Itraconazol AbZ Uses

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What is Itraconazol AbZ?

Itraconazol AbZ is used to treat serious fungal or yeast infections. Itraconazol AbZ oral solution is only used to treat oropharyngeal or esophageal candidiasis (thrush, oral thrush). Itraconazol AbZ capsule is used to treat fungal infections, such as aspergillosis (fungal infection in the lungs), blastomycosis (Gilchrist’s disease), histoplasmosis (Darling’s disease), or onychomycosis (fungal infection in the fingernails or toenails). Itraconazol AbZ tablet is only used to treat onychomycosis of the toenails. Itraconazol AbZ works by killing the fungus or yeast and preventing its growth.

Itraconazol AbZ is available only with your doctor's prescription.

Itraconazol AbZ indications

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Itraconazol AbZ® (Itraconazol AbZ) Injection/Oral Solution is indicated for empiric therapy of febrile neutropenic patients with suspected fungal infections. (NOTE: In a comparative trial, the overall response rate for Itraconazol AbZ-treated subjects was higher than for amphotericin B-treated subjects. However, compared to amphotericin B-treated subjects, a larger number of Itraconazol AbZ-treated subjects discontinued treatment due to persistent fever and a change in antifungal medication due to fever. Whereas, a larger number of amphotericin B-treated subjects discontinued due to drug intolerance.

Itraconazol AbZ® (Itraconazol AbZ) Injection is also indicated for the treatment of the following fungal infections in immunocompromised and non-immunocompromised patients:

  1. Blastomycosis, pulmonary and extrapulmonary;
  2. Histoplasmosis, including chronic cavitary pulmonary disease and disseminated, non-meningeal histoplasmosis; and
  3. Aspergillosis, pulmonary and extrapulmonary, in patients who are intolerant of or who are refractory to amphotericin B therapy.

Specimens for fungal cultures and other relevant laboratory studies (wet mount, histopathology, serology) should be obtained prior to therapy to isolate and identify causative organisms. Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, anti-infective therapy should be adjusted accordingly.

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How should I use Itraconazol AbZ?

Use Itraconazol AbZ tablets as directed by your doctor. Check the label on the medicine for exact dosing instructions.

Ask your health care provider any questions you may have about how to use Itraconazol AbZ tablets.

Uses of Itraconazol AbZ in details

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Use: Labeled Indications

Aspergillosis (capsules): Treatment of pulmonary and extrapulmonary aspergillosis in immunocompromised and nonimmunocompromised patients who are intolerant of or refractory to amphotericin B therapy. Note: IDSA Aspergillosis guidelines recommend amphotericin B formulations for invasive aspergillosis (initial or salvage) only when voriconazole is contraindicated or not tolerated (IDSA [Patterson 2016]).

Blastomycosis (capsules): Treatment of pulmonary and extrapulmonary blastomycosis in immunocompromised and nonimmunocompromised patients.

Histoplasmosis (capsules): Treatment of histoplasmosis, including chronic cavitary pulmonary disease and disseminated, nonmeningeal histoplasmosis in immunocompromised and nonimmunocompromised patients.

Onychomycosis:

Capsules (100 mg [Itraconazol AbZ]): Treatment of onychomycosis of the toenail, with or without fingernail involvement, and onychomycosis of the fingernail caused by dermatophytes (tinea unguium) in nonimmunocompromised patients

Tablets: Treatment of onychomycosis of the toenail caused by Trichophyton rubrum or Trichophyton mentagrophytes in nonimmunocompromised patients

Oropharyngeal/Esophageal candidiasis (oral solution): Treatment of oropharyngeal and esophageal candidiasis

Canadian labeling:

Oral capsules: Additional indications (not in US labeling):

Candidiasis, oral and/or esophageal: Treatment of oral and/or esophageal candidiasis in immunocompromised and immunocompetent patients

Chromomycosis: Treatment of chromomycosis in immunocompromised and immunocompetent patients

Dermatomycoses: Treatment of dermatomycoses due to tinea pedis, tinea cruris, tinea corporis, and of pityriasis versicolor in patients for whom oral therapy is appropriate

Onychomycosis: Treatment of onychomycosis in immunocompromised and immunocompetent patients

Paracoccidioidomycosis: Treatment of paracoccidioidomycosis in immunocompromised and immunocompetent patients

Sporotrichosis: Treatment of cutaneous and lymphatic sporotrichosis in immunocompromised and immunocompetent patients

Off Label Uses

Candidiasis, vulvovaginal in HIV-infected patients

Based on the US Department of Health and Human Services (HHS) Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents, Itraconazol AbZ oral solution is an effective and recommended alternative agent in the management of vulvovaginal candidiasis in HIV-infected patients.

Coccidioidal meningitis in HIV-infected patients

Based on the US Department of Health and Human Services (HHS) Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents, Itraconazol AbZ is an effective and recommended alternative agent in the treatment of and as chronic suppressive therapy of coccidioidal meningitis in HIV-infected patients.

Coccidioidal pneumonia in HIV-infected patients

Based on the US Department of Health and Human Services (HHS) Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents, Itraconazol AbZ is an effective and recommended agent in the treatment of coccidioidal pneumonia (focal pneumonia) in HIV-infected patients.

Coccidioidomycosis (non-HIV infected)

Based on the Infectious Diseases Society of America (IDSA) guidelines for the treatment of coccidioidomycosis, Itraconazol AbZ is an effective and recommended agent for the treatment of coccidioidomycosis, including coccidioidal meningitis and certain types of pulmonary and extrapulmonary infections.

