• Congestive Heart Failure

Itraconazole can cause or exacerbate congestive heart failure (CHF). When itraconazole was administered intravenously to healthy human volunteers and dogs, negative inotropic effects were seen. If signs or symptoms of congestive heart failure occur or worsen during administration of Itraconazole, reassess the benefit and risk of continuing treatment.

• Drug Interactions

Co-administration of certain drugs that are metabolized by human CYP3A4 enzymes are contraindicated with Itraconazole because plasma concentrations of such drugs are increased, which may also increase or prolong both the pharmacologic effects and/or adverse reactions to these drugs [see Contraindications and Drug Interactions ] Co-administration with colchicine, fesoterodine and solifenacin is contraindicated in subjects with varying degrees of renal or hepatic impairment, and Co-administration with eliglustat is contraindicated in subjects that are poor or intermediate metabolizers of CYP2D6 and in subjects taking strong or moderate CYP2D6 inhibitors.
Increased plasma concentrations of some of these drugs caused by coadministration with Itraconazole can lead to QT prolongation and/or ventricular tachyarrhythmias, including occurrences of torsades de pointes, a potentially fatal arrhythmia [see Contraindications , Warnings and Precautions and Drug Interactions ].

Itraconazole Capsules BP 130 mg
(Supra-Bioavailable formulation)

Each hard gelatin capsule contains:
Itraconazole I.P. 130 mg
Excipients q.s.
Approved colours used in capsule shells

Hard Gelatin capsules & 130 mg

4.1 Therapeutic indication
For the treatment of the following fungal infections in immunocompromised and non-immunocompromised adult patients:

• Blastomycosis, Pulmonary and Extrapulmonary
• Histoplasmosis, including chronic cavitary pulmonary disease and disseminated, non-meningeal histoplasmosis.
• Aspergillosis pulmonary and extra-pulmonary, in patients who are intolerant of or who are refractory to amphotericin B therapy.

Limitations of Use:

Itraconazole is not indicated for the treatment of onychomycosis.

Itraconazole is NOT interchangeable or substitutable with other itraconazole products due to the differences in the dosing between Itraconazole and other itraconazole products. Therefore, follow the specific dosage recommendations for Itraconazole.

Itraconazole must be administered with food.

Itraconazole capsules must be swallowed whole. Do not chew, crush or break Itraconazole capsules.

Table 1 below describes the recommended dosage for Itraconazole.

Table 1: Dosage and Administration of Itraconazole

Specimens for fungal cultures and other relevant laboratory studies (wet mount, histopathology, serology) should be obtained before therapy to isolate and identify causative organisms. Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, anti-fungal therapy should be adjusted accordingly.

Drug Interactions

• Co-administration of certain drugs that are metabolized by human CYP3A4 substrates are contraindicated with Itraconazole because plasma concentrations of such drugs are increased, which may also increase or prolong both the pharmacologic effects and/or adverse reactions to these drugs
• Co-administration with colchicine, fesoterodine and solifenacin is contraindicated in subjects with varying degrees of renal or hepatic impairment.
• Co-administration with eliglustat is contraindicated in subjects that are poor or intermediate metabolizers of CYP2D6 and in subjects taking strong or moderate CYP2D6 inhibitors.
• Increased plasma concentrations of some of these drugs due to co-administration of Itraconazole can lead to QT prolongation and ventricular tachyarrhythmias including occurrences of torsade de pointes, a potentially fatal arrhythmia.

Hypersensitivity
Itraconazole is contraindicated in patients with known hypersensitivity to itraconazole. There is limited information regarding cross-hypersensitivity between itraconazole and other azole antifungal agents.

