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Irunin

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Irunin uses


WARNING: CONGESTIVE HEART FAILURE, CARDIAC EFFECTS, AND DRUG INTERACTIONS

Do not administer Irunin for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. When Irunin was administered intravenously to dogs and healthy human volunteers, negative inotropic effects were seen. If signs or symptoms of congestive heart failure occur during administration of Irunin, discontinue administration.

Drug Interactions: Co-administration of cisapride, pimozide, quinidine, dofetilide, levacetylmethadol (levomethadyl), felodipine, oral midazolam, nisoldipine, triazolam, lovastatin, simvastatin, ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine) or methadone with Irunin is contraindicated. Irunin, a potent cytochrome P450 3A4 isoenzyme system (CYP3A4) inhibitor, may increase plasma concentrations of drugs metabolized by this pathway. Serious cardiovascular events, including QT prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest, and/or sudden death have occurred in patients using cisapride, pimozide, levacetylmethadol (levomethadyl), methadone or quinidine concomitantly with Irunin and/or other CYP3A4 inhibitors.

WARNING: CONGESTIVE HEART FAILURE, CARDIAC EFFECTS AND DRUG INTERACTIONS

See full prescribing information for complete boxed warning.

1 INDICATIONS AND USAGE

Irunin is indicated for the treatment of onychomycosis of the toenail due to Trichophyton rubrum or T. mentagrophytes in non-immunocompromised patients. 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. [See Contraindications (4), Warnings and Precautions (5), Drug Interactions (7), and Clinical Pharmacology (12) .]

2 DOSAGE AND ADMINISTRATION

Irunin should be taken with a full meal at the same time each day. The recommended dose is 200 mg (one tablet) once daily for 12 consecutive weeks.


Use in Patients with Renal Impairment:

Limited data are available on the use of oral Irunin in patients with renal impairment. Caution should be exercised when Irunin is administered to patients with renal impairment.

Use in Patients with Hepatic Impairment:

Limited data are available on the use of oral Irunin in patients with hepatic impairment. Caution should be exercised when Irunin is administered to patients with hepatic impairment.

3 DOSAGE FORMS AND STRENGTHS

Irunin contain 200 mg of Irunin, as a white to slightly grey, oblong, biconvex tablet engraved with "BARRIER" on one side and "It 200" on the other side.

4 CONTRAINDICATIONS


Congestive Heart Failure: Do not administer Irunin 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: Concomitant administration of Irunin and certain drugs that are metabolized by the cytochrome P450 3A4 isoenzyme system (CYP3A4) or where gastrointestinal absorption is regulated by P-gp may result in increased plasma concentrations of those drugs, leading to potentially serious and/or life-threatening adverse events.

Co-administration of cisapride, dofetilide, ergot alkaloids such as dihydroergotamine, ergotamine, ergometrine (ergonovine), and methylergometrine (methylergonovine), felodipine, levacetylmethadol (levomethadyl), lovastatin, methadone, oral midazolam, nisoldipine, pimozide, quinidine, simvastatin, and triazolam with Irunin is contraindicated.

Do not administer Irunin for the treatment of onychomycosis to pregnant patients or to women contemplating pregnancy.

Anaphylaxis and hypersensitivity have been reported with use of Irunin. Irunin is contraindicated for patients who have shown hypersensitivity to Irunin products.

5 WARNINGS AND PRECAUTIONS

5.1 Congestive Heart Failure, Peripheral Edema, and Pulmonary Edema

Cases of CHF, peripheral edema, and pulmonary edema have been reported with Irunin administration among patients being treated for onychomycosis and/or systemic fungal infections. [See Contraindications (4), Warnings and Precautions (5), and Clinical Pharmacology (12) .]

5.2 Cardiac Dysrhythmias

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

5.3 Cardiac Disease

Irunin should not be administered in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF.

Irunin has been shown to have a negative inotropic effect. When Irunin was administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was documented. In a healthy volunteer study of Irunin injection, transient, asymptomatic decreases in left ventricular ejection fraction were observed using gated SPECT imaging; these resolved before the next infusion, 12 hours later.

For patients with risk factors for congestive heart failure, physicians should carefully review the risks and benefits of Irunin 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. Such patients should be informed of the signs and symptoms of CHF, should be treated with caution, and should be monitored for signs and symptoms of CHF during treatment. If signs or symptoms of CHF appear during administration of Irunin, discontinue administration.

5.4 Hepatic Effects

Irunin 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 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 hepatotoxicity, treatment should be discontinued immediately and liver function testing performed.

In patients with elevated or abnormal liver enzymes or active liver disease, or who have experienced liver toxicity with other drugs, treatment with Irunin is not recommended. Liver function monitoring should be done in patients with pre-existing hepatic function abnormalities or those who have experienced liver toxicity with other medications and should be considered in all patients receiving Irunin.

