ITRACONAZOLE Drug Interactions: What You Need to Know

Drug Interactions: Co-administration of a number of CYP3A4 substrates are contraindicated with itraconazole. Some examples of drugs for which plasma concentrations increase are: methadone, disopyramide, dofetilide, dronedarone, quinidine, isavuconazole, ergot alkaloids (such as dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine)), irinotecan, lurasidone, oral midazolam, pimozide, triazolam, felodipine, nisoldipine, ivabradine, ranolazine, eplerenone, cisapride, naloxegol, lomitapide, lovastatin, simvastatin, avanafil, ticagrelor, finerenone, voclosporin. In addition, co-administration with colchicine, fesoterodine, and solifenacin is contraindicated in subjects with varying degrees of renal or hepatic impairment, and co-administration with eliglustat is contraindicated in subjects that are poor or intermediate metabolizers of CYP2D6 and in subjects taking strong or moderate CYP2D6 inhibitors (see PRECAUTIONS: Drug Interactions Section for specific examples). This increase in drug concentrations caused by co-administration with itraconazole may increase or prolong both the pharmacologic effects and/or adverse reactions to these drugs. For example, increased plasma concentrations of some of these drugs can lead to QT prolongation and ventricular tachyarrhythmias including occurrences of torsade de pointes, a potentially fatal arrhythmia. Some specific examples are listed in PRECAUTIONS: Drug Interactions . Co-administration with venetoclax is contraindicated in patients with CLL/SLL during the dose initiation and ramp-up phase of venetoclax due to the potential for an increased risk of tumor lysis syndrome. Itraconazole oral solution is contraindicated for patients who have shown hypersensitivity to itraconazole. There is limited information regarding cross-hypersensitivity between itraconazole and other azole antifungal agents. Caution should be used when prescribing itraconazole to patients with hypersensitivity to other azoles.

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 it 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 Examples of Concomitant Drugs 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 Alfuzosin Silodosin Tamsulosin 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.

Alfentanil

Buprenorphine (IV and sublingual) Oxycodone a Sufentanil Monitor for adverse reactions. Concomitant drug dose reduction may be necessary.

Antiarrhythmics Disopyramide Dofetilide Dronedarone

Quinidine a Contraindicated during and 2 weeks after itraconazole treatment. Digoxin a Monitor for adverse reactions. Concomitant drug dose reduction may be necessary.

Antibacterials

Bedaquiline b 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 2.

Clarithromycin

Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. See also Table 2.

Trimetrexate

Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. Anticoagulants and Antiplatelets Ticagrelor Contraindicated during and 2 weeks after itraconazole treatment.

Apixaban Rivaroxaban Vorapaxar

Not recommended during and 2 weeks after itraconazole treatment.

Cilostazol Dabigatran Warfarin

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 2.

Antidiabetic Drugs

Repaglinide a 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-lumefantrine Quinine a 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.

Venetoclax

Contraindicated during the dose initiation and ramp-up phase in patients with CLL/SLL. Refer to the venetoclax prescribing information for dosing and safety monitoring instructions. Mobocertinib a Avoid use during and 2 weeks after itraconazole treatment.

Axitinib Bosutinib Cabazitaxel Cabozantinib Ceritinib

Cobimetinib a Crizotinib Dabrafenib Dasatinib Docetaxel Ibrutinib Lapatinib Nilotinib Olaparib a Pazopanib Sunitinib Trabectedin Trastuzumab-emtansine Vinca alkaloids Avoid use during and 2 weeks after itraconazole treatment. Entrectinib a Pemigatinib a Talazoparib a Refer to the entrectinib, pemigatinib and talazoparib prescribing information for dosing instructions if concomitant use cannot be avoided.

Glasdegib

Refer to the glasdegib prescribing information for safety monitoring if concomitant use cannot be avoided.

Bortezomib

Brentuximab- vedotin Busulfan Erlotinib Gefitinib a Idelalisib Imatinib Ixabepilone Nintedanib Panobinostat Ponatinib Ruxolitinib Sonidegib Tretinoin (oral) Vandetanib a Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. For idelalisib: see also Table 2. Antipsychotics, Anxiolytics and Hypnotics Alprazolam a Aripiprazole a Buspirone a Cariprazine Diazepam a Haloperidol a Midazolam (IV) a Quetiapine Ramelteon Risperidone a Suvorexant Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. Zopiclone a Monitor for adverse reactions. Concomitant drug dose reduction may be necessary.