• Congestive Heart Failure

Itraconazole can cause or exacerbate congestive heart failure (CHF). For patients with evidence of ventricular dysunction such as CHF, history or risk factors for CHF, physicians should carefully review the risks and benefits of Itraconazole therapy. These risk factors include cardiac disease such as ischemic and valvular disease; significant pulmonary disease such as chronic obstructive pulmonary disease; and renal failure and other edematous disorders. Inform such patients of the signs and symptoms of CHF and monitor carefully for signs and symptoms of CHF during treatment. If signs or symptoms of CHF appear or worsen during administration of Itraconazole, reassess the benefit-risk of continuing treatment.
When itraconazole was administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was demonstrated. In a healthy volunteer study of itraconazole intravenous infusion, transient, asymptomatic decreases in left ventricular ejection fraction were observed using gated SPECT imaging; these resolved before the next infusion, 12 hours later.

Itraconazole has been associated with reports of CHF, peripheral edema, and pulmonary edema. In post-marketing experience, heart failure was more frequently reported in patients receiving higher total daily doses of itraconazole of 400 mg although there were also cases reported among those receiving lower total daily doses.

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, when co-administering itraconazole and calcium channel blockers, monitor carefully for signs and symptoms of CHF during treatment due to an increased risk of CHF. Concomitant administration of Itraconazole and felodipine or nisoldipine is contraindicated.

• Hepatotoxicity

Itraconazole has been associated with cases of serious hepatotoxicity, including liver failure and death. Some of these cases had neither pre-existing liver disease nor a serious underlying medical condition, and some of these cases developed within the first week of treatment. If clinical signs or symptoms develop that are consistent with liver disease, discontinue treatment and perform testing for liver disease. Continued Itraconazole use or reinstitution of treatment with Itraconazole is strongly discouraged unless there is a serious or life-threatening situation where the expected benefit exceeds the risk.

• Cardiac Dysrhythmias

Life-threatening cardiac dysrhythmias and/or sudden death have occurred in patients using drugs such as, pimozide, methadone, or quinidine concomitantly with oral itraconazole and/or other CYP3A4 inhibitors. Concomitant administration of these drugs with Itraconazole is contraindicated.

• Drug Interaction Potential

Itraconazole has a potential for clinically important drug interactions. Co-administration of specific drugs with Itraconazole may result in changes in the efficacy of itraconazole and/or the co-administered drug, life-threatening effects and/or sudden death.

• Peripheral Neuropathy

Cases of peripheral neuropathy have been reported in patients on long-term therapy with itraconazole. Monitor for and promptly evaluate neurologic symptoms. If neuropathy attributable to Itraconazole occurs, discontinue treatment.

• Hearing Loss

Reversible 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. The hearing loss usually resolves when treatment is stopped but can persist in some patients

• Hypersensitivity Reactions

Itraconazole is contraindicated in patients with a known hypersensitivity to itraconazole Hypersensitivity reactions have been reported with the use of itraconazole. Due to the limited information regarding cross hypersensitivity between itraconazole and other azole antifungal drugs, careful enquiry about previous hypersensitivity to other azole antifungal drugs should be made when prescribing Itraconazole. If hypersensitivity reactions to Itraconazole occurs, discontinue the drug and institute appropriate therapy.

Effect of Itraconazole on Other Drugs
Itraconazole and its major metabolite, hydroxy-itraconazole, are potent CYP3A4 inhibitors.
Itraconazole is an inhibitor of the drug transporters P-glycoprotein and breast cancer resistance protein (BCRP). Consequently, itraconazole has the potential to interact with many concomitant drugs resulting in either increased or sometimes decreased concentrations of the concomitant drugs. Increased concentrations may increase the risk of adverse reactions associated with the concomitant drug which can be severe or life-threatening in some cases (e.g., QT prolongation, Torsade de Pointes, respiratory depression, hepatic adverse reactions, hypersensitivity reactions, myelosuppression, hypotension, seizures, angioedema, atrial fibrillation, bradycardia, priapism). Reduced concentrations of concomitant drugs may reduce their efficacy. Table 4 lists examples of drugs that may have their concentrations affected by itraconazole, but is not a comprehensive list. Refer to the approved product labeling to become familiar with the interaction pathways, risk potential, and specific actions to be taken with regards to each concomitant drug prior to initiating therapy with itraconazole.
Although many of the clinical drug interactions in Table 4 are based on information with a similar azole antifungal, ketoconazole, these interactions are expected to occur with itraconazole