Cryptococcosis in HIV-infected patients

Based on the HHS Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents, Itraconazol AbZ is an effective and recommended alternative agent in the treatment (consolidation therapy) of cryptococcal meningitis in HIV-infected patients.

Microsporidiosis, disseminated in HIV-infected patients

Based on the US Department of Health and Human Services (HHS) Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents, Itraconazol AbZ is an effective and recommended agent in the management of disseminated microsporidiosis caused by Trachipleistophora or Anncaliia in HIV-infected patients.

Penicilliosis in HIV-infected patients

Based on the US Department of Health and Human Services (HHS) Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents, Itraconazol AbZ is an effective and recommended agent in the treatment or primary prophylaxis of penicilliosis in HIV-infected patients.

Itraconazol AbZ description

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Each capsule contains Itraconazole 100 mg in a pellet formulation for oral administration. The inactive ingredients are sucrose, corn starch, hydrolysed starch syrup, hypromellose and macrogol. The capsule itself contains titanium dioxide, indigotindisulfonate sodium, coccine nouvelle and gelatin.

Itraconazol AbZ oral solution also contains hydroxypropyl β-cyclodextrin, sorbitol, propylene glycol, hydrochloric acid, cherry flavour 1, cherry flavour 2, caramel flavour, sodium saccharin, sodium hydroxide and purified water.

Itraconazol AbZ dosage

Itraconazol AbZ Dosage

Generic name: Itraconazol AbZ 200mg

Dosage form: tablet

The information at Drugs.com is not a substitute for medical advice. Always consult your doctor or pharmacist.

Itraconazol AbZ 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 Itraconazol AbZ in patients with renal impairment. Caution should be exercised when Itraconazol AbZ is administered to patients with renal impairment.

Use in Patients with Hepatic Impairment:

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

More about Itraconazol AbZ (Itraconazol AbZ)

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Itraconazol AbZ interactions

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What other drugs will affect Itraconazol AbZ?

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Itraconazol AbZ and its major metabolite, hydroxyitraconazole, are inhibitors of CYP3A4. Therefore, the following drug interactions may occur :

  1. Itraconazol AbZ® (Itraconazol AbZ injection) may decrease the elimination of drugs metabolized by CYP3A4, resulting in increased plasma concentrations of these drugs when they are administered with Itraconazol AbZ® (Itraconazol AbZ injection). These elevated plasma concentrations may increase or prolong both therapeutic and adverse effects of these drugs. Whenever possible, plasma concentrations of these drugs should be monitored, and dosage adjustments made after concomitant Itraconazol AbZ® (Itraconazol AbZ injection) therapy is initiated. When appropriate, clinical monitoring for signs or symptoms of increased or prolonged pharmacologic effects is advised. Upon discontinuation, depending on the dose and duration of treatment, Itraconazol AbZ 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 Itraconazol AbZ.
  2. Inducers of CYP3A4 may decrease the plasma concentrations of Itraconazol AbZ. Itraconazol AbZ® (Itraconazol AbZ injection) may not be effective in patients concomitantly taking Itraconazol AbZ® (Itraconazol AbZ injection) and one of these drugs. Therefore, administration of these drugs with Itraconazol AbZ® (Itraconazol AbZ injection) is not recommended.
  3. Other inhibitors of CYP3A4 may increase the plasma concentrations of Itraconazol AbZ. Patients who must take Itraconazol AbZ® (Itraconazol AbZ injection) concomitantly with one of these drugs should be monitored closely for signs or symptoms of increased or prolonged pharmacologic effects of Itraconazol AbZ® (Itraconazol AbZ injection).

Table 1: Selected Drugs that are Predicted to Alter the Plasma Concentration of Itraconazol AbZ or Have Their Plasma Concentration Altered by Itraconazol AbZ® (Itraconazol AbZ injection) 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 Itraconazol AbZ® (Itraconazol AbZ injection) may increase plasma concentrations of quinidine or dofetilide which could result in serious cardiovascular events. Therefore, concomitant administration of Itraconazol AbZ® (Itraconazol AbZ 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 Itraconazol AbZ® (Itraconazol AbZ injection) and disopyramide are administered concomitantly.

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

Anticonvulsants

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

Antineoplastics

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

Benzodiazepines

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

Gastrointestinal Motility Agents

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

HMG CoA-Reductase Inhibitors

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

Immunosuppressants

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

Polyenes

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

Itraconazol AbZ side effects

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What are the possible side effects of Itraconazol AbZ?

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

Itraconazol AbZ contraindications

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What is the most important information I should know about Itraconazol AbZ?

Drug Interactions

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

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

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

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



Active ingredient matches for Itraconazol AbZ:

Itraconazole in Germany.


List of Itraconazol AbZ substitutes (brand and generic names)

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Unit description / dosage (Manufacturer)Price, USD
Capsule; Oral; Itraconazole 100 mg
Itraconazole 28 100 mg capsule Disp Pack$ 270.89
Itraconazole powder$ 32.13
Sporanox 100 mg capsule$ 12.14
Itraconazole 100 mg capsule$ 9.46
Sporanox 10 mg/ml Solution$ 1.41
Itraconazole capsule 100 mg/1 (Carilion Materials Management (US))
ITRACONAZOLE 100MG CAPSULE 1 strip / 4 capsules each (Jan Aushadhi)$ 0.24
Itraconazole TV Pharm 100 mg x 1 Blister xeГ№ x 4 Tablet

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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