1.  Vulvovaginal candidosis

2.  Pityriasis versicolor

3.  Dermatophytoses caused by organisms susceptible to itraconazole

4.  Oral candidosis

5.  Fungal keratitis

6.  Systemic mycoses

7.  Onychomycosis

TRACON® 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:

Short-Term Usage

 

Use in Children (below 12 years):

Clinical data on the use of  TRACON® capsules in paediatric patients are limited. TRACON® capsules should not be used in children unless the potential benefit outweighs the potential risks. (See Section 4.4)

Use in Elderly:

As for use in children

Use in patients with renal impairment:

Limited data are available on the use of oral itraconazole in patients with renal impairment. Caution should be exercised when this drug is administered in this patient population.

Use in patients with hepatic impairment:

Limited data are available on the use of oral itraconazole in patients with hepatic impairment. Caution should be exercised when this drug is administered in this patient population. (See Section 5.2).

TRACON® capsules are contra-indicated in patients with known hypersensitivity to itraconazole or to any of the excipients. Coadministration of a number of CYP3A4 substrates is contraindicated with TRACON® Capsules (see sections 4.4 and 4.5). These include: Analgesics; Anaesthetics Methadone Ergot alkaloids (e.g. dihydroergotamine, ergometrine, ergotamine, methylergometrine) Anti-bacterials for Systemic Use; Anti-mycobacterials; Antimycotics for Systemic Use Isavuconazole Anthelmintics; Antiprotozoals Halofantrine Antihistamines for Systemic Use Astemizole Mizolastine Terfenadine Antineoplastic Agents Irinotecan Antithrombotic Agents Dabigatran Ticagrelor Antivirals for Systemic Use Ombitasvir/Paritaprevir/Ritonavir (with or without Dasabuvir) Cardiovascular System (Agents Acting on the Renin-Angiotensin System; Antihypertensives; Beta Blocking Agents; Calcium Channel Blockers; Cardiac Therapy; Diuretics) Felodipine* Finerenone Aliskiren Dronedarone Nisoldipine Bepridil Eplerenone Quinidine Disopyramide Ivabradine Ranolazine Dofetilide Lercanidipine Sildenafil (pulmonary hypertension) Gastrointestinal Drugs, including Antidiarrheals, Intestinal Anti- inflammatory/Anti-infective Agents; Antiemetics and Antinauseants; Drugs for Constipation; Drugs for Functional Gastrointestinal Disorders Cisapride Domperidone Naloxegol Lipid Modifying Agents Lovastatin Lomitapide Simvastatin Immunosuppressants Voclosporin Psychoanaleptics; Psycholeptics (eg, antipsychotics, anxiolytics, and hypnotics) Lurasidone Pimozide Sertindole Midazolam (oral) Quetiapine Triazolam Urologicals Avanafil Darifenacin Solifenacin (in patients with severe renal impairment or moderate to severe hepatic impairment) Dapoxetine Fesoterodine (in patients with moderate or severe renal or hepatic impairment) Vardenafil (in patients older than 75 years) Miscellaneous Drugs and Other Substances Colchicine (in patients with renal or hepatic impairment) Eliglustat (in patients that are CYP2D6 poor metabolisers (PM), CYP2D6 intermediate metabolisers (IMs) or extensive metabolisers (EMs) that are taking a strong or moderate CYP2D6 inhibitor) *Based on clinical drug interaction information with itraconazole Increased plasma concentrations of these drugs, caused by coadministration with itraconazole, may increase or prolong both therapeutic and adverse effects to such an extent that a potentially serious situation may occur. For example, increased plasma concentrations of some of these drugs can lead to QT prolongation and ventricular tachyarrhythmias including occurrences of torsade de pointes, a potentially fatal arrhythmia. Specific examples are listed in section 4.5 Interaction with other medicinal products and other forms of interaction TRACON® capsules should not be administered to patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF except for the treatment of life-threatening or other serious infections. (See Section 4.4) TRACON® capsules must not be used during pregnancy (except for life-threatening cases). (See section 4.6). Women of childbearing potential taking TRACON® should use contraceptive precautions. Effective contraception should be continued until the menstrual period following the end of TRACON® therapy. Coadministration with venetoclax is contraindicated in patients with CLL/SLL during the dose initiation and ramp-up phase of venetoclax due to the potential for an increased risk of tumor lysis syndrome.