Table 4: Drug Interactions with Itraconazole that Affect Concomitant Drug

Concentrations

^aBased on clinical drug interaction information with itraconazole.^b
Based on 400 mg Bedaquiline once daily for 2 weeks. c EMs: extensive metabolizers; IMs: intermediate metabolizers, PMs: poor metabolizers.
Effect of Other Drugs on Itraconazole
Itraconazole is mainly metabolized through CYP3A4. Other substances that either share this metabolic pathway or modify CYP3A4 activity may influence the pharmacokinetics of itraconazole. Some concomitant drugs have the potential to interact with Itraconazole resulting in either increased or sometimes decreased concentrations of Itraconazole. Increased concentrations may increase the risk of adverse reactions associated with Itraconazole. Decreased concentrations may reduce Itraconazole efficacy.
Table 4 lists examples of drugs that may affect itraconazole concentrations, but is not a comprehensive list. Refer to the approved product labeling to become familiar with the interaction pathways, risk potential and specific actions to be taken with regards to each concomitant drug prior to initiating therapy with Itraconazole.

Although many of the clinical drug interactions in Table 5 are based on information with a similar azole antifungal, ketoconazole, these interactions are expected to occur with Itraconazole.

Table 5: Drug Interactions with Other Drugs that Affect Itraconazole Concentrations

^aBased on clinical drug interaction information with itraconazole.

Pregnancy

There are no data on exposure to itraconazole during pregnancy for the approved indications. Published epidemiologic studies of women exposed to short courses of treatment with itraconazole in the first trimester of pregnancy have reported no risk of major birth defects overall and inconclusive findings on the risk of miscarriage .

In animal reproduction studies, itraconazole was found to cause a dose-related increase in maternal toxicity, embryotoxicity, and teratogenicity in rats at dosage levels of approximately (625 times the maximum recommended human dose [MRHD] of 390 mg/day based on mg/kg comparisons), and in mice at dosage levels of approximately 80 mg/kg/day (12 times the MRHD).

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Human Data

Published prospective and retrospective cohort studies of women exposed to short courses of treatment with itraconazole in the first trimester of pregnancy (sample size 198-687) have reported no increase in the rate of major birth defects. The most important methodological limitation of these studies is the short duration of exposure in pregnancy (mean duration 6.9 to 8.5 days), or the lack of information on treatment duration. The risk of prolonged exposure in pregnancy is not known

Published prospective and retrospective cohort studies of pregnant women exposed to itraconazole (sample size 131-198) have reported inconsistent findings on the risk of miscarriage. Available data are inconclusive and limited by possible bias due to earlier enrollment and possible residual confounding in the exposed group compared to the unexposed group

Animal Data

Itraconazole has been shown to cross the placenta in a rat model. In animal reproduction studies, itraconazole administration to rats and mice during organogenesis resulted in maternal toxicity, embryotoxicity and teratogenicity at and above 40 and 80 mg/kg respectively (doses equivalent to 6- and 12-times the MRHD of 390 mg/day, based on mg/kg comparisons). In rats, the teratogenicity consisted of major skeletal defects; in mice, it consisted of encephaloceles and/or macroglossia.

Lactation:

Itraconazole is excreted in human milk; however, there are no data on the amount of itraconazole in human milk, the effects on the breastfed child, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Itraconazole and any potential adverse effects on the breastfed child from Itraconazole or from the underlying maternal condition.

Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
The long-term effects of itraconazole on bone growth in children are unknown. Bone lesions were observed in the young adult rats dosed with oral itraconazole for 3 to 12 months.

Geriatric Use
Clinical studies of itraconazole did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. 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. Reversible or permanent hearing loss has been reported in elderly patients receiving treatment with itraconazole. Several of these reports included concurrent administration of quinidine which is contraindicated.

