Symptoms:
In general, adverse events reported with overdose have been consistent with adverse drug reactions already listed in this SmPC for Itrac 3.
Treatment:
In the event of an overdose, supportive measures should be employed. Activated charcoal may be given if considered appropriate. Itrac 3 cannot be removed by haemodialysis. No specific antidote is available.
Symptoms and signs
Undesirable effects)Treatment
In the event of overdosage, supportive measures should be employed. Activated charcoal may be given if considered appropriate. Itraconazole cannot be removed by haemodialysis. No specific antidote is available.
Itrac 3 oral solution is contraindicated in patients with a known hypersensitivity to Itrac 3 or to any of the excipients.
Co-administration of the following drugs is contraindicated with Itrac 3 oral solution (see also 4.5 Interaction with other medicinal products and other forms of interaction):
- CYP3A4 metabolised substrates that can prolong the QT-interval e.g., astemizole, bepridil, cisapride, dofetilide, levacetylmethadol (levomethadyl), mizolastine, pimozide, quinidine, sertindole and terfenadine are contraindicated with Itrac 3 oral solution.).
Fertility, pregnancy and lactation)- Women of childbearing potential taking Itrac 3 Capsules should use contraceptive precautions. Effective contraception should be continued until the menstrual period following the end of Itrac 3 Capsules therapy.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
Not applicable.
Approximately 9% of patients can be expected to experience adverse reactions while taking Itrac 3. In patients receiving prolonged (approximately 1 month) continuous treatment especially, the incidence of adverse events has been higher (about 15%). The most frequently reported adverse experiences have been of gastrointestinal, hepatic and dermatological origin.
The table below presents adverse drug reactions by System Organ Class. Within each System Organ Class, the adverse drug reactions are presented by incidence, using the following convention:
Very common ( > 1/10); Common ( > 1/100 to < 1/10); Uncommon ( > 1/1,000 to < 1/100); Rare ( > 1/10,000 to < 1/1,000); Very rare (< 1/10,000), Not known (cannot be estimated from the available data).
| Adverse Drug Reactions | |
| Blood and lymphatic system disorders | |
| Uncommon | Leucopenia, Neutropenia, Thrombocytopenia |
| Immune system disorders | |
| Not Known | Serum Sickness, Angioneurotic Oedema, Anaphylactic Reaction, Anaphylactoid Reaction, Hypersensitivity* |
| Metabolism and nutrition disorders | |
| Uncommon | Hypokalaemia |
| Not Known | Hypertriglyceridemia |
| Nervous system disorders | |
| Common | Headache |
| Uncommon | Peripheral Neuropathy*, Dizziness |
| Not Known | Paraesthesia, Hypoaesthesia |
| Eye disorders | |
| Uncommon | Visual Disorders, including Vision Blurred and Diplopia |
| Ear and labyrinth disorder | |
| Not Known | Tinnitus; Transient or permanent hearing loss* |
| Cardiac disorders | |
| Not Known | Congestive Heart Failure* |
| Respiratory, thoracic and mediastinal disorders | |
| Common | Dyspnoea |
| Not Known | Pulmonary Oedema |
| Gastrointestinal disorders | |
| Common | Abdominal Pain, Vomiting, Nausea, Diarrhoea, Dysgeusia |
| Uncommon | Dyspepsia, Constipation |
| Not Known | Pancreatitis |
| Hepato-biliary disorders | |
| Common | Hepatic enzyme increased |
| Uncommon | Hepatitis, Hyperbilirubinaemia |
| Not Known | Hepatotoxicity*, Acute hepatic failure* |
| Skin and subcutaneous tissue disorders | |
| Common | Rash |
| Uncommon | Pruritus |
| Not Known | Toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalised exanthematous pustulosis, erythema multiforme, exfoliative dermatitis, leukocytoclastic vasculitis, urticaria, alopecia, photosensitivity |
| Musculoskeletal and connective tissue disorders | |
| Not Known | Myalgia, arthralgia |
| Renal and urinary disorders | |
| Not Known | Pollakiuria, urinary incontinence |
| Reproductive system and breast disorders | |
| Not Known | Menstrual disorders, erectile dysfunction |
| General disorders and administration site conditions | |
| Common | Pyrexia |
| Uncommon | Oedema Paediatric Population The safety of Itrac 3 oral solution was evaluated in 250 paediatric patients aged 6 months to 14 years who participated in five open-label clinical trials. These patients received at least one dose of Itrac 3 for prophylaxis of fungal infections or for treatment of oral thrush or systemic fungal infections and provided safety data. Based on pooled safety data from these clinical trials, the very common reported ADRs in paediatric patients were Vomiting (36.0%), Pyrexia (30.8%), Diarrhoea (28.4%), Mucosal inflammation (23.2%), Rash (22.8%), Abdominal pain (17.2%), Nausea (15.6%), Hypertension (14.0%), and Cough (11.2%). The nature of ADRs in paediatric patients is similar to that observed in adult subjects, but the incidence is higher in the paediatric patients. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the following: UK: Yellow Card Scheme at: www.mhra.gov.uk/yellowcard. IE: HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: [email protected] |
Summary of the safety profile
The most frequently reported adverse drug reactions (ADRs) with Itrac 3 Capsules treatment identified from clinical trials and/or from spontaneous reporting were headache, abdominal pain, and nausea.Special warnings and precautions for use for additional information on other serious effects.
Tabulated list of adverse reactions
The ADRs in the table below were derived from open-label and double-blind clinical trials with Itrac 3 Capsules involving 8499 patients in the treatment of dermatomycoses or onychomycosis, and from spontaneous reporting.
The table below presents ADRs by System Organ Class. Within each System Organ Class, the ADRs are presented by incidence, using the following convention:
Very common (> 1/10); Common (> 1/100 to < 1/10); Uncommon (> 1/1,000 to < 1/100); Rare (> 1/10,000 to < 1/1,000); Very rare (< 1/10,000).
| Adverse Drug Reactions | |
| Infections and infestations | |
| Uncommon | Sinusitis, Upper respiratory tract infection, Rhinitis |
| Blood and lymphatic system disorders | |
| Rare | Leukopenia |
| Immune system disorders | |
| Uncommon | Hypersensitivity* |
| Rare | Serum sickness, Angioneurotic oedema, Anaphylactic reaction |
| Metabolism and nutrition disorders | |
| Rare | Hypertriglyceridaemia |
| Nervous system disorders | |
| Common | Headache |
| Rare | Paraesthesia, Hypoaesthesia, Dysgeusia |
| Eye disorders | |
| Rare | Visual disturbance (including diplopia and blurred vision) |
| Ear and labyrinth disorder | |
| Rare | Transient or permanent hearing loss*, Tinnitus |
| Cardiac disorders | |
| Rare | Congestive heart failure* |
| Respiratory, thoracic and mediastinal disorders | |
| Rare | Dyspnoea |
| Gastrointestinal disorders | |
| Common | Abdominal pain, Nausea |
| Uncommon | Diarrhoea, Vomiting, Constipation, Dyspepsia, Flatulence |
| Rare | Pancreatitis |
| Hepatobiliary disorders | |
| Uncommon | Hepatic function abnormal |
| Rare | Serious hepatotoxicity (including some cases of fatal acute liver failure)*, Hyperbilirubinaemia |
| Skin and subcutaneous tissue disorders | |
| Uncommon | Urticaria, Rash, Pruritus |
| Rare | Toxic epidermal necrolysis, Stevens-Johnson syndrome, Acute generalised exanthematous pustulosis, Erythema multiforme, Exfoliative dermatitis, Leukocytoclastic vasculitis, Alopecia, Photosensitivity |
| Renal and urinary disorders | |
| Rare | Pollakiuria |
| Reproductive system and breast disorders | |
| Uncommon | Menstrual disorder |
| Rare | Erectile dysfunction |
| General disorders and administration site conditions | |
| Rare | Oedema |
| Investigations | |
| Rare | Blood creatine phosphokinase increased |
Description of selected adverse reactions
The following is a list of ADRs associated with itraconazole that have been reported in clinical trials of Itrac 3 Oral Solution and Itrac 3 I.V., excluding the ADR term “Injection site inflammationâ€, which is specific to the injection route of administration.
