Itraconazole Oral (Page 3 of 7)

WARNINGS

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 liver disease, treatment should be discontinued and liver function testing performed. Continued itraconazole use or reinstitution of treatment with itraconazole is strongly discouraged unless there is a serious or life-threatening situation where the expected benefit exceeds the risk. (See PRECAUTIONS: Information for Patients and ADVERSE REACTIONS.)

Cardiac Dysrhythmias:

Life-threatening cardiac dysrhythmias and/or sudden death have occurred in patients using drugs such as cisapride, pimozide, methadone, or quinidine concomitantly with itraconazole and/or other CYP3A4 inhibitors. Concomitant administration of these drugs with itraconazole oral solution is contraindicated. (See BOXED WARNING, CONTRAINDICATIONS, and PRECAUTIONS: Drug Interactions.)

Cardiac Disease:

Itraconazole oral solution should not be used in patients with evidence of ventricular dysfunction unless the benefit clearly outweighs the risk. For patients with risk factors for congestive heart failure, physicians should carefully review the risks and benefits of itraconazole 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 itraconazole oral solution, monitor carefully and consider other treatment alternatives which may include discontinuation of itraconazole oral solution administration.

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 intravenous infusion, transient, asymptomatic decreases in left ventricular ejection fraction were observed using gated SPECT imaging; these resolved before the next infusion, 12 hours later.

Itraconazole oral solution has been associated with reports of congestive heart failure. In post-marketing experience, heart failure was more frequently reported in patients receiving a total daily dose of 400 mg although there were also cases reported among those receiving lower total daily doses.

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 itraconazole and felodipine or nisoldipine is contraindicated.

Cases of CHF, peripheral edema, and pulmonary edema have been reported in the post-marketing period among patients being treated for onychomycosis and/or systemic fungal infections. (See CONTRAINDICATIONS, CLINICAL PHARMACOLOGY: Special Populations, PRECAUTIONS: Drug Interactions, and ADVERSE REACTIONS: Postmarketing Experience for more information.)

Interaction potential:

Itraconazole has a potential for clinically important drug interactions. Coadministration of specific drugs with itraconazole may result in changes in efficacy of itraconazole and/or the coadministered drug, life-threatening effects and/or sudden death. Drugs that are contraindicated, not recommended or recommended for use with caution in combination with itraconazole are listed in PRECAUTIONS: Drug Interactions.

Interchangeability:

Itraconazole oral solution and itraconazole capsules should not be used interchangeably. This is because drug exposure is greater with the oral solution than with the capsules when the same dose of drug is given. Only itraconazole oral solution has been demonstrated effective for oral and/or esophageal candidiasis.

Hydroxypropyl-β-cyclodextrin:

Itraconazole oral solution contains the excipient hydroxypropyl-β-cyclodextrin which produced adenocarcinomas in the large intestine and exocrine pancreatic adenocarcinomas in a rat carcinogenicity study. These findings were not observed in a similar mouse carcinogenicity study. The clinical relevance of these adenocarcinomas is unknown. (See PRECAUTIONS: Carcinogenesis, Mutagenesis, and Impairment of Fertility.)

Treatment of Severely Neutropenic Patients:

Itraconazole oral solution as treatment for oropharyngeal and/or esophageal candidiasis was not investigated in severely neutropenic patients. Due to its pharmacokinetic properties, itraconazole oral solution is not recommended for initiation of treatment in patients at immediate risk of systemic candidiasis.

PRECAUTIONS

Hepatotoxicity:

Rare cases of serious hepatotoxicity have been observed with itraconazole treatment, including some cases within the first week. It is recommended that liver function monitoring be considered in all patients receiving itraconazole. Treatment should be stopped immediately and liver function testing should be conducted in patients who develop signs and symptoms suggestive of liver dysfunction.

Neuropathy:

If neuropathy occurs that may be attributable to itraconazole oral solution, the treatment should be discontinued.

Cystic Fibrosis:

If a patient with cystic fibrosis does not respond to itraconazole oral solution, consideration should be given to switching to alternative therapy (see CLINICAL PHARMACOLOGY: Special Populations).