Renal Impairment
Limited data are available on the use of oral itraconazole in patients with renal impairment. It is recommended that patients with renal impairment be carefully monitored when taking Itraconazole.

Hepatic Impairment
Limited data are available on the use of oral itraconazole in patients with hepatic impairment. It is recommended that patients with impaired hepatic function be carefully monitored when taking Itraconazole. It is recommended that the prolonged elimination half-life of 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.

4.6 Effects on ability to drive and use machines

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.

The most frequently reported adverse drug reactions (ADRs) based on clinical trials and or spontaneous reports from treatment with conventional Itraconazole capsules were headache, abdominal pain and nausea. The most serious ADRs were serious allergic reactions, cardiac failure/congestive heart failure/ pulmonary oedema, pancreatitis, serious hepatotoxicity(including some cases of fatal acute liver failure) and serious skin reactions. Adverse drug reactions are tabulated below. The ADRs are derived from open-label and double-blind clinical trials with conventional Itraconazole capsules for 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 (≥1/1000 to <1/100), Rare (≥1/10,000 to < 1/1000); Very rare (<1/10,000)

Paediatric Population
Information from studies of conventional Itraconazole capsules in paediatric patients, show that in general, the nature of ADRs in paediatric is similar to that observed in adult subjects, but the incidence is higher in the paediatric patients.

Intravenous and oral solutions of Itraconazole
The following is a list of ADRs associated with Itraconazole that have been reported in clinical trials of intravenous and oral solutions of Itraconazole, excluding the ADR term “Injection site
Inflammation”, which is specific to the injection route of administration.
Metabolism and system disorders:Granulocytopenia, Thrombocytopenia
Immune system disorders: Anaphylactoid reaction
Metabolism and nutrition disorders: Hyperglycaemia, Hyperkalaemia,Hypomagnesaemia
Psychiatric disorders: Confusional state Nervous system disorder: Peripheral neuropathy,Dizziness,Somnolence,Tremor
Cardiac Disorders: Cardiac failure left ventricular failure, tachycardia
Vascular disorders: Hypertension, Hypotension
Respiratory, thoracic and mediastinaldisorders: Pulmonary oedema, Dysphonia, cough
Gastrointestinal disorders: Gastrointestinal disorder
Hepatobillarydisorders: Hepatic failure, Hepatitis, Jaundice
Skin & 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: Generalisedoedema, 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-glutamyltranferase increased, Hepatic enzyme increased, urine analysis abnormal.

Reversible or permanent hearing loss has been reported in elderly patients receiving treatment with itraconazole. Several of these reports included concurrent administration of quinidine which is contraindicated.

Renal Impairment
Limited data are available on the use of oral itraconazole in patients with renal impairment. It is recommended that patients with renal impairment be carefully monitored when taking Itraconazole.

Hepatic Impairment
Limited data are available on the use of oral itraconazole in patients with hepatic impairment. It is recommended that patients with impaired hepatic function be carefully monitored when taking Itraconazole. It is recommended that the prolonged elimination half-life of 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.

Itraconazole is not removed by dialysis. In the event of accidental overdosage, supportive measures should be employed. Activated charcoal may be given if considered appropriate.

5.1 Mechanism of action

Itraconazole inhibits fungal 14α-demethylase, resulting in the depletion of ergosterol and disruption of membrane synthesis by fungi.

5.2 Pharmacokinetic/Pharmacodynamic relationship

The most important parameter for Itraconazole is the AUC/MIC ratio. This PK-PD parameter demonstrate that Itraconazole capsules 50 mg achieves the AUC/MIC ratio which should be greater than 25 for optimal efficacy in both the fed and fasted state for the organisms relevant to the indicated mycoses.

Mechanism of resistance

Resistance of fungi to azoles appears to develop slowly and is often the result of svereal genetic mutation. Mechanism that have been described are:

Over expression of ERG11, the gene that encodes 14-alpha-demethylase (the target enzyme)

Point mutation in ERG11, that lead to decreased affinity of 14-alpha-demethylase for Itraconazole.