Blood and lymphatic system disorders: Granulocytopenia, Thrombocytopenia
Immune system disorders: Anaphylactoid reaction
Metabolism and nutrition disorders: Hyperglycaemia, Hyperkalaemia, Hypokalaemia, Hypomagnesaemia
Psychiatric disorders: Confusional state
Nervous system disorders: Peripheral neuropathy*, Dizziness, Somnolence, Tremor
Cardiac disorders: Cardiac failure, Left ventricular failure, Tachycardia
Vascular disorders: Hypertension, Hypotension
Respiratory, thoracic and mediastinal disorders: Pulmonary oedema, Dysphonia, Cough
Gastrointestinal disorders: Gastrointestinal disorder
Hepatobiliary disorders: Hepatic failure*, Hepatitis, Jaundice
Skin and subcutaneous tissue disorders: Rash erythematous, Hyperhidrosis
Musculoskeletal and connective tissue disorders: Myalgia, Arthralgia
Renal and urinary disorders: Renal impairment, Urinary incontinence
General disorders and administration site conditions: Generalised oedema, Face oedema, Chest pain, Pyrexia, Pain, Fatigue, Chills
Investigations: Alanine aminotransferase increased, Aspartate aminotransferase increased, Blood alkaline phosphatase increased, Blood lactate dehydrogenase increased, Blood urea increased, Gamma-glutamyltransferase increased, Hepatic enzyme increased, Urine analysis abnormal
Paediatric population
The safety of Itrac 3 Capsules was evaluated in 165 paediatric patients aged 1 to 17 years who participated in 14 clinical trials (4 double-blind, placebo controlled trials; 9 open-label trials; and 1 trial had an open-label phase followed by a double-blind phase). These patients received at least one dose of Itrac 3 Capsules for the treatment of fungal infections and provided safety data.
Based on pooled safety data from these clinical trials, the commonly reported adverse drug reactions (ADRs) in paediatric patients were Headache (3.0%), Vomiting (3.0%), Abdominal pain (2.4%), Diarrhoea (2.4%), Hepatic function abnormal (1.2%), Hypotension (1.2%), Nausea (1.2%), and Urticaria (1.2%). In general, the nature of ADRs in paediatric patients is similar to that observed in adult subjects, but the incidence is higher in the paediatric patients.
Epidemiological data on exposure to Itrac 3 during the first trimester of pregnancy - mostly in patients receiving short-term treatment for vulvovaginal candidosis - did not show an increased risk for malformations as compared to control subjects not exposed to any known teratogens.
Women of child-bearing potential:
Women of childbearing potential taking Itrac 3 oral solution should use contraceptive precautions. Effective contraception should be continued until the next menstrual period following the end of Itrac 3 therapy.
Fertility:
In the rat, Itrac 3 had no effect on male or female fertility at doses which exhibited signs of general toxicity. The effect in humans is unknown.
Lactation:
A very small amount of Itrac 3 is excreted in human milk. Itrac 3 Oral Solution must not be used during lactation.
4.7 Effects on ability to drive and use machinesNo studies on the effects on the ability to drive and use machines have been performed.
When driving vehicles and operating machinery the possibility of adverse reactions such as dizziness, visual disturbances and hearing loss , which may occur in some instances, must be taken into account.
4.8 Undesirable effectsApproximately 9% of patients can be expected to experience adverse reactions while taking Itrac 3. In patients receiving prolonged (approximately 1 month) continuous treatment especially, the incidence of adverse events has been higher (about 15%). The most frequently reported adverse experiences have been of gastrointestinal, hepatic and dermatological origin.
The table below presents adverse drug reactions by System Organ Class. Within each System Organ Class, the adverse drug reactions are presented by incidence, using the following convention:
Very common ( > 1/10); Common ( > 1/100 to < 1/10); Uncommon ( > 1/1,000 to < 1/100); Rare ( > 1/10,000 to < 1/1,000); Very rare (< 1/10,000), Not known (cannot be estimated from the available data).
| Adverse Drug Reactions | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Blood and lymphatic system disorders | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Uncommon | Leucopenia, Neutropenia, Thrombocytopenia | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Immune system disorders | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Not Known | Serum Sickness, Angioneurotic Oedema, Anaphylactic Reaction, Anaphylactoid Reaction, Hypersensitivity* | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Metabolism and nutrition disorders | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Uncommon | Hypokalaemia | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Not Known | Hypertriglyceridemia | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Nervous system disorders | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Common | Headache | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Uncommon | Peripheral Neuropathy*, Dizziness | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Not Known | Paraesthesia, Hypoaesthesia | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Eye disorders | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Uncommon | Visual Disorders, including Vision Blurred and Diplopia | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ear and labyrinth disorder | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Not Known | Tinnitus; Transient or permanent hearing loss* | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cardiac disorders | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Not Known | Congestive Heart Failure* | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respiratory, thoracic and mediastinal disorders | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Common | Dyspnoea | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Not Known | Pulmonary Oedema | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Gastrointestinal disorders | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Common | Abdominal Pain, Vomiting, Nausea, Diarrhoea, Dysgeusia | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Uncommon | Dyspepsia, Constipation | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Not Known | Pancreatitis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hepato-biliary disorders | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Common | Hepatic enzyme increased | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Uncommon | Hepatitis, Hyperbilirubinaemia | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Not Known | Hepatotoxicity*, Acute hepatic failure* | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skin and subcutaneous tissue disorders | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Common | Rash | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Uncommon | Pruritus | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Not Known | Toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalised exanthematous pustulosis, erythema multiforme, exfoliative dermatitis, leukocytoclastic vasculitis, urticaria, alopecia, photosensitivity | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Musculoskeletal and connective tissue disorders | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Not Known | Myalgia, arthralgia | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Renal and urinary disorders | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Not Known | Pollakiuria, urinary incontinence | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Reproductive system and breast disorders | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Not Known | Menstrual disorders, erectile dysfunction | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| General disorders and administration site conditions | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Common | Pyrexia | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Uncommon | Oedema Paediatric Population The safety of Itrac 3 oral solution was evaluated in 250 paediatric patients aged 6 months to 14 years who participated in five open-label clinical trials. These patients received at least one dose of Itrac 3 for prophylaxis of fungal infections or for treatment of oral thrush or systemic fungal infections and provided safety data. Based on pooled safety data from these clinical trials, the very common reported ADRs in paediatric patients were Vomiting (36.0%), Pyrexia (30.8%), Diarrhoea (28.4%), Mucosal inflammation (23.2%), Rash (22.8%), Abdominal pain (17.2%), Nausea (15.6%), Hypertension (14.0%), and Cough (11.2%). The nature of ADRs in paediatric patients is similar to that observed in adult subjects, but the incidence is higher in the paediatric patients. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the following: UK: Yellow Card Scheme at: www.mhra.gov.uk/yellowcard. IE: HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: [email protected] 4.9 OverdoseSymptoms: In general, adverse events reported with overdose have been consistent with adverse drug reactions already listed in this SmPC for Itrac 3. Treatment: In the event of an overdose, supportive measures should be employed. Activated charcoal may be given if considered appropriate. Itrac 3 cannot be removed by haemodialysis. No specific antidote is available. 5. Pharmacological properties 5.1 Pharmacodynamic propertiesPharmacotherapeutic group: Antimycotic for systemic use, triazole derivative. ATC code: J02A C02 Mode of action Itrac 3 inhibits fungal 14α-demethylase, resulting in a depletion of ergosterol and disruption of membrane synthesis by fungi. PK/PD relationship The PK/PD relationship for Itrac 3, and for triazoles in general, is poorly understood and is complicated by limited understanding of antifungal pharmacokinetics. Mechanism(s) of resistance Resistance of fungi to azoles appears to develop slowly and is often the result of several genetic mutations. Mechanisms that have been described are - Over-expression of ERG11, the gene that encodes 14-alpha-demethylase (the target enzyme) - Point mutations in ERG11 that lead to decreased affinity of 14-alpha-demethylase for Itrac 3 - Drug-transporter over-expression resulting in increased efflux of Itrac 3 from fungal cells (i.e., removal of Itrac 3 from its target) - Cross-resistance. Cross-resistance amongst members of the azole class of drugs has been observed within Candida species though resistance to one member of the class does not necessarily confer resistance to other azoles. Breakpoints Breakpoints for candida species are in preparation.