Cross-hypersensitivity

There is no information regarding cross-hypersensitivity between itraconazole and other azole antifungal agents. Caution should be used in prescribing TRACON® capsules to patients with hypersensitivity to other azoles.

Cardiac effects

In a healthy volunteer study with itraconazole IV, a transient asymptomatic decrease of the left ventricular ejection fraction was observed; this resolved before the next infusion. The clinical relevance of these findings to the oral formulations is unknown. Itraconazole has been shown to have a negative inotropic effect and itraconazole has been associated with reports of congestive heart failure. Heart failure was more frequently reported among spontaneous reports of 400 mg total daily dose than among those of lower total daily doses, suggesting that the risk of heart failure might increase with the total daily dose of itraconazole.

TRACON® should not be used in patients with congestive heart failure or with a history of congestive heart failure unless the benefit clearly outweighs the risk. This individual benefit/risk assessment should take into consideration factors such as the severity of the indication, the dosing regimen (e.g. total daily dose), and individual risk factors for congestive heart failure    

These risk factors include cardiac disease, such as ischaemic and valvular disease; significant pulmonary disease, such as chronic obstructive pulmonary disease; and renal failure and other oedematous disorders. Such patients should be informed of the signs and symptoms of congestive heart failure, should be treated with caution, and should be monitored for signs and symptoms of congestive heart failure during treatment; if such signs or symptoms do occur during treatment, TRACON® should be discontinued.

Calcium channel blockers can have negative inotropic effects which may be additive to those of itraconazole. In addition, itraconazole can inhibit the metabolism of calcium channel blockers. Therefore, caution should be used when co-administering itraconazole and calcium channel blockers due to an increased risk of CHF (see Section 4.5).

Hepatic effects

Very rare cases of serious hepatotoxicity, including some cases of fatal acute liver failure, have occurred with the use of TRACON®. Most of these cases 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. Some patients had no obvious risk factors for liver disease. Some of these cases were observed within the first month of treatment, including some within the first week. Liver function monitoring should be considered in patients receiving TRACON® 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. 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 such cases liver enzyme monitoring is necessary.

Reduced gastric acidity

Absorption of itraconazole from TRACON® capsules is impaired when gastric acidity is reduced. In patients also receiving acid neutralising medicines (eg aluminium hydroxide), these should be administered at least 2 hours after the intake of TRACON® capsules. In patients with achlorhydria such as certain AIDS patients and patients on acid secretion suppressors (eg H2-antagonists, proton pump inhibitors), it is advisable to administer TRACON® capsules with a cola beverage.

Use in children

Clinical data on the use of TRACON® capsules in paediatric patients is limited. TRACON® capsules should not be used in paediatric patients unless the potential benefit outweighs the potential risks.

Use in elderly

Clinical data on the use of TRACON® capsules in elderly patients is limited. TRACON® capsules should not be used in these patients unless the potential benefit outweighs the potential risks.

Hepatic impairment

Limited data are available on the use of oral itraconazole in patients with hepatic impairment. Caution should be exercised when the drug is administered in this patient population. (See Section 5.2)

Renal impairment

Limited data are available on the use of oral itraconazole in patients with renal impairment. Caution should be exercised when this drug is administered in this patient population. The oral bioavailability of itraconazole may be lower in patients with renal insufficiency. Dose adaptation may be considered.