5.5 Calcium Channel Blockers

Calcium channel blockers can have negative inotropic effects which may be additive to those of Irunin. In addition, Irunin can inhibit the metabolism of calcium channel blockers. Therefore, caution should be used when co-administering Irunin and calcium channel blockers due to an increased risk of CHF. Concomitant administration of Irunin and nisoldipine is contraindicated.

5.6 Neuropathy

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

5.7 Hearing Loss

Transient or permanent hearing loss has been reported in patients receiving treatment with Irunin. 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.

6 ADVERSE REACTIONS


To report SUSPECTED ADVERSE REACTIONS, contact Merz Pharmaceuticals, LLC at 1-877-743-8454 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the adverse reaction rate observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Patients in the trial for toenail onychomycosis were treated with a dosing regimen of 200 mg once daily for 12 consecutive weeks.

The most commonly reported adverse reaction leading to discontinuation of Irunin was increased hepatic enzyme (6 subjects, 1.0%), followed by dizziness (3 subjects, 0.5%). No other adverse reaction leading to discontinuation occurred in more than one subject.

The table below lists all adverse reactions reported by at least 1% of patients who received Irunin during 12 weeks of treatment:

Incidence (%) Incidence (%)
BODY SYSTEM/ADVERSE REACTION Irunin Placebo tablet
(N = 582) (N = 191)
INFECTIONS AND INFESTATIONS
Upper respiratory tract infections 6.0% 7.3%
Bacteriuria 1.4% 1.6%
Urinary tract infection 1.0% 0.5%
INVESTIGATIONS
Hepatic enzymes increased 2.9% 0.0%
Electrocardiogram abnormal 1.4% 1.6%
EAR AND LABYRINTH DISORDERS
Hypoacusis 3.3% 3.1%
NERVOUS SYSTEM DISORDERS
Headache 2.2% 1.6%
Dizziness 1.2% 0.0%
GASTROINTESTINAL DISORDERS
Abdominal pain or discomfort 1.7% 2.6%
Diarrhea 1.7% 3.1%
Nausea 1.7% 1.6%
GENERAL DISORDERS OF ADMINISTRATION SITE CONDITIONS
Fatigue 1.5% 2.6%
CARDIAC DISORDERS
Sinus Bradycardia 1.0% 0.0%
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS
Cough 1.2% 0.0%
Pharyngolaryngeal pain 1.0% 0.5%
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS
Back pain 1.2% 2.1%

6.2 Post Marketing Experience

The following adverse reactions have been identified during post-approval use of Irunin (all formulations) and are listed in Table 2 below. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establishing a causal relationship to drug exposure.

Blood and lymphatic system disorders: Leukopenia, neutropenia, thrombocytopenia
Immune system disorders: Anaphylaxis; anaphylactic, anaphylactoid and allergic reactions; serum sickness; angioneurotic edema
Metabolism and nutritional disorders: Hypertriglyceridemia, hypokalemia
Nervous system disorders: Peripheral neuropathy, paresthesia, hypoesthesia, headache, dizziness
Eye disorders: Visual disturbances, including vision blurred and diplopia
Ear and labyrinth disorders: Transient or permanent hearing loss, tinnitus
Cardiac disorders: Congestive heart failure
Respiratory, thoracic and mediastinal disorders: Pulmonary edema
Gastrointestinal disorders: Abdominal pain, vomiting, dyspepsia, nausea, diarrhea, constipation, dysgeusia
Hepato-biliary disorders: Serious hepatotoxicity (including some cases of fatal acute liver failure), hepatitis, reversible increases in hepatic enzymes
Skin and subcutaneous tissue disorders: Toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, leukocytoclastic vasculitis, erythema multiforme, alopecia, photosensitivity, rash, urticaria, pruritus
Musculoskeletal and connective tissue disorders: Myalgia, arthralgia
Renal and urinary disorders: Urinary incontinence, pollakiuria
Reproductive system and breast disorders: Menstrual disorders, erectile dysfunction
General disorders and administration site conditions: Peripheral edema

7 DRUG INTERACTIONS

7.1 Effects of Irunin on Other Drugs

Irunin and its major metabolite, hydroxy-itraconazole, are strong inhibitors of the cytochrome P450 3A4 isoenzyme system (CYP3A4). Therefore, concomitant administration of Irunin and certain drugs metabolized by the cytochrome CYP3A4 may result in increased plasma concentrations of those drugs due to decreased elimination, leading to potentially serious and/or life-threatening adverse events. Irunin is also an inhibitor of P-glycoprotein (P-gp) transporter and may result in increased plasma concentrations of drugs whose gastrointestinal absorption is regulated by P-gp. Whenever possible, plasma concentrations of these drugs should be monitored, and dosage adjustments made after concomitant Irunin therapy is initiated. When appropriate, clinical monitoring for signs or symptoms of increased or prolonged pharmacologic effects is advised. Upon discontinuation, Irunin plasma concentrations decline gradually (especially in patients with hepatic cirrhosis or in those receiving CYP3A4 inhibitors). This is particularly important when initiating therapy with drugs whose metabolism is affected by Irunin.

