ITRACONAZOLE: 4,009 Adverse Event Reports & Safety Profile

DESCRIPTION Itraconazole, an azole antifungal agent. Itraconazole 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 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 or almost white powder. Freely soluble in methylene chloride, sparingly soluble in tetrahydrofuran, very slightly soluble in alcohol and practically insoluble in water. 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 capsules contain 100 mg of itraconazole coated on sugar spheres (composed of sucrose, maize starch and purified water). Inactive ingredients are hard gelatin capsule, hypromellose, poloxamer 188, ethanol absolute, methylene chloride, polyethylene glycol 20000, talc, colloidal silicon dioxide, SLS, titanium dioxide, FD&C blue 1, FD&C red 40, FD&C red 3 and white ink (containing: shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, titanium dioxide and potassium hydroxide). FDA approved dissolution test specifications differ from USP itraconazole-struct

INDICATIONS AND USAGE Itraconazole capsules are indicated for the treatment of the following fungal infections in immunocompromised and non-immunocompromised patients: Blastomycosis, pulmonary and extrapulmonary Histoplasmosis, including chronic cavitary pulmonary disease and disseminated, non-meningeal histoplasmosis, and 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 before 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, antiinfective therapy should be adjusted accordingly. Itraconazole capsules are also indicated for the treatment of the following fungal infections in non-immunocompromised patients: Onychomycosis of the toenail, with or without fingernail involvement, due to dermatophytes (tinea unguium), and Onychomycosis of the fingernail due to dermatophytes (tinea unguium). Prior to initiating treatment, appropriate nail specimens for laboratory testing (KOH preparation, fungal culture, or nail biopsy) should be obtained to confirm the diagnosis of onychomycosis (see CLINICAL PHARMACOLOGY : Special Populations, CONTRAINDICATIONS , WARNINGS , and ADVERSE REACTIONS : Post-marketing Experience for more information). Description of Clinical Studies: Blastomycosis: Analyses were conducted on data from two open-label, non-concurrently controlled studies (N=73 combined) in patients with normal or abnormal immune status. The median dose was 200 mg/day. A response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 6 months. Results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole for the treatment of blastomycosis compared with the natural history of untreated cases. Histoplasmosis: Analyses were conducted on data from two open-label, non-concurrently controlled studies (N=34 combined) in patients with normal or abnormal immune status (not including HIV-infected patients). The median dose was 200 mg/day. A response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 12 months. Results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole for the treatment of histoplasmosis, compared with the natural history of untreated cases. Histoplasmosis in HIV-infected patients: Data from a small number of HIV-infected patients suggested that the response rate of histoplasmosis in HIV-infected patients is similar to that of non-HIV-infected patients. The clinical course of histoplasmosis in HIV-infected patients is more severe and usually requires maintenance therapy to prevent relapse. Aspergillosis: Analyses were conducted on data from an open-label, “single-patient-use” protocol designed to make itraconazole available in the U.S. for patients who either failed or were intolerant of amphotericin B therapy (N=190). The findings were corroborated by two smaller open-label studies (N=31 combined) in the same patient population. Most adult patients were treated with a daily dose of 200 mg to 400 mg, with a median duration of 3 months. Results of these studies demonstrated substantial evidence of effectiveness of itraconazole as a second-line therapy for the treatment of aspergillosis compared with the natural history of the disease in patients who either failed or were intolerant of amphotericin B therapy. Onychomycosis of the toenail: Analyses were conducted on data from three double-blind, placebo-controlled studies (N=214 total; 110 given itraconazole capsules) in which patients with onychomycosis of the toenails received 200 mg of itraconazole capsules once daily for 12 consecutive weeks. Results of these studies demonstrated mycologic cure, defined as simultaneous occurrence of negative KOH plus negative culture, in 54% of patients. Thirty-five percent (35%) of patients were considered an overall success (mycologic cure plus clear or minimal nail involvement with significantly decreased signs) and 14% of patients demonstrated mycologic cure plus clinical cure (clearance of all signs, with or without residual nail deformity). The mean time to overall success was approximately 10 months. Twenty-one percent (21%) of the overall success group had a relapse (worsening of the global score or conversion of KOH or culture from negative to positive). Onychomycosis of the fingernail: Analyses were conducted on data from a double-blind, placebo-controlled study (N=73 total; 37 given itraconazole capsules) in which patients with onychomycosis of the fingernails received a 1-week course (pulse) of 200 mg of itraconazole capsules b.i.d., followed by a 3-week period without itraconazole capsules, which was followed by a second 1-week pulse of 200 mg of itraconazole capsules b.i.d. Results demonstrated mycologic cure in 61% of patients. Fifty-six percent (56%) of patients were considered an overall success and 47% of patients demonstrated mycologic cure plus clinical cure. The mean time to overall success was approximately 5 months. None of the patients who achieved overall success relapsed.

