CANDITRAL Capsule

Indication:

For the treatment of the following fungal infections in Immunocompromised and non-immunocompromised patients:

1. Blastomycosis, pulmonary and extra pulmonary

2. Histoplasmosis, including chronic cavitary pulmonary disease and disseminated, nonmeningealhistoplasmosis,

3. Aspergillosis, pulmonary and extra pulmonary, in patients who are intolerant of or who are refractory to amphotericin B therapy.

4. Tinea versicolor

5. Tinea corporis, Tinea cruris

6. Dermatomycosis of palms and soles (tinea manuum, tinea pedis)

Specimens for cultures and other relevant laboratory studies (wet mount, histopathology, and 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-infective therapy should be adjusted accordingly.

ITRACONAZOLE capsules are also indicated for the treatment of the following fungal infections in non-immunocompromised patients:

1. Onychomycosis of the toenail, with or without fingernail involvement, due to dermatophytes (tineaunguium),

2. Onychomycosis of the fingernail due to dermatophytes (tineaunguium).

Prior to initiating treatment, appropriate nail specimens for laboratory testing (KOH preparation, fungal culture, or nail biopsy) should be obtained to confirm the diagnosis of onychomycosis.

Dosage and Administration:

These capsules should be taken with a full meal to ensure maximal absorption. These capsules must be swallowed whole.

Solution and should not be used interchangeably.

Treatment of Blastomycosis and Histoplasmosis:

The recommended dose is 200mg once daily. If there is no obvious improvement, or there is evidence of progressive fungal disease, the dose should be increased in 100mg increments to a maximum of 400mg daily. Doses above 200mg/day should be given in two divided doses.

Treatment of Aspergillosis

A daily dose of 200-400mg is recommended.

Treatment in life-threatening situations: in life-threatening situations, a loading dose should be used. Although clinical studies did not provide for a loading dose, it is recommended, based on pharmacokinetic data, that a loading dose of 200mg (2 capsules) three times daily (600mg/day) be given for the first 3 days of treatment. Treatment should be continued for a minimum of three months and until clinical parameters and laboratory test indicate that the active fungal infection has subsided. An inadequate period of treatment may lead to recurrence of active infection. ITRACONAZOLE capsules and ITRACONAZOLE Oral solution should not be used interchangeably. only the oral solution has been demonstrated effective for oral and/or esophageal candidiasis.

Treatment of Onychomycosis

Toenails with or without fingernail involvement: The recommended dose is 200mg once daily for 12 consecutive weeks.

Treatment of Onychomycosis

Fingernails only: The recommended dosing regimen is 2 treatment pulses, each consisting of 200mg bi. 400mg/day for 1 week. The pulses are separated by a 3-week period without ITRACONAZOLE.

Use in Patients with renal impairment

Limited data are avilable on the use of oral itraconazole in patients with renal impairment. Caution should be exercised when this drug is administered in this patient population. (See CLINICAL PHARMACOLOGY: Special populations, WARNINGS, and PRECAUTIONS).

Use in Patients with Hepatic impairment

Limited data are avilable 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 CLINICAL PHARMACOLOGY: Special populations, WARNINGS, and PRECAUTIONS).

Treatment of tineaversicolor: 2 capsules once daily (equivalent to 200mg itraconazole) for the duration of 7 days.

Treatment of Tineacorporis, Tineacruris: 1 capsule once daily (equivalent to 100mg itraconazole) for the duration of 2 weeks.

Treatment of dermatomycosis of palms and soles (tineamanus, tineapdedis): 1 capsule once daily (equivalent to 100mg itraconazole itraconazole) for the duration of 4 weeks itraconazole remains substantially longer in the skin than in the blood. Optimal healing is thus achieved 2-4weeks after withdrawing itraconazole in case of mycoses of the skin.

Congestive Heart Failure

These capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF.

Drug interactions-Calcium Channel blockers, adverse reactions.

See the package insert about the details.

Gastrointestinal: Nausea, vomiting, diarrhea, abdominal pain, anorexia

Body as a whole: Edema, fatigue, fever, malaise

Skin and Appendages: Rash, pruritus

Central/Peripheral Nervous System: Headache, dizziness

Psychiatric: Libido decreased, somnolence

Metabolic/Nutritional: Hypokalemia

Urinary System: Albuminuria

Liver and Biliary System: Hepatic function abnormal

Reproductive System, Male: Impotence

See the package insert about the details below:

Plasma concentrations increase for the following drugs: methadone, disopyramide, dofetilide, dronedarone, quinidine, ergot alkaloids (such as dihydroergatamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine)), irinotecan, lurasidone, oral midazolam, pimozide, triazolam, felodipine, nisoldipine, ranolazine, eplerenone, cisapride, lovastatin, simvastatin and, in subjects with renal or hepatic impairment, colchicine. This increase in drug concentrations caused by co-administration with itraconazole may increase or prolong both the pharmacologic effect and/or adverse reactions to these drugs. For example, increased plasma concentrations of some these drugs can lead to QT prolongation and ventricular tachyarrhythmias including occurrences of torsade de pointes, a potentially fatal ITRACONAZOLE should not be administered for the treatment of onychomycosis to pregnant patients or to women contemplating pregnancy.

ITRACONAZOLE is contraindicated for patients who have shown hypersensitivity to itraconazole.

There is limited information regarding cross-hypersensitivity between itraconazole and other azole antifungal agents. Caution should be used when prescribing ITRACONAZOLE to patients with hypersensitivity to other azoles.