The prevalence of acquired resistance may vary geographically and with time for selected species, and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable. The in vitro susceptibility of fungi to Itrac 3 depends on the inoculum size, incubation temperature, growth phase of the fungi, and the culture medium used. For these reasons, the minimum inhibitory concentration of Itrac 3 may vary widely. Susceptibility in the table below is based on MIC90 < 1 mg Itrac 3/L. There is no correlation between in vitro susceptibility and clinical efficacy.
1 These organisms may be encountered in patients who have returned from travel outside Europe. 2 Itrac 3-resistant strains of Aspergillus fumigatus have been reported. 3 Natural intermediate susceptibility. Paediatric Population The tolerability and safety of Itrac 3 oral solution was studied in the prophylaxis of fungal infections in 103 neutropenic paediatric patients aged 0 to14 years (median 5 years) in an open-label uncontrolled phase III clinical study. Most patients (78%) were undergoing allogenic bone marrow transplantation for haematological malignancies. All patients received 5 mg/kg/day of Itrac 3 oral solution as a single or divided dose. Due to the design of the study, no formal conclusion with regard to efficacy could be derived. The most common adverse events considered definitely or possibly related to Itrac 3 were vomiting, abnormal liver function, and abdominal pain. 5.2 Pharmacokinetic propertiesItrac 3 General pharmacokinetic characteristics Peak plasma concentrations are reached within 2.5 hours following administration of the oral solution. As a consequence of non-linear pharmacokinetics, Itrac 3 accumulates in plasma during multiple dosing. Steady-state concentrations are generally reached within about 15 days, with Cmax and AUC values 4 to 7-fold higher than those seen after a single dose. Steady-state Cmax values of about 2 μg/ml are reached after oral administration of 200 mg once daily. The terminal half-life of Itrac 3 generally ranges from 16 to 28 hours after single dose and increases to 34 to 42 hours with repeated dosing. Once treatment is stopped, Itrac 3 plasma concentrations decrease to an almost undetectable concentration within 7 to 14 days, depending on the dose and duration of treatment. Itrac 3 mean total plasma clearance following intravenous administration is 278 ml /min. Itrac 3 clearance decreases at higher doses due to saturable hepatic metabolism. Absorption Itrac 3 is rapidly absorbed after administration of the oral solution. Peak plasma concentrations of the unchanged drug are reached within 2.5 hours following an oral dose under fasting conditions. The observed absolute bioavailability of Itrac 3 under fed conditions is about 55% and increases by 30 % when the oral solution is taken in fasting conditions. Itrac 3 exposure is greater with the oral solution than with the capsule formulation when the same dose of drug is given.. Distribution Most of the Itrac 3 in plasma is bound to protein (99.8%) with albumin being the main binding component (99.6% for the hydroxy- metabolite). It has also a marked affinity for lipids. Only 0.2% of the Itrac 3 in plasma is present as free drug. Itrac 3 is distributed in a large apparent volume in the body (> 700 L), suggesting its extensive distribution into tissues: Concentrations in lung, kidney, liver, bone, stomach, spleen and muscle were found to be two to three times higher than corresponding concentrations in plasma, and the uptake into keratinous tissues, skin in particular, up to four times higher. Concentrations in the cerebrospinal fluid are much lower than in plasma, but efficacy has been demonstrated against infections present in the cerebrospinal fluid. Metabolism Itrac 3 is extensively metabolised by the liver into a large number of metabolites. The main metabolite is hydroxy-Itrac 3, which has in vitro antifungal activity comparable to Itrac 3. Trough plasma concentrations of the hydroxy-Itrac 3 are about twice those of Itrac 3. As shown in in vitro studies, CYP 3A4 is the major enzyme that is involved in the metabolism of Itrac 3. Elimination Itrac 3 is excreted mainly as inactive metabolites to about 35% in urine and to about 54% with faeces within one week of an oral solution dose. Renal excretion of Itrac 3 and the active metabolite hydroxy-Itrac 3 account for less than 1% of an intravenous dose. Based on an oral radiolabeled dose, faecal excretion of unchanged drug ranges from 3% to 18% of the dose. As re-distribution of Itrac 3 from keratinous tissues appears to be negligible, elimination of Itrac 3 from these tissues is related to epidermal regeneration. Contrary to plasma, the concentration in skin persists for 2 to 4 weeks after discontinuation of a 4-week treatment and in nail keratin - where Itrac 3 can be detected as early as 1 week after start of treatment - for at least six months after the end of a 3-month treatment period. Special Populations Hepatic Impairment: Itrac 3 is predominantly metabolised in the liver. A pharmacokinetic study using a single 100 mg dose of Itrac 3 (one 100 mg capsule) was conducted in 6 healthy and 12 cirrhotic subjects. A statistically significant reduction in average Cmax (47%) and a two fold increase in the elimination half-life (37 ± 17 versus 16 ±5 hours) of Itrac 3 were noted in cirrhotic subjects compared with healthy subjects. However, overall exposure to Itrac 3, based on AUC, was similar in cirrhotic patients and in healthy subjects.Data are not available in cirrhotic patients during long-term use of Itrac 3. Renal Impairment: Limited data are available on the use of oral Itrac 3 in patients with renal impairment. A pharmacokinetic study using a single 200-mg dose of Itrac 3 (four 50-mg capsules) was conducted in three groups of patients with renal impairment (uremia: n=7; hemodialysis: n=7; and continuous ambulatory peritoneal dialysis: n=5). In uremic subjects with a mean creatinine clearance of 13 ml/min. × 1.73 m2, the exposure, based on AUC, was slightly reduced compared with normal population parameters. This study did not demonstrate any significant effect of hemodialysis or continuous ambulatory peritoneal dialysis on the pharmacokinetics of Itrac 3 (Tmax, Cmax, and AUC0-8h). Plasma concentration-versus-time profiles showed wide intersubject variation in all three groups. After a single intravenous dose, the mean terminal half-lives of Itrac 3 in patients with mild (defined in this study as CrCl 50-79 ml/min), moderate (defined in this study as CrCl 20-49 ml/min), and severe renal impairment (defined in this study as CrCl <20 ml/min) were similar to that in healthy subjects (range of means 42-49 hours vs 48 hours in renally impaired patients and healthy subjects, respectively). Overall exposure to Itrac 3, based on AUC, was decreased in patients with moderate and severe renal impairment