are employees of Glenmark Pharmaceuticals Ltd. Rest authors declare no conflict of interest. The design or procedure of the consensus and the content of the paper are in no way influenced by the grant provider.

This consensus was carried out with the grant from Glenmark Pharmaceuticals Limited, as an unrestricted educational grant.

Abir Saraswat, Sunil Dogra, Manjunath Shenoy, Shyam Verma, and Dhiraj Dhoot have made substantial contributions to conception and design. Seethram, Anil Ganjoo, and Sunil Ghate contributed for acquisition of data and analysis, and all the authors were involved in interpretation of data. Sunil Dogra, Manjunath Shenoy, Seetharam, Sunil Ghate, and Dhiraj Dhoot have been involved in drafting the manuscript or revising it critically for important intellectual content. All authors were involved in review of manuscript and had given final approval of the version to be published. Each author had participated sufficiently in the work to take public responsibility for appropriate portions of the content. Dhiraj Dhoot agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Consensus data are not publically available due to ethical reasons but will be made available by the corresponding author upon reasonable request.

1.
Gnat
S
,
Łagowski
D
,
Nowakiewicz
A
.
Major challenges and perspectives in the diagnostics and treatment of dermatophyte infections
.
J Appl Microbiol
.
2020
;
129
(
2
):
212
32
.
2.
Bishnoi
A
,
Vinay
K
,
Dogra
S
.
Emergence of recalcitrant dermatophytosis in India
.
Lancet Infect Dis
.
2018
;
18
(
3
):
250
1
.
3.
Dogra
S
,
Ramam
M
.
Difficult dermatophytosis
.
JAMA Dermatol
.
2022
;
158
(
11
):
1243
4
.
4.
Naglot
A
,
Shrimali
DD
,
Nath
BK
,
Gogoi
HK
,
Veer
V
,
Chander
J
, et al
.
Recent trends of dermatophytosis in Northeast India (Assam) and interpretation with published studies
.
Int J Curr Microbiol App Sci
.
2015
;
4
:
111
20
.
5.
Dogra
S
,
Uprety
S
.
The menace of chronic and recurrent dermatophytosis in India: is the problem deeper than we perceive
.
Indian Dermatol Online J
.
2016
;
7
(
2
):
73
6
.
6.
Nenoff
P
,
Verma
SB
,
Vasani
R
,
Burmester
A
,
Hipler
UC
,
Wittig
F
, et al
.
The current Indian epidemic of superficial dermatophytosis due to Trichophyton mentagrophytes: a molecular study
.
Mycoses
.
2019
;
62
(
4
):
336
56
.
7.
Kano
R
,
Kimura
U
,
Kakurai
M
,
Hiruma
J
,
Kamata
H
,
Suga
Y
, et al
.
Trichophyton indotineae sp. nov.: a new highly terbinafine-resistant anthropophilic dermatophyte species
.
Mycopathologia
.
2020
;
185
(
6
):
947
58
.
8.
Uhrlaß
S
,
Verma
SB
,
Gräser
Y
,
Rezaei-Matehkolaei
A
,
Hatami
M
,
Schaller
M
, et al
.
Trichophyton indotineae: an emerging pathogen causing recalcitrant dermatophytoses in India and worldwide–a multidimensional perspective
.
J Fungi
.
2022
;
8
(
7
):
757
74
.
9.
Tang
C
,
Kong
X
,
Ahmed
SA
,
Thakur
R
,
Chowdhary
A
,
Nenoff
P
, et al
.
Taxonomy of the Trichophyton mentagrophytes/T. interdigitale species complex harboring the highly virulent, multiresistant genotype T. indotineae
.
Mycopathologia
.
2021
;
186
(
3
):
315
26
.
10.
Verma
SB
,
Panda
S
,
Nenoff
P
,
Singal
A
,
Rudramurthy
SM
,
Uhrlass
S
, et al
.
The unprecedented epidemic-like scenario of dermatophytosis in India: I. Epidemiology, risk factors and clinical features
.