Lurasidone

Midazolam (oral) a Pimozide Triazolam a Contraindicated during and 2 weeks after itraconazole treatment.

Antivirals Daclatasvir

Indinavir a Maraviroc Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. For indinavir: see also Table 2.

Cobicistat

Elvitegravir (ritonavir-boosted) Ombitasvir/Paritaprevir/Ritonavir with or without Dasabuvir Ritonavir Saquinavir (unboosted) a Monitor for adverse reactions. Elbasvir/grazoprevir Glecaprevir/pibrentasvir Tenofovir disoproxil fumarate Not recommended during and 2 weeks after itraconazole treatment. Monitor for adverse reactions. Monitor for adverse reactions.

Beta Blockers

Nadolol a Monitor for adverse reactions. Concomitant drug dose reduction may be necessary.

Calcium Channel Blockers

Felodipine a Nisoldipine Contraindicated during and 2 weeks after itraconazole treatment.

Diltiazem

Other dihydropyridines Verapamil Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. For diltiazem: see also Table 2.

Cardiovascular

Drugs, Miscellaneous Ivabradine Ranolazine Contraindicated during and 2 weeks after itraconazole treatment. Aliskiren a Riociguat Sildenafil (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.

Bosentan Guanfacine

Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. Contraceptives* Dienogest Ulipristal Monitor for adverse reactions.

Diuretics Eplerenone Finerenone

Contraindicated during and 2 weeks after itraconazole treatment.

Gastrointestinal Drugs Cisapride Naloxegol

Contraindicated during and 2 weeks after itraconazole treatment.

Aprepitant

Loperamide a Monitor for adverse reactions. Concomitant drug dose reduction may be necessary.

Netupitant

Monitor for adverse reactions.

Immunosuppressants Voclosporin

Contraindicated during and for 2 weeks after itraconazole treatment.

Everolimus Sirolimus

Temsirolimus (IV) Not recommended during and 2 weeks after itraconazole treatment. Budesonide (inhalation) a Budesonide (non- inhalation) Ciclesonide (inhalation) Cyclosporine (IV) a Cyclosporine (non- IV) Dexamethasone a Fluticasone (inhalation) a Fluticasone (nasal) Methylprednisolone a Tacrolimus (IV) a Tacrolimus (oral) Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. Lipid-Lowering Drugs Lomitapide Lovastatin a Simvastatin a Contraindicated during and 2 weeks after itraconazole treatment. Atorvastatin a 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.

Darifenacin Vardenafil

Not recommended during and 2 weeks after itraconazole treatment.

Dutasteride

Oxybutynin a 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)

Cabergoline Cannabinoids Cinacalcet Galantamine Ivacaftor

Monitor for adverse reactions. Concomitant drug dose reduction may be necessary.

Valbenazine

Concomitant drug dose reduction is necessary. Refer to the valbenazine prescribing information for dosing instructions.

Vasopressin Receptor Antagonists Conivaptan Tolvaptan

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 Meloxicam a Concomitant drug dose increase may be necessary. * 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 Effect of Other Drugs on Itraconazole Itraconazole is mainly metabolized through CYP3A4. Other substances that either share this metabolic pathway or modify CYP3A4 activity may influence the pharmacokinetics of itraconazole. Some concomitant drugs have the potential to interact with itraconazole resulting in either increased or sometimes decreased concentrations of itraconazole. Increased concentrations may increase the risk of adverse reactions associated with itraconazole. Decreased concentrations may reduce itraconazole efficacy. The table below lists examples of drugs that may affect itraconazole concentrations, but it 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 2 below are based on information with a similar azole antifungal, ketoconazole, these interactions are expected to occur with itraconazole.

Table

2: Drug Interactions with Other Drugs that Affect Itraconazole Concentrations Examples of Concomitant Drugs Within Class Prevention or Management Drug Interactions with Other Drugs that Increase Itraconazole Concentrations and May Increase Risk of Adverse Reactions Associated with Itraconazole Antibacterials Ciprofloxacin a Erythromycin a Clarithromycin a Monitor for adverse reactions. Itraconazole dose reduction may be necessary.

Antineoplastics Idelalisib

Monitor for adverse reactions. Itraconazole dose reduction may be necessary. See also Table 1.