DOSAGE AND ADMINISTRATION Itraconazole Capsules should be taken with a full meal to ensure maximal absorption.

Itraconazole

Capsules must be swallowed whole.

Itraconazole

Capsules are a different preparation than SPORANOX ® (itraconazole)

Oral

Solution and should not be used interchangeably. Treatment of Blastomycosis and Histoplasmosis The recommended dose is 200 mg once daily (2 capsules). If there is no obvious improvement, or there is evidence of progressive fungal disease, the dose should be increased in 100-mg increments to a maximum of 400 mg daily. Doses above 200 mg/day should be given in two divided doses. Treatment of Aspergillosis A daily dose of 200 to 400 mg is recommended. Treatment in Life-Threatening Situations In life-threatening situations, a loading dose should be used. Although clinical studies did not provide for a loading dose, it is recommended, based on pharmacokinetic data, that a loading dose of 200 mg (2 capsules) three times daily (600 mg/day) be given for the first 3 days of treatment. Treatment should be continued for a minimum of three months and until clinical parameters and laboratory tests indicate that the active fungal infection has subsided. An inadequate period of treatment may lead to recurrence of active infection.

Itraconazole

Capsules and SPORANOX ® (itraconazole)

Oral

Solution should not be used interchangeably. Only the Oral Solution has been demonstrated effective for oral and/or esophageal candidiasis. Treatment of Onychomycosis Toenails with or without fingernail involvement The recommended dose is 200 mg (2 capsules) once daily for 12 consecutive weeks. Treatment of Onychomycosis Fingernails only The recommended dosing regimen is 2 treatment pulses, each consisting of 200 mg (2 capsules) b.i.d. (400 mg/day) for 1 week. The pulses are separated by a 3-week period without itraconazole. 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 .)

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.

ADVERSE REACTIONS 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).

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.

PRECAUTIONS General: Itraconazole Capsules should be administered after a full meal. (See CLINICAL PHARMACOLOGY: Pharmacokinetics and Metabolism ). Under fasted conditions, itraconazole absorption was decreased in the presence of decreased gastric acidity. The absorption of itraconazole may be decreased with the concomitant administration of antacids or gastric acid secretion suppressors. Studies conducted under fasted conditions demonstrated that administration with 8 ounces of a non-diet cola beverage resulted in increased absorption of itraconazole in AIDS patients with relative or absolute achlorhydria. This increase relative to the effects of a full meal is unknown. (See CLINICAL PHARMACOLOGY: Pharmacokinetics and Metabolism ). 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 Capsules, the treatment should be discontinued.

Immunocompromised

Patients: In some immunocompromised patients (e.g., neutropenic, AIDS or organ transplant patients), the oral bioavailability of Itraconazole capsules may be decreased. Therefore, the dose should be adjusted based on the clinical response in these patients.

Cystic

Fibrosis: If a cystic fibrosis patient does not respond to Itraconazole Capsules, consideration should be given to switching to alternative therapy. For more information concerning the use of itraconazole in cystic fibrosis patients see the prescribing information for SPORANOX ® Oral Solution.