Drug transporter over expression resulting in increased efflux of Itraconazole from fungal cells(i.e removal of Itraconazole from its target).

Cross-resistance : Cross resistance amongst members of the azole class of drugs has been observed within candida species through resistance to one member of the class does not necessarily confer resistance to other azoles.

Break points:

Breakpoints for Itraconazole have not yet been established for fungi using EUCAST method.

Using CLSI methods, breakpoints for Itraconazole have only been established for candida species from superficial mycoticinfections . The CLSI breakpoints are susceptible ≤0.125 mg/l and resistant 1 mg/l.
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 infection is questionable.
The in vitro susceptibility of fungi to Itraconazole 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 Itraconazole may vary widely. Susceptibility in the table below is based on MIC90 < 1 mg Itraconazole /l. There is no correlation between in vitro susceptibility and clinical efficacy.

Itraconazole –resistant strains of Aspergillus fumigates have been reported.
Natural intermediate suspectibility.

Pharmacotherapeutic group:Antimycotic for systemic use, triazolederivative ATC code J02AC02

General Physicochemical properties

The steady-state pharmacokinetics of itraconazole following administration of a 130 mg twice daily dose regimen of Itraconazole (2 x 65 mg) was compared with a 200 mg twice daily dose regimen of itraconazole capsules (2 x 100 mg) immediately after a meal for 14.5 days in 16 healthy volunteers; the results from this study are presented in Table 6 below

Table 6: Pharmacokinetics of Itraconazole Following Administration of Itraconazole and Itraconazole Capsules Given Twice Daily for 14.5 Days Under Fed Conditions¹ in 16 Healthy Subjects

¹Standardized high-fat, high-calorie breakfast was given 30 minutes prior to dosing on the morning of Day 15; standardized meals given prior to all other doses. 2 Geometric means ± standard deviation

³T_max presented as median (range)

Peak plasma concentrations of itraconazole after administration of a single dose of Itraconazole are reached within 2 to 6 hours following oral administration in either the fasted or fed states. As a consequence of non-linear pharmacokinetics, itraconazole accumulates in plasma during multiple dosing of Itraconazole. Steady-state concentrations are generally reached within about 15 days, with mean C^max values of 0.6 mcg/ml and 1.7 mcg/ml after oral administration of 130 mg once daily and 130 mg twice daily, respectively

Absorption

Effect of Food
The effect of food on the steady-state pharmacokinetics of itraconazole following administration of a 130 mg twice daily dose regimen of Itraconazole (2 x 65 mg) for 14.5 days under fed and fasted conditions was evaluated in 20 healthy volunteers. A high-fat meal with total caloric content of 919 calories (526 fat calories, 260 carbohydrate calories and 133 protein calories) was used in the study. The results are shown in Table 7 below

Table 7: Pharmacokinetic Parameters of Itraconazole Following Administration of Itraconazole 130 mg (2 x 65 mg capsules) Given Twice Daily for 14.5 Days

Under Fed and Fasted Conditions in 20 Healthy Subjects

Distribution

Most of the Itraconazole in plasma is bound to protein (99.8%) with albumin being the main binding component (99.6% for the hydroxyl metabolite).It has also a marked affinity for lipids. Only 0.2 %
Of theitraconazole in plasma is present as free drug. Itraconazole is distributed in a large apparent volume in the body(.700 ml), suggesting the extensive distribution into tissues : concentrations in lung. Kidney, liver ,bone, stomach,spleen and muscle were found to be two of three times higher than corresponding concentration in plasma. Brain to plasma rations were about 1 as measured in beagle dogs.the uptake into keratinous tissues, skin in particular , is up to four times higher than in plasma.

Elimination

The terminal half-life of itraconazole following repeated dose administration of Itraconazole ranges between 34 to 42 hours under fed conditions.

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 feces (54%) within one week of an oral solution dose. Renal excretion of itraconazole and the active metabolite hydroxyitraconazole account for less than 1% of an intravenous dose. Based on an oral radiolabeled dose, fecal 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.