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: Drug Interactions, CONTRAINDICATIONS: Drug Interactions and PRECAUTIONS: Drug Interactions). The hearing loss usually resolves when treatment is stopped, but can persist in some patients.

Information for Patients:

  • Only itraconazole oral solution has been demonstrated effective for oral and/or esophageal candidiasis.
  • Itraconazole oral solution contains the excipient hydroxypropyl-β-cyclodextrin which produced adenocarcinomas in the large intestine and exocrine pancreatic adenocarcinomas in a rat carcinogenicity study. These findings were not observed in a similar mouse carcinogenicity study. The clinical relevance of these adenocarcinomas is unknown. (See Carcinogenesis, Mutagenesis, and Impairment of Fertility.)
  • Taking itraconazole oral solution under fasted conditions improves the systemic availability of itraconazole. Instruct patients to take itraconazole oral solution without food, if possible.
  • Itraconazole oral solution should not be used interchangeably with itraconazole capsules.
  • Instruct patients about the signs and symptoms of congestive heart failure, and if these signs or symptoms occur during itraconazole administration, they should discontinue itraconazole and contact their healthcare provider immediately.
  • Instruct patients to stop itraconazole treatment immediately and contact their healthcare provider if any signs and symptoms suggestive of liver dysfunction develop. Such signs and symptoms may include unusual fatigue, anorexia, nausea and/or vomiting, jaundice, dark urine, or pale stools.
  • Instruct patients to contact their physician before taking any concomitant medications with itraconazole to ensure there are no potential drug interactions.
  • 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 discontinue therapy and inform their physicians if any hearing loss symptoms occur.
  • Instruct patients that dizziness or blurred/double vision can sometimes occur with itraconazole. Advise patients that if they experience these events, they should not drive or use machines.

Drug Interactions:

Effect of Itraconazole on Other Drugs

Itraconazole and its major metabolite, hydroxy-itraconazole, are potent CYP3A4 inhibitors. Itraconazole is an inhibitor of the drug transporters P-glycoprotein and breast cancer resistance protein (BCRP). Consequently, itraconazole has the potential to interact with many concomitant drugs resulting in either increased or sometimes decreased concentrations of the concomitant drugs. Increased concentrations may increase the risk of adverse reactions associated with the concomitant drug which can be severe or life-threatening in some cases (e.g., QT prolongation, Torsade de Pointes, respiratory depression, hepatic adverse reactions, hypersensitivity reactions, myelosuppression, hypotension, seizures, angioedema, atrial fibrillation, bradycardia, priapism). Reduced concentrations of concomitant drugs may reduce their efficacy. The table below lists examples of drugs that may have their concentrations affected by itraconazole, but is not a comprehensive list. Refer to the approved product labeling to become familiar with the interaction pathways risk potential and specific actions to be taken with regards to each concomitant drug prior to initiating therapy with itraconazole.

Although many of the clinical drug interactions in Table 1 below are based on information with a similar azole antifungal, ketoconazole, these interactions are expected to occur with itraconazole.

Table 1: Drug Interactions with Itraconazole that Affect Concomitant Drug Concentrations
Concomitant Drug Within Class Prevention or Management
Drug Interactions with Itraconazole that Increase Concomitant Drug Concentrations and May Increase Risk of Adverse Reactions Associated with the Concomitant Drug
Alpha Blockers
AlfuzosinSilodosinTamsulosin Not recommended during and 2 weeks after itraconazole treatment.
Analgesics
Methadone Contraindicated during and 2 weeks after itraconazole treatment.
Fentanyl Not recommended during and 2 weeks after itraconazole treatment.
AlfentanilBuprenorphine (IV and sublingual)Oxycodonea Sufentanil Monitor for adverse reactions. Concomitant drug dose reduction may be necessary.
Antiarrhythmics
DisopyramideDofetilideDronedaroneQuinidinea Contraindicated during and 2 weeks after itraconazole treatment.
Digoxina Monitor for adverse reactions. Concomitant drug dose reduction may be necessary.
Antibacterials
Bedaquilineb Concomitant itraconazole not recommended for more than 2 weeks at any time during bedaquiline treatment.
Rifabutin Not recommended 2 weeks before, during, and 2 weeks after itraconazole treatment.See also Table 4.
Clarithromycin Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. See also Table 4.
Trimetrexate Monitor for adverse reactions. Concomitant drug dose reduction may be necessary.
Anticoagulants and Antiplatelets
Ticagrelor Contraindicated during and 2 weeks after itraconazole treatment.
ApixabanRivaroxabanVorapaxar Not recommended during and 2 weeks after itraconazole treatment.
CilostazolDabigatranWarfarin Monitor for adverse reactions. Concomitant drug dose reduction may be necessary.
Anticonvulsants
Carbamazepine Not recommended 2 weeks before, during, and 2 weeks after itraconazole treatment. See also Table 4.
Table 1: Drug Interactions with Itraconazole that Affect Concomitant Drug Concentrations