7.2 Effects of Other Drugs on Irunin

Inducers of CYP3A4 may decrease the plasma concentrations of Irunin. Irunin may not be effective in patients concomitantly taking Irunin and one of these drugs. Therefore, administration of these drugs with Irunin is not recommended.

Inhibitors of CYP3A4 may increase the plasma concentrations of Irunin. Patients who must take Irunin concomitantly with one of these drugs should be monitored closely for signs or symptoms of increased or prolonged pharmacologic effects of Irunin.

Drug plasma concentration increased by Irunin
Antiarrhythmics digoxin, dofetilide, quinidine, disopyramide
Anticonvulsants carbamazepine
Anti-HIV Agents indinavir, ritonavir, saquinavir, maraviroc
Antineoplastics busulfan, docetaxel, vinca alkaloids
Antipsychotics pimozide
Benzodiazepines alprazolam, diazepam, midazolam,For information on parenterally administered midazolam, see the Benzodiazepine paragraph below. triazolam
Calcium Channel Blockers dihydropyridines (including nisoldipine and felodipine), verapamil
Gastrointestinal Motility Agents cisapride
HMG CoA-Reductase Inhibitors atorvastatin, cerivastatin, lovastatin, simvastatin
Immunosuppressants Cyclosporine, tacrolimus, sirolimus
Oral Hypoglycemics oral hypoglycemics (repaglinide)
Opiate Analgesics fentanyl, levacetylmethadol (levomethadyl), methadone
Polyene Antifungals amphotericin B
Other ergot alkaloids, halofantrine, alfentanil, buspirone, methylprednisolone, budesonide, dexamethasone, fluticasone, warfarin, cilostazol, eletriptan, fexofenadine, loperamide
Decrease plasma concentration of Irunin
Anticonvulsants carbamazepine, phenobarbital, phenytoin
Anti-HIV Agents nevirapine, efavirenz
Antimycobacterials isoniazid, rifabutin, rifampin
Gastric Acid Suppressors/Neutralizers antacids, H2-receptor antagonists, proton pump inhibitors
Increase plasma concentration of Irunin
Macrolide Antibiotics clarithromycin, erythromycin
Anti-HIV Agents indinavir, ritonavir
Antipsychotics pimozide
Antiarrhythmics dofetilide, quinidine
Benzodiazepines oral midazolamFor information on parenterally administered midazolam, see the Benzodiazepine paragraph below., triazolam
Calcium Channel Blockers Nisoldipine, felodipine
Ergot Alkaloids dihydroergotamine, ergotamine, ergometrine (ergonovine), methylergometrine (methylergonovine)
Gastrointestinal Motility Agents cisapride
HMG CoA-Reductase Inhibitors lovastatin, simvastatin
Opiate Analgesics levacetylmethadol (levomethadyl), methadone

Antiarrhythmics

The Class IA antiarrhythmic, quinidine and class III antiarrhythmic, dofetilide are known to prolong the QT interval. Co-administration of quinidine or dofetilide with Irunin may increase plasma concentrations of quinidine or dofetilide, which could result in serious cardiovascular events. Therefore, concomitant administration of Irunin and quinidine or dofetilide is contraindicated.

The Class IA antiarrhythmic, disopyramide has the potential to increase the QT interval at high plasma concentrations. Caution is advised when Irunin and disopyramide are administered concomitantly.

Concomitant administration of digoxin and Irunin has led to increased plasma concentrations of digoxin via inhibition of P-glycoprotein.

Anticonvulsants

Carbamazepine, phenobarbital, and phenytoin are all inducers of CYP3A4. Reduced plasma concentrations of Irunin were reported when Irunin was administered concomitantly with phenytoin. Although interactions with carbamazepine and phenobarbital have not been studied, concomitant administration of Irunin and these drugs would be expected to result in decreased plasma concentrations of Irunin. In addition, in vivo studies have demonstrated an increase in plasma carbamazepine concentrations in subjects concomitantly receiving ketoconazole. Although there are no data regarding the effect of Irunin on carbamazepine metabolism, because of the similarities between ketoconazole and Irunin, concomitant administration of Irunin and carbamazepine may inhibit the metabolism of carbamazepine.

Anti-HIV Agents

Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI) such as nevirapine and efavirenz are inducers of CYP3A4. Human pharmacokinetic studies have shown that efavirenz, when concomitantly administered with Irunin, greatly decreased serum concentrations of Irunin and hydroxyl-itraconazole. Concomitant use of Irunin and efavirenz is not recommended.