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: The topical effects of mucosal exposure may be different between Itraconazole Capsules and SPORANOX ® (itraconazole)

Oral

Solution. Only the Oral Solution has been demonstrated effective for oral and/or esophageal candidiasis.

Itraconazole

Capsules should not be used interchangeably with SPORANOX ® (itraconazole)

Oral

Solution. Instruct patients to take Itraconazole Capsules with a full meal.

Itraconazole

Capsules must be swallowed whole. 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 Capsules 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 Capsules 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.

Table

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

Table

1: Drug Interactions with Itraconazole Capsules that Affect Concomitant Drug Concentrations Examples of Concomitant Drugs Within Class Prevention or Management Drug Interactions with Itraconazole Capsules 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 Capsules treatment.

Analgesics Methadone

Contraindicated during and 2 weeks after Itraconazole Capsules treatment.

Fentanyl

Not recommended during and 2 weeks after Itraconazole Capsules treatment.

Alfentanil

Buprenorphine (IV and sublingual)

Oxycodone

Based on clinical drug interaction information with itraconazole.

Sufentanil

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

Antiarrhythmics Disopyramide Dofetilide Dronedarone Quinidine

Contraindicated during and 2 weeks after Itraconazole Capsules treatment.

Digoxin

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

Antibacterials Bedaquiline

Based on 400 mg bedaquiline once daily for 2 weeks.

Concomitant Itraconazole

Capsules 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 Capsules 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 Capsules treatment.

Apixaban Rivaroxaban Vorapaxar

Not recommended during and 2 weeks after Itraconazole Capsules 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 Capsules treatment. See also Table 2 .

Antidiabetic Drugs Repaglinide Saxagliptin

Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. Antihelminthics, Antifungals and Antiprotozoals Isavuconazonium Contraindicated during and 2 weeks after Itraconazole Capsules treatment.

Praziquantel

Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. Artemether-lumefantrine Quinine Monitor for adverse reactions.

Antimigraine Drugs

Ergot alkaloids (e.g., dihydroergotamine, ergotamine) Contraindicated during and 2 weeks after Itraconazole Capsules treatment.

Eletriptan

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

Antineoplastics Irinotecan

Contraindicated during and 2 weeks after Itraconazole Capsules 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

Avoid use during and 2 weeks after Itraconazole Capsules treatment.

Axitinib Bosutinib Cabazitaxel Cabozantinib Ceritinib

Cobimetinib Crizotinib Dabrafenib Dasatinib Docetaxel Ibrutinib Lapatinib Nilotinib Olaparib Pazopanib Sunitinib Trabectedin Trastuzumab- emtansine Vinca alkaloids Avoid use during and 2 weeks after Itraconazole Capsules treatment.

Entrectinib Pemigatinib Talazoparib

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 Idelalisib Imatinib Ixabepilone Nintedanib Panobinostat Ponatinib Ruxolitinib Sonidegib Tretinoin (oral)

Vandetanib

Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. For idelalisib, see also Table 2 . Antipsychotics, Anxiolytics and Hypnotics Alprazolam Aripiprazole Buspirone Cariprazine Diazepam Haloperidol Midazolam (IV)

Quetiapine Ramelteon Risperidone Suvorexant

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

Zopiclone

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

Lurasidone

Midazolam (oral)

Pimozide Triazolam

Contraindicated during and 2 weeks after Itraconazole Capsules treatment.

Antivirals Daclatasvir Indinavir 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) Monitor for adverse reactions. See also Table 2 . Elbasvir/grazoprevir Not recommended during and 2 weeks after Itraconazole Capsules treatment. Glecaprevir/pibrentasvir Monitor for adverse reactions. Tenofovir disoproxil fumarate Monitor for adverse reactions.