*CYP3A4 inhibitors (including itraconazole) may increase systemic contraceptive hormone concentrations.

a Based on clinical drug interaction information with itraconazole.

b Based on 400 mg bedaquiline once daily for 2 weeks.

c EMs: extensive metabolizers; IMs: intermediate metabolizers, PMs: poor metabolizers

Concomitant Drug Within Class Prevention or Management
Antidiabetic Drugs
Repaglinidea Saxagliptin Monitor for adverse reactions. Concomitant drug dose reduction may be necessary.
Antihelminthics, Antifungals and Antiprotozoals
Isavuconazonium Contraindicated during and 2 weeks after itraconazole treatment.
Praziquantel Monitor for adverse reactions. Concomitant drug dose reduction may be necessary.
Artemether-lumefantrineQuininea Monitor for adverse reactions.
Antimigraine Drugs
Ergot alkaloids (e.g., dihydroergotamine, ergotamine) Contraindicated during and 2 weeks after itraconazole treatment.
Eletriptan Monitor for adverse reactions. Concomitant drug dose reduction may be necessary
Antineoplastics
Irinotecan Contraindicated during and 2 weeks after itraconazole treatment.
AxitinibBosutinibCabazitaxelCabozantinibCeritinibCobimetiniba CrizotinibDabrafenibDasatinib DocetaxelIbrutinibLapatinibNilotinibOlapariba PazopanibSunitinibTrabectedinTrastuzumabemtansineVinca alkaloids Not recommended during and 2 weeks after itraconazole treatment.
BortezomibBrentuximab-vedotinBusulfanErlotinibGefitiniba IdelalisibImatinibIxabepilone NintedanibPanobinostatPonatinibRuxolitinibSonidegibVandetaniba Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. For idelalisib: see also Table 4.
Antipsychotics, Anxiolytics and Hypnotics
Alprazolama Aripiprazolea Buspironea Cariprazine Diazepama Haloperidola Midazolam (IV)a QuetiapineRamelteon Risperidonea Suvorexant Monitor for adverse reactions. Concomitant drug dose reduction may be necessary.
Zopiclonea Monitor for adverse reactions. Concomitant drug dose reduction may be necessary.
LurasidoneMidazolam (oral)a PimozideTriazolama Contraindicated during and 2 weeks after itraconazole treatment.
Antivirals
Simeprevir Not recommended during and 2 weeks after itraconazole treatment.
DaclatasvirIndinavira Maraviroc Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. For indinavir: see also Table 4.
CobicistatElvitegravir (ritonavir-boosted)Ombitasvir/Paritaprevir/Ritonavir with or withoutDasabuvirRitonavirSaquinavir (unboosted)a Monitor for adverse reactions.
Elbasvir/grazoprevirGlecaprevir/pibrentasvirTenofovir disoproxil fumarate Not recommended during and 2 weeks after itraconazole treatment.Monitor for adverse reactions.Monitor for adverse reactions.
Beta Blockers
Nadolola Monitor for adverse reactions. Concomitant drug dose reduction may be necessary.
Calcium Channel Blockers
Felodipinea Nisoldipine Contraindicated during and 2 weeks after itraconazole treatment.
DiltiazemOther dihydropyridinesVerapamil Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. For diltiazem: see also Table 4.
Cardiovascular Drugs, Miscellaneous
IvabradineRanolazine Contraindicated during and 2 weeks after itraconazole treatment.
Aliskirena RiociguatSildenafil (for pulmonary hypertension)Tadalafil (for pulmonary hypertension) Not recommended during and 2 weeks after itraconazole treatment. For sildenafil and tadalafil, see also Urologic Drugs below.
BosentanGuanfacine Monitor for adverse reactions. Concomitant drug dose reduction may be necessary.
Contraceptives*
DienogestUlipristal Monitor for adverse reactions.
Diuretics
