ITRACONAZOLE

Itraconazole, USP is an azole antifungal agent. Itraconazole, USP is a 1:1:1:1 racemic mixture of four diastereomers (two enantiomeric pairs), each possessing three chiral centers. It may be represented by the following structural formula and nomenclature: (±)-1-[(R*)-sec-butyl]-4-[p-[4-[p-[[(2R*,4S*)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ 2 -1,2,4-triazolin-5-one mixture with (±)-1-[(R*)-sec-butyl]-4-[p-[4-[p-[[(2S*,4R*)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ 2 -1,2,4-triazolin-5-one or (±)-1-[(RS)-sec-butyl]-4-[p-[4-[p-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ 2 -1,2,4-triazolin-5-one. Itraconazole, USP has a molecular formula of C 35 H 38 Cl 2 N 8 O 4 and a molecular weight of 705.64. It is a white to slightly yellowish powder. It is insoluble in water, very slightly soluble in alcohols, and freely soluble in dichloromethane. It has a pKa of 3.70 (based on extrapolation of values obtained from methanolic solutions) and a log (n-octanol/water) partition coefficient of 5.66 at pH 8.1. Itraconazole oral solution contains 10 mg of itraconazole, USP per mL, solubilized by hydroxypropyl-β-cyclodextrin (400 mg/mL) as a molecular inclusion complex. Itraconazole oral solution is clear and yellowish in color with a target pH of 2. Other ingredients are caramel flavor, cherry flavor, hydrochloric acid, propylene glycol, purified water, sodium hydroxide, sodium saccharin, and sorbitol. Hydrochloric acid solution or sodium hydroxide solution may be added for adjustment of pH. 4

Itraconazole oral solution is indicated for the treatment of oropharyngeal and esophageal candidiasis. (see CLINICAL PHARMACOLOGY: Special Populations , WARNINGS , and ADVERSE REACTIONS: Postmarketing Experience for more information).

Treatment of Oropharyngeal and Esophageal Candidiasis: The solution should be vigorously swished in the mouth (10 mL at a time) for several seconds and swallowed. The recommended dosage of itraconazole oral solution for oropharyngeal candidiasis is 200 mg (20 mL) daily for 1 to 2 weeks. Clinical signs and symptoms of oropharyngeal candidiasis generally resolve within several days. For patients with oropharyngeal candidiasis unresponsive/refractory to treatment with fluconazole tablets, the recommended dose is 100 mg (10 mL) b.i.d. For patients responding to therapy, clinical response will be seen in 2 to 4 weeks. Patients may be expected to relapse shortly after discontinuing therapy. Limited data on the safety of long-term use (> 6 months) of itraconazole oral solution are available at this time. The recommended dosage of itraconazole oral solution for esophageal candidiasis is 100 mg (10 mL) daily for a minimum treatment of three weeks. Treatment should continue for 2 weeks following resolution of symptoms. Doses up to 200 mg (20 mL) per day may be used based on medical judgment of the patient’s response to therapy. Itraconazole oral solution and itraconazole capsules should not be used interchangeably. Patients should be instructed to take itraconazole oral solution without food, if possible. Only itraconazole oral solution has been demonstrated effective for oral and/or esophageal candidiasis. Use in Patients with Renal Impairment: Limited data are available on the use of oral itraconazole in patients with renal impairment. Caution should be exercised when this drug is administered in this patient population (see CLINICAL PHARMACOLOGY: Special Populations and PRECAUTIONS ). Use in Patients with Hepatic Impairment: Limited data are available on the use of oral itraconazole in patients with hepatic impairment. Caution should be exercised when this drug is administered in this patient population (see CLINICAL PHARMACOLOGY: Special Populations , WARNINGS, and PRECAUTIONS ).