Indian J Dermatol Venereol Leprol
.
2021
;
87
(
2
):
154
75
.
11.
Nenoff
P
,
Uhrlaß
S
,
Verma
SB
,
Panda
S
.
Trichophyton mentagrophytes ITS genotype VIII and Trichophyton indotineae: a terminological maze, or is it
.
Indian J Dermatol Venereol Leprol
.
2022
;
88
(
5
):
586
9
.
12.
Sardana
K
,
Kaur
R
,
Arora
P
,
Goyal
R
,
Ghunawat
S
.
Is antifungal resistance a cause for treatment failure in dermatophytosis: a study focused on tinea corporis and cruris from a tertiary centre
.
Indian Dermatol Online J
.
2018
;
9
(
2
):
90
5
.
13.
Verma
SB
.
Emergence of recalcitrant dermatophytosis in India
.
Lancet Infect Dis
.
2018
;
18
(
7
):
718
9
.
14.
Rajagopalan
M
,
Inamadar
A
,
Mittal
A
,
Miskeen
AK
,
Srinivas
CR
,
Sardana
K
, et al
.
Expert consensus on the management of dermatophytosis in India (ECTODERM India)
.
BMC Dermatol
.
2018
;
18
(
1
):
6
16
.
15.
Rengasamy
M
,
Shenoy
MM
,
Dogra
S
,
Asokan
N
,
Khurana
A
,
Poojary
S
, et al
.
Indian Association of Dermatologists, Venereologists and Leprologists (IADVL) task force against recalcitrant tinea (ITART) consensus on the management of glabrous tinea (INTACT)
.
Indian Dermatol Online J
.
2020
;
11
(
4
):
502
19
.
16.
Sardana
K
,
Mathachan
SR
.
Super bioavailable itraconazole and its place and relevance in recalcitrant dermatophytosis: revisiting skin levels of itraconazole and minimum inhibitory concentration data
.
Indian Dermatol Online J
.
2021
;
12
:
1
5
.
17.
Das
S
,
De
A
,
Saha
R
,
Sharma
N
,
Khemka
M
,
Singh
S
, et al
.
The current Indian epidemic of dermatophytosis: a study on causative agents and sensitivity patterns
.
Indian J Dermatol
.
2020
;
65
(
2
):
118
22
.
18.
SUBA® bioavailability technology. Available from: https://www.maynepharma.com/innovation/specialty-technologies/suba-bioavailability-technology/ Accessed December 16, 2022.
19.
Abuhelwa
AY
,
Foster
DJ
,
Mudge
S
,
Hayes
D
,
Upton
RN
.
Population pharmacokinetic modeling of itraconazole and hydroxyitraconazole for oral suba-itraconazole and sporanox capsule formulations in healthy subjects in fed and fasted states
.
Antimicrob Agents Chemother
.
2015
;
59
(
9
):
5681
96
.
20.
FDA approves SUBA-itraconazole for treatment of systemic fungal infections
. Available from: https://www.contagionlive.com/view/fda-approves-subaitraconazole-for-treatment-of-systemic-fungal-infections. Accessed December 23, 2022.
21.
Center for drug evaluation and research
. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/208901Orig1s000Approv.pdf Accessed January 25, 2023.
22.
Gintjee
TJ
,
Donnelley
MA
,
Thompson
GR
3rd
.
Aspiring antifungals: review of current antifungal pipeline developments
.
J Fungi
.
2020
;
6
(
1
):
28
38
.
23.
Mahajan
H
,
Dhoot
D
,
Deshmukh
G
,
Barkate
H
.
Comparative clinical effectiveness and safety of super bioavailable itraconazole and conventional itraconazole in management of dermatophytosis: a retrospective data analysis
.
J Res Dermatol
.
2021
;
7
(
3
):
388
94
.
24.
Thompson
GR
3rd
,
Lewis
P
,
Mudge
S
,
Patterson
TF
,
Burnett
BP
.