Eplerenone Contraindicated during and 2 weeks after itraconazole treatment.
Gastrointestinal Drugs
CisaprideNaloxegol Contraindicated during and 2 weeks after itraconazole treatment.
AprepitantLoperamidea Monitor for adverse reactions. Concomitant drug dose reduction may be necessary.
Netupitant Monitor for adverse reactions.
Immunosuppressants
EverolimusSirolimusTemsirolimus (IV) Not recommended during and 2 weeks after itraconazole treatment.
Budesonide (inhalation)a Budesonide (non-inhalation)Ciclesonide (inhalation)Cyclosporine (IV)a Cyclosporine(non-IV)Dexamethasonea Fluticasone (inhalation)a Fluticasone (nasal)Methylprednisolonea Tacrolimus (IV)a Tacrolimus (oral) Monitor for adverse reactions. Concomitant drug dose reduction may be necessary.
Lipid-Lowering Drugs
LomitapideLovastatinaSimvastatina Contraindicated during and 2 weeks after itraconazole treatment.
Atorvastatina Monitor for drug adverse reactions. Concomitant drug dose reduction may be necessary.
Respiratory Drugs
Salmeterol Not recommended during and 2 weeks after itraconazole treatment.
SSRIs, Tricyclics and Related Antidepressants
Venlafaxine Monitor for adverse reactions. Concomitant drug dose reduction may be necessary.
Urologic Drugs
Avanafil Contraindicated during and 2 weeks after itraconazole treatment.
Fesoterodine Patients with moderate to severe renal or hepatic impairment: Contraindicated during and 2 weeks after itraconazole treatment.Other patients: Monitor for adverse reactions. Concomitant drug dose reduction may be necessary.
Solifenacin Patients with severe renal or moderate to severe hepatic impairment: Contraindicated during and 2 weeks after itraconazole treatment.Other patients: Monitor for adverse reactions. Concomitant drug dose reduction may be necessary.
DarifenacinVardenafil Not recommended during and 2 weeks after itraconazole treatment.
DutasterideOxybutynina Sildenafil (for erectile dysfunction)Tadalafil (for erectile dysfunction and benign prostatic hyperplasia)Tolterodine Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. For sildenafil and tadalafil, see also Cardiovascular Drugs above.
Miscellaneous Drugs and Other Substances
Colchicine Patients with renal or hepatic impairment: Contraindicated during and 2 weeks after itraconazole treatment.Other patients: Not recommended during and 2 weeks after itraconazole treatment.
Eliglustat CYP2D6 EMs c taking a strong or moderate CYP2D6 inhibitor, CYP2D6 IMs c , or CYP2D6 PMs c :Contraindicated during and 2 weeks after itraconazole treatment.CYP2D6 EMs c not taking a strong or moderate CYP2D6 inhibitor: Monitor for adverse reactions.Eliglustat dose reduction may be necessary.
Lumacaftor/Ivacaftor Not recommended 2 weeks before, during, and 2 weeks after itraconazole treatment.
Alitretinoin (oral)CabergolineCannabinoidsCinacalcetGalantamineIvacaftor Monitor for adverse reactions. Concomitant drug dose reduction may be necessary.
Vasopressin Receptor Antagonists
ConivaptanTolvaptan Not recommended during and 2 weeks after itraconazole treatment.
Drug Interactions with Itraconazole that Decrease Concomitant Drug Concentrations and May Reduce Efficacy of the Concomitant Drug
Antineoplastics
Regorafenib Not recommended during and 2 weeks after itraconazole treatment.
Gastrointestinal Drugs
Saccharomyces boulardii Not recommended during and 2 weeks after itraconazole treatment.
Nonsteroidal Anti-Inflammatory Drugs
Meloxicama Concomitant drug dose increase may be necessary.

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