Onmel

Description

ONMEL (itraconazole) is a synthetic triazole antifungal agent for oral use. Itraconazole 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-(1 H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolane-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-(1-methylpropyl)-3 H-1,2,4-triazol-3-one

Itraconazole has a molecular formula of C H Cl N O 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 ONMEL is formulated for melt extrusion technology and contains 200 mg of itraconazole and the following inactive ingredients: colloidal silicon dioxide, crospovidone, hydrogenated vegetable oil, hypromellose, lactose, microcrystalline cellulose, magnesium stearate, propylene glycol, talc, and titanium dioxide.

Indications

ONMEL 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, WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS, and CLINICAL PHARMACOLOGY]

Dosage And Administration

ONMEL 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 itraconazole in patients with renal impairment. Caution should be exercised when ONMEL is administered to patients with renal impairment. [See CLINICAL PHARMACOLOGY and WARNINGS AND PRECAUTIONS]

Use In Patients With Hepatic Impairment

Limited data are available on the use of oral itraconazole in patients with hepatic impairment. Caution should be exercised when ONMEL is administered to patients with hepatic impairment. [See CLINICAL PHARMACOLOGY and WARNINGS AND PRECAUTIONS]

How Supplied

Dosage Forms And Strengths

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

Storage And Handling

ONMEL is available containing 200 mg of itraconazole, 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.

Manufactured by: Sanico N.V., 2300 Turnhout, Belgium. Manufactured for: Merz Pharmaceuticals, LLC, 4215 Tudor Lane, Greensboro, NC 27410. Revised: Nov 2012

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 ONMEL 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 ONMEL during 12 weeks of treatment:

Table 1: Adverse Reactions Occurring at Frequencies ≥ 1% in the Onychomycosis Clinical Trial

BODY SYSTEM/ADVERSE REACTION	Incidence (%) ONMEL (N = 582)	Incidence (%) Placebo tablet (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%
I NVESTIGATIONS
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%

 

Post Marketing Experience

The following adverse reactions have been identified during post-approval use of itraconazole (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.

Table 2: Postmarketing Reports of Adverse Reactions for Itraconazole

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

 

Effects Of ONMEL On Other Drugs

Itraconazole and its major metabolite, hydroxy-itraconazole, are strong inhibitors of the cytochrome P450 3A4 isoenzyme system (CYP3A4). Therefore, concomitant administration of ONMEL 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. Itraconazole 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 ONMEL therapy is initiated. When appropriate, clinical monitoring for signs or symptoms of increased or prolonged pharmacologic effects is advised. Upon discontinuation, itraconazole 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 itraconazole.

Effects Of Other Drugs On ONMEL

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

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

Table 3: Selected Drugs that altered or are predicted to alter the plasma concentration of itraconazole or have their plasma concentration altered by ONMEL*

Drug plasma concentration increased by itraconazole
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, † 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 itraconazole
Anticonvulsants	carbamazepine, phenobarbital, phenytoin
Anti-HIV Agents	nevirapine, efavirenz
Antimycobacterials	isoniazid, rifabutin, rifampin
Gastric Acid Suppressors/Neutralizers	antacids, H 2-receptor antagonists, proton pump inhibitors
Increase plasma concentration of itraconazole
Macrolide Antibiotics	clarithromycin, erythromycin
Anti-HIV Agents	indinavir, ritonavir
*This list is not all-inclusive. † For information on parenterally administered midazolam, see the Benzodiazepine paragraph below.

 

Table 4: Selected Drugs that are contraindicated for use with itraconazole*

Antipsychotics	pimozide
Antiarrhythmics	dofetilide, quinidine
Benzodiazepines	oral midazolam †, 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
*This list is not all-inclusive. †For information on parenterally administered midazolam, see the Benzodiazepine paragraph below.