Beta Blockers Nadolol

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

Calcium Channel Blockers Felodipine Nisoldipine

Contraindicated during and 2 weeks after Itraconazole Capsules 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 Capsules treatment.

Aliskiren Riociguat

Sildenafil (for pulmonary hypertension) Tadalafil (for pulmonary hypertension) Not recommended during and 2 weeks after Itraconazole Capsules treatment. For sildenafil and tadalafil, see also Urologic Drugs below.

Bosentan Guanfacine

Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. Contraceptives CYP3A4 inhibitors (including itraconazole) may increase systemic contraceptive hormone concentrations.

Dienogest Ulipristal

Monitor for adverse reactions.

Diuretics Eplerenone Finerenone

Contraindicated during and 2 weeks after Itraconazole Capsules treatment.

Gastrointestinal Drugs Cisapride Naloxegol

Contraindicated during and 2 weeks after Itraconazole Capsules treatment.

Aprepitant Loperamide

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

Netupitant

Monitor for adverse reactions.

Immunosuppressants Voclosporin

Contraindicated during and 2 weeks after Itraconazole Capsules treatment.

Everolimus Sirolimus

Temsirolimus (IV) Not recommended during and 2 weeks after Itraconazole Capsules treatment. Budesonide (inhalation) Budesonide (non-inhalation) Ciclesonide (inhalation) Cyclosporine (IV) Cyclosporine (non-IV)

Dexamethasone

Fluticasone (inhalation) Fluticasone (nasal)

Methylprednisolone

Tacrolimus (IV) Tacrolimus (oral) Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. Lipid-Lowering Drugs Lomitapide Lovastatin Simvastatin Contraindicated during and 2 weeks after Itraconazole Capsules treatment.

Atorvastatin

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

Respiratory Drugs Salmeterol

Not recommended during and 2 weeks after Itraconazole Capsules 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 Capsules treatment.

Fesoterodine

Patients with moderate to severe renal or hepatic impairment : Contraindicated during and 2 weeks after Itraconazole Capsules 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 Capsules treatment. Other patients : Monitor for adverse reactions. Concomitant drug dose reduction may be necessary.

Darifenacin Vardenafil

Not recommended during and 2 weeks after Itraconazole Capsules treatment.

Dutasteride Oxybutynin

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 Capsules treatment. Other patients : Not recommended during and 2 weeks after Itraconazole Capsules treatment. Eliglustat CYP2D6 EMs EMs: extensive metabolizers; IMs: intermediate metabolizers, PMs: poor metabolizers taking a strong or moderate CYP2D6 inhibitor, CYP2D6 IMs , or CYP2D6 PMs : Contraindicated during and 2 weeks after Itraconazole Capsules treatment. CYP2D6 EMs 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 Capsules 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 Capsules treatment.

Drug

Interactions with Itraconazole Capsules that Decrease Concomitant Drug Concentrations and May Reduce Efficacy of the Concomitant Drug Antineoplastics Regorafenib Not recommended during and 2 weeks after Itraconazole Capsules treatment.

Gastrointestinal Drugs

Saccharomyces boulardii Not recommended during and 2 weeks after Itraconazole Capsules treatment.

Nonsteroidal

Anti-Inflammatory Drugs Meloxicam Concomitant drug dose increase may be necessary. Effect of Other Drugs on Itraconazole Capsules 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 Capsules resulting in either increased or sometimes decreased concentrations of Itraconazole Capsules. Increased concentrations may increase the risk of adverse reactions associated with Itraconazole Capsules. Decreased concentrations may reduce Itraconazole Capsules efficacy.

Table

2 lists examples of drugs that may affect itraconazole concentrations, 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 Capsules. Although many of the clinical drug interactions in Table 2 are based on information with a similar azole antifungal, ketoconazole, these interactions are expected to occur with Itraconazole Capsules.