by approximately 30% and 40%, respectively, as compared with subjects with normal renal function. Data are not available in renally impaired patients during long-term use of Itrac 3. Dialysis has no effect on the half-life or clearance of Itrac 3 or hydroxy-Itrac 3. Paediatric Population: Two pharmacokinetic studies have been conducted in neutropenic children aged 6 months to 14 years in which Itrac 3 oral solution was administered 5 mg/kg once or twice daily. The exposure to Itrac 3 was somewhat higher in older children (6 to 14 years) compared to younger children. In all children, effective plasma concentrations of Itrac 3 were reached within 3 to 5 days after initiation of treatment and maintained throughout treatment. Hydroxypropyl-ß-Cyclodextrin The oral bioavailability of hydroxypropyl-β-cyclodextrin given as a solubilizer of Itrac 3 in oral solution is on average lower than 0.5% and is similar to that of hydroxypropyl-β-cyclodextrin alone. This low oral bioavailability of hydroxypropyl-β-cyclodextrin is not modified by the presence of food and is similar after single and repeated administrations. 5.3 Preclinical safety dataItrac 3 Nonclinical data on Itrac 3 revealed no indications for genotoxicity, primary carcinogenicity or impairment of fertility. At high doses, effects were observed in the adrenal cortex, liver and the mononuclear phagocyte system but appear to have a low relevance for the proposed clinical use. Itrac 3 was found to cause a dose-related increase in maternal toxicity, embryotoxicity and teratogenicity in rats and mice at high doses. A global lower bone mineral density was observed in juvenile dogs after chronic Itrac 3 administration, and in rats, a decreased bone plate activity, thinning of the zona compacta of the large bones, and an increased bone fragility was observed. Hydroxypropyl-β-cyclodextrin Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity, genotoxicity, and toxicity to reproduction and development. In a rat carcinogenicity study hydroxypropyl-β-cyclodextrin produced adenocarcinomas in the large intestine and exocrine pancreatic adenocarcinomas. These findings were not observed in a similar mouse carcinogenicity study. The clinical relevance of the large intestine adenocarcinomas is low and the mechanism of exocrine pancreatic adenocarcinomas induction not considered relevant to humans. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Nonclinical data on itraconazole revealed no indications for gene toxicity, primary carcinogenicity or impairment of fertility. At high doses, effects were observed in the adrenal cortex, liver and the mononuclear phagocyte system but appear to have a low relevance for the proposed clinical use. Itraconazole was found to cause a dose-related increase in maternal toxicity, embryotoxicity and teratogenicity in rats and mice at high doses. A global lower bone mineral density was observed in juvenile dogs after chronic itraconazole administration, and in rats, a decreased bone plate activity, thinning of the zona compacta of the large bones, and an increased bone fragility was observed.
Itrac 3 oral solution is indicated:
- For the treatment of oral and/or oesophageal candidosis in HIV-positive or other immunocompromised patients.
- As prophylaxis of deep fungal infections anticipated to be susceptible to Itrac 3, when standard therapy is considered inappropriate, in patients with haematological malignancy or undergoing bone marrow transplant, and who are expected to become neutropenic (i.e. < 500 cells/µl). At present there are insufficient clinical efficacy data in the prevention of aspergillosis.
Itrac 3 oral solution is indicated for use in adults.
Consideration should be given to national and/or local guidance regarding the appropriate use of antifungal agents.
1. Vulvovaginal candidosis.
2. Pityriasis versicolor.
3. Dermatophytoses caused by organisms susceptible to itraconazole (Trichophyton spp., Microsporum spp., Epidermophyton floccosum) e.g. tinea pedis, tinea cruris, tinea corporis, tinea manuum.
4. Oropharyngeal candidosis.
5. Onychomycosis caused by dermatophytes and/or yeasts.
6. The treatment of histoplasmosis.
7. Itrac 3 is indicated in the following systemic fungal conditions when first-line systemic anti-fungal therapy is inappropriate or has proved ineffective. This may be due to underlying pathology, insensitivity of the pathogen or drug toxicity.
| - Treatment of aspergillosis and candidosis | |
| - Treatment of cryptococcosis (including cryptococcal meningitis): in immunocompromised patients with cryptococcosis and in all patients with cryptococcosis of the central nervous system. | |
| - Maintenance therapy in AIDS patients to prevent relapse of underlying fungal infection. |
Itrac 3 is also indicated in the prevention of fungal infection during prolonged neutropenia when standard therapy is considered inappropriate.
Pharmacotherapeutic group: Antimycotic for systemic use, triazole derivative.
ATC code: J02A C02
Mode of action
Itrac 3 inhibits fungal 14α-demethylase, resulting in a depletion of ergosterol and disruption of membrane synthesis by fungi.
PK/PD relationship
The PK/PD relationship for Itrac 3, and for triazoles in general, is poorly understood and is complicated by limited understanding of antifungal pharmacokinetics.
Mechanism(s) of resistance
Resistance of fungi to azoles appears to develop slowly and is often the result of several genetic mutations. Mechanisms that have been described are
- Over-expression of ERG11, the gene that encodes 14-alpha-demethylase (the target enzyme)
- Point mutations in ERG11 that lead to decreased affinity of 14-alpha-demethylase for Itrac 3
- Drug-transporter over-expression resulting in increased efflux of Itrac 3 from fungal cells (i.e., removal of Itrac 3 from its target)
- Cross-resistance. Cross-resistance amongst members of the azole class of drugs has been observed within Candida species though resistance to one member of the class does not necessarily confer resistance to other azoles.
Breakpoints
Breakpoints for candida species are in preparation.
| Aspergillus Species1 | MIC breakpoint (mg/L) | |
| ≤ S (Susceptible) | >R (Resistant) | |
| Aspergillus flavus | 1 | 2 |
| Aspergillus fumigatus | 1 | 2 |
| Aspergillus nidulans | 1 | 2 |
| Aspergillus niger | Insufficient evidence | |
| Aspergillus terreus | Insufficient evidence | |
| Non species related breakpoints2 | Insufficient evidence | |
| 1monitoring of Itrac 3 trough concentrations in patients treated for fungal infection is recommended 2 The MIC values for isolates of A.niger and A.versicolor are in general higher than those for A.fumigatus. Whether this translates into a poorer clinical response is unknown | ||
The prevalence of acquired resistance may vary geographically and with time for selected species, and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.
