Itraconazole 100mg Capsules Taj Pharma

  1. Name of the medicinal product

Itraconazole 100mg Capsules Taj Pharma

  1. Qualitative and quantitative composition

Each hard-gelatin capsule conatins:
Itraconazole Pellets equivalent to
Itraconazole BP                           100mg
Excipients                                      q.s

For the full list of excipients, see section 6.1.

  1. Pharmaceutical form

Capsule, hard

Opaque green capsule, containing yellowish-beige beads.

  1. Clinical particulars

4.1 Therapeutic indications

Itraconazole is indicated for the treatment of the following fungal infections when thought likely to be susceptible:

  • Vulvovaginal candidiasis.
  • Pityriasis versicolor.
  • Dermatophytoses caused by organisms susceptible to itraconazole (Trichophyton spp. Microsporum spp. Epidermophyton floccosum) e.g. tinea pedis, tinea cruris, tinea corporis, tinea manuum.
  • Oral candidiasis.
  • Onychomycosis caused by dermatophytes and/or yeasts.

Consideration should be given to official guidance regarding the appropriate use of antifungal agents.

For further information please refer to section 5.1.

4.2 Posology and method of administration

Posology

Treatment schedules in adults for each indication are as follows:

Indication Dose
Vulvovaginal candidiasis 200 mg twice daily for 1 day
Pityriasis versicolor 200 mg once daily for 7 days
Tinea corporis, tinea cruris 100 mg once daily for 15 days
Tinea pedis, tinea manuum 100 mg once daily for 30 days
Oral candidiasis 100 mg once daily for 14 days
Onychomycosis 200 mg once daily for 3 months

For skin infections, optimal clinical and mycological effects are reached at 1 – 4 weeks after cessation of treatment and for nail infections at 6 – 9 months after the cessation of treatment. This is because elimination of itraconazole from skin and nails is slower than from plasma.

In Acquired Immune Deficiency Syndrome and neutropenic patients: for the treatment of oral candidiasis 200 mg once daily for 14 days is recommended due to the impaired absorption of itraconazole in these patient groups.

The length of treatment for systemic fungal infections should be dictated by the mycological and clinical response to therapy.

Paediatric population:

Since clinical data on the use of itraconazole in paediatric patients is limited, its use in children is not recommended unless the potential benefit outweighs the potential risks (see section 4.4).

Prophylaxis of fungal infections: there are no efficacy data available in neutropenic children. Limited safety experience is available with a dose of 5 mg/kg per day administered in two intakes (see section 4.8).

Elderly:

There are inadequate data on itraconazole in elderly for its use to be recommended, unless the potential benefits outweigh the risks.

Hepatic impairment:

Itraconazole is predominantly metabolised by the liver. A slight decrease in oral bioavailability in cirrhotic patients has been observed, although this was not of statistical significance. The terminal half-life was significantly increased. The dose should be adapted if necessary. Monitoring of plasma levels may be necessary.

Renal impairment:

The oral bioavailability of itraconazole may be lower in patients with renal insufficiency. Dose adjustment may be considered. Monitoring of plasma levels may be necessary. Itraconazole cannot be removed by dialysis.

Decreased gastric acidity:

Absorption of itraconazole is impaired when gastric acidity is decreased. For information on patients with achlorhydria and patients on acid secretion suppressors or taking acid neutralising medicinal products (see section 4.4).

Method of administration

Itraconazole is for oral administration and must be taken immediately after a meal for maximal absorption.

4.3 Contraindications

Itraconazole is contraindicated in patients with known hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Co-administration of the following substances is contraindicated with Itraconazole (see also section 4.5):

– substrates metabolized via cytochrome P450 3A4, that can prolong the QT interval, such as astemizole, bepridil, cisapride, dofetilide, levacetylmethadole (levomethadyl), mizolastine, pimozide, quinidine, sertindole and terfenadine. Co-administration may result in increased plasma concentrations of these substrates, which can lead to QT prolongation and rare occurrences of torsade de pointes.

– HMG-CoA reductase inhibitors metabolized via cytochrome P450 3A4 such as atorvastatin, lovastatin and simvastatin

– triazolam and oral midazolam

– ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine)

– eletriptan

– nisoldipine

Itraconazole must not be used during pregnancy, except in life-threatening situations (see section 4.6).

Itraconazole 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).