Itraconazole is mainly metabolized through CYP3A4. Other drugs that either share this metabolic pathway or modify CYP3A4 activity may influence the pharmacokinetics of itraconazole. Similarly, itraconazole may modify the pharmacokinetics of other drugs 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 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 inhibitor) impair the absorption of itraconazole from itraconazole capsules. It is recommended that these drugs be used with caution when co administered with itraconazole capsules:

- It is recommended that itraconazole capsules 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 these capsules.

- Upon co administration, it is recommended that the antifungal activity be monitored and the itraconazole dose increased as deemed necessary.

Co administration 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 reduced. Examples include:

- Antibacterials: isoniazid, rifabutin, rifampicin

- Anticonvulsants: carbamazepine, 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 co administration, 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, ritonavir. It is recommended that these drugs be used with caution when co administered 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.

Drugs that may have their plasma concentrations increased by itraconazole

Itraconazole and its major metabolite, hydroxy-itraconazole, can inhibit the metabolism of drugs metabolized by CYP3A4 and can inhibit the drugs 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 torsade de pointes, a potentially fatal arrhythmia. Once treatment is stopped, itraconazole plasma concentration decrease to an almost undetectable concentration within 7-14 days, depending on the dose and duration of treatment in patients with hepatic cirrhosis or in subjects receiving CYP3A4 inhibitors, the decline in plasma concentrations may be even more gradual. This is particularly important when initiating therapy with drugs whose metabolism is affected by itraconazole.

See the package insert about the details below:

Pregnancy

There are no studies in pregnant women. ITRACONAZOLE should not be used for the treatment of systemic fungal infections in pregnancy only if the benefit outweighs the potential risk.

Lactation

The expected benefits of ITRACONAZOLE therapy for the mother should be weighed against the potential risk from exposure of itraconazole to the infant.

See the package insert about the details.

Hepatic effects:

ITRCONAZOLE has been associated with rare cases of serious hepatotoxicity, including liver failure and death. Some of these cases had neither pre-existing liver disease nor 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, treatment should be discontinued and liver function testing performed.

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 disease:

ITRACONAZOLE capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF.

Interaction potential:

ITRACONAZOLE has a potential for clinically important drug interactions. Co administration of specific drugs with itraconazole may result in changes in efficacy of itraconazole and/or the co-administered 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 PRECAUTIONS; Drug interactions.

Interchangeability

PRECAUTIONS

General: ITRACONAZOLE capsules should be administered after a full meal.

Hepatotoxicity

Neuropathy

Hearing Loss

Information for patients:

- The topical effects of mucosal exposure may be different between the ITRACONAZOLE capsules and oral solution. Only the oral solution has been demonstrated effective for oral and/or esophageal candidiasis. ITRACONAZOLE capsules should not be used interchangeably with ITRACONAZOLE oral solution.

Instruct patients to take ITRACONAZOLE capsules with a full meal.

ITRACONAZOLE capsules must be swallowed whole.

- Instruct patients about the signs and symptoms of congestive heart failure, and if these signs or symptoms occur during ITRACONAZOLE administration, they should discontinue ITRACONAZOLE and contact their healthcare provider immediately.

- Instruct patients to stop ITRACONAZOLE 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.

- Instruct patients to contact their physician before taking any concomitant medications with itraconazole to ensure there are no potential drug interactions.

- Instruct patients that hearing loss can occur with the use of itraconazole. The hearing loss usually resolves when treatment is stopped, but can persist in some patients. Advise patients to discontinue therapy and inform their physicians if any hearing loss symptoms occur.

- Instruct patients that dizziness or blurred/double vision can sometimes occur with itraconazole. Advice patients that if they experience these events, they should not drive or use machines.

In vitro studies have demonstrated that itraconazole inhibits the cytochrome P450-dependent synthesis of ergosterol, which is a vital component of fungal cell membranes.

Activity in Vitro and In Vivo

Itraconazole exhibits in vitro activity against Blastomyces dermatitidis, Histoplasma capsulatum, Histoplasmaduboisii, Aspergillusflavus, Aspergillusfumigatus, and Trichophytonspecies.

Correlation between minimum inhibitory concentration (MIC) results in vitro and clinical outcome has yet to be established for azole antifungal agents.

Drug resistance

Isolates from several fungal species with decreased susceptibility to itraconazole have been isolated in vitro and from patients receiving prolonged therapy.

Itraconazole is not active against Zygomycetes (e.g. Rhizopusspp., Rhizomucorspp., Mucorspp. and Absidiaspp.), Fusariumspp., Scedosporiumspp., and scopulariopsisspp.

Cross-resistance

Several in vitro studies have reported that some fungal clinical isolates with reduced susceptibility to one azole antifungal agent may also be less susceptible to other azole derivatives. The finding of cross-resistance is dependent on a number of factors, including the species evaluated, its clinical history, the particular azole compounds compared, and the type of susceptibility test that is performed.

Studies (both in vitro and in vivo) suggest that the activity of amphotericin B may be suppressed by prior azole antifungal therapy. As with other azoles, itraconazole inhibits the 14C-demethylation step in the synthesis of ergosterol, a cell wall component of fungi.

Ergosterol is the active site for amphotericin B. In one study the antifungal activity of amphotericin B against Aspergillusfumigatus infections in mice was inhibited by ketoconazole therapy. The clinical significance of test results obtained in this study is unknown.