Size 00, hard gelatin capsule with a red opaque cap and red opaque body printed axially with "MYLAN" over "IE 100" in white ink on cap and body and containing white to off-white coloured pellets. Each capsule contains 100 mg itraconazole.
Itraconazole is a synthetic triazole derivative. When administered orally, it has shown fungistatic activity against superficial dermatophytes and Candida species including C. albicans and C. glabrata. Itraconazole has shown in vitro antifungal activity against a variety of fungi and yeasts. This spectrum includes superficial dermatophytes (Trichophyton spp., Microsporum spp., Epidermophyton floccosum), yeasts (Cryptococcus neoformans, Pityrosporum spp., Candida spp. including C. albicans, C. glabrata and
krusei), Aspergillus spp., Histoplasma spp., Paracoccidioides brasiliensis, Sporothrix schenckii, Fonsecaea spp., Cladosporium spp., Blastomyces dermatitidis.
In vitro
studies have demonstrated that itraconazole inhibits the cytochrome P450-dependent synthesis of ergosterol, which is a vital component of fungal cell membranes.
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 ug/ml, 1.1 ug/ml and 2.0 ug/ml after oral administration of 100 mg once daily, 200 mg once daily and 200 mg twice daily 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
Itraconazole is rapidly absorbed after oral administration. Peak plasma concentrations of the unchanged drug are reached within 2 to 5 hours following an oral capsule dose. The observed absolute oral bioavailability of itraconazole is about 55%. Oral bioavailability is maximal when the capsules are taken immediately after a full meal. Absorption of itraconazole capsules is reduced in subjects with reduced gastric acidity, such as subjects taking medications known as gastric acid secretion suppressors (e.g., H2. receptor antagonists, proton pump inhibitors) or subjects with achlorhydria caused by certain diseases (see Warnings and Precautions, and Interactions section). Absorption of itraconazole under fasted conditions in these subjects is increased when the capsules are administered with an acidic beverage (such as a non-diet cola). When itraconazole capsules were administered as a single 200-mg dose under fasted conditions with non-diet cola after ranitidine pretreatment, a H2-receptor antagonist, itraconazole absorption was comparable to that observed when Itraconazole capsules were administered alone (see Interactions section.)
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 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
Itraconazole is extensively metabolized 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 this metabolite are about twice those of itraconazole.
Excretion
Itraconazole is excreted mainly as inactive metabolites in urine (35%) and in 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 radiolabeled dose, faecal excretion of unchanged drug ranges from 3% to 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 metabolized in the liver. A pharmacokinetic study was conducted in 6 healthy and 12 cirrhotic subjects who were administered a single 100-mg dose of itraconazole as a capsule. A statistically significant reduction in mean Cmax (47%) and a twofold increase in the elimination half-life (37 +- 17 hours vs. 16 +- 5 hours) of itraconazole were noted in cirrhotic subjects compared with healthy subjects. However, 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 Dosage and Administration and Warnings and Precautions section.
Renal Impairment
Limited data are available on the use of oral itraconazole in patients with renal impairment. A pharmacokinetic study using a single 200-mg dose of itraconazole (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. x 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 itraconazole (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 itraconazole 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 itraconazole, 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 itraconazole. Dialysis has no effect on the half-life or clearance of itraconazole or hydroxy-itraconazole. See also Dosage and Administration and Warnings and Precautions section.
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.
Itraconazole capsules are indicated for the treatment of: vulvovaginal candidiasis. pityriasis versicolor, dermatomycosis, fungal keratitis, oral candidiasis. onychomycosis caused by dermatophytes and/or yeasts. systemic mycoses, including aspergillosis and non-invasive systemic candidiasis (without underlying immunosuppression), histoplasmosis, sporotrichosis, paracoccidioidomycosis, blastomycosis, and other rarely occurring systemic or tropical mycoses.