4.4 Special warnings and precautions for use

Cardiac effects

In a healthy volunteer study with intravenous itraconazole, 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 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. 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 ischemic and valvular disease; significant pulmonary disease, such as chronic obstructive pulmonary disease; and renal failure and other edematous 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, itraconazole 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 metabolisms of calcium channel blockers.Therefore, concurrent administration of itraconazole and calcium channel blockers should be carried out with caution (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 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 were 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. 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 close liver enzyme monitoring is necessary.

Reduced gastric acidity

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

Paediatric population

Clinical data on the use of Itraconazole capsules in paediatric patients is limited. Itraconazole 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 itraconazole in elderly patients is limited. Itraconazole 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.

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 sections 4.3 and 4.5). The hearing loss usually resolves when treatment is stopped, but can persist in some patients.

Women of childbearing potential

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

Immunocompromised patients

In some immunosuppressed patients (e.g. in neutropenia, AIDS or after organ transplantation), the oral bioavailability of itraconazole may be decreased.

Patients with immediately life-threatening systemic fungal infections

Due to the pharmacokinetic properties (see section 5.2), itraconazole capsules are not recommended for initiation of treatment in patients with immediately life-threatening systemic fungal infections.

Patients with AIDS

In patients with AIDS having received treatment for a systemic fungal infection such as sporotrichosis, blastomycosis, histoplasmosis or cryptococcosis (meningeal and non-meningeal) and who are considered at risk for relapse, the treating physician should evaluate the need for a maintenance treatment.

Cross-hypersensitivity

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

Neuropathy

If neuropathy occurs that may be attributable to Itraconazole, the treatment should be discontinued.

Cross-resistance

In systemic candidosis, if fluconazole-resistant strains of Candida species are suspected, it cannot be assumed that these are sensitive to itraconazole, hence their sensitivity should be tested before the start of itraconazole therapy.

Interaction potential

Itraconazole has a potential for clinically important drug interactions (see section 4.5).

Itraconazole should not be used within 2 weeks after discontinuation of treatment with CYP3A4 inducing agents (rifampicin, rifabutin, phenobarbital, phenytoin, carbamazepine, Hypericum perforatum (St. John´s wort)). The use of itraconazole with these drugs may lead to subtherapeutic plasma levels of itraconazole and thus treatment failure.

This product contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

  1. Medicinal products influencing the absorption of itraconazole

Medicinal products that reduce the gastric acidity impair the absorption of itraconazole (see section 4.4).

  1. Medicinal products affecting the metabolism of itraconazole

Itraconazole is metabolized mainly via cytochrome P450 3A4.

Interaction studies have been performed with rifampicin, rifabutin and phenytoin, which are potent enzyme inducers of CYP3A4. Since the bioavailability of itraconazole and hydroxy-itraconazole was decreased in these studies to such an extent that efficacy may be largely reduced, the combination of itraconazole with these potent enzyme inducers is not recommended. No formal study data are available for other enzyme inducers, such as carbamazepine, Hypericum perforatum (St John’s Wort), phenobarbital and isoniazid, but similar effects should be anticipated.

Potent inhibitors of this enzyme such as ritonavir, indinavir, clarithromycin and erythromycin may increase the bioavailability of itraconazole.

  1. Effect of itraconazole on the metabolism of other medicinal products

3.1 Itraconazole can inhibit the metabolism of medicinal products metabolized via enzymes of the cytochrome 3A family. This may result in a higher and/or prolonged action of these agents including side effects. When using concomitant medication, the corresponding label should be consulted for information on the route of metabolism.

After stopping treatment, itraconazole plasma concentrations decline gradually, depending on the dose and duration of treatment (see section 5.2). This should be taken into account when the inhibitory effect of itraconazole on co-medicated drugs is considered.

Examples are:

The following medicinal products are contraindicated with itraconazole:

astemizole, bepredil, cisapride, dofetilide, levacetylmethadole (levomethadyl), mizolastine, pimozide, quinidine, sertindole and terfenadine, since co-administration may result in increased plasma concentrations of these substrates, which can lead to QT prolongation and rare occurrences of torsade de pointes.

– HMG-CoA reductase inhibitors metabolized via cytochrome P450 3A4 such as atorvastatin, lovastatin and simvastatin

– triazolam and oral midazolam

– ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine)

– nisoldipine

– eletriptan

Caution should be exercised when co-administering itraconazole with calcium channel blockers due to an increased risk of CHF. In addition to possible pharmacokinetic interactions involving the drug metabolizing enzyme CYP3A4, calcium channel blockers can have negative inotropic effects which may be additive to those of itraconazole.