 

Antiarrhythmics

The Class IA antiarrhythmic, quinidine and class III antiarrhythmic, dofetilide are known to prolong the QT interval. Coadministration of quinidine or dofetilide with itraconazole may increase plasma concentrations of quinidine or dofetilide, which could result in serious cardiovascular events. Therefore, concomitant administration of ONMEL and quinidine or dofetilide is contraindicated. [See BOXED WARNING, CONTRAINDICATIONS, and WARNINGS AND PRECAUTIONS]

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

Concomitant administration of digoxin and itraconazole 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 itraconazole were reported when itraconazole was administered concomitantly with phenytoin. Although interactions with carbamazepine and phenobarbital have not been studied, concomitant administration of ONMEL and these drugs would be expected to result in decreased plasma concentrations of itraconazole. 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 itraconazole on carbamazepine metabolism, because of the similarities between ketoconazole and itraconazole, concomitant administration of ONMEL 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 itraconazole, greatly decreased serum concentrations of itraconazole and hydroxyl-itraconazole. Concomitant use of ONMEL 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 itraconazole have not been conducted. However, because of the similarities between ketoconazole and itraconazole, concomitant administration of ONMEL and nevirapine is not recommended.

Concomitant administration of ONMEL 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 ONMEL and indinavir and ritonavir (but not saquinavir) may increase plasma concentrations of itraconazole. Caution is advised when ONMEL and protease inhibitors must be given concomitantly.

Concomitant administration of ONMEL 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 itraconazole.

Antimycobacterials

Drug interaction studies have demonstrated that plasma concentrations of azole antifungal agents and their metabolites, including itraconazole 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. ONMEL may inhibit the metabolism of rifabutin. Although no formal study data are available for isoniazid, similar effects should be anticipated. Therefore, the efficacy of ONMEL could be substantially reduced if given concomitantly with one of these agents and coadministration is not recommended.

Antineoplastics

ONMEL 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 itraconazole could result in serious cardiovascular events. Therefore, concomitant administration of ONMEL and pimozide is contraindicated. [See BOXED WARNING, CONTRAINDICATIONS, and WARNINGS AND PRECAUTIONS]

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 itraconazole, a similar dose reduction for aripiprazole is recommended when patients concomitantly receive itraconazole and aripiprazole.

Benzodiazepines

Concomitant administration of itraconazole 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 ONMEL and oral midazolam or triazolam is contraindicated. [See CONTRAINDICATIONS, and WARNINGS AND PRECAUTIONS] 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 itraconazole; itraconazole 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 itraconazole and calcium channel blockers due to an increased risk of CHF.

Concomitant administration of ONMEL and nisoldipine results in clinically significant increases in nisoldipine plasma concentrations, which cannot be managed by dosage reduction, therefore the concomitant administration of ONMEL and nisoldipine is contraindicated. A clinical study showed that felodipine exposure was increased by co-administration of itraconazole, resulting in approximately 6-fold increase in the AUC and 8-fold increase in the Cmax. The concomitant use of ONMEL and felodipine is contraindicated. [See CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS, and CLINICAL PHARMACOLOGY]

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

Gastric Acid Suppressors/Neutralizers

Reduced plasma concentrations of itraconazole were reported when administered concomitantly with H2-receptor antagonists. Studies have shown that absorption of itraconazole is impaired when gastric acid production is decreased. ONMEL 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 ONMEL. In a clinical study, when itraconazole capsules were administered with omeprazole (a proton pump inhibitor), the bioavailability of itraconazole was significantly reduced.

Gastrointestinal Motility Agents

Co-administration of itraconazole with cisapride can elevate plasma cisapride concentrations, which could result in serious cardiovascular events. Therefore, concomitant administration of ONMEL with cisapride is contraindicated. [See BOXED WARNING, CONTRAINDICATIONS, and WARNINGS AND PRECAUTIONS]

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

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

Immunosuppressants

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

Monitoring of blood concentrations of cyclosporine, tacrolimus, or sirolimus are recommended when ONMEL are coadministered with these immunosuppressants and appropriate dosage adjustments should be made.

Macrolide Antibiotics

Erythromycin and clarithromycin are known inhibitors of CYP3A4 (See Table 3) and may increase plasma concentrations of itraconazole.

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 itraconazole and a single dose of repaglinide (on the third day of a regimen of 200 mg initial dose, twice-daily 100 mg itraconazole) resulted in a 1.4-fold higher repaglinide AUC. Blood glucose concentrations should be carefully monitored when ONMEL and oral hypoglycemic agents are coadministered.

Polyenes Antifungal Agents

Prior treatment with itraconazole, 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. Coadministration of methadone or levacetylmethadol with itraconazole could result in serious cardiovascular events. Therefore, concomitant administration of ONMEL and methadone or levacetylmethadol are contraindicated.