Hearing Loss

Transient or permanent hearing loss has been reported in patients receiving treatment with itraconazole. Several of these reports included concurrent administration of quinidine which is contraindicated (see Section 4.3 Contraindications and 4.5 Interaction with other medicinal products and other forms of interaction, 3. Effect of itraconazole on the metabolism of other drugs). 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 TRACON® capsules may be decreased.

Patients with immediately life-threatening systemic fungal infections

Due to the pharmacokinetic properties (see section 5.2), TRACON® capsules are not recommended for initiation of treatment 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 and 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 that may be attributable to TRACON® 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 itraconazole therapy.

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. Drugs that are contraindicated, not recommended or recommended for use with caution in combination with itraconazole are listed in section 4.3 Contraindications and section 4.5 Interaction with other medicinal products and other forms of interaction.

Itraconazole is mainly metabolised through CYP3A4. Other substances that either share this metabolic pathway or modify CYP3A4 activity may influence the pharmacokinetics of itraconazole. Itraconazole is a strong CYP3A4 inhibitor and, a P-glycoprotein inhibitor and Breast Cancer Resistance Protein (BCRP) inhibitor.

Itraconazole may modify the pharmacokinetics of other substances that share this metabolic or these protein transporter pathways. Examples of drugs that may impact on the plasma concentration of itraconazole are presented by drug class in Table 1 below. Examples of drugs that may have their plasma concentrations impacted by itraconazole are presented in Table 2 below.

Due to the number of interactions, the potential changes in safety or efficacy of the interacting drugs are not included. Please refer to the prescribing information of the interacting drug for more information.

The interactions described in these tables are categorised as contraindicated, not recommended or to be used with caution with itraconazole taking into account the extent of the concentration increase and the safety profile of the interacting drug (see also sections 4.3 and 4.4 for further information). The interaction potential of the listed drugs was evaluated based on human pharmacokinetic studies with itraconazole, and/or human pharmacokinetic studies with other strong CYP3A4 inhibitors (e.g. ketoconazole) and/or in vitro data:

•  ‘Contraindicated’: Under no circumstances is the drug to be co-administered with itraconazole, and up to two weeks after discontinuation of treatment with itraconazole.

•  Not recommended’: The use of the drug should be avoided during and up to two weeks after discontinuation of treatment with itraconazole, unless the benefits outweigh the potentially increased risks of side effects. If co-administration cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged effects or side effects of the concomitantly administered drug is recommended, and its dosage be reduced or

• interrupted as deemed necessary. When appropriate, it is recommended that plasma concentrations of the co-administered drug be measured.

• ‘Use with caution’: Careful monitoring is recommended when the drug is co-administered with itraconazole. Upon co-administration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of the interacting drug, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations of the co-administered drug be measured.

The interactions listed in these tables have been characterised in studies that were performed with recommended doses of itraconazole. However, the extent of interaction may be dependent on the dose of itraconazole administered. A stronger interaction may occur at a higher dose or with a shorter dosing interval. Extrapolation of the findings with other dosing scenarios or different drugs should be done with caution.

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. In patients with hepatic cirrhosis or in subjects receiving CYP3A4 inhibitors, the decline in plasma concentrations may be even more gradual. This is particularly important when initiating therapy with drugs whose metabolism is affected by itraconazole. (see section 5.2).

 

 

 

 

 

 

 

 

 

 

 

* Based on clinical drug interaction information with itraconazole.

 

 

Pregnancy

TRACON® 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 section 4.3).

In animal studies itraconazole has shown reproduction toxicity (see section 5.3). There is limited information on the use of TRACON® during pregnancy. During post-

marketing experience, cases of congenital abnormalities have been reported. These cases  included skeletal, genitourinary tract, cardiovascular and ophthalmic malformations as well as chromosomal and multiple malformations. A causal relationship with TRACON® has not been established.

Epidemiological data on exposure to TRACON® 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 childbearing potential

Women of childbearing potential taking TRACON® capsules should use contraceptive precautions. Effective contraception should be continued until the menstrual period following the end of TRACON® therapy.