The following agents should be used with caution and their plasma concentrations, effects or side effects be monitored. If necessary, their dosage should be reduced when administered concomitantly with itraconazole:

– oral anticoagulants;

– HIV protease inhibitors such as indinavir, ritonavir, saquinavir;

– certain antineoplastic agents such as busulfan, docetaxel, trimetrexate and vinca alkaloids;

– calcium channel blockers metabolized via cytochrome P450 3A4 such as dihydropyridines and verapamil;

– certain immunosuppressive agents: ciclosporin, rapamycin (also known as sirolimus) and tacrolimus;

– certain glucocorticoids such as budesonide, dexamethasone, fluticasone and methylprednisolone;

– Digoxin (via inhibition of P-glycoprotein)

– others: alfentanil, alprazolam, brotizolam, buspirone, carbamazepine, cilostazole, disopyramide, ebastine, fentanyl, halofantrine, midazolam i.v., reboxetine, repaglinide, rifabutin

3.2 No interactions between itraconazole and zidovudine (AZT) or fluvastatin have been observed.

No enzyme-inducing effects on the metabolism of ethinylestradiol and norethisterone caused by itraconazole have been observed.

  1. Effect on plasma protein binding

In vitro studies have shown that there are no interactions on plasma protein binding between itraconazole and imipramine, propranolol, diazepam, cimetidine, indomethacin, tolbutamide and sulfamethazine.

4.6 Fertility, pregnancy and lactation

Pregnancy

Itraconazole must not be used during pregnancy except for life-threatening cases where the potential benefit to the mother outweighs the potential harm to the fetus (see section 4.3).

In animal studies itraconazole has shown reproduction toxicity (see section 5.3).

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 causal 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 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 itraconazole capsules should use contraceptive precautions. Effective contraception should be continued until the menstrual period following the end of itraconazole therapy.

Breastfeeding

A very small amount of itraconazole is excreted in human milk. The expected benefits of itraconazole capsules therapy should therefore be weighed against the potential risk of breast-feeding. In case of doubt, the patient should not breast-feed.

Fertility

There was no evidence of a primary influence on fertility based on preclinical safety data (see section 5.3).

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

4.8 Undesirable effects

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 clinical trials involving 2104 itraconazole-treated patients in the treatment of dermatomycoses or onychomycosis, the most frequently reported adverse experiences 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, 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)

System Organ Class Common

≥ 1/100 to < 1/10

Uncommon

≥ 1/1000 to < 1/100

Rare

≥ 1/10 000 to < 1/1000

Not known

(frequency cannot be estimated from the available postmarketing data)

Blood and lymphatic system disorders Leukopenia Neutropenia,

thrombocytopenia

Immune system disorders Hypersensitivity* Anaphylactic reaction,

anaphylactoid reaction,

angioneurotic oedema,

serum sickness

Metabolism and nutrition disorders Hypokalemia,

hypertriglyceridemia

Nervous system disorders Headache,

dizziness,

paraesthesia

Hypoaesthesia Peripheral neuropathy*
Eye disorders Visual disturbance Vision blurred and diplopia
Ear and labyrinth disorders Tinnitus Transient or permanent hearing loss*
Cardiac disorders Congestive heart failure*
Respiratory, thoracic and mediastinal disorders Dyspnoe Pulmonary oedema
Gastrointestinal disorders Abdominal pain,

nausea

Vomiting,

diarrhoea,

constipation,

dyspepsia,

dysgeusia,

flatulence

Pancreatitis
Hepatobiliary disorders Hyperbilirubinaemia,

Alanine aminotransferase increased,

Aspartate aminotransferase increased

Hepatic enzyme increased Acute hepatic failure*,

hepatitis,

hepatotoxicity*

Skin and subcutaneous tissue disorders Rash Urticaria,

alopecia,

pruritus

Toxic epidermal necrolysis,

Stevens-Johnson Syndrome,

acute generalised exenthematous pustulosis,

erythema multiforme,

exfoliative dermatitis,

leukocytoclastic vasculitis,

photosensitivity

Musculoskeletal and connective tissue disorders Myalgia,

arthralgia

Renal and urinary disorders Pollakiuria Urinary incontinence
Reproductive system and breast disorders Menstrual disorder Erectile dysfunction
General disorders and administration site conditions Oedema Pyrexia

* see section 4.4.