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

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

Other

• Elevated concentrations of ergot alkaloids can cause ergotism, i.e., a risk for vasospasm potentially leading to cerebral ischemia and/or ischemia of the extremities. Concomitant administration of ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine) with ONMEL is contraindicated.
• Halofantrine has the potential to prolong the QT interval at high plasma concentrations. Caution is advised when ONMEL and halofantrine are administered concomitantly.
• Human pharmacokinetic data suggest that concomitant administration of itraconazole and buspirone results in significant increases in plasma concentrations of buspirone.
• Itraconazole may inhibit the metabolism of certain glucocorticosteroids such as budesonide, dexamethasone, fluticasone and methylprednisolone.
• Itraconazole enhances the anticoagulant effect of coumarin-like drugs, such as warfarin.
• Cilostazol and eletriptan are CYP3A4 metabolized drugs that should be used with caution when co-administered with ONMEL.
• Co-administration of itraconazole with meloxicam decreased peak plasma concentrations and the exposure of meloxicam by 64% and 37%, respectively. Monitor patients for responses to meloxicam when itraconazole is concomitantly administered and dose adjustment should be considered if warranted.
• Co-administration of itraconazole with fexofenadine increased the peak plasma concentration and the total exposure of fexofenadine by approximately 3-fold and augmented its anti-histamine effects.
• Co-administration of itraconazole with loperamide increased peak plasma concentrations of loperamide by 3-fold and the total exposure by 3.9-fold. In addition, itraconazole is an inhibitor of P-glycoprotein and may inhibit the transport of loperamide out of the brain, leading to elevated concentrations of loperamide in the brain. Patients should be monitored for signs and symptoms of loperamide overdose, such as CNS depression, including drowsiness, dizziness and respiratory depression, and a dose or dosing frequency should be adjusted as necessary.

Included as part of the PRECAUTIONS section.

Precautions

Congestive Heart Failure, Peripheral Edema, And Pulmonary Edema

Cases of CHF, peripheral edema, and pulmonary edema have been reported with itraconazole administration among patients being treated for onychomycosis and/or systemic fungal infections. [See CONTRAINDICATIONS and CLINICAL PHARMACOLOGY]

Cardiac Dysrhythmias

Life-threatening cardiac dysrhythmias and/or sudden death have occurred in patients using cisapride, pimozide, levacetylmethadol (levomethadyl), methadone, or quinidine concomitantly with itraconazole and/or other CYP3A4 inhibitors. Concomitant administration of these drugs with ONMEL is contraindicated. [See BOXED WARNING, CONTRAINDICATION, and DRUG INTERACTIONS]

Cardiac Disease

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

Itraconazole has been shown to have a negative inotropic effect. When itraconazole was administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was documented. In a healthy volunteer study of itraconazole 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 ONMEL 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 ONMEL, discontinue administration.

Hepatic Effects

Itraconazole 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 itraconazole 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 ONMEL.

Calcium Channel Blockers

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

Neuropathy

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

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 BOXED WARNING and DRUG INTERACTIONS] The hearing loss usually resolves when treatment is stopped, but can persist in some patients.

Patient Counseling Information

[See FDA-approved Patient Labeling.]

Information For Patients

• 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 inform their physicians if any hearing loss occurs.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

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

Itraconazole 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 itraconazole 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.

Itraconazole 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.

Itraconazole 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).

Clinical Studies

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

In the clinical study, 791 subjects with diagnosis of distal and/or lateral subungual onychomycosis were randomized to ONMEL (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 ONMEL and Placebo:

Table 7: Primary Efficacy Results at Week 52

Endpoint	ONMEL N=593	Placebo N=198
Complete Cure*	22.3%	1.0%
* Complete 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)

 

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

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

Use In Specific Populations

Pregnancy

Teratogenic effects

Pregnancy Category C

There are no adequate and well-controlled clinical trials in the pregnant women with itraconazole. However, cases of congenital abnormalities have been reported with itraconazole drug products in post-marketing reports. Therefore, ONMEL 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. ONMEL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Itraconazole 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.

Nursing Mothers

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

Pediatric Use

The safety and effectiveness of ONMEL in pediatric patients

Warnings

Included as part of the PRECAUTIONS section.