Open-label crossover oral bioequivalence pharmacokinetics comparison for a 3-day loading dose regimen and 15-day steady-state administration of SUBA-itraconazole and conventional itraconazole capsules in healthy adults
.
Antimicrob Agents Chemother
.
2020
;
64
(
8
):
e00400
20
.
25.
Pappas
PG
,
Spec
A
,
Miceli
MH
,
Proia
L
,
Arauz
AB
,
Hayes
J
, et al
.
144. MSG-15: Pharmacokinetic (PK), Adverse Events (AEs), and tolerability data from an open label Randomized Clinical Trial (RCT) comparing oral suba-itraconazole (SUBA-ITC) to Conventional Itraconazole (C-ITC) for treatment of Endemic Mycosis (EM)
.
Open Forum Infect Dis
.
2020
;
7
(
Suppl_1
):
S202
3
.
26.
Drugs@CDSCO. Available from: https://cdscoonline.gov.in/CDSCO/Drugs. Accessed December 21, 2022.
27.
Recommendations of the SEC (Dermatology & Allergy) made in its 46th meeting held on 19.06.2020 at CDSCO HQ New Delhi. Available from: https://cdsco.gov.in/opencms/resources/UploadCDSCOWeb/2018/UploadCommitteeFiles/46thSECDermatology%20%20AllergyRecommendation19.06.2020.pdf Accessed January 2, 2023.
28.
Recommendations of the SEC (Antimicrobial & Antiviral) made in its 102nd meeting held on 27.07.2021 at CDSCO HQ, New Delhi. Available from: https://www.cdsco.gov.in/opencms/resources/UploadCDSCOWeb/2018/UploadCommitteeFiles/Recommendations%20Antimicrobial%20&%20Antiviral%2027.07.2021.pdf Accessed December 2, 2023.
29.
Recommendations of the SEC (Dermatology & Allergy) made in its 61st meeting held on 14.09.2021 at CDSCO HQ New Delhi. Available from: https://cdsco.gov.in/opencms/resources/UploadCDSCOWeb/2018/UploadCommitteeFiles/Recommendations%20of%20the%20SEC%20(Dermatology%20&%20Allergy)%2014-09-2021.pdf Accessed December 16, 2022.
30.
Mahadkar
N
,
Dhoot
DS
,
Barkate
H
.
Comparative real-world effectiveness and safety of super-bioavailable itraconazole 50 mg bd and 65 mg bd in the management of dermatophytosis
.
Int J Res Dermatol
.
2022
;
8
(
4
):
433
6
.
31.
Dhoot
D
,
Ghate
S
,
Mahajan
H
,
Barkate
H
.
Clinical assessment of super bioavailable itraconazole 50 mg in dermatophytosis (Clear 50)
.
IP Indian J Clin Exp Dermatol
.
2021
;
7
(
2
):
125
9
.
32.
Shenoy
M
,
Dhoot
D
,
Mahajan
H
,
Barkate
H
.
An open-label, randomized, double-arm clinical trial to compare the effectiveness and safety of super bioavailable itraconazole capsules and itraconazole capsules in the management of dermatophytosis in India
.
Clin Cosmet Investig Dermatol
.
2021
;
14
:
1367
76
.
33.
Dhoot
DS
,
Mahadkar
N
,
Jain
G
,
Kesharwani
P
.
Comparative analysis of serum and sebum concentration of super-bioavailable itraconazole 50 versus 65 mg in healthy adult volunteers
.
Int J Res Dermatol
.
2022
;
9
(
1
):
59
60
.
34.
Dhoot
D
,
Jain
GK
,
Manjhi
M
,
Kesharwani
P
,
Mahadkar
N
,
Barkate
H
.
Pharmacokinetic and clinical comparison of super-bioavailable itraconazole and conventional itraconazole at different dosing in dermatophytosis
.
Drugs Context
.
2022
;
11
:
8
18
.
35.
Zhou
YB
,
Xiao
YY
,
Chao
JJ
,
Ma
L
.