Paediatric population

The safety of itraconazole was evaluated in 250 paediatric patients aged 6 months to 14 years who participated in five open-label clinical trials. These patients received at least one dose of itraconazole oral solution for prophylaxis of fungal infections or for treatment of oral thrush or systemic fungal infections and provided safety data. Based on pooled safety data from these clinical trials, the very common reported ADRs in paediatric patients were vomiting (36.0%), pyrexia (30.8%), diarrhoea (28.4%), mucosal inflammation (23.2%), rash (22.8%), abdominal pain (17.2%), nausea (15.6%), hypertension (14.0%), and cough (11.2%). The nature of ADRs in paediatric patients is similar to that observed in adult subjects, but the incidence is higher in the paediatric patients.

4.9 Overdose

No data are available.

In the event of 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.

  1. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antimycotics for systemic use, triazole derivatives.

Mechanism of action

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

Pharmacokinetic/pharmacodynamic relationship

The PK/PD relationship for itraconazole, and for triazoles in general, is poorly understood and is complicated by limited understanding of antifungal pharmacokinetics.

Mechanisms of resistance

Resistance of fungi to azoles appears to develop slowly and is often the result of several genetic mutations. Mechanisms that have been described are:

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

– Point mutations in ERG11 that lead to decreased affinity of 14-alpha-demethylase for 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 though resistance to one member of the class does not necessarily confer resistance to other azoles.

Breakpoints

Using EUCAST methods, breakpoints for itraconazole have only been established for aspergillus species. These breakpoints are given in the table below, according to EUCAST Antifungal Clinical Breakpoint Table v. 4.1, valid from 2012-03-05)

Antifungal agent Species-related breakpoints (S≤/R>) (mg/L) Non-species related breakpointsS≤/R>
A. flavus A. fumigatus A. nidulans A. niger A. terreus
Itraconazole1 1/2 1/2 1/2 IE2,3 1/2 IE3
  1. = Aspergillus

S = Susceptible, R = Resistant

  1. Monitoring of itraconazole trough concentrations in patients treated for fungal infection is recommended.
  2. The ECOFFs for these species are in general one step higher than for A. fumigatus.
  3. The MIC values for isolates of A. niger and A. versicolor are in general higher than those for A. fumigatus. Whether this translates into a poorer clinical response is unknown.

IE = There is insufficient evidence (IE) to set breakpoints for these species.

Using CLSI methods, breakpoints for itraconazole have only been established for Candida species from superficial mycotic infections. 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 infections 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.

Commonly susceptible species
Aspergillus spp.2
Blastomyces dermatitidis1
Candida albicans
Candida parapsilosis
Cladosporium spp.
Coccidioides immitis1
Cryptococcus neoformans
Epidermophyton floccosum
Fonsecaea spp. 1
Geotrichum spp.
Histoplasma spp.
Malassezia (formerly Pityrosporumspp.
Microsporum spp.
Paracoccidioides brasiliensis1
Penicillium marneffei1
Pseudallescheria boydii
Sporothrix schenckii
Trichophyton spp.
Trichosporon spp.
Species for which acquired resistance may be a problem
Candida glabrata3
Candida krusei
Candida tropicalis3
Inherently resistant organisms
Absidia spp.
Fusarium spp.
Mucor spp.
Rhizomucor spp.
Rhizopus spp.
Scedosporium proliferans
Scopulariopsis spp.

These organisms may be encountered in patients who have returned from travel outside Europe.

Itraconazole-resistant strains of Aspergillus fumigatus have been reported.

Natural intermediate susceptibility.

Paediatric population

The tolerability and safety of itraconazole was studied in the prophylaxis of fungal infections in 103 neutropenic paediatric patients aged 0 to 14 years (median 5 years) in an open-label uncontrolled phase III clinical study. Most patients (78%) were undergoing allogenic bone marrow transplantation for haematological malignancies. All patients received 5 mg/kg/day of itraconazole oral solution as a single or divided dose. Due to the design of the study, no formal conclusion with regard to efficacy could be derived. The most common adverse events considered definitely or possibly related to itraconazole were vomiting, abnormal liver function, and abdominal pain.

5.2 Pharmacokinetic properties

General pharmacokinetic characteristics

The pharmacokinetics of itraconazole has been investigated in healthy subjects, special populations and patients after single and multiple dosing.