Pharmacokinetics in special populations:

Patients with 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 oral dose of itraconazole 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 itraconazole (tmax, Cmax, and AUC0-8h). Plasma concentration versus-time profiles showed wide intersubject variation in all three groups. After a single intravenous 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 halflife or clearance of itraconazole or hydroxy-itraconazole.

Patients with 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 capsules. 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. Drug Interaction Studies

Omeprazole
The effect of multiple daily oral 40 mg doses (steady-state conditions) of the proton pump inhibitor, omeprazole, on the exposure to itraconazole from a single 130 mg dose of Itraconazole (2 x 65 mg capsules) when dosed under fasted conditions was evaluated in 30 healthy adult subjects. As illustrated in Table 8 below, the mean itraconazole AUC∞ was 22% higher and mean Cmax 31% higher when Itraconazole was co-administered with omeprazole.

Table 8: Pharmacokinetics of Itraconazole Following Single Dose Administration of Itraconazole 130 mg (2 x 65mg capsules) Alone or with Omeprazole 40 mg QD

Administered for 7 Days Under Fasted Conditions in Healthy Volunteers

¹Treatment A:
Itraconazole²
Treatment B:
Omeprazole *T_max
is given as median
(Range)

6.1 Animal Toxicology or Pharmacology

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.

Pink/transparent size ‘0’ hard gelatin capsule filled with off white colored powder.

8.1 Incompatibilities

Not applicable

8.2 Shelf Life

Refer pack

8.3 Packaging Information

10 capsules in blister pack.

8.4 Storage and handling instructions

Store below 30°C. Protect from light and moisture.

Medicine:Keep out of reach of children.

Important Administration Instructions

Instruct the patients that Itraconazole Capsules BP 130 mg (Supra Bioavailable)

• Cannot be interchanged or substituted with other itraconazole products.
• Must be swallowed whole and administered with food.

Congestive Heart Failure
Inform patients about the signs and symptoms of congestive heart failure. Instruct them to discontinue Itraconazole Capsules BP 130 mg (Supra Bioavailable) and contact their healthcare provider immediately, if these signs or symptoms occur during administration.

Hepatoxicity
Instruct patients to stop Itraconazole Capsules BP 130 mg (Supra Bioavailable) treatment immediately and contact their healthcare provider if any signs and symptoms suggestive of liver dysfunction develop. Such signs and symptoms may include unusual fatigue, anorexia, nausea and/or vomiting, jaundice, dark urine, or pale stools.
Use with Proton Pump Inhibitors and Potential Drug Interactions
Advise patients to discuss with their physician the use of Itraconazole Capsules BP 130 mg (Supra Bioavailable) with proton pump inhibitors, such as omeprazole. Instruct patients to contact their physician before taking any other concomitant medications with Itraconazole Capsules BP 130 mg (Supra Bioavailable) to ensure there are no potential drug interactions.

Hearing Loss
Instruct patients that hearing loss can occur with the use of Itraconazole Capsules BP 130 mg (Supra Bioavailable). The hearing loss usually resolves when treatment is stopped but can persist in some patients. Advise patients to inform their healthcare provider if any hearing loss symptoms occur.

Vision Problem
Instruct patients that dizziness or blurred/double vision can sometimes occur with Itraconazole Capsules BP 130 mg (Supra Bioavailable). Advise patients that if they experience these dizziness or blurred/double vision, they should contact their healthcare provider, and instruct the patient not to drive or use machines.

Pregnancy
Advise patients to notify their physician if they become pregnant or intend to become pregnant during therapy.

Manufactured by:
Ravenbhel Healthcare Pvt. Ltd.
At: EPIP, SIDCO, Kartholi, Bari Brahmana,
Jammu – 181133, India.

Marketed by:
Abbott Healthcare Pvt. Ltd.
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Mfg. Lic. No. JK/01/17-18/LL/251 dated 28.03.2023

Version No. 1.0. dated 21.06.2023