The in vitro susceptibility of fungi to Itrac 3 depends on the inoculum size, incubation temperature, growth phase of the fungi, and the culture medium used. For these reasons, the minimum inhibitory concentration of Itrac 3 may vary widely. Susceptibility in the table below is based on MIC90 < 1 mg Itrac 3/L. There is no correlation between in vitro susceptibility and clinical efficacy.
| Commonly susceptible species |
| Aspergillus spp.2 |
| Blastomyces dermatitidis1 |
| Candida albicans |
| Candida parapsilosis |
| Cladosporium spp. |
| Coccidioides immitis1 |
| Cryptococcus neoformans |
| Epidermophyton floccosum |
| Fonsecaea spp. 1 |
| Geotrichum spp. |
| Histoplasma spp. |
| Malassezia (formerly Pityrosporum) spp. |
| Microsporum spp. |
| Paracoccidioides brasiliensis1 |
| Penicillium marneffei1 |
| Pseudallescheria boydii |
| Sporothrix schenckii |
| Trichophyton spp. |
| Trichosporon spp. |
| Species for which acquired resistance may be a problem |
| Candida glabrata3 |
| Candida krusei |
| Candida tropicalis3 |
| Inherently resistant organisms |
| Absidia spp. |
| Fusarium spp. |
| Mucor spp. |
| Rhizomucor spp. |
| Rhizopus spp. |
| Scedosporium proliferans |
| Scopulariopsis spp. |
1 These organisms may be encountered in patients who have returned from travel outside Europe.
2 Itrac 3-resistant strains of Aspergillus fumigatus have been reported.
3 Natural intermediate susceptibility.
Paediatric Population
The tolerability and safety of Itrac 3 oral solution was studied in the prophylaxis of fungal infections in 103 neutropenic paediatric patients aged 0 to14 years (median 5 years) in an open-label uncontrolled phase III clinical study. Most patients (78%) were undergoing allogenic bone marrow transplantation for haematological malignancies. All patients received 5 mg/kg/day of Itrac 3 oral solution as a single or divided dose. Due to the design of the study, no formal conclusion with regard to efficacy could be derived. The most common adverse events considered definitely or possibly related to Itrac 3 were vomiting, abnormal liver function, and abdominal pain.
Pharmacotherapeutic classification: (Antimycotics for systemic use, triazole derivatives).
ATC code: J02A C02
Itraconazole, a triazole derivative, has a broad spectrum of activity.
In vitro studies have demonstrated that itraconazole impairs the synthesis of ergosterol in fungal cells. Ergosterol is a vital cell membrane component in fungi. Impairment of its synthesis ultimately results in an antifungal effect.
For itraconazole, breakpoints have only been established for Candida spp. from superficial mycotic infections (CLSI M27-A2, breakpoints have not been established for EUCAST methodology). The CLSI breakpoints are as follows: susceptible ≤0.125; susceptible, dose-dependent 0.25-0.5 and resistant > 1μg/mL. Interpretive breakpoints have not been established for the filamentous fungi.
In vitro studies demonstrate that itraconazole inhibits the growth of a broad range of fungi pathogenic for humans at concentrations usually ≤ 1 µg/ml. These include:
dermatophytes (Trichophyton spp., Microsporum spp., Epidermophyton floccosum); yeasts (Candida spp., including C. albicans, C. tropicalis, C. parapsilosis and C. krusei, Cryptococcus neoformans, Malassezia spp., Trichosporon spp., Geotrichum spp.); Aspergillus spp.; Histoplasma spp., including H. capsulatum; Paracoccidioides brasiliensis; Sporothrix schenckii; Fonsecaea spp.; Cladosporium spp.; Blastomyces dermatitidis; Coccidiodes immitis; Pseudallescheria boydii; Penicillium marneffei; and various other yeasts and fungi.
Candida krusei, Candida glabrata and Candida tropicalis are generally the least susceptible Candida species, with some isolates showing unequivocal resistance to itraconazole in vitro.
The principal fungus types that are not inhibited by itraconazole are Zygomycetes (e.g. Rhizopus spp., Rhizomucor spp., Mucor spp. and Absidia spp.), Fusarium spp., Scedosporium proliferans and Scopulariopsis spp.
Azole resistance appears to develop slowly and is often the result of several genetic mutations. Mechanisms that have been described are overexpression of ERG11, which encodes the target enzyme 14α-demethylase, point mutations in ERG11 that lead to decreased target affinity and/or transporter overexpression resulting in increased efflux. Cross resistance between members of the azole class has been observed within Candida spp., although resistance to one member of the class does not necessarily confer resistance to other azoles. Itraconazole-resistant strains of Aspergillus fumigatus have been reported.
Use in patients with renal impairment
Limited data are available on the use of oral Itrac 3 in patients with renal impairment. Caution should be exercised when this drug is administered in this patient population.
4.3 ContraindicationsItrac 3 oral solution is contraindicated in patients with a known hypersensitivity to Itrac 3 or to any of the excipients.
Co-administration of the following drugs is contraindicated with Itrac 3 oral solution (see also 4.5 Interaction with other medicinal products and other forms of interaction):
- CYP3A4 metabolised substrates that can prolong the QT-interval e.g., astemizole, bepridil, cisapride, dofetilide, levacetylmethadol (levomethadyl), mizolastine, pimozide, quinidine, sertindole and terfenadine are contraindicated with Itrac 3 oral solution.).
4.4 Special warnings and precautions for useCross-hypersensitivity
There is no information regarding cross hypersensitivity between Itrac 3 and other azole antifungal agents. Caution should be used in prescribing Itrac 3 Oral Solution to patients with hypersensitivity to other azoles.
Cardiac effects
In a healthy volunteer study with Itrac 3 IV, a transient asymptomatic decrease of the left ventricular ejection fraction was observed.
Itrac 3 has been shown to have a negative inotropic effect and has been associated with reports of congestive heart failure. Interaction with other medicinal products).
Hepatic effects
Very rare cases of serious hepatotoxicity, including some cases of fatal acute liver failure, have occurred with the use of Itrac 3. Some of these cases involved patients with no pre-existing liver disease. Some of these cases have been observed within the first month of treatment, including some within the first week. Liver function monitoring should be considered in patients receiving Itrac 3 treatment. Patients should be instructed to promptly report to their physician signs and symptoms suggestive of hepatitis such as anorexia, nausea, vomiting, fatigue, abdominal pain or dark urine. In these patients treatment should be stopped immediately and liver function testing should be conducted. Most cases of serious hepatotoxicity involved patients who had pre-existing liver disease, were treated for systemic indications, had significant other medical conditions and/or were taking other hepatotoxic drugs. In patients with raised liver enzymes or active liver disease, or who have experienced liver toxicity with other drugs, treatment should not be started unless the expected benefit exceeds the risk of hepatic injury. In patients with impaired hepatic function liver enzyme should be carefully monitored when taking Itrac 3.
Use in children
Since clinical data on the use of Itrac 3 oral solution in paediatric patients is limited, its use in children is not recommended unless the potential benefit outweighs the potential risks.
Use in elderly
Since clinical data on the use of Itrac 3 oral solution in elderly patients is limited, it is advised to use Itrac 3 oral solution in these patients only if the potential benefit outweighs the potential risks.
Hepatic impairment
Limited data are available on the use of oral Itrac 3 in patients with hepatic impairment. Caution should be exercised when the drug is administered in this patient population. (See 5.2 Pharmacokinetic properties, Special populations, Hepatic impairment)
Renal impairment
Limited data are available on the use of oral Itrac 3 in patients with renal impairment. Caution should be exercised when this drug is administered in this patient population.
Prophylaxis in neutropenic patients
In clinical trials diarrhoea was the most frequent adverse event. This disturbance of the gastrointestinal tract may result in impaired absorption and may alter the microbiological flora potentially favouring fungal colonisation. Consideration should be given to discontinuing Itrac 3 oral solution in these circumstances.