Table

2: Drug Interactions with Other Drugs that Affect Itraconazole Capsules Concentrations Examples of Concomitant Drugs Within Class Prevention or Management Drug Interactions with Other Drugs that Increase Itraconazole Capsules Concentrations and May Increase Risk of Adverse Reactions Associated with Itraconazole Capsules Antibacterials Ciprofloxacin Based on clinical drug interaction information with itraconazole.

Erythromycin Clarithromycin

Monitor for adverse reactions.

Itraconazole

Capsules dose reduction may be necessary.

Antineoplastics Idelalisib

Monitor for adverse reactions.

Itraconazole

Capsules dose reduction may be necessary. See also Table 1 .

Antivirals Cobicistat

Darunavir (ritonavir-boosted) Elvitegravir (ritonavir-boosted) Fosamprenavir (ritonavir-boosted)

Indinavir

Ombitasvir/ Paritaprevir/ Ritonavir with or without Dasabuvir Ritonavir Saquinavir Monitor for adverse reactions.

Itraconazole

Capsules dose reduction may be necessary. For, 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

Capsules dose reduction may be necessary. See also Table 1 .

Drug

Interactions with Other Drugs that Decrease Itraconazole Capsules Concentrations and May Reduce Efficacy of Itraconazole Capsules Antibacterials Isoniazid Rifampicin Not recommended 2 weeks before and during Itraconazole Capsules treatment.

Rifabutin

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

Anticonvulsants Phenobarbital Phenytoin

Not recommended 2 weeks before and during Itraconazole Capsules treatment.

Carbamazepine

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

Antivirals Efavirenz Nevirapine

Not recommended 2 weeks before and during Itraconazole Capsules treatment.

Gastrointestinal Drugs

Drugs that reduce gastric acidity e.g. acid neutralizing medicines such as aluminum hydroxide, or acid secretion suppressors such as H 2 - receptor antagonists and proton pump inhibitors. Use with caution. Administer acid neutralizing medicines at least 2 hours before or 2 hours after the intake of Itraconazole Capsules.

Miscellaneous

Drugs and Other Substances Lumacaftor/Ivacaftor Not recommended 2 weeks before, during, and 2 weeks after Itraconazole Capsules treatment.

Pediatric Population

Interaction studies have only been performed in adults. Carcinogenesis, Mutagenesis, and Impairment of Fertility Itraconazole showed no evidence of carcinogenicity potential in mice treated orally for 23 months at dosage levels up to 80 mg/kg/day (approximately 1 time the maximum recommended human dose [MRHD] of 400 mg/day based on body surface area comparisons). Male rats treated with 25 mg/kg/day (0.6 times the MRHD based on body surface area comparisons) had a slightly increased incidence of soft tissue sarcoma. These sarcomas may have been a consequence of hypercholesterolemia, which is a response of rats, but not dogs or humans, to chronic itraconazole administration. Female rats treated with 50 mg/kg/day (1.2 times the MRHD based on body surface area comparisons) had an increased incidence of squamous cell carcinoma of the lung (2/50) as compared to the untreated group. Although the occurrence of squamous cell carcinoma in the lung is extremely uncommon in untreated rats, the increase in this study was not statistically significant. Itraconazole produced no mutagenic effects when assayed in DNA repair test (unscheduled DNA synthesis) in primary rat hepatocytes, in Ames tests with Salmonella typhimurium (6 strains) and Escherichia coli , in the mouse lymphoma gene mutation tests, in a sex-linked recessive lethal mutation ( Drosophila melanogaster ) test, in chromosome aberration tests in human lymphocytes, in a cell transformation test with C3H/10T½ C18 mouse embryo fibroblasts cells, in a dominant lethal mutation test in male and female mice, and in micronucleus tests in mice and rats. Itraconazole did not affect the fertility of male or female rats treated orally with dosage levels of up to 40 mg/kg/day (1 time the MRHD based on body surface area comparisons), even though parental toxicity was present at this dosage level. More severe signs of parental toxicity, including death, were present in the next higher dosage level, 160 mg/kg/day (4 times the MRHD based on body surface area comparisons). Pregnancy: Teratogenic Effects Itraconazole was found to cause a dose-related increase in maternal toxicity, embryotoxicity, and teratogenicity in rats at dosage levels of approximately 40–160 mg/kg/day (1–4 times the MRHD based on body surface area comparisons), and in mice at dosage levels of approximately 80 mg/kg/day (1 time the MRHD based on body surface area comparisons). Itraconazole has been shown to cross the placenta in a rat model. In rats, the teratogenicity consisted of major skeletal defects; in mice, it consisted of encephaloceles and/or macroglossia. There are no studies in pregnant women. Itraconazole should be used for the treatment of systemic fungal infections in pregnancy only if the benefit outweighs the potential risk. Itraconazole should not be administered for the treatment of onychomycosis to pregnant patients or to women contemplating pregnancy. Itraconazole should not be administered to women of childbearing potential for the treatment of onychomycosis unless they are using effective measures to prevent pregnancy and they begin therapy on the second or third day following the onset of menses. Highly effective contraception should be continued throughout itraconazole therapy and for 2 months following the end of treatment. During postmarketing experience, cases of congenital abnormalities have been reported. (See ADVERSE REACTIONS: Postmarketing Experience .)