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 dose. The observed absolute bioavailability of itraconazole 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 as measured in beagle dogs. The uptake into keratinous tissues, skin in particular, is up to four times higher than in plasma.

Biotransformation

Itraconazole is extensively metabolised by the liver into a large number of metabolites. One of the main metabolites is hydroxy-itraconazole, which has in vitro antifungal activity comparable to itraconazole. Plasma concentrations of the hydroxy-itraconazole 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.

Elimination

Itraconazole is excreted as inactive metabolites to about 35% in urine within one week and to about 54% with feces. Renal excretion of the parent drug accounts for less than 0.03% of the dose, whereas fecal excretion of unchanged drug varies between 3 – 18% of the dose. Itraconazole clearance decreases at higher doses due to saturable hepatic metabolism.

Linearity/non-linearity

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 and AUC values 4 to 7-fold higher than those seen after a single dose. The mean elimination half-life of itraconazole is about 40 hours after repeated dosing.

Special Populations

Hepatic Insufficiency: A pharmacokinetic study using a single 100 mg dose of itraconazole (one 100 mg capsule) was conducted in 6 healthy and 12 cirrhotic subjects. No statistically significant differences in AUC were seen between these two groups. A statistically significant reduction in average Cmax (47%) and a two fold increase in the elimination half-life (37 ± 17 versus 16 ±5 hours) of itraconazole were noted in cirrhotic subjects compared with healthy subjects.

Data are not available in cirrhotic patients during long-term use of itraconazole.

Renal Insufficiency: 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.

Paediatric population

Two pharmacokinetic studies have been conducted in neutropenic children aged 6 months to 14 years in which itraconazole oral solution was administered 5 mg/kg once or twice daily. The exposure to itraconazole was somewhat higher in older children (6 to 14 years) compared to younger children. In all children, effective plasma concentrations of itraconazole were reached within 3 to 5 days after initiation of treatment and maintained throughout treatment.

5.3 Preclinical safety data

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.

  1. Pharmaceutical particulars

6.1 List of excipients

Sugar spheres, Poloxamer 188, Hypromellose

Capsule shell.

Titanium dioxide, Indigo carmine, Gelatin, Quinoline yellow

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years.

6.4 Special precautions for storage

Do not store above 25°C.

Store in the original package in order to protect from moisture.

6.5 Nature and contents of container

OPA/Aluminium/PVC-Aluminium blisters

Pack sizes: 4, 6, 14, 15, 18, 28, 60, 84, 100 capsules.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

7.Manufactured in India by:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com

Itraconazole 100 mg capsules Taj Pharma

Package leaflet: information for the user
Itraconazole
Itraconazole  is a registered trademark

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

  • Keep this leaflet. You may need to read it again
  • If you have any further questions, ask your doctor or pharmacist
  • This medicine has been prescribed for you Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours
  • If you get any side effects, talk to your doctor or This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

  1. What Itraconazole capsules are and what they are used for
  2. What you need to know before you take Itraconazole capsules
  3. How to take Itraconazole capsules
  4. Possible side effects
  5. How to store Itraconazole capsules
  6. Contents of the pack and other information

 

  1. What Itraconazole capsules are and what they are used for

Itraconazole  capsules contain a medicine called itraconazole. This belongs to a group of medicines called ‘antifungals’.

Itraconazole  capsules are used for infections caused by fungi or yeasts in adults. They are used for:

  • Infections of the mouth or vagina causing ‘thrush’
  • Skin infections
  • Infections affecting other parts of the body

Patches of skin may take a few weeks to completely clear up after you have finished your treatment with Itraconazole  capsules. Finger and toe nails may take several months to completely clear up. This is because your skin or nail will only look normal after new skin or nail has grown, even though the medicine has killed the fungus that caused the infection.

  1. What you need to know before you take Itraconazole capsules

Do not take Itraconazole  capsules:

  • If you are allergic to anything in Itraconazole capsules (listed in section 6 below)
  • If you are pregnant or could become pregnant unless your doctor has told you to (see ‘Pregnancy and breast-feeding’ below)

Do not takethis medicine if any of the above applies to you. If you are not sure, talk to your doctor or pharmacist before taking Itraconazole  capsules.