Treatment of severely neutropenic patients
Itrac 3 oral solution as treatment for oral and/or esophageal candidosis was not investigated in severely neutropenic patients. Due to the pharmacokinetic properties (See 5.2 Pharmacokinetic properties), Itrac 3 oral solution is not recommended for initiation of treatment in patients at immediate risk of systemic candidosis.
Hearing Loss
Transient or permanent hearing loss has been reported in patients receiving treatment with Itrac 3. Several of these reports included concurrent administration of quinidine which is contraindicated. The hearing loss usually resolves when treatment is stopped, but can persist in some patients.
Neuropathy
If neuropathy occurs that may be attributable to Itrac 3 oral solution, the treatment should be discontinued.
Cross-resistance
In systemic candidosis, if fluconazole-resistant strains of Candida species are suspected, it cannot be assumed that these are sensitive to Itrac 3, hence their sensitivity should be tested before the start of Itrac 3 therapy
Interaction potential
Itrac 3 Oral Solution has a potential for clinically important drug interactions.
Itrac 3 should not be used within 2 weeks after discontinuation of treatment with CYP 3A4 inducing agents (rifampicin, rifabutin, phenobarbital, phenytoin, carbamazepine, Hypericum perforatum (St. John´s wort)). The use of Itrac 3 with these drugs may lead to subtherapeutic plasma levels of Itrac 3 and thus treatment failure.
Itrac 3 oral solution contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine. Also contains ethanol less than 100mg per dose.
4.5 Interaction with other medicinal products and other forms of interaction4.5.1. Drugs affecting the metabolism of Itrac 3:
Itrac 3 is mainly metabolised through the cytochrome CYP3A4. Interaction studies have been performed with rifampicin, rifabutin and phenytoin, which are potent enzyme inducers of CYP3A4. Since the bioavailability of Itrac 3 and hydroxy-Itrac 3 was decreased in these studies to such an extent that efficacy may be largely reduced, the combination of Itrac 3 with these potent enzyme inducers is not recommended. No formal study data are available for other enzyme inducers, such as carbamazepine, Hypericum perforatum (St John's Wort), phenobarbital and isoniazid, but similar effects should be anticipated.
Potent inhibitors of this enzyme such as ritonavir, indinavir, clarithromycin and erythromycin may increase the bioavailability of Itrac 3.
4.5.2. Effect of Itrac 3 on the metabolism of other drugs:
4.5.2.1 Itrac 3 can inhibit the metabolism of drugs metabolised by the cytochrome 3A family. Pharmacokinetic Properties). This should be taken into account when the inhibitory effect of Itrac 3 on co-medicated drugs is considered.
The following drugs are contraindicated with Itrac 3:
- Astemizole, bepridil, cisapride, dofetilide, levacetylmethadol (levomethadyl), mizolastine, pimozide, quinidine, sertindole and terfenadine are contraindicated with Itrac 3 oral solution since co-administration may result in increased plasma concentrations of these substrates, which can lead to QT prolongation and rare occurrences of torsade de pointes.
- CYP3A4 metabolized HMG-CoA reductase inhibitors such as atorvastatin, lovastatin and simvastatin.
- Triazolam and oral midazolam.
- Ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine).
- Eletriptan
- Nisoldipine
Caution should be exercised when co-administering Itrac 3 with calcium channel blockers due to an increased risk of congestive heart failure. In addition to possible pharmacokinetic interactions involving the drug metabolising enzyme CYP3A4, calcium channel blockers can have negative inotropic effects which may be additive to those of Itrac 3.
The following drugs should be used with caution, and their plasma concentrations, effects or side effects should be monitored. Their dosage, if co-administered with Itrac 3, should be reduced if necessary:
- Oral anticoagulants;
- HIV protease inhibitors such as ritonavir, indinavir, saquinavir;
- Certain antineoplastic agents such as busulfan, docetaxel, trimetrexate and vinca alkaloids;
- CYP3A4 metabolised calcium channel blockers such as dihydropyridines and verapamil;
- Certain immunosuppressive agents: ciclosporin, tacrolimus, rapamycin (also known as sirolimus);
- Certain glucocorticosteroids such as budesonide, dexamethasone, fluticasone and methylprednisolone;
- Digoxin (via inhibition of P-glycoprotein)
- Others: cilostazol, disopyramide, carbamazepine, buspirone, alfentanil, alprazolam, brotizolam, midazolam IV, rifabutin, ebastine, repaglinide, fentanyl, halofantrine, reboxetine and loperamide. The importance of the concentration increase and the clinical relevance of these changes during the co-administration with Itrac 3 remain to be established.
4.5.2.2 No interaction of Itrac 3 with zidovudine (AZT) and fluvastatin has been observed.
No inducing effects of Itrac 3 on the metabolism of ethinyloestradiol and norethisterone were observed.
4.5.3. Effect on protein binding:
In vitro studies have shown that there are no interactions on the plasma protein binding between Itrac 3 and imipramine, propranolol, diazepam, cimetidine, indometacin, tolbutamide and sulfamethazine.
4.6 Fertility, pregnancy and lactationPregnancy:
Itrac 3 oral solution must not be used during pregnancy except for life-threatening cases where the potential benefit to the mother outweighs the potential harm to the foetus (see 4.3 Contraindications).
In animal studies Itrac 3 has shown reproduction toxicity (see
General pharmacokinetic characteristics
Peak plasma concentrations of itraconazole are reached within 2 to 5 hours following oral administration. As a consequence of non-linear pharmacokinetics, itraconazole accumulates in plasma during multiple dosing. Steady-state concentrations are generally reached within about 15 days, with Cmax values of 0.5 µg/ml, 1.1 µg/ml and 2.0 µg/ml after oral administration of 100 mg once daily, 200 mg once daily and 200 mg b.i.d., respectively. The terminal half-life of itraconazole generally ranges from 16 to 28 hours after single dose and increases to 34 to 42 hours with repeated dosing. Once treatment is stopped, itraconazole plasma concentrations decrease to an almost undetectable concentration within 7 to 14 days, depending on the dose and duration of treatment. Itraconazole mean total plasma clearance following intravenous administration is 278 ml/min. Itraconazole clearance decreases at higher doses due to saturable hepatic metabolism.
Absorption
Interactions).Special Warnings and Precautions for use.)Distribution
Most of the itraconazole in plasma is bound to protein (99.8%) with albumin being the main binding component (99.6% for the hydroxy- metabolite). It has also a marked affinity for lipids. Only 0.2% of the itraconazole in plasma is present as free drug. Itraconazole is distributed in a large apparent volume in the body (> 700 L), suggesting its extensive distribution into tissues: Concentrations in lung, kidney, liver, bone, stomach, spleen and muscle were found to be two to three times higher than corresponding concentrations in plasma, and the uptake into keratinous tissues, skin in particular, is up to four times higher than in plasma. Concentrations in the cerebrospinal fluid are much lower than in plasma, but efficacy has been demonstrated against infections present in the cerebrospinal fluid.
Metabolism
Itraconazole is extensively metabolised by the liver into a large number of metabolites. In vitro studies have shown that CYP3A4 is the major enzyme involved in the metabolism of itraconazole. The main metabolite is hydroxy-itraconazole, which has in vitro antifungal activity comparable to Itraconazole; trough plasma concentrations of the hydroxy-itraconazole are about twice those of itraconazole.