In vivo studies have shown that nevirapine induces the metabolism of ketoconazole, significantly reducing the bioavailability of ketoconazole. Studies involving nevirapine and Irunin have not been conducted. However, because of the similarities between ketoconazole and Irunin, concomitant administration of Irunin and nevirapine is not recommended.

Concomitant administration of Irunin and protease inhibitors metabolized by CYP3A4, such as indinavir, ritonavir, and saquinavir, may increase plasma concentrations of these protease inhibitors. In addition, concomitant administration of Irunin and indinavir and ritonavir (but not saquinavir) may increase plasma concentrations of Irunin. Caution is advised when Irunin and protease inhibitors must be given concomitantly.

Concomitant administration of Irunin and maraviroc has been reported to increase plasma concentration of maraviroc. The dose of maraviroc should be decreased to 150 mg twice daily when given in combination with Irunin.

Antimycobacterials

Drug interaction studies have demonstrated that plasma concentrations of azole antifungal agents and their metabolites, including Irunin and hydroxyitraconazole, were significantly decreased when these agents were given concomitantly with rifabutin or rifampin. In vivo data suggest that rifabutin is metabolized in part by CYP3A4. Irunin may inhibit the metabolism of rifabutin. Although no formal study data are available for isoniazid, similar effects should be anticipated. Therefore, the efficacy of Irunin could be substantially reduced if given concomitantly with one of these agents and co-administration is not recommended.

Antineoplastics

Irunin may inhibit the metabolism of busulfan, docetaxel, and vinca alkaloids.

Antipsychotics

Pimozide is known to prolong the QT interval and is partially metabolized by CYP3A4. Co-administration of pimozide with Irunin could result in serious cardiovascular events. Therefore, concomitant administration of Irunin and pimozide is contraindicated.

Increases in plasma aripiprazole concentrations have been demonstrated in subjects concomitantly receiving ketoconazole, requiring a reduction of the aripiprazole dose. Because of the similarities between ketoconazole and Irunin, a similar dose reduction for aripiprazole is recommended when patients concomitantly receive Irunin and aripiprazole.

Benzodiazepines

Concomitant administration of Irunin and alprazolam, diazepam, oral midazolam, or triazolam could lead to increased plasma concentrations of these benzodiazepines. Increased plasma concentrations could potentiate and prolong hypnotic and sedative effects. Concomitant administration of Irunin and oral midazolam or triazolam is contraindicated. If midazolam is administered parenterally, special precaution and patient monitoring is required since the sedative effect may be prolonged.

Calcium Channel Blockers

Calcium channel blockers can have a negative inotropic effect which may be additive to those of Irunin; Irunin can inhibit the metabolism of calcium channel blockers such as dihydropyridines (e.g., nifedipine, nisoldipine, and felodipine) and verapamil. Therefore, caution should be used when co-administering Irunin and calcium channel blockers due to an increased risk of CHF.

Concomitant administration of Irunin and nisoldipine results in clinically significant increases in nisoldipine plasma concentrations, which cannot be managed by dosage reduction, therefore the concomitant administration of Irunin and nisoldipine is contraindicated. A clinical study showed that felodipine exposure was increased by co-administration of Irunin, resulting in approximately 6-fold increase in the AUC and 8-fold increase in the Cmax. The concomitant use of Irunin and felodipine is contraindicated.

Edema has been reported in patients concomitantly receiving Irunin and dihydropyridine calcium channel blockers. Appropriate dosage adjustment may be necessary.

Gastric Acid Suppressors/Neutralizers

Reduced plasma concentrations of Irunin were reported when administered concomitantly with H2-receptor antagonists. Studies have shown that absorption of Irunin is impaired when gastric acid production is decreased. Irunin should be administered with a cola beverage if the patient has achlorhydria or is taking H2-receptor antagonists or other gastric acid suppressors. It is advised that antacids be administered at least 1 hour before or 2 hours after administration of Irunin. In a clinical study, when Irunin capsules were administered with omeprazole (a proton pump inhibitor), the bioavailability of Irunin was significantly reduced.

Gastrointestinal Motility Agents

Co-administration of Irunin with cisapride can elevate plasma cisapride concentrations, which could result in serious cardiovascular events. Therefore, concomitant administration of Irunin with cisapride is contraindicated.

3-Hydroxy-3-Methyl-Glutaryl CoA-Reductase Inhibitors

Human pharmacokinetic data suggest that Irunin inhibits the metabolism of atorvastatin, cerivastatin, lovastatin, and simvastatin, which may increase the risk of skeletal muscle toxicity, including rhabdomyolysis. Concomitant administration of Irunin with 3-Hydroxy-3-Methyl-Glutaryl (HMG) CoA-Reductase inhibitors, such as lovastatin and simvastatin, is contraindicated.