Warnings and precautions

Talk to your doctor or pharmacist before taking this medicine:

  • If you have ever had kidney problems. Your dose of Itraconazole capsules may have to be changed
  • If you have ever had liver problems such as yellow skin (jaundice). Your dose of Itraconazole capsules may have to be changed. If after taking this medicine you have a severe lack of appetite, feel sick (nausea), are sick (vomiting), feel unusually tired, get stomach pain, muscle weakness, yellowing of the skin or whites of the eyes, unusually dark urine, pale stools or hair loss, stop taking Itraconazole  capsules and tell your doctor straight away
  • If you have ever had a heart problem including heart failure (also called congestive heart failure or CHF). Itraconazole capsules could make it If after taking this medicine you get any of the following:
    • shortness of breath
    • unexpected weight gain
    • swelling of your legs or tummy
    • feel unusually tired
    • wake up short of breath at night

stop taking Itraconazole  capsules and tell your doctor straight away. These may be signs of heart failure

  • If you have Acquired Immunodeficiency Syndrome (AIDS) or your immune system is not working as well as it should
  • If you have had an allergic reaction to another antifungal product in the past

If you are not sure if any of the above applies to you, talk to your doctor or pharmacist before taking Itraconazole  capsules.

Children and the elderly

Itraconazole  capsules are not normally given to children under the age of 12 or the elderly. However, your doctor may prescribe them in special cases.

Blood tests

If your Itraconazole  capsules course is for more than one month, your doctor may want to check your liver by testing your blood.

Other medicines and Itraconazole  capsules

Tell your doctor or pharmacist if you are taking or have recently taken or might take any other medicines. This includes medicines that you buy without a prescription or herbal medicines.

In particular, do not take the following list of medicines with Itraconazole  capsules and tell your doctor if you are taking any of these:

  • Medicines for hay fever or allergy called terfenadine, astemizole or mizolastine
  • Medicines to lower cholesterol called lovastatin or simvastatin
  • Medicines for an irregular heart beat called quinidine, disopyramide, dronedarone or dofetilide
  • Medicines used to treat angina (crushing chest pain) and high blood pressure called bepridil, felodipine, lercanidipine, ivabradine, ranolazine and nisoldipine
  • Medicines for migraine headaches called dihydroergotamine and ergotamine
  • Medicines for the treatment of drug abuse called levacetylmethadol and methadone
  • Cisapride – for digestive problems
  • Colchicine (in patients with kidney and liver problems as well) – for gout
  • Eplerenone – a diuretic
  • Ergometrine (ergonovine) and methylergometrine (methylergonovine) – used after giving birth
  • Halofantrine – for malaria
  • Irinotecan – for cancer
  • Midazolam (by mouth) or triazolam – for anxiety or to help you sleep
  • Pimozide, lurasidone and sertindole – for conditions affecting thoughts, feelings and behaviour

Do not start taking Itraconazole  capsules and tell your doctor if you are taking any of the above. Also, upon completing your course of Itraconazole  capsules, do not take any of the medicines listed above for 2 weeks.

Tell your doctor if you are taking the following medicines as they are not recommended with Itraconazole  capsules unless your doctor feels it is necessary.

  • Medicines for the treatment of cancer called dasatinib, nilotinib and trabectedin
  • Aliskiren – for high blood pressure
  • Colchicine – for gout
  • Everolimus – usually given after an organ transplant
  • Fentanyl – a strong painkiller
  • Rivaroxaban – a medicine to thin blood
  • Salmeterol – for asthma and other breathing problems
  • Tamsulosin – for urinary incontinence in men
  • Vardenafil – for erection problems

Also, upon completing your course of Itraconazole  capsules, do not take any of the medicines listed above for 2 weeks.

Do not take any of following medicines 2 weeks before and while you are taking Itraconazole  capsules unless your doctor tells you otherwise:

  • Medicines for tuberculosis called rifampicin, rifabutin or isoniazid
  • Medicines for epilepsy called carbamazepine, phenytoin or phenobarbital
  • Medicines to treat viral infections called efavirenz or nevirapine

Tell your doctor before taking, or if you are already taking, any of the following medicines. They may stop Itraconazole  capsules from working properly. Your doctor may need to alter the dose of Itraconazole  capsules or your other medicine:

  • Strong painkillers called alfentanil, buprenorphine (by injection or under your tongue) and oxycodone

Medicines for indigestion, stomach ulcers or heartburn can affect the stomach producing acid. There must be enough acid in your stomach to make sure that your body can use the medicine. For this reason you should wait at least an hour after taking one of these other medicines before taking Itraconazole  capsules or wait for two hours after taking Itraconazole  capsules before taking any of these other medicines. If you take medicines that stop the production of stomach acid, you should take Itraconazole  capsules with a drink of cola (not diet cola)