Excretion
Itraconazole is excreted mainly as inactive metabolites in urine (35%) and faeces (54%) within one week of an oral solution dose. Renal excretion of itraconazole and the active metabolite hydroxy-itraconazole account for less than 1% of an intravenous dose.Based on an oral radiolabelled dose, faecal excretion of unchanged drug varies between 3 - 18% of the dose.
Special Populations
Special warnings and precautions for use.)Paediatrics:
Limited pharmacokinetic data are available on the use of itraconazole in the paediatric population. Clinical pharmacokinetic studies in children and adolescents aged between 5 months and 17 years were performed with itraconazole capsules, oral solution or intravenous formulation. Individual doses with the capsule and oral solution formulation ranged from 1.5 to 12.5 mg/kg/day, given as once-daily or twice-daily administration. The intravenous formulation was given either as a 2.5 mg/kg single infusion, or a 2.5 mg/kg infusion given once daily or twice daily. For the same daily dose, twice daily dosing compared to single daily dosing yielded peak and trough concentrations comparable to adult single daily dosing. No significant age dependence was observed for itraconazole AUC and total body clearance, while weak associations between age and itraconazole distribution volume, Cmax and terminal elimination rate were noted. Itraconazole apparent clearance and distribution volume seemed to be related to weight.
Cross-hypersensitivity
There is no information regarding cross hypersensitivity between Itrac 3 and other azole antifungal agents. Caution should be used in prescribing Itrac 3 Oral Solution to patients with hypersensitivity to other azoles.
Cardiac effects
In a healthy volunteer study with Itrac 3 IV, a transient asymptomatic decrease of the left ventricular ejection fraction was observed.
Itrac 3 has been shown to have a negative inotropic effect and has been associated with reports of congestive heart failure. Interaction with other medicinal products).
Hepatic effects
Very rare cases of serious hepatotoxicity, including some cases of fatal acute liver failure, have occurred with the use of Itrac 3. Some of these cases involved patients with no pre-existing liver disease. Some of these cases have been observed within the first month of treatment, including some within the first week. Liver function monitoring should be considered in patients receiving Itrac 3 treatment. Patients should be instructed to promptly report to their physician signs and symptoms suggestive of hepatitis such as anorexia, nausea, vomiting, fatigue, abdominal pain or dark urine. In these patients treatment should be stopped immediately and liver function testing should be conducted. Most cases of serious hepatotoxicity involved patients who had pre-existing liver disease, were treated for systemic indications, had significant other medical conditions and/or were taking other hepatotoxic drugs. In patients with raised liver enzymes or active liver disease, or who have experienced liver toxicity with other drugs, treatment should not be started unless the expected benefit exceeds the risk of hepatic injury. In patients with impaired hepatic function liver enzyme should be carefully monitored when taking Itrac 3.
Use in children
Since clinical data on the use of Itrac 3 oral solution in paediatric patients is limited, its use in children is not recommended unless the potential benefit outweighs the potential risks.
Use in elderly
Since clinical data on the use of Itrac 3 oral solution in elderly patients is limited, it is advised to use Itrac 3 oral solution in these patients only if the potential benefit outweighs the potential risks.
Hepatic impairment
Limited data are available on the use of oral Itrac 3 in patients with hepatic impairment. Caution should be exercised when the drug is administered in this patient population. (See 5.2 Pharmacokinetic properties, Special populations, Hepatic impairment)
Renal impairment
Limited data are available on the use of oral Itrac 3 in patients with renal impairment. Caution should be exercised when this drug is administered in this patient population.
Prophylaxis in neutropenic patients
In clinical trials diarrhoea was the most frequent adverse event. This disturbance of the gastrointestinal tract may result in impaired absorption and may alter the microbiological flora potentially favouring fungal colonisation. Consideration should be given to discontinuing Itrac 3 oral solution in these circumstances.
Treatment of severely neutropenic patients
Itrac 3 oral solution as treatment for oral and/or esophageal candidosis was not investigated in severely neutropenic patients. Due to the pharmacokinetic properties (See 5.2 Pharmacokinetic properties), Itrac 3 oral solution is not recommended for initiation of treatment in patients at immediate risk of systemic candidosis.
Hearing Loss
Transient or permanent hearing loss has been reported in patients receiving treatment with Itrac 3. Several of these reports included concurrent administration of quinidine which is contraindicated. The hearing loss usually resolves when treatment is stopped, but can persist in some patients.
Neuropathy
If neuropathy occurs that may be attributable to Itrac 3 oral solution, the treatment should be discontinued.
Cross-resistance
In systemic candidosis, if fluconazole-resistant strains of Candida species are suspected, it cannot be assumed that these are sensitive to Itrac 3, hence their sensitivity should be tested before the start of Itrac 3 therapy
Interaction potential
Itrac 3 Oral Solution has a potential for clinically important drug interactions.
Itrac 3 should not be used within 2 weeks after discontinuation of treatment with CYP 3A4 inducing agents (rifampicin, rifabutin, phenobarbital, phenytoin, carbamazepine, Hypericum perforatum (St. John´s wort)). The use of Itrac 3 with these drugs may lead to subtherapeutic plasma levels of Itrac 3 and thus treatment failure.
Itrac 3 oral solution contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine. Also contains ethanol less than 100mg per dose.
.Elderly
Clinical data on the use of Itrac 3 Capsules in elderly patients are limited.Special warnings and precautions for use.
Renal impairment
Limited data are available on the use of oral itraconazole in patients with renal impairment. The exposure of itraconazole may be lower in some patients with renal insufficiency. Caution should be exercised when this drug is administered in this patient population and adjusting the dose may be considered.
Hepatic impairment
Limited data are available on the use of oral itraconazole in patients with hepatic impairment.Pharmacokinetic properties - Special Populations, Hepatic impairment)
4.3 Contraindications Fertility, pregnancy and lactation)- Women of childbearing potential taking Itrac 3 Capsules should use contraceptive precautions. Effective contraception should be continued until the menstrual period following the end of Itrac 3 Capsules therapy.
4.4 Special warnings and precautions for useCross-hypersensitivity
There is no information regarding cross hypersensitivity between itraconazole and other azole antifungal agents. Caution should be used in prescribing Itrac 3 Capsules to patients with hypersensitivity to other azoles.
Cardiac effects
In a healthy volunteer study with Itrac 3® IV, a transient asymptomatic decrease of the left ventricular ejection fraction was observed; this resolved before the next infusion.Interaction with other medicinal products and other forms of interaction) due to an increased risk of congestive heart failure.
Hepatic effects
Very rare cases of serious hepatotoxicity, including some cases of fatal acute liver failure, have occurred with the use of Itrac 3 Capsules.Pharmacokinetic properties - Special Populations, Hepatic impairment.)
Reduced gastric acidity
Absorption of itraconazole from Itrac 3 Capsules is impaired when gastric acidity is reduced. Interaction with other medicinal products and other forms of interaction.
Paediatrics
Clinical data on the use of Itrac 3 Capsules in paediatric patients is limited. The use of Itrac 3 Capsules in paediatric patients is not recommended unless it is determined that the potential benefit outweighs the potential risks.
Elderly
Clinical data on the use of Itrac 3 Capsules in elderly patients are limited. It is advised to use Itrac 3 Capsules in these patients only if it is determined that the potential benefit outweighs the potential risks. In general, it is recommended that the dose selection for an elderly patient should be taken into consideration, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Renal impairment
Limited data are available on the use of oral itraconazole in patients with renal impairment. The exposure of itraconazole may be lower in some patients with renal insufficiency. Caution should be exercised when this drug is administered in this patient population and adjusting the dose may be considered.