For optimal absorption, it is essential to administer itraconazole capsules immediately after a full meal. The capsules must be swallowed whole. Treatment schedules are as follows:
| Indication | Dose | Duration |
| Vulvovaginal candidiasis | 200 mg twice daily or 200 mg once daily | 1 day 3 days |
| Pityriasis versicolor | 200 mg once daily | 7 days |
| Dermatomycosis | 100 mg once daily or 200 mg once daily | 15 days 7 days |
| Highly keratinised regions as in plantar tinea pedis and palmar tinea manus require an additional treatment of 15 days at 100 mg daily. | ||
| Oral candidiasis | 100 mg once daily | 15 days |
| In some immunocompromised patients, e.g. neutropenic, AIDS or organ transplant patients, the oral bioavailability of itraconazole may be decreased. Therefore, the doses may need to be doubled. | ||
| Fungal keratitis | 200 mg once daily | 21 days |
Onychomycosis
Pulse treatment (see table below):
A pulse treatment consists of two capsules (200 mg) twice daily for one week. Two pulse treatments are recommended for fingernail infections and three pulse treatments for toenail infections. Pulse treatments are always separated by a 3-week treatment-free interval. Clinical response will become evident as the nail regrows, following discontinuation of the treatment.
| Site of onychomycosis | Week 1 | Weeks 2, 3, 4 | Week 5 | Weeks 6, 7, 8 | Week 9 |
| Toenails with or without fingernail involvement | Pulse 1 | Itraconazole- free | Pulse 2 | Itraconazole- free | Pulse 3 |
| Fingernails only | Pulse 1 | Itraconazole- free | Pulse 2 | Itraconazole- free | - |
Continuous Treatment: 200 mg once daily for 3 months. Elimination of itraconazole from skin and nail tissue is slower than from plasma. Optimal clinical and mycological response is thus reached 2 to 4 weeks after the cessation of treatment for skin infections and 6 to 9 months after the cessation of treatment for nail infections.
Systemic mycoses
Dosage recommendations for systemic mycoses vary according to the infection treated and are as follows:
| Indication | Dose | Median duration | Remarks |
| Aspergillosis | 200 mg once daily | 2-5 months | Increase dose to 200 mg twice daily in case of invasive or disseminated disease |
| Non-invasive systemic candidiasis | 100-200 mg once daily | 3 weeks - 7 months | |
| Histoplasmosis | 200 mg once daily to 200 mg twice daily | 8 months | |
| Sporotrichosis | 100 mg once daily | 3 months | |
| Paracoccidioido- mycosis | 100 mg once daily | 6 months | |
| Chromomycosis | 100-200 mg once daily | 6 months | |
| Blastomycosis | 100 mg once daily - 200 mg twice daily | 6 months |
Special population
Paediatrics
Clinical data on the use of itraconazole capsules in paediatric patients are limited. The use of itraconazole capsules in paediatric patients is not recommended unless it is determined that the potential benefit outweighs the potential risks. See Warnings and Precautions section.
Elderly
Clinical data on the use of itraconazole capsules in elderly patients are limited. It is advised to use itraconazole 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. See Warnings and Precautions section.
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 Pharmacokinetics section.
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.
Itrazole capsules are contraindicated in patients who have shown hypersensitivity to itraconazole or any of the excipients (see Further Information). Itrazole capsules are contraindicated in pregnant women except for the treatment of systemic mycoses, where the potential advantages must be weighed against the potential harm to the foetus. Adequate contraceptive precautions should be used by women of childbearing potential throughout itraconazole therapy, and continued until the next menstrual period following the end of itraconazole therapy. Coadministration of a number of CYP3A4 substrates is contraindicated 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 tachyarrythmias including, occurrences of torsades de pointes, a potentially fatal arrhythmia. Specific examples are listed in Interactions section. Itrazole 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 Warnings and Precautions).
Itraconazole has a potential for clinically important interactions with other medicines (see Interactions).