Precautions

Congestive Heart Failure, Peripheral Edema, And Pulmonary Edema

Cases of CHF, peripheral edema, and pulmonary edema have been reported with itraconazole administration among patients being treated for onychomycosis and/or systemic fungal infections. [ See CONTRAINDICATIONS, and CLINICAL PHARMACOLOGY]

Cardiac Dysrhythmias

Life-threatening cardiac dysrhythmias and/or sudden death have occurred in patients using cisapride, pimozide, levacetylmethadol (levomethadyl), methadone, or quinidine concomitantly with itraconazole and/or other CYP3A4 inhibitors. Concomitant administration of these drugs with ONMEL is contraindicated. [See BOXED WARNING, CONTRAINDICATIONS, and DRUG INTERACTIONS]

Cardiac Disease

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

Itraconazole has been shown to have a negative inotropic effect. When itraconazole was administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was documented. In a healthy volunteer study of itraconazole 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 ONMEL 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 ONMEL, discontinue administration.

Hepatic Effects

Itraconazole 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 itraconazole 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 ONMEL.

Calcium Channel Blockers

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

Neuropathy

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

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 BOXED WARNING, WARNINGS AND PRECAUTIONS, and DRUG INTERACTIONS] The hearing loss usually resolves when treatment is stopped, but can persist in some patients.

Patient Counseling Information

Information For Patients

• 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 inform their physicians if any hearing loss occurs.

[See FDA-approved Patient Labeling.]

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

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

Itraconazole 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 itraconazole 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.

Itraconazole 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/10T C18 mouse embryo fibroblasts), in a dominant lethal mutation test in male and female mice, and in micronucleus tests in mice and rats.

Itraconazole 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).

Use In Specific Populations

Pregnancy

Teratogenic Effects.

Pregnancy Category C

There are no adequate and well-controlled clinical trials in the pregnant women with itraconazole. However, cases of congenital abnormalities have been reported with itraconazole drug products in post-marketing reports. Therefore, ONMEL 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. ONMEL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Itraconazole 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/m /day comparisons), and in mice at 80 mg/kg/day (2 times MRHD, based on mg/m /day comparisons). Teratogenic changes in rats included major skeletal defects; encephalocele and/or macroglossia developed in mice.

Nursing Mothers

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

Pediatric Use

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

Geriatric Use

ONMEL was evaluated in 42 of 593 subjects (7.1%) greater than 65 years of age.

Transient or permanent hearing loss has been reported in elderly patients receiving treatment with itraconazole. Several of these reports included concurrent administration of quinidine which is contraindicated. [See BOXED WARNING, CONTRAINDICATIONS, DRUG INTERACTIONS, and WARNINGS AND PRECAUTIONS] Itraconazole should be used with care in elderly patients. [See WARNINGS AND PRECAUTIONS]

Renal Impairment

Limited data are available on the use of oral itraconazole in patients with renal impairment. Caution should be exercised when ONMEL is administered to patients with renal impairment. [See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION]

Hepatic Impairment

Limited data are available on the use of oral itraconazole in patients with hepatic impairment. Caution should be exercised when ONMEL is administered to patients with hepatic impairment. [See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION]

have not been established. No pharmacokinetic data on ONMEL are available in children. 

Geriatric Use

ONMEL was evaluated in 42 of 593 subjects (7.1%) greater than 65 years of age.

Transient or permanent hearing loss has been reported in elderly patients receiving treatment with itraconazole. Several of these reports included concurrent administration of quinidine which is contraindicated. [See BOXED WARNING, CONTRAINDICATIONS, DRUG INTERACTIONS, and WARNINGS AND PRECAUTIONS] Itraconazole should be used with care in elderly patients. [See WARNINGS AND PRECAUTIONS]

Renal Impairment

Limited data are available on the use of oral itraconazole in patients with renal impairment. Caution should be exercised when ONMEL is administered to patients with renal impairment. [See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION]

Hepatic Impairment

Limited data are available on the use of oral itraconazole in patients with hepatic impairment. Caution should be exercised when ONMEL is administered to patients with hepatic impairment. [See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION]

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

Contraindications

Congestive Heart Failure

Do not administer ONMEL for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. [See WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS, and CLINICAL PHARMACOLOGY]

Drug Interactions

Concomitant administration of ONMEL 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 ONMEL is contraindicated.

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

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

Mechanism Of Action

Itraconazole, an azole, is an antifungal agent [ See CLINICAL PHARMACOLOGY and Microbiology].

