The class IA antiarrhythmic quinidine and class III antiarrhythmic dofetilide are known to prolong the QT interval. Coadministration of quinidine or dofetilide with Itrizole 1%® (Itrizole 1% injection) may increase plasma concentrations of quinidine or dofetilide which could result in serious cardiovascular events. Therefore, concomitant administration of Itrizole 1%® (Itrizole 1% injection) 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 Itrizole 1%® (Itrizole 1% injection) and disopyramide are administered concomitantly.

Concomitant administration of digoxin and Itrizole 1%® (Itrizole 1% injection) has led to increased plasma concentrations of digoxin via inhibition of P-glycoprotein.

Anticonvulsants

Reduced plasma concentrations of Itrizole 1% were reported when Itrizole 1%® (Itrizole 1% injection) was administered concomitantly with phenytoin. Carbamazepine, phenobarbital, and phenytoin are all inducers of CYP3A4. Although interactions with carbamazepine and phenobarbital have not been studied, concomitant administration of Itrizole 1%® (Itrizole 1% injection) and these drugs would be expected to result in decreased plasma concentrations of Itrizole 1%. 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 Itrizole 1% on carbamazepine metabolism, because of the similarities between ketoconazole and Itrizole 1%, concomitant administration of Itrizole 1%® (Itrizole 1% injection) and carbamazepine may inhibit the metabolism of carbamazepine.

Antimycobacterials

Drug interaction studies have demonstrated that plasma concentrations of azole antifungal agents and their metabolites, including Itrizole 1% 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. Itrizole 1%® (Itrizole 1% injection) may inhibit the metabolism of rifabutin. Although no formal study data are available for isoniazid, similar effects should be anticipated. Therefore, the efficacy of Itrizole 1%® (Itrizole 1% injection) could be substantially reduced if given concomitantly with one of these agents. Coadministration is not recommended.

Antineoplastics

Itrizole 1%® (Itrizole 1% injection) 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. Coadministration of pimozide with Itrizole 1%® (Itrizole 1% injection) could result in serious cardiovascular events. Therefore, concomitant administration of Itrizole 1%® (Itrizole 1% injection) and pimozide is contraindicated.

Benzodiazepines

Concomitant administration of Itrizole 1%® (Itrizole 1% injection) 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 Itrizole 1%® (Itrizole 1% injection) 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

Edema has been reported in patients concomitantly receiving Itrizole 1%® (Itrizole 1% injection) and dihydropyridine calcium channel blockers. Appropriate dosage adjustment may be necessary.

Calcium channel blockers can have a negative inotropic effect which may be additive to those of Itrizole 1%; Itrizole 1% can inhibit the metabolism of calcium channel blockers such as dihydropyridines (e.g., nifedipine and felodipine) and verapamil. Therefore, caution should be used when co-administering Itrizole 1% and calcium channel blockers due to an increased risk of CHF. Concomitant administration of Itrizole 1%® (Itrizole 1% injection) and nisoldipine results in clinically significant increases in nisoldipine plasma concentrations which cannot be managed by dosage reduction, therefore the concomitant administration of Itrizole 1%® (Itrizole 1% injection) and nisoldipine is contraindicated.

Gastrointestinal Motility Agents

Coadministration of Itrizole 1%® (Itrizole 1% injection) with cisapride can elevate plasma cisapride concentrations which could result in serious cardiovascular events. Therefore, concomitant administration of Itrizole 1%® (Itrizole 1% injection) with cisapride is contraindicated.

HMG CoA-Reductase Inhibitors

Human pharmacokinetic data suggest that Itrizole 1%® (Itrizole 1% injection) inhibits the metabolism of atorvastatin, cerivastatin, lovastatin, and simvastatin, which may increase the risk of skeletal muscle toxicity, including rhabdomyolysis. Concomitant administration of Itrizole 1%® (Itrizole 1% injection) with HMG CoA-reductase inhibitors, such as lovastatin and simvastatin, is contraindicated.