Lactation

A very small amount of itraconazole is excreted in human milk. The expected benefits of TRACON® therapy should be weighed against the risks of breast feeding. In case of doubt, the patient should not breast feed.

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 (see Section 4.8), which may occur in some instances, must be taken into account.

a)      Tabulated list of AE:

Undesirable effects listed below have been reported in clinical trials with itraconazole capsules and/or from spontaneous reports from post-marketing experience for all itraconazole formulations

In double-blind, controlled clinical trials involving 2104 itraconazole-treated patients in the treatment of dermatomycoses or onychomycosis, the most frequently reported adverse experiences in clinical trials were of gastrointestinal, dermatological, and hepatic 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 category, 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).

 

a)      Other special population:

Use in Children (below 12 years):

Clinical data on the use of TRACON® capsules in paediatric patients are limited. TRACON® capsules should not be used in children unless the potential benefit outweighs the potential risks. (See Section 4.4 )

Use in Elderly :

As for use in children

Use in patients with renal impairment:

Limited data are available on the use of oral itraconazole in patients with renal impairment. Caution should be exercised when this drug is administered in this patient population.

Use in patients with hepatic impairment:

Limited data are available on the use of oral itraconazole in patients with hepatic impairment. Caution should be exercised when this drug is administered in this patient population. (See Section 5.2).

To report any side effect (s): Saudi Arabia:

The National Pharmacovigilance Centre (NPC): • Fax: +966-11-205-7662 • Call NPC at +966-11-2038222, Ext 2317-2356-2340 • SFDA Call Center: 19999 • E-mail: npc.drug@sfda.gov.sa • Website: https://ade.sfda.gov.sa

 

Other GCC states and other countries:

Please contact to the relevant competent Authority.

 

 

No data are available.

In the event of an overdose, supportive measures should be employed. Within the first hour after ingestion gastric lavage may be performed. Activated charcoal may be given if  considered appropriate. Itraconazole cannot be removed by haemodialysis.

No specific antidote is available.

Pharmacotherapeutic classification

Antimycotic 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 >1 µg/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, Cryptococcus neoformans, Malassezia spp., Trichosporon spp., Geotrichum spp.); Aspergillus spp.; Histoplasma spp.; Paracoccidioides brasiliensis; Sporothrix schenckii; Fonsecaea spp.; Cladosporium spp.; Blastomyces dermatitidis; Coccidioides 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 spp. 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.

General pharmacokinetic characteristics:

The pharmacokinetics of itraconazole has been investigated in healthy subjects, special populations and patients after single and multiple dosing. In general, itraconazole is well absorbed. Peak plasma concentrations are reached within 2 to 5 hours following administration of the oral solution. Itraconazole undergoes extensive hepatic metabolism to give numerous metabolites. The main metabolite is hydroxy- itraconazole, with plasma concentrations about twice those of the unchanged drug. The terminal half-life of itraconazole is about 40 hours after repeated dosing. The pharmacokinetics of itraconazole is characterised by non-linearity and, consequently, shows accumulation in plasma after multiple dose administration. Steady-state concentrations are reached within 15 days, with Cmax values of about 2 μg/ml after oral administration of 200 mg once daily. Itraconazole clearance decreases at higher doses due to a saturable mechanism of its hepatic metabolism. Itraconazole is excreted as inactive metabolites in urine (~35%) and in faeces (~54%). Absorption:

Itraconazole is rapidly absorbed after administration of the oral solution. Peak plasma concentrations of the unchanged drug are reached within 2 to 5 hours following an oral dose. The observed absolute bioavailability of itraconazole under fed conditions is about 55% Oral bioavailability is maximal when the capsules are taken immediately after a full meal.

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. Brain to plasma ratios were about 1.

The uptake into keratinous tissues, skin in particular, is up to four times higher than in plasma.