Immunosuppressants

Concomitant administration of Irunin and cyclosporine or tacrolimus has led to increased plasma concentrations of these immunosuppressants. Similarly, concomitant administration of Irunin and sirolimus could increase plasma concentrations of sirolimus.

Monitoring of blood concentrations of cyclosporine, tacrolimus, or sirolimus are recommended when Irunin are co-administered with these immunosuppressants and appropriate dosage adjustments should be made.

Macrolide Antibiotics

Erythromycin and clarithromycin are known inhibitors of CYP3A4 and may increase plasma concentrations of Irunin.

Oral Hypoglycemic Agents

Severe hypoglycemia has been reported in patients concomitantly receiving azole antifungal agents and oral hypoglycemic agents. A human pharmacokinetic study showed that co-administration with Irunin and a single dose of repaglinide (on the third day of a regimen of 200 mg initial dose, twice-daily 100 mg Irunin) resulted in a 1.4-fold higher repaglinide AUC. Blood glucose concentrations should be carefully monitored when Irunin and oral hypoglycemic agents are co-administered.

Polyenes Antifungal Agents

Prior treatment with Irunin, like other azoles, may reduce or inhibit the activity of polyenes such as amphotericin B. However, the clinical significance of this drug effect has not been clearly defined.

Opiate Analgesics

Levacetylmethadol (levomethadyl) and methadone are known to prolong the QT interval and are metabolized by CYP3A4. Co-administration of methadone or levacetylmethadol with Irunin could result in serious cardiovascular events. Therefore, concomitant administration of Irunin and methadone or levacetylmethadol are contraindicated.

Fentanyl plasma concentrations could be increased or prolonged by concomitant use of Irunin and may cause potentially fatal respiratory depression.

In vitro data suggest that alfentanil is metabolized by CYP3A4. Administration with Irunin may increase plasma concentrations of alfentanil.

Other

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic effects. Pregnancy Category C

There are no adequate and well-controlled clinical trials in the pregnant women with Irunin. However, cases of congenital abnormalities have been reported with Irunin drug products in post-marketing reports. Therefore, Irunin should not be administered to pregnant women, women planning pregnancy, or women of child bearing potential unless these onychomycosis patients are using effective contraception measures to prevent pregnancy. Effective contraceptive measures should continue throughout the treatment period and for two months thereafter. Irunin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Irunin produced a significant dose-related increase in maternal toxicity, embryotoxicity, and teratogenicity in rats at dose levels of 40-160 mg/kg/day (2-10 times the maximum recommended human dose [MRHD], based on mg/m2/day comparisons), and in mice at 80 mg/kg/day (2 times MRHD, based on mg/m2/day comparisons). Teratogenic changes in rats included major skeletal defects; encephalocele and/or macroglossia developed in mice.

8.3 Nursing Mothers

Irunin is excreted in human milk; therefore, the expected benefits of Irunin therapy for the mother should be weighed against the potential risk from exposure of Irunin to the infant.

8.4 Pediatric Use

The safety and effectiveness of Irunin in pediatric patients have not been established. No pharmacokinetic data on Irunin are available in children.

8.5 Geriatric Use

Irunin was evaluated in 42 of 593 subjects greater than 65 years of age.

Transient or permanent hearing loss has been reported in elderly patients receiving treatment with Irunin. Several of these reports included concurrent administration of quinidine which is contraindicated. Irunin should be used with care in elderly patients.

8.6 Renal Impairment

Limited data are available on the use of oral Irunin in patients with renal impairment. Caution should be exercised when Irunin is administered to patients with renal impairment.

8.7 Hepatic Impairment

Limited data are available on the use of oral Irunin in patients with hepatic impairment. Caution should be exercised when Irunin is administered to patients with hepatic impairment.

10 OVERDOSAGE

Irunin is not removed by dialysis. In the event of accidental overdosage, supportive measures, including gastric lavage with sodium bicarbonate, should be employed.

11 DESCRIPTION

Irunin (itraconazole) is a synthetic triazole antifungal agent for oral use. Irunin is a 1:1:1:1 racemic mixture of four diastereomers (two enantiomeric pairs), each possessing three chiral centers. It may be represented by the following structural formula and nomenclature:

(±)-cis-4-[4-[4-[4[[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolane-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one

Irunin has a molecular formula of C35H38Cl2N8O4 and a molecular weight of 705.64. It is a white to slightly yellowish powder. It is insoluble in water, very slightly soluble in alcohols, and freely soluble in dichloromethane. It has a pKa of 3.70 (based on extrapolation of values obtained from methanolic solutions) and a log (n-octanol/water) partition coefficient of 5.66 at pH 8.1.