A novel itraconazole pulse therapy schedule in the treatment of Tinea capitis in children
.
Clin Cosmet Investig Dermatol
.
2021
;
14
:
1799
803
.
36.
Dhoot
D
,
Mahajan
H
,
Jain
G
,
Deshmukh
GA
,
Barkate
HV
.
Serum and sebum pharmacokinetics evaluation of a novel formulation of itraconazole in healthy volunteers
.
Indian J Drugs Dermatol
.
2022
;
8
(
1
):
7
14
.
37.
Pathania
S
,
Rudramurthy
SM
,
Narang
T
,
Saikia
UN
,
Dogra
S
.
A prospective study of the epidemiological and clinical patterns of recurrent dermatophytosis at a tertiary care hospital in India
.
Indian J Dermatol Venereol Leprol
.
2018
;
84
(
6
):
678
84
.
38.
Payne
KD
,
Hall
RG
.
Dosing of antifungal agents in obese people
.
Expert Rev Anti Infect Ther
.
2016
;
14
(
2
):
257
67
.
39.
Pappas
PG
,
Spec
A
,
Miceli
M
,
McGwin
G
,
McMullen
R
,
Thompson III
GRR
.
120. An open-label comparative trial of SUBA-itraconazole (SUBA) versus conventional itraconazole (C-ITRA) for treatment of proven and probable endemic mycoses (MSG-15): a PHARMACOKINETIc (PK) and Adverse Event (AE) analysis
.
Open Forum Infect Dis
.
2021
;
8
(
Suppl_1
):
S72
.
40.
Lindsay
J
,
Sandaradura
I
,
Wong
K
,
Arthur
C
,
Stevenson
W
,
Kerridge
I
, et al
.
New formulation SUBA-itraconazole prophylaxis in patients with haematological malignancy or undergoing allogeneic stem cell transplantation
.
Biol Blood Marrow Transplant
.
2018
;
24
(
3
):
S335
6
.
41.
Rahman
MH
.
Role of itraconazole pulse therapy with adjuvant isotretinoin in treating recur-rent and recalcitrant dermatophytosis
.
Gulf J Dermatol Venereol
.
2019
;
26
(
2
):
11
4
.
42.
Khattab
F
,
Elkholy
BM
,
Taha
M
,
Abd-Elbaset
A
,
Fawzy
M
.
Voriconazole is superior to combined itraconazole/isotretinoin therapy and itraconazole monotherapy in recalcitrant dermatophytosis
.
Mycoses
.
2022
;
65
(
12
):
1194
201
.
43.
Roberts
DT
,
Taylor
WD
,
Boyle
J
;
British Association of Dermatologists
.
Guidelines for treatment of onychomycosis
.
Br J Dermatol
.
2003
;
148
(
3
):
402
10
.
44.
Khanna
V
,
Hussain
J
,
Patel
S
,
Patel
D
,
Chaturvedi
A
,
Shah
A
.
A multicenter, retrospective study to evaluate the effectiveness, safety, and utilization patterns of super bioavailable itraconazole 50 mg in superficial dermatophytic infections
.
Int J Res Dermatol
.
2022
;
8
(
6
):
522
8
.
45.
Dinesh
K
,
Saikumar
C
.
A study on the dermatophytic pattern in diabetic and nondiabetic patient
.
J Res Med Dent Sci
.
2021
;
9
:
101
6
.
46.
Nabeela
S
,
Date
A
,
Ibrahim
AS
,
Uppuluri
P
.
Antifungal activity of alexidine dihydrochloride in a novel diabetic mouse model of dermatophytosis
.
Front Cell Infect Microbiol
.
2022
;
12
:
958497
506
.
47.
Sacheli
R
,
Hayette
MP
.
Antifungal resistance in dermatophytes: genetic considerations, clinical presentations and alternative therapies
.
J Fungi
.
2021
;
7
(
11
):
983
1005
.
48.
