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 (4), Warnings and Precautions (5), Drug Interactions (7), and Clinical Pharmacology (12).]
Onmel 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 (12) and Warnings and Precautions (5).]
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 (12) and Warnings and Precautions (5).]
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.
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 (5), Drug Interactions (7), and Clinical Pharmacology (12).]
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.
Warnings and 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 (4), Warnings and Precautions (5), and Clinical Pharmacology (12).]
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 (4), Warnings and Precautions (5), and Drug Interactions (7).]
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 (5), and Drug Interactions (7).] The hearing loss usually resolves when treatment is stopped, but can persist in some patients.
Adverse Reactions
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
Bacteriuria
Urinary tract infection |
6.0%
1.4%
1.0% |
7.3%
1.6%
0.5% |
INVESTIGATIONS
Hepatic enzymes increased
Electrocardiogram abnormal |
2.9%
1.4% |
0.0%
1.6% |
EAR AND LABYRINTH DISORDERS
Hypoacusis |
3.3%
|
3.1%
|
NERVOUS SYSTEM DISORDERS
Headache
Dizziness |
2.2%
1.2% |
1.6%
0.0% |
GASTROINTESTINAL DISORDERS
Abdominal pain or discomfort
Diarrhea
Nausea |
1.7%
1.7%
1.7% |
2.6%
3.1%
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
Pharyngolaryngeal pain |
1.2%
1.0% |
0.0%
0.5% |
MUSCULOSCELETAL 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: |
Leaukopenia, 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 |
Drug Interactions
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, H2-receptor antagonists, proton pump inhibitors |
|
| Increase plasma concentration of itraconazole |
| Macrolide Antibiotics |
clarithromycin, erythromycin |
| Anti-HIV Agents |
indinavir, ritonavir |
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 |
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 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 (4), and Warnings and Precautions (5).]
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 co-administration 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 (4), and Warnings and Precautions (5).]
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 (4), and Warnings and Precautions (5).] 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 (4), Warnings and Precautions (5), Drug Interactions (7), and Clinical Pharmacology (12).]
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
Coadministration 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 (4), and Warnings and Precautions (5).]
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 (4), and Warnings and Precautions (5).]
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 co-administered.
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. Co-administration 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.
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 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 (4), Drug Interactions (7), and Warnings and Precautions (5).] Itraconazole should be used with care in elderly patients. [See Warnings and Precautions (5).]
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 (12) and Dosage and Administration (2).]
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 (12) and Dosage and Administration (2).]
Overdosage
Itraconazole is not removed by dialysis. In the event of accidental overdosage, supportive measures, including gastric lavage with sodium bicarbonate, should be employed.
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 - (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
Itraconazole 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 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.
Onmel - Clinical Pharmacology
Mechanism of Action
Itraconazole, an azole, is an antifungal agent [See Clinical Pharmacology (12) and Microbiology(12.4)].
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 |
|
| Cmax (ng/mL) |
213 ± 117 |
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 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
|