Immunosuppressants

Concomitant administration of Itrizole 1%® (Itrizole 1% injection) and cyclosporine or tacrolimus has led to increased plasma concentrations of these immunosuppressants. Concomitant administration of Itrizole 1%® (Itrizole 1% injection) and sirolimus could increase plasma concentrations of sirolimus.

Macrolide Antibiotics

Erythromycin and clarithromycin are known inhibitors of CYP3A4 and may increase plasma concentrations of Itrizole 1%. In a small pharmacokinetic study involving HIV infected patients, clarithromycin was shown to increase plasma concentrations of Itrizole 1%. Similarly, following administration of 1 gram of erythromycin ethyl succinate and 200 mg Itrizole 1% as single doses, the mean Cmax and AUC 0-∞ of Itrizole 1% increased by 44% (90% CI: 119-175%) and 36% (90% CI: 108-171%), respectively.

Oral Hypoglycemic Agents

Severe hypoglycemia has been reported in patients concomitantly receiving azole antifungal agents and oral hypoglycemic agents. Blood glucose concentrations should be carefully monitored when Itrizole 1%® (Itrizole 1% injection) and oral hypoglycemic agents are coadministered.

Polyenes

Prior treatment with Itrizole 1%, 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.

Protease Inhibitors

Concomitant administration of Itrizole 1%® (Itrizole 1% injection) 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 Itrizole 1%® (Itrizole 1% injection) and indinavir and ritonavir (but not saquinavir) may increase plasma concentrations of Itrizole 1%. Caution is advised when Itrizole 1%® (Itrizole 1% injection) and protease inhibitors must be given concomitantly.

Reverse Transcriptase Inhibitors

Nevirapine is an inducer of CYP3A4. In vivo studies have shown that nevirapine induces the metabolism of ketoconazole, significantly reducing the bioavailability of ketoconazole. Studies involving nevirapine and Itrizole 1% have not been conducted. However, because of the similarities between ketoconazole and Itrizole 1%, concomitant administration of Itrizole 1%® (Itrizole 1% injection) and nevirapine is not recommended. In a clinical study, when 8 HIV-infected subjects were treated concomitantly with Itrizole 1%® (Itrizole 1% injection) Capsules 100 mg twice daily and the nucleoside reverse transcriptase inhibitor zidovudine 8 ± 0.4 mg/kg/day, the pharmacokinetics of zidovudine were not affected. Other nucleoside reverse transcriptase inhibitors have not been studied.

Other

• Levacetylmethadol (levomethadyl) is known to prolong the QT interval and is metabolized by CYP3A4. Co-administration of levacetylmethadol with Itrizole 1%® (Itrizole 1% injection) could result in serious cardiovascular events. Therefore, concomitant administration of Itrizole 1%® (Itrizole 1% injection) and levacetylmethadol is contraindicated.
• Elevated concentrations of ergot alkaloids can cause ergotism, ie. 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 Itrizole 1%® (Itrizole 1% injection) is contraindicated.
• Halofantrine has the potential to prolong the QT interval at high plasma concentrations. Caution is advised when Itrizole 1%® (Itrizole 1% injection) and halofantrine are administered concomitantly.
• In vitro data suggest that alfentanil is metabolized by CYP3A4. Administration with Itrizole 1%® (Itrizole 1% injection) may increase plasma concentrations of alfentanil.
• Human pharmacokinetic data suggest that concomitant administration of Itrizole 1%® (Itrizole 1% injection) and buspirone results in significant increases in plasma concentrations of buspirone.
• Itrizole 1%® (Itrizole 1% injection) may inhibit the metabolism of certain glucocorticosteroids such as budesonide, dexamethasone, fluticasone and methylprednisolone.
• In vitro data suggest that trimetrexate is extensively metabolized by CYP3A4. In vitro animal models have demonstrated that ketoconazole potently inhibits the metabolism of trimetrexate. Although there are no data regarding the effect of Itrizole 1% on trimetrexate metabolism, because of the similarities between ketoconazole and Itrizole 1%, concomitant administration of Itrizole 1%® (Itrizole 1% injection) and trimetrexate may inhibit the metabolism of trimetrexate.
• Cilostazol and eletriptan are CYP3A4 metabolized drugs that should be used with caution when co-administered with Itrizole 1%® (Itrizole 1% injection).
• Itrizole 1%® (Itrizole 1% injection) enhances the anticoagulant effect of coumarin-like drugs, such as warfarin.
• Fentanyl plasma concentrations could be increased or prolonged by concomitant use of Itrizole 1%® (Itrizole 1% injection) and may cause potentially fatal respiratory depression.