Drug Interactions between itraconazole and tecovirimat
. Available from: https://www.drugs.com/drug-interactions/itraconazole-with-tecovirimat-1406-0-3925-0.html Accessed December 08, 2023.
49.
Lindsay
J
,
Mudge
S
.
1354. Novel formulation suba-itraconazole in fed and fasted healthy volunteers: expanding the clinical utility of the established mold active agent
.
Open Forum Infect Dis
.
2018
;
5
(
Suppl_1
):
S414
5
.
50.
Hassanein
M
,
Al-Arouj
M
,
Hamdy
O
,
Bebakar
WMW
,
Jabbar
A
,
Al-Madani
A
, et al
.
Diabetes and ramadan: practical guidelines
.
Diabetes Res Clin Pract
.
2017
;
126
:
303
16
.
51.
Itsaradisaikul
S
,
Pakakasama
S
,
Boonsathorn
S
,
Techasaensiri
C
,
Rattanasiri
S
,
Apiwattanakul
N
.
Invasive fungal disease among pediatric and adolescent patients undergoing itraconazole prophylaxis after hematopoietic stem cell transplantation
.
Transplant Proc
.
2021
;
53
(
6
):
2021
8
.
52.
Bentley
S
,
Gupta
A
,
Balfour-Lynn
IM
.
Subtherapeutic itraconazole and voriconazole levels in children with cystic fibrosis
.
J Cyst Fibros
.
2013
;
12
(
4
):
418
9
.
53.
Leong
YH
,
Boast
A
,
Cranswick
N
,
Curtis
N
,
Gwee
A
.
Itraconazole dosing and drug monitoring at a tertiary children’s hospital
.
Pediatr Infect Dis J
.
2019
;
38
(
1
):
60
4
.
54.
Abbotsford
J
,
Foley
DA
,
Goff
Z
,
Bowen
AC
,
Blyth
CC
,
Yeoh
DK
.
Clinical experience with SUBA-itraconazole at a tertiary paediatric hospital
.
J Antimicrob Chemother
.
2021
;
76
(
1
):
249
52
.
55.
Antifungal therapy in children. Available from: https://www.cure4kids.org/private/oncochap/ocrev_222/OncoCh45-Antifungal_Therapy_Children.pdf Accessed January 25, 2023.
56.
Drogouti
E
,
Pana
ZD
,
Tragiannidis
A
,
Hempel
G
,
Groll
AH
.
Clinical pharmacology of itraconazole in children and adolescents
.
Curr Fungal Infect Rep
.
2015
;
9
(
2
):
65
73
.
57.
De Santis
M
,
Di Gianantonio
E
,
Cesari
E
,
Ambrosini
G
,
Straface
G
,
Clementi
M
.
First-trimester itraconazole exposure and pregnancy outcome: a prospective cohort study of women contacting teratology information services in Italy
.
Drug Saf
.
2009
;
32
(
3
):
239
44
.
58.
Kaul
S
,
Yadav
S
,
Dogra
S
.
Treatment of dermatophytosis in elderly, children, and pregnant women
.
Indian Dermatol Online J
.
2017
;
8
(
5
):
310
8
.
59.
Liu
D
,
Zhang
C
,
Wu
L
,
Zhang
L
,
Zhang
L
.
Fetal outcomes after maternal exposure to oral antifungal agents during pregnancy: a systematic review and meta-analysis
.
Int J Gynaecol Obstet
.
2020
;
148
(
1
):
6
13
.
60.
Pilmis
B
,
Jullien
V
,
Sobel
J
,
Lecuit
M
,
Lortholary
O
,
Charlier
C
.
Antifungal drugs during pregnancy: an updated review
.
J Antimicrob Chemother
.
2015
;
70
(
1
):
14
22
.
61.
Study comparing SUBA™-itraconazole with SPORANOX® (itraconazole) in the treatment of onychomycosis
. Available from: https://clinicaltrials.gov/ct2/show/NCT00791219 Accessed February 20, 2023.