Congestive Heart Failure: Itraconazole oral solution should not be administered to patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF except for the treatment of life-threatening or other serious infections (see BOXED WARNING , WARNINGS , PRECAUTIONS: Drug Interactions -Calcium Channel Blockers, ADVERSE REACTIONS: Postmarketing Experience , and CLINICAL PHARMACOLOGY: Special Populations ). 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.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. 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. If clinical signs or symptoms develop that are consistent with liver disease, treatment should be discontinued and liver function testing performed. The risks and benefits of itraconazole use should be reassessed (see WARNINGS: Hepatic Effects and PRECAUTIONS: Hepatotoxicity and Information for Patients ). Adverse Events Reported in Oropharyngeal or Esophageal Candidiasis Trials U.S. adverse experience data are derived from 350 immunocompromised patients (332 HIV seropositive/AIDS) treated for oropharyngeal or esophageal candidiasis. Table 3 below lists adverse events reported by at least 2% of patients treated with itraconazole oral solution in U.S. clinical trials. Data on patients receiving comparator agents in these trials are included for comparison. Table 3: Summary of Adverse Events Reported by ≥ 2% of Itraconazole Treated Patients in U.S. Clinical Trials (Total) Body System/ Adverse Event Itraconazole Total (n = 350 * ) % All controlled studies (n = 272) % Fluconazole (n = 125 † ) % Clotrimazole (n = 81 ‡ ) % Gastrointestinal disorders Nausea 11 10 11 5 Diarrhea 11 10 10 4 Vomiting 7 6 8 1 Abdominal pain 6 4 7 7 Constipation 2 2 1 0 Body as a whole Fever 7 6 8 5 Chest pain 3 3 2 0 Pain 2 2 4 0 Fatigue 2 1 2 0 Respiratory disorders Coughing 4 4 10 0 Dyspnea 2 3 5 1 Pneumonia 2 2 0 0 Sinusitis 2 2 4 0 Sputum increased 2 3 3 1 Skin and appendages disorders Rash 4 5 4 6 Increased sweating 3 4 6 1 Skin disorder unspecified 2 2 2 1 Central/peripheral nervous system Headache 4 4 6 6 Dizziness 2 2 4 1 Resistance mechanism disorders Pneumocystis carinii infection 2 2 2 0 Psychiatric disorders Depression 2 1 0 1 * Of the 350 patients, 209 were treated for oropharyngeal candidiasis in controlled studies, 63 were treated for esophageal candidiasis in controlled studies and 78 were treated for oropharyngeal candidiasis in an open study. † Of the 125 patients, 62 were treated for oropharyngeal candidiasis and 63 were treated for esophageal candidiasis. ‡ All 81 patients were treated for oropharyngeal candidiasis. Adverse events reported by less than 2% of patients in U.S. clinical trials with itraconazole included: adrenal insufficiency, asthenia, back pain, dehydration, dyspepsia, dysphagia, flatulence, gynecomastia, hematuria, hemorrhoids, hot flushes, implantation complication, infection unspecified, injury, insomnia, male breast pain, myalgia, pharyngitis, pruritus, rhinitis, rigors, stomatitis ulcerative, taste perversion, tinnitus, upper respiratory tract infection, vision abnormal, and weight decrease. Edema, hypokalemia and menstrual disorders have been reported in clinical trials with itraconazole capsules. Adverse Events Reported from Other Clinical Trials A comparative clinical trial in patients who received intravenous itraconazole followed by itraconazole oral solution or received Amphotericin B reported the following adverse events in the itraconazole intravenous/ itraconazole oral solution treatment arm which are not listed above in the subsection “Adverse Events Reported in Oropharyngeal or Esophageal Candidiasis Trials” or listed below as postmarketing reports of adverse drug reactions: serum creatinine increased, blood urea nitrogen increased, renal function abnormal, hypocalcemia, hypomagnesemia, hypophosphatemia, hypotension, tachycardia and pulmonary infiltration. In addition, the following adverse drug reactions were reported in patients who participated in itraconazole oral solution clinical trials: Cardiac Disorders: cardiac failure; General Disorders and Administration Site Conditions: edema; Hepatobiliary Disorders: hepatic failure, hyperbilirubinemia; Metabolism and Nutrition Disorders: hypokalemia; Reproductive System and Breast Disorders: menstrual disorder The following is a list of additional adverse drug reactions associated with itraconazole that have been reported in clinical trials of itraconazole capsules and itraconazole IV excluding the adverse reaction term “Injection site inflammation” which is specific to the injection route of administration: Cardiac Disorders: left ventricular failure; Gastrointestinal Disorders: gastrointestinal disorder; General Disorders and Administration Site Conditions: face edema; Hepatobiliary Disorders: jaundice, hepatic function abnormal; Investigations: alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, blood lactate dehydrogenase increased, gamma-glutamyltransferase increased, urine analysis abnormal; Metabolism and Nutrition Disorders: hyperglycemia, hyperkalemia; Nervous System Disorders: somnolence; Psychiatric Disorders: confusional state; Renal and Urinary Disorders: renal impairment; Respiratory, Thoracic and Mediastinal Disorders: dysphonia; Skin and Subcutaneous Tissue Disorders: rash erythematous; Vascular Disorders: hypertension In addition, the following adverse drug reaction was reported in children only who participated in itraconazole oral solution clinical trials: mucosal inflammation. To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . Postmarketing Experience Adverse drug reactions that have been first identified during postmarketing experience with itraconazole (all formulations) are listed in Table 4 below. Because these reactions are reported voluntarily from a population of uncertain size, reliably estimating their frequency or establishing a causal relationship to drug exposure is not always possible. Table 4: Postmarketing Reports of Adverse Drug Reactions Blood and Lymphatic System Disorders: Leukopenia, neutropenia, thrombocytopenia Immune System Disorders: Anaphylaxis; anaphylactic, anaphylactoid and allergic reactions; serum sickness; angioneurotic edema Endocrine Disorders: Pseudoaldosteronism Metabolism and Nutrition Disorders: Hypertriglyceridemia Nervous System Disorders: Peripheral neuropathy, paresthesia, hypoesthesia, tremor Eye Disorders: Visual disturbances, including vision blurred and diplopia Ear and Labyrinth Disorders: Transient or permanent hearing loss Cardiac Disorders: Congestive heart failure, bradycardia Respiratory, Thoracic and Mediastinal Disorders: Pulmonary edema Gastrointestinal Disorders: Pancreatitis Hepatobiliary Disorders: Serious hepatotoxicity (including some cases of fatal acute liver failure), hepatitis, reversible increases in hepatic enzymes Skin and Subcutaneous Tissue Disorders: Toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, erythema multiforme, exfoliative dermatitis, leukocytoclastic vasculitis, alopecia, photosensitivity, urticaria Musculoskeletal and Connective Tissue Disorders: Arthralgia Renal and Urinary Disorders: Urinary incontinence, pollakiuria Reproductive System and Breast Disorders: Erectile dysfunction General Disorders and Administration Site Conditions: Peripheral edema Investigations: Blood creatine phosphokinase increased There is limited information on the use of itraconazole during pregnancy. Cases of congenital abnormalities including skeletal, genitourinary tract, cardiovascular and ophthalmic malformations as well as chromosomal and multiple malformations have been reported during postmarketing experience. A causal relationship with itraconazole has not been established (see CLINICAL PHARMACOLOGY: Special Populations , CONTRAINDICATIONS , WARNINGS, and PRECAUTIONS: Drug Interactions for more information).

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.