Antivirals Cobicistat

Darunavir (ritonavir-boosted) Elvitegravir (ritonavir-boosted) Fosamprenavir (ritonavir-boosted) Indinavir a Ombitasvir/Paritaprevir/Ritonavir with or without Dasabuvir Ritonavir Saquinavir Monitor for adverse reactions. Itraconazole dose reduction may be necessary.

For

Boceprevir, cobicistat, elvitegravir, indinavir, ombitasvir/paritaprevir/ritonavir with or without dasabuvir, ritonavir and saquinavir, see also Table 1.

Calcium Channel Blockers Diltiazem

Monitor for adverse reactions. Itraconazole dose reduction may be necessary. See also the table above.

Drug

Interactions with Other Drugs that Decrease Itraconazole Concentrations and May Reduce Efficacy of Itraconazole Antibacterials Isoniazid Rifampicin a Not recommended 2 weeks before and during itraconazole treatment. Rifabutin a Not recommended 2 weeks before, during, and 2 weeks after itraconazole treatment. See also Table 1.

Anticonvulsants Phenobarbital

Phenytoin a Not recommended 2 weeks before and during itraconazole treatment.

Carbamazepine

Not recommended 2 weeks before, during, and 2 weeks after itraconazole treatment. See also Table 1.

Antivirals

Efavirenz a Nevirapine a Not recommended 2 weeks before and during itraconazole treatment.

Miscellaneous

Drugs and Other Substances Lumacaftor/Ivacaftor Not recommended 2 weeks before, during, and 2 weeks after itraconazole treatment. a Based on clinical drug interaction information with itraconazole.

CONTRAINDICATIONS Congestive Heart Failure: Itraconazole capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. (See BOXED WARNING , WARNINGS, PRECAUTIONS : Drug Interactions-Calcium Channel Blockers , ADVERSE REACTIONS : Postmarketing Experience , and CLINICAL PHARMACOLOGY : Special Populations .)

Drug

Interactions: Coadministration of a number of CYP3A4 substrates are contraindicated with itraconazole capsules. Some examples of drugs for which plasma concentrations increase are: methadone, disopyramide, dofetilide, dronedarone, quinidine, isavuconazole, ergot alkaloids (such as dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine)), irinotecan, lurasidone, oral midazolam, pimozide, triazolam, felodipine, nisoldipine, ivabradine, ranolazine, eplerenone, cisapride, naloxegol, lomitapide, lovastatin, simvastatin, avanafil, ticagrelor, finerenone, voclosporin. In addition, coadministration with colchicine, fesoterodine and solifenacin is contraindicated in subjects with varying degrees of renal or hepatic impairment, and coadministration with eliglustat is contraindicated in subjects that are poor or intermediate metabolizers of CYP2D6 and in subjects taking strong or moderate CYP2D6 inhibitors. (See PRECAUTIONS: Drug Interactions Section for specific examples.) This increase in drug concentrations caused by coadministration with itraconazole may increase or prolong both the pharmacologic effects and/or adverse reactions to these drugs. For example, increased plasma concentrations of some of these drugs can lead to QT prolongation and ventricular tachyarrhythmias including occurrences of torsade de pointes, a potentially fatal arrhythmia. Some specific examples are listed in PRECAUTIONS: Drug Interactions. Coadministration with venetoclax is contraindicated in patients with CLL/SLL during the dose initiation and ramp-up phase of venetoclax due to the potential for an increased risk of tumor lysis syndrome. Itraconazole capsules should not be administered for the treatment of onychomycosis to pregnant patients or to women contemplating pregnancy. Itraconazole capsules are contraindicated for patients who have shown hypersensitivity to itraconazole. There is limited information regarding cross-hypersensitivity between itraconazole and other azole antifungal agents. Caution should be used when prescribing itraconazole capsules to patients with hypersensitivity to other azoles.

AND PRECAUTIONS Hepatotoxicity : Serious hepatotoxicity, including liver failure and death were reported with the use of itraconazole. Discontinue treatment if signs of liver dysfunction occur ( 5.2 )

Cardiac

Dysrhythmias : Life-threatening cardiac dysrhythmias and/or sudden death have occurred in patients using certain drugs that are metabolized by human CYP450 enzymes concomitantly with oral itraconazole and/or other CYP3A4 inhibitors. ( 4 , 5.3 , 5.5 ) Pseudoaldosteronism : Manifested by the onset or worsening of hypertension, and abnormal laboratory findings. Monitor blood pressure and potassium levels and manage as necessary ( 5.4 ).