In a study with itraconazole IV in healthy volunteers a transient asymptomatic decrease of the left ventricular ejection fraction, which resolved before the next infusion, was observed. The clinical relevance of these findings to the oral formulations is not known. Itraconazole has been shown to have a negative inotropic effect. 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. Itraconazole 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. The risk benefit assessment should consider factors such as the severity of the indication, the dosing regimen (e.g. total daily dose) and individual risk factors for congestive heart failure. 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. Patients with these risk factors, who are being treated with itraconazole, should be informed of the signs and symptoms of congestive heart failure. Caution should be exercised and the patient monitored for the signs and symptoms of congestive heart failure. Itraconazole should be discontinued if such symptoms occur during treatment. 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.
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 Interactions.
There is no information regarding cross-hypersensitivity between itraconazole and other azole antifungal agents. Caution should be used in prescribing Itraconazole capsules to patients with hypersensitivity to other azoles.
Absorption of itraconazole from itraconazole capsules is impaired when the gastric acidity is decreased In patients with reduced gastric acidity, whether from disease (e.g. patients with achlorydria) or from concomitant medication (e.g. patients taking drugs to reduce gastric acidity), it is advisable to administer itraconazole capsules with an acidic beverage beverage (such as non-diet cola). The antifungal activity should be monitored and the itraconazole dose increased as deemed necessary. See Interactions and Pharmacokinetics section.
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. Dose adjustments may be considered in these patients. Very rare cases of serious hepatotoxicity, including some cases of fatal acute liver failure, have occurred with the use of itraconazole. 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 have been observed within the first month of treatment, including some within the first week. Liver function monitoring should be considered in patients receiving itraconazole 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. 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. It is recommended that patients with impaired hepatic function be carefully monitored when taking itraconazole. It is recommended that the prolonged elimination of half-life itraconazole observed in the single oral dose clinical trial with itraconazole capsules in cirrhotic patients be considered when deciding to initiate therapy with other medications metabolized by CYP3A4. In patients with elevated or abnormal liver enzymes or active liver disease, or who have experienced liver toxicity with other drugs, treatment with itraconazole is strongly discouraged unless there is a serious or life- threatening situation where the expected benefit exceeds the risk. It is recommended that liver function monitoring be done in patients with pre-existing hepatic function abnormalities or those who have experienced liver toxicity with other medications. See Pharmacokinetics section.
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.
Isolated cases of peripheral neuropathy have been reported, predominantly during long-term treatment with itraconazole. If neuropathy occurs which may be attributable to itraconazole, the treatment should be discontinued.
There is no information regarding cross hypersensitivity between itraconazole and other azole antifungal agents. Caution should be used in prescribing itraconazole capsules to patients with hypersensitivity to other azoles.
In some immunocompromised patients (e.g. neutropenic, AIDS or organ transplant patients) the oral bioavailability of itraconazole capsules may be decreased.
Due to the pharmacokinetic properties itraconazole capsules are not recommended for initiation of treatment in patients with immediately life-threatening systemic fungal infections.
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 therapy.
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 Contraindications and Interactions). The hearing loss usually resolves when treatment is stopped, but can persist in some patients.
In systemic candidosis, if fluconazole-resistant strains of Candida species are suspected, it cannot be assumed that these are sensitive to itraconazole, hence it is recommended to have their sensitivity tested before the start of itraconazole therapy.
It is not recommended that itraconazole capsules and itraconazole oral solution be used interchangeably. This is because drug exposure is greater with the oral solution than with the capsules when the same dose is given.
The efficacy and safety of itraconazole capsules have not been established in children. Since clinical data for the use of itraconazole in children is limited, the use of itraconazole capsules is not recommended unless it is determined that the potential benefit outweighs the potential risks. Toxicological studies have shown that itraconazole, when administered to rats, can produce bone toxicity. While such toxicity has not been reported in adult patients, the long-term effect of itraconazole in children is unknown (see Further Information - Toxicology).
Clinical data on the use of Itraconazole capsules in elderly patients are limited. It is advised to use Itraconazole 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.