Nursing

Mothers: Itraconazole is excreted in human milk; therefore, the expected benefits of itraconazole therapy for the mother should be weighed against the potential risk from exposure of itraconazole to the infant. The U.S.

Public Health Service

Centers for Disease Control and Prevention advises HIV-infected women not to breast-feed to avoid potential transmission of HIV to uninfected infants.

Pediatric

Use: The efficacy and safety of itraconazole have not been established in pediatric patients. The long-term effects of itraconazole on bone growth in children are unknown. In three toxicology studies using rats, itraconazole induced bone defects at dosage levels as low as 20 mg/kg/day (0.5 times the MRHD of 400 mg based on body surface area comparisons). The induced defects included reduced bone plate activity, thinning of the zona compacta of the large bones, and increased bone fragility. At a dosage level of 80 mg/kg/day (2 times the MRHD based on body surface area comparisons) over 1 year or 160 mg/kg/day (4 times the MRHD based on body surface area comparisons) for 6 months, itraconazole induced small tooth pulp with hypocellular appearance in some rats.

Geriatric

Use: Clinical studies of Itraconazole Capsules did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. It is advised to use Itraconazole Capsules in these patients only if it is determined that the potential benefit outweighs the potential risks. In general, it is recommended that the dose selection for an elderly patient should be taken into consideration, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Transient or permanent hearing loss has been reported in elderly 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 ). HIV-Infected Patients: Because hypochlorhydria has been reported in HIV-infected individuals, the absorption of itraconazole in these patients may be decreased.

Renal

Impairment: Limited data are available on the use of oral itraconazole in patients with renal impairment. The exposure of itraconazole may be lower in some patients with renal impairment. Caution should be exercised when itraconazole is administered in this patient population and dose adjustment may be needed. (See CLINICAL PHARMACOLOGY: Special Populations and DOSAGE AND ADMINISTRATION .)

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. It is recommended that patients with impaired hepatic function be carefully monitored when taking itraconazole. It is recommended that the prolonged elimination half-life of itraconazole observed in the single oral dose clinical trial with Itraconazole Capsules in cirrhotic patients be considered when deciding to initiate therapy with other medications metabolized by CYP3A4. In patients with elevated or abnormal liver enzymes or active liver disease, or who have experienced liver toxicity with other drugs, treatment with itraconazole is strongly discouraged unless there is a serious or life-threatening situation where the expected benefit exceeds the risk. It is recommended that liver function monitoring be done in patients with pre-existing hepatic function abnormalities or those who have experienced liver toxicity with other medications. (See CLINICAL PHARMACOLOGY: Special Populations and DOSAGE AND ADMINISTRATION .)

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.