  • Medicines used for anxiety or to help you sleep (tranquillisers), such as buspirone, alprazolam or brotizolam
  • Medicines used in the treatment of cancer such as bortezomib, busulphan, docetaxel, erlotinib, ixabepilone, lapatinib, trimetrexate and a group of medicines known as ‘vinca alkaloids’
  • Medicines for conditions affecting thoughts, feelings and behaviour called aripiprazole, haloperidol, perospirone, quetiapine, ramelteon and risperidone
  • Medicines to thin the blood (anticoagulants) such as warfarin and dabigatran
  • Medicines for HIV infection such as ritonavir, darunavir, indinavir, fosamprenavir and (They are called ‘antiviral protease inhibitors’.) Also maraviroc
  • Medicines for bacterial infections called ciprofloxacin, clarithromycin or erythromycin
  • Medicines that act on the heart and blood vessels called nadolol, digoxin and cilostazol or ‘calcium channel-blockers’ such as dihydropyridines and verapamil
  • Medicines for inflammation, asthma or allergies (given by mouth or injection) called methylprednisolone, fluticasone, budesonide or dexamethasone
  • Medicines that are usually given after an organ transplant called ciclesonide, ciclosporin, tacrolimus, rapamycin (also known as sirolimus) or temsirolimus.
  • Medicines to treat and overactive bladder – fesoterodine, imidafenacin, solifenacin or tolterodine
  • Alitretinoin (by mouth) – for eczema
  • Aprepitant and domperidone – to stop you feeling and being sick
  • Atorvastatin – to lower cholesterol
  • Cinacalcet – for an over active parathyroid gland
  • Ebastine – for allergy
  • Eletriptan – for migraine headaches
  • Mozavaptan or tolvaptan – for low sodium blood levels
  • Praziquantel – for treatment of worms
  • Reboxetine – for depression
  • Repaglinide or saxagliptin – for diabetes
  • Meloxicam – to reduce inflammation and pain
  • Midazolam – to help you relax or sleep when given into a vein
  • Sildenafil and tadalafil – for erection problems

Tell your doctor before taking, or if you are already taking any of the above. They may need to alter the dose of Itraconazole  capsules or your other medicine.

Itraconazole  capsules with food and drink

Always take Itraconazole  capsules straight after a meal as this helps your body to use the medicine.

Pregnancy, breast-feeding and Fertility

  • Do not take Itraconazole capsules if you are pregnant unless your doctor has told you You should use contraception to make sure that you do not become pregnant when taking this medicine
  • The medicine in Itraconazole capsules stays in your body for some time after you have stopped taking After your treatment has finished, you must use contraception up until your next period (menstrual bleed). Ask your doctor for advice on what type of contraception to use
  • If you become pregnant after starting a course of Itraconazole capsules, stop taking them and tell your doctor straight away
  • Do not breast-feed if you are taking Itraconazole capsules, as small amounts of the medicine could pass into your milk. Ask your doctor for advice

Ask your doctor or pharmacist for advice before taking any medicine if you are pregnant or breast-feeding.

Driving and using machines

Itraconazole  capsules can sometimes cause dizziness, blurred/double vision or hearing loss. If you have these symptoms do not drive or use machines.

Itraconazole  capsules contain sucrose (sugar)

If your doctor has told you that you are intolerant of some sugars, contact them before taking this medicine.

3.      How to take Itraconazole  capsules

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure.

Taking Itraconazole  capsules

  • Always take Itraconazole capsules straight after a meal as this helps your body to use the medicine
  • Swallow the capsules whole with some liquid
  • There must be enough acid in your stomach to make sure that your body can use the medicine. Medicines for indigestion, stomach ulcers or heartburn can affect the stomach producing acid. For this reason you should wait two hours after taking Itraconazole capsules before taking any of these other medicines. If you do take medicines that stop the production of stomach acid, you should take Itraconazole  capsules with a drink of cola

How much to take

Your doctor will tell you how many Itraconazole  capsules to take and for how long.

The recommended dose is:

Yeast infection of the vagina (thrush)

  • Take 2 capsules in the morning and two capsules 12 hours later for one day only

Yeast infection of the mouth (oral thrush)

  • Take 1 capsule each day for 15 days

Fungal infections of the skin

The dosage depends on your infection. Your doctor might tell you to take:

  • 2 capsules each day for 7 days, or
  • 1 capsule each day for 15 days, or
  • 1 capsule each day for 30 days

Fungal infections in other parts of the body

Your doctor will tell you how many Itraconazole  capsules to take and for how long depending on your infection.

