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

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

Anticonvulsants

Reduced plasma concentrations of Lorenzol were reported when Lorenzol® (Lorenzol 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 Lorenzol® (Lorenzol injection) and these drugs would be expected to result in decreased plasma concentrations of Lorenzol. 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 Lorenzol on carbamazepine metabolism, because of the similarities between ketoconazole and Lorenzol, concomitant administration of Lorenzol® (Lorenzol 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 Lorenzol 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. Lorenzol® (Lorenzol 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 Lorenzol® (Lorenzol injection) could be substantially reduced if given concomitantly with one of these agents. Coadministration is not recommended.

Antineoplastics

Lorenzol® (Lorenzol 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 Lorenzol® (Lorenzol injection) could result in serious cardiovascular events. Therefore, concomitant administration of Lorenzol® (Lorenzol injection) and pimozide is contraindicated.

Benzodiazepines

Concomitant administration of Lorenzol® (Lorenzol 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 Lorenzol® (Lorenzol 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 Lorenzol® (Lorenzol 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 Lorenzol; Lorenzol 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 Lorenzol and calcium channel blockers due to an increased risk of CHF. Concomitant administration of Lorenzol® (Lorenzol injection) and nisoldipine results in clinically significant increases in nisoldipine plasma concentrations which cannot be managed by dosage reduction, therefore the concomitant administration of Lorenzol® (Lorenzol injection) and nisoldipine is contraindicated.

Gastrointestinal Motility Agents

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

HMG CoA-Reductase Inhibitors

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

Immunosuppressants

Concomitant administration of Lorenzol® (Lorenzol injection) and cyclosporine or tacrolimus has led to increased plasma concentrations of these immunosuppressants. Concomitant administration of Lorenzol® (Lorenzol 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 Lorenzol. In a small pharmacokinetic study involving HIV infected patients, clarithromycin was shown to increase plasma concentrations of Lorenzol. Similarly, following administration of 1 gram of erythromycin ethyl succinate and 200 mg Lorenzol as single doses, the mean Cmax and AUC 0-∞ of Lorenzol 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 Lorenzol® (Lorenzol injection) and oral hypoglycemic agents are coadministered.

Polyenes

Prior treatment with Lorenzol, 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 Lorenzol® (Lorenzol 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 Lorenzol® (Lorenzol injection) and indinavir and ritonavir (but not saquinavir) may increase plasma concentrations of Lorenzol. Caution is advised when Lorenzol® (Lorenzol 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 Lorenzol have not been conducted. However, because of the similarities between ketoconazole and Lorenzol, concomitant administration of Lorenzol® (Lorenzol injection) and nevirapine is not recommended. In a clinical study, when 8 HIV-infected subjects were treated concomitantly with Lorenzol® (Lorenzol 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 Lorenzol® (Lorenzol injection) could result in serious cardiovascular events. Therefore, concomitant administration of Lorenzol® (Lorenzol 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 Lorenzol® (Lorenzol injection) is contraindicated.
• Halofantrine has the potential to prolong the QT interval at high plasma concentrations. Caution is advised when Lorenzol® (Lorenzol injection) and halofantrine are administered concomitantly.
• In vitro data suggest that alfentanil is metabolized by CYP3A4. Administration with Lorenzol® (Lorenzol injection) may increase plasma concentrations of alfentanil.
• Human pharmacokinetic data suggest that concomitant administration of Lorenzol® (Lorenzol injection) and buspirone results in significant increases in plasma concentrations of buspirone.
• Lorenzol® (Lorenzol 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 Lorenzol on trimetrexate metabolism, because of the similarities between ketoconazole and Lorenzol, concomitant administration of Lorenzol® (Lorenzol 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 Lorenzol® (Lorenzol injection).
• Lorenzol® (Lorenzol injection) enhances the anticoagulant effect of coumarin-like drugs, such as warfarin.
• Fentanyl plasma concentrations could be increased or prolonged by concomitant use of Lorenzol® (Lorenzol injection) and may cause potentially fatal respiratory depression.

Lorenzol side effects

See also:
What are the possible side effects of Lorenzol?

Interaction Potential: Lorenzol 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 Lorenzol 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 Lorenzol-treated patients. About 44% of patients treated with Lorenzol 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 Lorenzol (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.

Lorenzol contraindications

See also:
What is the most important information I should know about Lorenzol?

Drug Interactions

Concomitant administration of Lorenzol® (Lorenzol) 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 Lorenzol® (Lorenzol injection). HMG CoA-reductase inhibitors metabolized by CYP3A4, such as lovastatin and simvastatin, are also contraindicated with Lorenzol® (Lorenzol injection). Ergot alkaloids metabolized by CYP3A4 such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine) are contraindicated with Lorenzol®.

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

Lorenzol IV cannot be used when administration of Sodium Chloride Injection is contraindicated.

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

Active ingredient matches for Lorenzol:

Itraconazole in Greece.

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