Use in pregnancy
Category B3. Teratogenic effects: Itraconazole was found to cause a dosage related increase in maternal toxicity, embryotoxicity and teratogenicity in rats at dosage levels of approximately 40-160 mg/kg/day and in mice at dosage levels of approximately 80 mg/kg/day. In rats, the teratogenicity consisted of major skeletal defects and in mice it consisted of encephaloceles and/or macroglossia. Itraconazole capsules should not be used during pregnancy except in life threatening cases where the potential benefit to the mother outweighs the potential harm to the foetus (see Contraindications). There is limited information on the use of itraconazole 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 casual relationship with itraconazole has not been established. Epidemiological data on exposure to itraconazole during the first trimester of pregnancy (mostly in patients receiving short-term treatment for vulvovaginal candidiasis) did not show an increased risk of malformations as compared to control subjects not exposed to any known teratogens. Women of childbearing potential taking itraconazole should use contraceptive precautions. Effective contraception should be continued until the menstrual period following the end of itraconazole therapy.
Use in lactation
Based on the determination of itraconazole concentration in the breast milk of lactating mothers who received a single daily dose of 400 mg itraconazole (200 mg twice daily), it was calculated that the exposure in the infant to itraconazole would be around 450 times lower than in the mother. The expected benefits of itraconazole therapy should therefore be weighed against the potential risk of breast-feeding. In case of doubt the patient should not breast-feed.
Refer to Further Information - Carcinogenesis, mutagenicity, impairment of fertility section for further inf ormation
No studies on the effects on the ability to drive or to use machinery have been performed. When driving vehicles and operating machinery the possibility of adverse reactions such as dizziness, visual disturbances and hearing loss (see Adverse Effects), which may occur in some instances, must be taken into account.
Throughout this section, adverse reactions are presented. Adverse reactions are adverse events that were considered to be reasonably associated with the use of itraconazole based on the comprehensive assessment of the available adverse event information. A causal relationship with itraconazole cannot be reliably established in individual cases. Further, because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Clinical Trial Data
The safety of itraconazole capsules was evaluated in 8499 patients who participated in 107 open-label and double-blind clinical trials. Of the 8499 patients treated with itraconazole capsules, 2104 patients were treated with itraconazole capsules during double-blind trials. All 8499 patients received at least one dose of itraconazole capsules for the treatment of dermatomycoses or onychomycosis and provided safety data. Adverse drug reactions (ADRs) reported for >1% of patients treated with itraconazole capsules in these clinical trials are shown in Table 1.
| Table 1. Adverse Drug Reactions Reported by >1% of Patients Treated with Itraconazole Capsules in 107 Clinical Trials. | |
| System Organ Class Adverse Drug Reaction | Itraconazole Capsules % (N= 8499) |
| Nervous System Disorders Headache | 1.6 |
| Gastrointestinal Disorders Nausea Abdominal pain | 1.6 1.3 |
Adverse drug reactions that occurred in <1% of patients treated with itraconazole capsules in these clinical trials are listed in Table 2.
| Table 2 Adverse Drug Reactions Reported by <1% of Patients Treated with Itraconazole Capsules in 107 Clinical Trials |
| System Organ Class Adverse Drug Reaction |
| Infections and Infestations Rhinitis Sinusitis Upper respiratory tract infection |
| Blood and Lymphatic System Disorders Leukopenia |
| Immune System Disorders Hypersensitivity |
| Nervous System Disorders Dysgeusia Hypoesthesia Paresthesia |
| Ear and Labyrinth Disorders Tinnitus |
| Gastrointestinal Disorders Constipation Diarrhoea Dsypepsia Flatulence Vomiting |
| Hepatobiliary Disorders Hepatic function abnormal Hyperbilirubinemia |
| Skin and Subcutaneous Tissue Disorders Pruritus Rash Urticaria |
| Renal and Urinary Disorders Pollakiuria |
| Reproductive System and Breast Disorders Erectile dysfunction Menstrual disorder |
| General Disorders and Administration Site Conditions Oedema |
Paediatrics
The safety of itraconazole 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 itraconazole 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.