If you take more Itraconazole  capsules than you should

If you take more Itraconazole  capsules than you were told to, talk to your doctor or go to the nearest hospital casualty department straight away.

If you forget to take Itraconazole  capsules

  • If you forget to take your capsules, take them as soon as you remember. However, if it is nearly time for the next capsules, skip the missed capsules
  • Do not take a double dose to make up for a forgotten dose

If you stop taking Itraconazole  capsules

Keep taking Itraconazole  capsules for as long as your doctor has told you. Do not stop your treatment just because you feel better.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

4.      Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Stop taking Itraconazole  capsules and tell your doctor straight away if you notice or suspect any of the following. You may need urgent medical treatment.

  • Sudden signs of allergy such as rash, hives (also known as nettle rash or urticaria), severe irritation of your skin, swelling of the face, lips, tongue or other parts of the body. These may be signs of a severe allergic This only happens in a small number of people
  • Severe skin disorders with peeling and/or rashes with small pustules (with a fever) or blistering of the skin, mouth, eyes and genitals, with fever, chills, aching muscles and generally feeling unwell. (This occurs rarely)
  • A tingling sensation, numbness or weakness in your (This occurs rarely)
  • Severe lack of appetite, feeling sick (nausea), being sick (vomiting), unusual tiredness, stomach pain, muscle weakness, yellowing of your skin or whites of your eyes (jaundice), unusually dark urine, pale stools or hair These may be signs of a liver problem. (This only happens in a small number of people)
  • Shortness of breath, unexpected weight gain, swelling of your legs or abdomen, feeling unusually tired or waking up short of breath at These may be signs of heart failure. Shortness of breath can also be a sign of fluid on the lungs. (This occurs rarely)

Tell your doctor or pharmacist if you notice any of the following side effects:

Common (affects less than 1 in 10 people)

  • Stomach ache, feeling sick (nausea)
  • Headache

Uncommon (affects less than 1 in 100 people)

  • Problems with periods
  • Sinusitis, runny nose, coughs and colds
  • Constipation, diarrhoea, wind, being sick (vomiting), indigestion

Rare (affects less than 1 in 1000 people)

  • Increases in liver function tests (shown by blood tests)
  • Unexpected passing of urine or need to urinate (pass water) more often
  • Problems with sight including blurred vision and double vision
  • Change in taste
  • Certain blood disorders which may increase the risk of infections
  • Ringing in your ears
  • Hearing loss (may be permanent)
  • Severe upper stomach pain, often with nausea and vomiting (inflammation of the pancreas)
  • Swelling due to fluid under the skin
  • Unusual hair loss or thinning (alopecia)
  • High levels of triglycerides in the blood (shown by blood tests)
  • Red, itchy, flaking or peeling skin
  • Sensitivity of the skin to light
  • Erection difficulties

Reporting of side-effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet.

  1. How to store Itraconazole  capsules

Keep out of the sight and reach of children.

  • Store the capsules in their carton to protect from light
  • Do not store above 30oC
  • Do not use this medicine after the expiry date which is stated on the The expiry date refers to the last day of that month

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

 

6.      Contents of the pack and other information

What Itraconazole  capsules contains

The active substance is itraconazole. Each capsule contains 100 mg of itraconazole.

The other ingredients are sugar spheres, hypromellose and macrogol. The capsule is made of gelatin and the colours titanium dioxide, indigotin disulphonate sodium and erythrosine. See section 2 ‘Itraconazole  capsules contain sucrose (sugar)’ for further information.

What Itraconazole  capsules looks like and contents of the pack

  • Itraconazole capsules are hard capsules coloured pink and They are supplied in blister packs of 4, 15 or 60 capsules.

7.Manufactured in India by:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com

 

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Taj Generics (Taj Pharma) provides a wide range of products to the Indian market, including an extensive range of generics and specialty products; Our products cover a vast array of therapeutic categories, and we offer an extensive range of dosage forms and delivery systems including oral solids, controlled-release, steriles, injectables, topicals, liquids, transdermals, semi-solids and high-potency products. Our Generics portfolio offers over 1500 products in the major therapeutic areas of gastro-intestinal, cardiovascular, pain management, oncology, anti-infectives, paediatrics and dermatology.