Pharmacokinetics

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

Table 5: Pharmacokinetic Parameters Following a Single Dose of ONMEL (mean ± SD)*

	Itraconazole		Hydroxy-itraconazole
	Fed	Fasted	Fed	Fasted
C max (ng/mL)	213 ± 117†	162 ± 107	332 ± 118	264 ± 109
T max (hours)	4.6 ± 2.2	2.9 ± 0.8	5.7 ± 2.6	3.4 ± 0.8
AUC 0-∞(μg•h/mL)	3.34 ± 1.98	2.27 ± 1.44	7.05 ± 3.94	4.58 ± 2.80
*Drug given after FDA standard high-fat breakfast †mean ± standard deviation

 

The steady-state pharmacokinetics of itraconazole and hydroxy-itraconazole were analyzed after oral dosing of 16 healthy volunteers with one ONMEL following a moderate-fat breakfast once daily for 14 days in an open-label study. Mean maximum plasma levels of itraconazole 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:

Table 6: Pharmacokinetic Parameters Following Multiple Doses of ONMEL (mean ± SD) Taken with Moderate-fat Breakfasts*

	Statistic	Day	Itraconazole N=16	Hydroxy-itraconazole N=16
C max (ng*/mL)	Mean (SD)	1	116.8 (43.34)	221.7 (69.21)
		14	658.1 (362.16)	974.2 (479.92)
AUC 0-24	Mean (SD)	1	905.09 (384.239)	2538.33 (1057.872)
		14	9046.81 (5320.516)	19054.95 (10443.214)
T max (h)	Median	1	4.00 (2.00-5.00)	4.00 (2.00-5.00)
	(Min-Max)	14	4.00 (1.00-24.00)	4.00 (3.00-24.00)
T½	Mean (SD)	14	36.84 (10.378)	20.06 (6.998)
*Meal containing approximately 500 calories, 30% of which were derived from fat.

 

In a 2-period, open-label, randomized, cross-over, pivotal bioequivalence study to assess the comparative bioavailability of the ONMEL and a marketed 100-mg itraconazole capsule, 28 male and 28 female healthy subjects were given as a single dose, 200 mg of itraconazole 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 ONMEL was comparable to that of the 2 itraconazole 100-mg capsules while AUCt and AUC∞ were about 15% higher with the ONMEL.

In another 2-period, open-label, randomized, cross-over, pivotal bioequivalence study, 28 male and 28 female healthy subjects were given one ONMEL or two 100-mg itraconazole capsules following the FDA standard high-fat breakfast. The Cmax and AUC∞ of the ONMEL were 20 and 30% lower, respectively, than those of two itraconazole 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%.

Itraconazole 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 itraconazole. Results of a pharmacokinetics study suggest that itraconazole 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. Itraconazole 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 itraconazole has been reported to be 99.8% and that of hydroxy-itraconazole is 99.5%. [See CONTRAINDICATIONS]

Microbiology

Mechanism Of Action

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

Activity In Vitro

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

Resistance

Isolates from several fungal species with decreased susceptibility to itraconazole 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 itraconazole in patients with renal impairment. A pharmacokinetic study using a single 200-mg dose of itraconazole was conducted in three groups of patients with renal impairment (uremia: n=7; hemodialysis: n=7; and continuous ambulatory peritoneal dialysis: n=5). In uremic subjects with a mean creatinine clearance of 13 mL/min. × 1.73 m², the exposure, based on AUC, was slightly reduced compared with normal population parameters. The study did not demonstrate any significant effect of hemodialysis or continuous ambulatory peritoneal dialysis on the pharmacokinetics of itraconazole (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. [See WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION]

Hepatic Insufficiency

Itraconazole is predominantly metabolized in the liver. Patients with impaired hepatic function should be carefully monitored when taking itraconazole. A pharmacokinetic study using a single oral 100 mg dose of itraconazole 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 itraconazole were noted in cirrhotic subjects compared with healthy subjects. However, overall exposure to itraconazole, based on AUC, was similar in cirrhotic patients and in healthy subjects. The prolonged elimination half-life of itraconazole observed in the single oral dose clinical trial with itraconazole 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 itraconazole. [See BOXED WARNING, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and DOSAGE AND ADMINISTRATION]

Clinical Studies

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

In the clinical study, 791 subjects with diagnosis of distal and/or lateral subungual onychomycosis were randomized to ONMEL (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 ONMEL and Placebo:

Table 7: Primary Efficacy Results at Week 52

Endpoint	ONMEL N=593	Placebo N=198
Complete Cure *	22.3%	1.0%
*Complete 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)

 

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

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