Postmarketing experience
Adverse drug reactions first identified during post-marketing experience with itraconazole (all formulations) are included in Table 3. In the table the frequencies are provided according to the following convention: Very common (>= 1/10); Common (>=1/100 and < 1/10); Uncommon (>=1/1,000 and < 1/100); Rare (>=1/10,000 and < 1/1000); Very rare (<1/10,000), including isolated reports. In Table 3, ADRs are presented by frequency category based on spontaneous reporting rates.
| Table 3: Adverse Drug Reactions Identified During Post-Marketing Experience with Itraconazole by Frequency Category Estimated from Spontaneous Reporting Rates | |
| Immune System Disorders | |
| Very rare | Serum sickness, Angioneurotic edema, Anaphylactic reaction |
| Metabolism and Nutrition Disorders | |
| Very rare | Hypertriglyceridemia |
| Eye Disorders | |
| Very rare | Visual disturbances (including diplopia and blurred vision) |
| Ear and Labyrinth Disorders | |
| Very rare | Transient or permanent hearing loss |
| Cardiac Disorders | |
| Very rare | Congestive heart failure |
| Respiratory, Thoracic and Mediastinal Disorders | |
| Very rare | Dyspnea |
| Gastrointestinal Disorders | |
| Very rare | Pancreatitis |
| Hepatobiliary Disorders | |
| Very rare | Serious hepatotoxicity (including some cases of fatal acute liver failure) |
| Skin and Subcutaneous Tissue Disorders | |
| Very rare | Toxic epidermal necrolysis, Stevens-Johnson syndrome, Acute generalised exanthematous pustulosis, Erythema multiforme, Exfoliative dermatitis, Leukocytoclastic vasculitis, Alopecia, Photosensitivity |
| Investigations | |
| Very rare | Blood creatine phosphokinase increased |
Itraconazole is mainly metabolized through CYP3A4. Other substances that either share this metabolic pathway or modify CYP3A4 activity may influence the pharmacokinetics of itraconazole. Similarly, itraconazole may modify the pharmacokinetics of other substances that share this metabolic pathway. Itraconazole is a potent CYP3A4 inhibitor and a P-glycoprotein inhibitor. When using concomitant medication, it is recommended that the corresponding label be consulted for information on the route of metabolism and the possible need to adjust the dosages.
Drugs that may decrease itraconazole plasma concentrations
Drugs that reduce the gastric acidity (e.g. acid neutralizing medicines such as aluminum hydroxide, or acid secretion suppressors such as H2-receptor antagonists and proton pump inhibitors) impair the absorption of itraconazole from itraconazole capsules It is recommended that these drugs be used with caution when coadministered with itraconazole capsules. It is recommended that itraconazole be administered with an acidic beverage (such as non-diet cola) upon co-treatment with drugs reducing gastric acidity. It is recommended that acid neutralizing medicines (e.g. aluminum hydroxide) be administered at least 1 hour before or 2 hours after the intake of itraconazole capsules. Upon coadministration, it is recommended that the antifungal activity be monitored, and the itraconazole dose increased as deemed necessary. Coadministration of itraconazole with potent enzyme inducers of CYP3A4 may decrease the bioavailability of itraconazole and hydroxy-itraconazole to such an extent that efficacy may be largely reduced. Examples include: Antibacterials: isoniazid, rifabutin (see also under Drugs that may have their plasma concentrations increased by itraconazole), rifampicin. Anticonvulsants: carbamazepine, (see also under Drugs that may have their plasma concentrations increased by itraconazole), phenobarbital, phenytoin. Antivirals: efavirenz, nevirapine. Therefore, administration of potent enzyme inducers of CYP3A4 with itraconazole is not recommended. It is recommended that the use of these drugs be avoided from 2 weeks before and during treatment with itraconazole, unless the benefits outweigh the risk of potentially reduced itraconazole efficacy. Upon coadministration, it is recommended that the antifungal activity be monitored and the itraconazole dose increased as deemed necessary
Drugs that may increase itraconazole plasma concentrations
Potent inhibitors of CYP3A4 may increase the bioavailability of itraconazole. Examples include: Antibacterials: ciprofloxacin, clarithromycin, erythromycin, Antivirals: ritonavir-boosted darunavir, ritonavir-boosted fosamprenavir, indinavir (see also under Drugs that may have their plasma concentrations increased by itraconazole), ritonavir (see also under Drugs that may have their plasma concentrations increased by itraconazole). It is recommended that these drugs be used with caution when coadministered with itraconazole capsules. It is recommended that patients who must take itraconazole concomitantly with potent inhibitors of CYP3A4 be monitored closely for signs or symptoms of increased or prolonged pharmacologic effects of itraconazole, and the itraconazole dose be decreased as deemed necessary. When appropriate, it is recommended that itraconazole plasma concentrations be measured.