Peripheral

Neuropathy : This has been reported in patients on long-term therapy with itraconazole. Monitor and promptly evaluate neurologic symptoms. ( 5.6 )

Hearing

Loss : Reversible or permanent has been reported in patients. Discontinue treatment if hearing loss occurs ( 5.7 )

5.1 Congestive Heart Failure TOLSURA can cause or exacerbate congestive heart failure (CHF) <span class="opacity-50 text-xs">[see Boxed Warning and Adverse Reactions (6.1) ]</span>. For patients with evidence of ventricular dysfunction such as CHF, history or risk factors for CHF, physicians should carefully review the risks and benefits of TOLSURA 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. Inform such patients of the signs and symptoms of CHF and monitor carefully for signs and symptoms of CHF during treatment. If signs or symptoms of CHF appear or worsen during administration of TOLSURA, reassess the benefit-risk of continuing treatment. When itraconazole was administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was demonstrated. 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 has been associated with reports of CHF, peripheral edema, and pulmonary edema. In post-marketing experience, heart failure was more frequently reported in patients receiving higher total daily doses of itraconazole of 400 mg although there were also cases reported among those receiving lower total daily doses <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) ]</span> . 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, when co-administering itraconazole and calcium channel blockers, monitor carefully for signs and symptoms of CHF during treatment due to an increased risk of CHF. Concomitant administration of TOLSURA and felodipine or nisoldipine is contraindicated <span class="opacity-50 text-xs">[see Contraindications (4.1) , Drug Interactions (7.1) and Adverse Reactions (6.2) ]</span>

5.2 Hepatotoxicity Itraconazole has been associated with 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, discontinue treatment and perform testing for liver disease. Continued TOLSURA use or reinstitution of treatment with TOLSURA is strongly discouraged unless there is a serious or life-threatening situation where the expected benefit exceeds the risk [ see Adverse Reactions (6.1) ].

5.3 Cardiac Dysrhythmias Life-threatening cardiac dysrhythmias and/or sudden death have occurred in patients using drugs such as, pimozide, methadone, or quinidine concomitantly with oral itraconazole and/or other CYP3A4 inhibitors. Concomitant administration of these drugs with TOLSURA is contraindicated <span class="opacity-50 text-xs">[see Boxed Warning , Contraindications (4) and Drug Interactions (7) ]</span>.

5.4 Pseudoaldosteronism Pseudoaldosteronism, manifested by the onset of hypertension or worsening of hypertension, and abnormal laboratory findings (hypokalemia, low serum renin and aldosterone, and elevate 11-deoxycortisol), has been reported with itraconazole use in the postmarketing setting. Monitor blood pressure and potassium levels and manage as necessary. Management of pseudoaldosteronism may include discontinuation of TOLSURA, substitution with an appropriate antifungal drug that is not associated with pseudoaldosteronism, or use of aldosterone receptor antagonists.

5.5 Drug Interaction Potential Itraconazole has a potential for clinically important drug interactions <span class="opacity-50 text-xs">[see Drug Interactions (7.1 , 7.2) ]</span> . Co-administration of specific drugs with TOLSURA may result in changes in the efficacy of itraconazole and/or the co-administered drug, life-threatening effects and/or sudden death. <span class="opacity-50 text-xs">[see Boxed Warning , Contraindications (4.1) and Drug Interactions (7.1 , 7.2) ]</span>.

5.6 Peripheral Neuropathy Cases of peripheral neuropathy have been reported in patients on long-term therapy with itraconazole. Monitor for and promptly evaluate neurologic symptoms. If neuropathy attributable to TOLSURA occurs, discontinue treatment.

5.7 Hearing Loss Reversible 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 <span class="opacity-50 text-xs">[see Boxed Warning , Contraindications (4.2) and Drug Interactions (7) ]</span> . The hearing loss usually resolves when treatment is stopped but can persist in some patients.

5.8 Hypersensitivity Reactions TOLSURA is contraindicated in patients with a known hypersensitivity to itraconazole <span class="opacity-50 text-xs">[see Contraindications (4.2) ]</span>. Hypersensitivity reactions have been reported with the use of itraconazole <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) ]</span> . Due to the limited information regarding cross-hypersensitivity between itraconazole and other azole antifungal drugs, careful enquiry about previous hypersensitivity to other azole antifungal drugs should be made when prescribing TOLSURA. If hypersensitivity reactions to TOLSURA occurs, discontinue the drug and institute appropriate therapy.