Each Irunin is formulated for melt extrusion technology and contains 200 mg of Irunin and the following inactive ingredients: colloidal silicon dioxide, crospovidone, hydrogenated vegetable oil, hypromellose, lactose, microcrystalline cellulose, magnesium stearate, propylene glycol, talc, and titanium dioxide.

Chemical Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Irunin, an azole, is an antifungal agent [See Clinical Pharmacology and Microbiology (12.4) ].

12.3 Pharmacokinetics

The oral bioavailability of Irunin is increased when Irunin is taken with a FDA standard high-fat meal. The pharmacokinetic parameters of Irunin and hydroxy-itraconazole after administration of one Irunin to 9 male and 9 female healthy subjects in fasting and in fed conditions are presented in the table below:

Irunin Hydroxy-itraconazole
Fed Fasted Fed Fasted
Cmax (ng/mL) 213 ± 117mean ± standard deviation 162 ± 107 332 ± 118 264 ± 109
Tmax (hours) 4.6 ± 2.2 2.9 ± 0.8 5.7 ± 2.6 3.4 ± 0.8
AUC0 -∞ (μg.h/mL) 3.34 ± 1.98 2.27 ± 1.44 7.05 ± 3.94 4.58 ± 2.80

The steady-state pharmacokinetics of Irunin and hydroxy-itraconazole were analyzed after oral dosing of 16 healthy volunteers with one Irunin following a moderate-fat breakfast once daily for 14 days in an open-label study. Mean maximum plasma levels of Irunin and hydroxy-itraconazole increased from Day 1 to Day 14 by approximately 6- and 4-fold, respectively. The respective pharmacokinetic parameters from this study are reflected in the table below:

Statistic Day Irunin

N=16

 Hydroxy-itraconazole

N=16
Cmax (ng/mL) Mean (SD) 1 116.8 (43.34) 221.7 (69.21)
14 658.1 (362.16) 974.2 (479.92)
AUC0-24 (ng*h/mL) Mean (SD) 1 905.09 (384.239) 2538.33 (1057.872)
14 9046.81 (5320.516) 19054.95 (10443.214)
Tmax (h) Median

(Min-Max)

 1 4.00 (2.00-5.00) 4.00 (2.00-5.00)
14 4.00 (1.00-24.00) 4.00 (3.00-24.00)
T1/2 (h) Mean (SD) 14 36.84 (10.378) 20.06 (6.998)

In a 2-period, open-label, randomized, cross-over, pivotal bioequivalence study to assess the comparative bioavailability of the Irunin and a marketed 100-mg Irunin capsule, 28 male and 28 female healthy subjects were given as a single dose, 200 mg of Irunin immediately after a moderate-fat breakfast (same caloric and fat contents as in the table above). Fifty-two subjects were included in the final analysis.

The Cmax of the Irunin was comparable to that of the 2 Irunin 100-mg capsules while AUCt and AUC∞ were about 15% higher with the Irunin.

In another 2-period, open-label, randomized, cross-over, pivotal bioequivalence study, 28 male and 28 female healthy subjects were given one Irunin or two 100-mg Irunin capsules following the FDA standard high-fat breakfast. The Cmax and AUC∞ of the Irunin were 20 and 30% lower, respectively, than those of two Irunin 100-mg capsules. Overall, the inter-subject variability was high and coefficient of variances (CV) for AUCs in the above two studies were 44-66%.

Irunin is metabolized predominately by the cytochrome P450 3A4 isoenzyme system (CYP3A4), resulting in the formation of several metabolites. Hydroxyitraconazole, the major metabolite, has in vitro antifungal activity comparable to Irunin. Results of a pharmacokinetics study suggest that Irunin may undergo saturable metabolism with multiple dosing. Based on an oral dose, fecal excretion of the parent drug varies between 3-18% of the dose. Irunin is excreted mainly as inactive metabolites in the urine (35%) and feces (54%) within one week of an oral dose. No single excreted metabolite represents more than 5% of a dose. The plasma protein binding of Irunin has been reported to be 99.8% and that of hydroxy-itraconazole is 99.5%.

12.4 Microbiology

Mechanism of Action

Irunin inhibits the cytochrome P450-dependent synthesis of ergosterol, which is a vital component of fungal cell membranes.

Activity In Vitro

Irunin exhibits in vitro activity against Trichophyton rubrum and Trichophyton mentagrophytes.

Resistance

Isolates from several fungal species with decreased susceptibility to Irunin have been isolated from patients receiving prolonged therapy.

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. The relevance of these in vitro susceptibility data to clinical outcome remains to be elucidated.

Special Populations

Renal Insufficiency

Limited data are available on the use of oral Irunin in patients with renal impairment. A pharmacokinetic study using a single 200-mg dose of Irunin 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. The study did not demonstrate any significant effect of hemodialysis or continuous ambulatory peritoneal dialysis on the pharmacokinetics of Irunin (Tmax, Cmax, and AUC0-8). Plasma concentration-versus-time profiles showed wide intersubject variation in all three groups. Caution should be exercised when the drug is administered in this population.