Itrizole 1% side effects

See also:
What are the possible side effects of Itrizole 1%?

Interaction Potential: Itrizole 1% oral solution has a potential for clinically important drug interactions. Clinical Trials: Table 1 shows the adverse events reported among patients in clinical trials (pooled data) of Itrizole 1% oral solution compared to fluconazole, in the treatment of oropharyngeal and esopharyngeal candidosis. It includes all adverse events (with an incidence of ≥2%) reported among Itrizole 1%-treated patients. About 44% of patients treated with Itrizole 1% oral solution and about 43% of patients treated with fluconazole experienced at least one adverse event. The adverse events reported are summarized irresponsive of the causality assessment of the investigators.

Post-Marketing Experience: Adverse drug reactions from spontaneous reports during the worldwide post-marketing experience with Itrizole 1% (all formulations) that meet threshold criteria are included in Table 2. The adverse drug reactions are ranked by frequency, using the following convention: Very common ≥1/10, common ≥1/100 and <1/10, uncommon ≥1/1000 and <1/100, rare ≥1/10,000 and <1/1000, very rare <1/10,000, including isolated reports.

The frequency in Table 2 reflect reporting rates for adverse drug reactions from spontaneous reports and do not represent more precise estimates of incidence that might be obtained in clinical or epidemiological studies.

Itrizole 1% contraindications

See also:
What is the most important information I should know about Itrizole 1%?

Drug Interactions

Concomitant administration of Itrizole 1%® (Itrizole 1%) Capsules, Injection, or

Oral Solution and certain drugs metabolized by the cytochrome P450 3A4 isoenzyme system (CYP3A4) may result in increased plasma concentrations of those drugs, leading to potentially serious and/or life-threatening adverse events. Cisapride, oral midazolam, nisoldipine, pimozide, quinidine, dofetilide, triazolam and levacetylmethadol (levomethadyl) are contraindicated with Itrizole 1%® (Itrizole 1% injection). HMG CoA-reductase inhibitors metabolized by CYP3A4, such as lovastatin and simvastatin, are also contraindicated with Itrizole 1%® (Itrizole 1% injection). Ergot alkaloids metabolized by CYP3A4 such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine) are contraindicated with Itrizole 1%®.

Itrizole 1%® (Itrizole 1% injection) is contraindicated for patients who have shown hypersensitivity to Itrizole 1% or its excipients. There is no information regarding cross-hypersensitivity between Itrizole 1% and other azole antifungal agents. Caution should be used when prescribing Itrizole 1%® (Itrizole 1% injection) to patients with hypersensitivity to other azoles.

Itrizole 1% IV cannot be used when administration of Sodium Chloride Injection is contraindicated.

The excipient hydroxypropyl-β-cyclodextrin is eliminated through glomerular filtration. Therefore, Itrizole 1% IV is contraindicated in patients with severe renal impairment (defined as creatinine clearance below 30 mL/min).

Active ingredient matches for Itrizole 1%:

Itraconazole in Japan.

References

1. 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/dailyme... (accessed September 17, 2018).
2. PubChem. "itraconazole". https://pubchem.ncbi.nlm.nih.gov/com... (accessed September 17, 2018).
3. DrugBank. "itraconazole". http://www.drugbank.ca/drugs/DB01167 (accessed September 17, 2018).

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Information checked by Dr. Sachin Kumar, MD Pharmacology