Metabolism:

 

Itraconazole is extensively metabolised by the liver into a large number of metabolites. The main metabolite is hydroxy-itraconazole which has in vitro antifungal activity comparable to itraconazole. Plasma concentrations of the hydroxy-metabolite are about twice those of itraconazole.

As shown in in vitro studies, CYP 3A4 is the major enzyme that is involved in the metabolism of itraconazole.

Excretion:

Itraconazole is excreted as inactive metabolites to about 35% in urine within one week and to about 54% with faeces. Renal excretion of the parent drug accounts for less than 0.03% of the dose, whereas faecal excretion of unchanged drug varies between 3-18% of the dose.

As re-distribution of itraconazole from keratinous tissues appears to be negligible, elimination of itraconazole 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 itraconazole 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

Itraconazole is predominantly metabolised in the liver. A single oral dose (100 mg capsule) was administered to 12 patients with cirrhosis and six healthy control subjects; Cmax, AUC and terminal half-life of itraconazole were measured and compared between groups. Mean itraconazole Cmax was reduced significantly (by 47%) in patients with cirrhosis. Mean elimination half-life was prolonged compared to that found in subjects without hepatic impairment (37 vs. 16 hours, respectively). Overall exposure to itraconazole, based on AUC was similar in cirrhotic patients and in healthy subjects. Data are not available in cirrhotic patients during long-term use of itraconazole. (See sections 4.2 Posology and method of administration, and 4.4 Special warnings and special precautions for use.)

Renal impairment

Limited data are available on the use of oral itraconazole in patients with renal impairment. Caution should be exercised when the drug is administered in this patient population.

Itraconazole:

Itraconazole has been tested in a standard battery of non-clinical safety studies. Acute toxicity studies with itraconazole in mice, rats, guinea pigs and dogs indicate a wide safety margin. Sub (chronic) oral toxicity studies in rats and dogs revealed several target organs or tissues: adrenal cortex, liver and mononuclear phagocyte system as well as disorders of the lipid metabolism presenting as xanthoma cells in various organs.

At high doses, histological investigations of adrenal cortex showed a reversible swelling with cellular hypertrophy of the zona reticularis and fasciculata, which was sometimes associated with a thinning of the zona glomerulosa. Reversible hepatic changes were found at high doses. Slight changes were observed in the sinusoidal cells and vacuolation of the hepatocytes, the latter indicating cellular dysfunction, but without visible hepatitis or hepatocellular necrosis. Histological changes of the mononuclear phagosystem were mainly characterised by macrophages with increased proteinaceous material in various parenchymal tissues.

There are no indications of a mutagenic potential of itraconazole.

Itraconazole is not a primary carcinogen in rats or mice. In male rats, however, there was a higher incidence of soft-tissue sarcoma, which is attributed to the increase in non-neoplastic, chronic inflammatory reactions of the connective tissue as a consequence of raised cholesterol levels and cholesterosis in connective tissue.

There is no evidence of a primary influence on fertility under treatment with itraconazole. Itraconazole was found to cause a dose-related increase in maternal toxicity, embryotoxicity, and teratogenicity in rats and mice at high doses. In rats, the teratogenicity consisted of major skeletal defects; in mice, it consisted of encephaloceles and macroglossia.

A global lower bone mineral density was observed in juvenile dogs after chronic itraconazole administration.

In three toxicology studies using rats, itraconazole induced bone defects. The induced defects included reduced bone plate activity, thinning of the zona compacta of the large bones, and increased bone fragility.

The inactive ingredients of the capsules are Sucrose, Hypromellose, Ammonio methacrylate copolymer, polyethylene glycol, Methylene dichloride, Ethanol, Quinoline Yellow, Erythrosin FD&C Red 3, Titanium Dioxide and Gelatin

Not applicable.

3 years.

Store below 30°C. Store the capsules in their carton to protect from light

Travsparent transformed PVC/PVDC blister with hard tempered Aluminium foil led

Packs with either 4 or 15 capsules

6.6. Special precautions for disposal and other handling

 

No special requirements.

No special requirements