Hepatic Insufficiency

Irunin is predominantly metabolized in the liver. Patients with impaired hepatic function should be carefully monitored when taking Irunin. A pharmacokinetic study using a single oral 100 mg dose of Irunin was conducted in 6 healthy and 12 cirrhotic subjects. 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 Irunin were noted in cirrhotic subjects compared with healthy subjects. However, overall exposure to Irunin, based on AUC, was similar in cirrhotic patients and in healthy subjects. The prolonged elimination half-life of Irunin observed in the single oral dose clinical trial with Irunin in cirrhotic patients should be considered when deciding to initiate therapy with other medications metabolized by CYP3A4. Data are not available in cirrhotic patients during long-term use of Irunin.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, mutagenicity, or impairment of fertility studies were conducted with Irunin.

Irunin did not exhibit any carcinogenic potential in mice receiving oral doses up to 80 mg/kg/day (2 times MRHD, based on mg/m2/day comparisons) for 23 months. A slightly increased incidence of soft tissue sarcoma was observed in male rats administered 25 mg/kg/day (1.3 times MRHD, based on mg/m2/day comparisons). These tumors may have been related to hypercholesterolemia caused by chronic treatment with Irunin in rats; hypercholesterolemia is not observed with such treatment in dogs or humans. Compared to untreated controls, female rats receiving 50 mg/kg/day (2.5 times MRHD, based on mg/m2/day comparisons) had a statistically insignificant increase in squamous cell carcinoma in lungs (2/50), an uncommon tumor in rats.

Irunin did not exhibit any mutagenic or genotoxic effects when evaluated in a DNA repair test (unscheduled DNA synthesis) in primary rat hepatocytes, in Ames tests (6 Salmonella strains and E. coli), in the mouse lymphoma gene mutation test, in a sex-linked recessive lethal mutation (Drosophila melanogaster) test, in chromosome aberration test (human lymphocytes), in a cell transformation assay (C3H/10T½ C18 mouse embryo fibroblasts), in a dominant lethal mutation test in male and female mice, and in micronucleus tests in mice and rats.

Irunin did not affect the fertility in male or female rats treated with oral doses up to 40 mg/kg/day (2 times MRHD, based on mg/m2/day comparisons); however, parental toxicity occurred at this dosage. More severe parental toxicity was observed at 160 mg/kg/day (10 times MRHD, based on mg/m2/day comparisons).

14 CLINICAL STUDIES

The efficacy of Irunin for the treatment of onychomycosis of the toenail was examined in a randomized, multi-center, placebo-controlled, third-party blinded trial comparing Irunin to two 100 mg Irunin capsules and placebo tablets.

In the clinical study, 791 subjects with diagnosis of distal and/or lateral subungual onychomycosis were randomized to Irunin (N= 593) or placebo tablets (N= 198) once daily for 12 consecutive weeks. The median age of subjects enrolled in the trial was 48 years and 75% were males. At baseline, 95.1% of subjects had onychomycosis due to T. rubrum with a baseline global severity score of 'Moderate' which was defined as a target toenail involvement ≤50% dystrophy and/or discoloration with clear evidence of subungual hyperkeratosis and/or onycholysis.

The primary endpoint was the proportion of subjects with a Complete Cure at Week 52, nine months after completion of study medication. A Complete Cure was defined as both a Clinical Cure (no evidence of onychomycosis in target nail; normal nail unit without subungual hyperkeratosis or onycholysis) and Mycological Cure (negative KOH and negative culture). The following table illustrates the study results for Irunin and Placebo:

Endpoint Irunin

N=593

 Placebo

N=198
Complete CureComplete Cure defined as Clinical Cure (no evidence of onychomycosis in target nail; normal nail unit without subungual hyperkeratosis or onycholysis) and Mycological Cure (negative KOH and negative culture) 22.3% 1.0%

The Mycologic Cure rate was 44% and the Clinical Cure rate was 26% for subjects treated with Irunin. Comparatively, the Mycological Cure rate was 6% and the Clinical Cure rate was 3% for subjects treated with Placebo Tablets.

Efficacy results comparing Irunin to 200 mg of Irunin capsules (two 100 mg capsules) were similar.

16 HOW SUPPLIED/STORAGE AND HANDLING

How Supplied

Irunin is available containing 200 mg of Irunin, as a white to slightly grey, oblong, biconvex tablet engraved with "BARRIER" on one side and "It 200" on the other side. Each carton (NDC 0259-1420-28) contains two blister cards of 14 tablets each (NDC 0259-1420-14).