Drugs that may have their plasma concentrations increased by itraconazole
Itraconazole and its major metabolite, hydroxyl-itraconazole, can inhibit the metabolism of medicines metabolised by CYP3A4 and can inhibit the drug transport by P-glycoprotein, which may result in increased plasma concentrations of these drugs and/or their active metabolite(s) when they are administered with itraconazole. These elevated plasma concentrations may increase or prolong both therapeutic and adverse effects of these drugs. CYP3A4-metabolized drugs known to prolong the QT interval may be contraindicated with itraconazole, since the combination may lead to ventricular tachyarrhythmias including occurrences of torsades de pointes, a potentially fatal arrhythmia. 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. The interacting drugs are categorised as follows: 'Contraindicated': Under no circumstances is the drug to be coadministered with itraconazole, and up to two weeks after discontinuation of treatment with itraconazole. 'Not recommended': It is recommended that the use of the drug 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 coadministration cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged effects or side effects of the interacting drug is recommended, and its dosage, be reduced or interrupted as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured. 'Use with caution': Careful monitoring is recommended when the drug is coadministered with itraconazole. Upon coadministration, 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 be measured. Examples of drugs that may have their plasma concentrations increased by itraconazole presented by drug class with advice regarding coadministration with itraconazole:
| Drug Class | Contraindicated | Not Recommended | Use with Caution |
| Alpha blockers | tamsulosin | ||
| Analgesics | levacetylmethadol (levomethadyl), methadone | fentanyl | alfentanil, buprenorphine IV and sublingual, oxycodone |
| Antiarrhytmics | disopyramide, dofetilide, dronedarone, quinidine | digoxin | |
| Antibacterials | rifabutin a | ||
| Anticoagulants and Antiplatelet Drugs | rivaroxaban | coumarins, cilostazol, dabigatran | |
| Anticonvulsants | carbamazepine a | ||
| Antidiabetics | repaglinide, saxagliptin | ||
| Antihelmintics and Antiprotozoals | halofantrine | praziquantel | |
| Antihistamines | astemizole, mizolastine, terfenadine | ebastine | |
| Antimigraine Drugs | ergot alkaloids, such as dihydroergotamine, ergometrine (ergonovine), methylergometrine (methylergonovine) | eletriptan | |
| Antineoplastics | irinotecan | dasatinib, nilotinib, trabectedin | bortezomib, busulphan, docetaxel, erlotinib, ixabepilone, lapatinib trimetrexate, vinca alkaloids |
| Antipsychotics, Anxiolytics and Hypnotics | lurasidone, oral midazolam, pimozide, sertindole, triazolam | alprazolam, aripiprazole, brotizolam, buspirone, haloperidol, midazolam IV, perospirone, quetiapine, ramelteon, risperidone | |
| Antivirals | maraviroc, indinavir b , ritonavir b , saquinavir | ||
| Beta Blockers | nadolol | ||
| Calcium Channel Blockers | bepridil, felodipine, lercanidipine, nisoldipine | other dihydropyridines, including verapamil | |
| Cardiovascular Drugs, Miscellaneous | ivabradine, ranolazine | aliskiren | |
| Diuretics | eplerenone | ||
| Gastrointestinal Drugs | cisapride | aprepitant, domperidone | |
| Immunosuppressants | everolimus | budesonide, ciclesonide, cyclosporine, | |
| dexamethasone, fluticasone, methylprednisolone, rapamycin (also known as sirolimus), tacrolimus, temsirolimus | |||
| Lipid Regulating Drugs | lovastatin, simvastatin | atorvastatin | |
| Respiratory Drugs | salmeterol | ||
| SSRIs, Tricyclics and Related Antidepressants | reboxetine | ||