Hearing Loss
Transient or permanent hearing loss has been reported in patients receiving treatment with itraconazole. Interaction with other medicinal products and other forms of interaction). The hearing loss usually resolves when treatment is stopped, but can persist in some patients.
Immunocompromised patients
In some immunocompromised patients (e.g., neutropenic, AIDS or organ transplant patients), the oral bioavailability of Itrac 3 Capsules may be decreased.
Patients with immediately life-threatening systemic fungal infections
Pharmacokinetic properties), Itrac 3 Capsules are not recommended for initiation of treatment in patients with immediately life-threatening systemic fungal infections.Patients with AIDS
In patients with AIDS having received treatment for a systemic fungal infection such as sporotrichosis, blastomycosis, histoplasmosis or cryptococcosis (meningeal or non-meningeal) and who are considered at risk for relapse, the treating physician should evaluate the need for a maintenance treatment.
Neuropathy
If neuropathy occurs which may be attributable to Itrac 3 Capsules, the treatment should be discontinued.
Disorders of Carbohydrate Metabolism
Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
Cross-resistance
In systemic candidosis, if fluconazole-resistant strains of Candida species are suspected, it cannot be assumed that these are sensitive to itraconazole, hence their sensitivity should be tested before the start of Itrac 3 therapy.
Interchangeability
It is not recommended that Itrac 3 Capsules and Itrac 3 Oral Solution be used interchangeably. This is because drug exposure is greater with the oral solution than with the capsules when the same dose of drug is given.
Interaction Potential
Coadministration of specific drugs with itraconazole may result in changes in efficacy of itraconazole and/or the coadministered drug, life-threatening effects and/or sudden death.Interaction with other medicinal products and other forms of interaction.
No studies on the effects on the ability to drive and use machines have been performed.
When driving vehicles and operating machinery the possibility of adverse reactions such as dizziness, visual disturbances and hearing loss , which may occur in some instances, must be taken into account.
No studies on the effects on the ability to drive and use machines have been performed. When driving vehicles and operating machinery the possibility of adverse reactions such as dizziness, visual disturbances and hearing loss , which may occur in some instances, must be taken into account.
For optimal absorption, Itrac 3 oral solution should be taken without food (patients are advised to refrain from eating for at least 1 hour after intake).
A graduated measuring cup is provided to measure out the correct dose.
For the treatment of oral and/or oesophageal candidosis, the liquid should be swished around the oral cavity (approx. 20 seconds) and swallowed. There should be no rinsing after swallowing.
Treatment of oral and/or oesophageal candidosis: 200 mg (20 ml) per day in two intakes, or alternatively in one intake, for 1 week. If there is no response after 1 week, treatment should be continued for another week.
Treatment of fluconazole resistant oral and/or oesophageal candidosis: 100 to 200 mg (10-20 ml) twice daily for 2 weeks. If there is no response after 2 weeks, treatment should be continued for another 2 weeks. The 400mg daily dose should not be used for longer than 14 days if there are no signs of improvement.
Prophylaxis of fungal infections: 5 mg/kg per day administered in two intakes. In clinical trials, prophylaxis treatment was started immediately prior to the cytostatic treatment and generally one week before transplant procedure. Almost all proven deep fungal infections occurred in patients reaching neutrophil counts below 100 cells/µl. Treatment was continued until recovery of neutrophils (i.e. > 1000 cells/µl).
Pharmacokinetic parameters from clinical studies in neutropenic patients demonstrate considerable intersubject variation. Blood level monitoring should be considered particularly in the presence of gastrointestinal damage, diarrhoea and during prolonged courses of Itrac 3 oral solution.
Use in children
Since clinical data on the use of Itrac 3 oral solution in paediatric patients is limited, its use in children is not recommended unless the potential benefit outweighs the potential risks.
Prophylaxis of fungal infections: there are no efficacy data available in neutropenic children. Limited safety experience is available with a dose of 5 mg/kg per day administered in two intakes.
Use in elderly
Since clinical data on the use of Itrac 3 oral solution in elderly patients is limited, it is advised to use Itrac 3 oral solution in these patients only if the potential benefit outweighs the potential risks.
Use in patients with hepatic impairment
Limited data are available on the use of oral Itrac 3 in patients with hepatic impairment. Caution should be exercised when this drug is administered in this patient population. (See 5.2 Pharmacokinetic properties, Special populations, Hepatic impairment)
Use in patients with renal impairment
Limited data are available on the use of oral Itrac 3 in patients with renal impairment. Caution should be exercised when this drug is administered in this patient population.
Itrac 3 is for oral administration and must be taken immediately after a meal for maximal absorption. The capsules must be swallowed whole.
Treatment schedules in adults for each indication are as follows:
| Indication | Dose | Remarks |
| Vulvovaginal candidosis | 200 mg twice daily for 1 day | |
| Pityriasis versicolor | 200 mg once daily for 7 days | |
| Tinea corporis, tinea cruris | 100 mg once daily for 15 days or 200 mg once daily for 7 days | |
| Tinea pedis, tinea manuum | 100 mg once daily for 30 days | |
| Oropharyngeal candidosis | 100 mg once daily for 15 days | Increase dose to 200 mg once daily for 15 days in AIDS or neutropenic patients because of impaired absorption in these groups. |
| Onychomycosis (toenails with or without fingernail involvement) | 200 mg once daily for 3 months |
For skin, vulvovaginal and oropharyngeal infections, optimal clinical and mycological effects are reached 1 - 4 weeks after cessation of treatment and for nail infections, 6 - 9 months after the cessation of treatment. This is because elimination of itraconazole from skin, nails and mucous membranes is slower than from plasma.
The length of treatment for systemic fungal infections should be dictated by the mycological and clinical response to therapy:
| Indication | Dose1 | Remarks |
| Aspergillosis | 200 mg once daily | Increase dose to 200 mg twice daily in case of invasive or disseminated disease |
| Candidosis | 100-200 mg once daily | Increase dose to 200 mg twice daily in case of invasive or disseminated disease |
| Non-meningeal Cryptococcosis | 200 mg once daily | |
| Cryptococcal meningitis | 200 mg twice daily | See 4.4. Special warnings and special precautions for use. |
| Histoplasmosis | 200 mg once daily - 200 mg twice daily | |
| Maintenance in AIDS | 200 mg once daily | See note on impaired absorption below |
| Prophylaxis in neutropenia | 200 mg once daily | See note on impaired absorption below |
1 The duration of treatment should be adjusted depending on the clinical response.
Impaired absorption in AIDS and neutropenic patients may lead to low itraconazole blood levels and lack of efficacy. In such cases, blood level monitoring and if necessary, an increase in itraconazole dose to 200 mg twice daily, is indicated.
Special populations
Paediatrics
Clinical data on the use of Itrac 3 Capsules in paediatric patients are limited.Special warnings and precautions for use.
Elderly
Clinical data on the use of Itrac 3 Capsules in elderly patients are limited.Special warnings and precautions for use.
Renal impairment
Limited data are available on the use of oral itraconazole in patients with renal impairment. The exposure of itraconazole may be lower in some patients with renal insufficiency. Caution should be exercised when this drug is administered in this patient population and adjusting the dose may be considered.
Hepatic impairment
Limited data are available on the use of oral itraconazole in patients with hepatic impairment.Pharmacokinetic properties - Special Populations, Hepatic impairment)
Any unused product or waste material should be disposed of in accordance with local requirements.
No special requirements.