Storage

Store at controlled room temperature 15° to 25°C (59° to 77°F). Excursions permitted to 15° to 30°C (59° to 86°F). Protect from light and moisture. Keep out of reach of children.

17 PATIENT COUNSELING INFORMATION


17.1 Information for Patients


ONM:3PI

FDA-Approved Patient Labeling

Irunin (itraconazole)

Read this Patient Information before you start using Irunin and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or treatment.

What is the most important information I should know about Irunin?

Irunin can cause serious life-threatening side effects, including:


What is Irunin?

Irunin is a prescription medicine used to treat fungal infections of the toenails. It is not known if Irunin is safe and effective in children under the age of 18.

Who should not take Irunin?

Do not take Irunin if you:


What should I tell my doctor before taking Irunin?

Before taking Irunin, tell your doctor if you:


Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.

Taking Irunin with certain other medicines could lead to serious or life-threatening medical problems.


Talk to your doctor or pharmacist before you start any new medicine. They can tell you if it is safe to take Irunin with your other medicines.

Know the medicines you take. Keep a list of your medicines and show it to your doctor and pharmacist when you get a new medicine.

How should I take Irunin?

Take Irunin exactly as prescribed by your doctor. Be sure to finish all of your Irunin as prescribed by your doctor.


What are the possible side effects of Irunin?

Irunin can cause serious side effects, including:


Common side effects of Irunin include:

  • increased liver enzyme in blood test results
  • upper respiratory infection or cold (runny nose, cough and sneeze)
  • urinary tract infection (burning and painful urination)
  • stomach pain
  • diarrhea
  • nausea
  • headache
  • tiredness
  • throat pain
  • back pain

These are not all of the possible side effects of Irunin. Tell your doctor if you any side effect that bothers you or that does not go away. For more information, ask your doctor.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Irunin?


General Information:

Medicines are sometimes prescribed for conditions that are not mentioned in Patient Information leaflets. Do not use Irunin for a condition for which it was not prescribed. Do not give Irunin to other people, even if they have the same symptoms that you have. It may harm them.

This leaflet summarizes the most important information about Irunin. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Irunin that is written for health professionals.

For more information about Irunin call 1-877-743-8454.

What are the ingredients in Irunin?

Active ingredient: Irunin

Inactive ingredients: colloidal silicon dioxide, crospovidone, hydrogenated vegetable oil, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, propylene glycol, talc, and titanium dioxide.

The following are registered trademarks of their respective manufacturers:

Dolophine® (Roxane Laboratories, Inc), Mevacor® (Merck & Co., Inc.), Advicor® (Kos Pharmaceuticals, Inc.), Altocor (Andrx Laboratories), Zocor® (Merck & Co., Inc.), Halcion® (Pharmacia), Versed® (Roche Pharmaceuticals), Cardioquin® (The Purdue Frederick Company), Quinaglute® (Berlex Laboratories), Quinidex® (A.H. Robins), Tikosyn (Pfizer, Inc.), Propulsid® (Janssen Pharmaceutica Products, L.P.), Orlaam® (Roxane Laboratories), Migranal® (Xcel Pharmaceuticals), Ergonovine (PDRX Pharmaceuticals), Cafergot® (Novartis Pharmaceuticals Corporation), Methergine® (Novartis Pharmaceuticals Corporation), Orap® (Gate Pharmaceuticals), and Sular® (First Horizon Pharmaceutical Corporation)

What happens if I have a fungal nail infection?

Anyone can have a fungal nail infection, but it is usually found in adults. When a fungus infects the nail, the infected part of the nail may turn yellow or brown. If not treated, the fungus may spread, and more of the nail may change color, may become thick or brittle, and the tip of the nail may become raised. In some patients, this can cause pain and discomfort.

Manufactured by:

Sanico N.V.

2300 Turnhout, Belgium

Manufactured for

Merz Pharmaceuticals, LLC

4215 Tudor Lane

Greensboro, NC 27410

5011889

10/2012

ONM:3PIL

PRINCIPAL DISPLAY PANEL - 28 Tablet Carton

NDC 0259-1420-28

Rx Only

MERZ

2 Blister Cards

28 Tablets Total

Each Blister card contains

14 Tablets

Irunin

(itraconazole) Tablets 200 mg

PRINCIPAL DISPLAY PANEL - 28 Tablet Carton

Irunin pharmaceutical active ingredients containing related brand and generic drugs:


Irunin available forms, composition, doses:


Irunin destination | category:


Irunin Anatomical Therapeutic Chemical codes:


Irunin pharmaceutical companies:


References

  1. Dailymed."ONMEL (ITRACONAZOLE) TABLET [MERZ PHARMACEUTICALS, LLC]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."ITRACONAZOLE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. "itraconazole". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Irunin?

Depending on the reaction of the Irunin after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Irunin not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Irunin addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology


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