| Urological Drugs | vardenafil | fesoterodine, imidafenacin, sildenafil, solifenacin, tadalafil, tolterodine | |
| Other | colchicine, in subjects with renal or hepatic impairment. | colchicine | alitretinoin (oral formulation), cinacalcet, mozavaptan, tolvaptan |
a
See also under Drugs that may decrease itraconazole plasma concentrations
b
See also under Drugs that may increase itraconazole plasma concentrations
Drugs that may have their plasma concentrations decreased by itraconazole
Coadministration of itraconazole with the NSAID meloxicam may decrease the plasma concentrations of meloxicam. It is recommended that meloxicam be used with caution when coadministered with itraconazole, its effects or side effects be monitored. It is recommended that the dosage of meloxicam, if coadministered with itraconazole, be adapted if necessary.
Paediatric Population
Interaction studies have only been performed in adults.
In general, adverse events reported with overdose have been consistent with those reported for itraconazole use. See Adverse Effects section.
In the event of accidental 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.
Shelf Life: 36 months.
Store below 25degC.
Prescription Medicine.
Blister packs containing 15 capsules.
Itrazole capsules contain sugar spheres, hydroxypropylmethylcellulose, sorbitan stearate and hydrated silica colloidal. The capsule is made of titanium dioxide, red iron oxide and gelatin. The printing ink is Opacode S- 1-7078 White.
Itraconazole showed no evidence of carcinogenicity potential in mice treated orally for 23 months at dosage levels of up to 80 mg/kg/day. Male rats treated with 25 mg/kg/day had a slightly increased incidence of soft tissue sarcoma. These sarcomas may have been a consequence of hypercholesterolaemia, which is a response of rats, but not dogs or humans to chronic itraconazole administration. Female rats treated with 50 mg/kg/day had an increased incidence of squamous cell carcinoma of the lung (2/50) as compared to the untreated group. Although the occurrence of squamous cell carcinoma in the lung is extremely uncommon in untreated rats, the increase in this study was not statistically significant. Itraconazole produced no mutagenic effects when assayed in appropriate bacterial, non-mammalian and mammalian test systems. Itraconazole did not affect the fertility of male or female rats treated orally with dosage levels of up to 40 mg/kg/day even though parental toxicity was present at this dosage level.
In three toxicology studies using rats, itraconazole induced bone defects at dosage levels as low as 20 mg/kg/day. The induced defects included reduced bone plate activity, thinning of the zona compacta of the large bones and increased bone fragility. At a dosage level of 80 mg/kg/day over one year or 160 mg/kg/day for six months, itraconazole induced small tooth pulp with hypocellular appearance in some rats. Increased relative adrenal weights and swollen adrenals (reversible) were seen in rats and dogs where plasma levels were comparable to those of human therapeutic doses. Adrenocortical function was not affected in studies in humans after the recommended daily doses; with higher doses (600 mg/day for 3 months), adrenal cortex response to ACTH stimulation was reduced in 1 of 8 patients, but returned to normal when the dosage was reduced.
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 mg/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 ug/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. caosulatum; 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 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 14a- 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.
Mylan New Zealand Ltd PO Box 11183 Ellerslie Auckland Telephone: 09-579-2792
24 May 2013