Itraconazole 10 mg/mL Solution — NDC 65162-087-34 (Billing 65162-0087-34)

WARNINGS Hepatic Effects: Itraconazole has been associated with rare cases of serious hepatotoxicity, including liver failure and death. Some of these cases had neither pre-existing liver disease nor a serious underlying medical condition, and some of these cases developed within the first week of treatment. If clinical signs or symptoms develop that are consistent with liver disease, treatment should be discontinued and liver function testing performed.

Continued itraconazole use or reinstitution of treatment with itraconazole is strongly discouraged unless there is a serious or life-threatening situation where the expected benefit exceeds the risk (see PRECAUTIONS : Information for Patients and ADVERSE REACTIONS ). Cardiac Dysrhythmias: Life-threatening cardiac dysrhythmias and/or sudden death have occurred in patients using drugs such as cisapride, pimozide, methadone, or quinidine concomitantly with itraconazole and/or other CYP3A4 inhibitors. Concomitant administration of these drugs with itraconazole is contraindicated (see BOXED WARNING , CONTRAINDICATIONS, and PRECAUTIONS: Drug Interactions ).

Cardiac Disease: Itraconazole oral solution should not be used in patients with evidence of ventricular dysfunction unless the benefit clearly outweighs the risk. For patients with risk factors for congestive heart failure, physicians should carefully review the risks and benefits of itraconazole therapy. These risk factors include cardiac disease such as ischemic and valvular disease; significant pulmonary disease such as chronic obstructive pulmonary disease; and renal failure and other edematous disorders.

Such patients should be informed of the signs and symptoms of CHF, should be treated with caution, and should be monitored for signs and symptoms of CHF during treatment. If signs or symptoms of CHF appear during administration of itraconazole oral solution, monitor carefully and consider other treatment alternatives which may include discontinuation of itraconazole oral solution administration. Itraconazole has been shown to have a negative inotropic effect.

When itraconazole was administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was documented. In a healthy volunteer study of itraconazole intravenous infusion, transient, asymptomatic decreases in left ventricular ejection fraction were observed using gated SPECT imaging; these resolved before the next infusion, 12 hours later. Itraconazole has been associated with reports of congestive heart failure.

In postmarketing experience, heart failure was more frequently reported in patients receiving a total daily dose of 400 mg although there were also cases reported among those receiving lower total daily doses. Calcium channel blockers can have negative inotropic effects which may be additive to those of itraconazole. In addition, itraconazole can inhibit the metabolism of calcium channel blockers.

Therefore, caution should be used when co-administering itraconazole and calcium channel blockers due to an increased risk of CHF. Concomitant administration of itraconazole and felodipine or nisoldipine is contraindicated. Cases of CHF, peripheral edema, and pulmonary edema have been reported in the postmarketing period among patients being treated for onychomycosis and/or systemic fungal infections (see CONTRAINDICATIONS , CLINICAL PHARMACOLOGY: Special Populations , PRECAUTIONS: Drug Interactions , and ADVERSE REACTIONS: Postmarketing Experience for more information).

Pseudoaldosteronism: Pseudoaldosteronism, manifested by the onset of hypertension or worsening of hypertension, and abnormal laboratory findings (hypokalemia, low serum renin and aldosterone, and elevated 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 itraconazole, substitution with an appropriate antifun… [Excerpted — this section continues on DailyMed.]

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 Disorde… [Excerpted — this section continues on DailyMed.]

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 durin… [Excerpted — this section continues on DailyMed.]

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

Neuropathy: If neuropathy occurs that may be attributable to itraconazole oral solution, the treatment should be discontinued. Cystic Fibrosis: If a patient with cystic fibrosis does not respond to itraconazole oral solution, consideration should be given to switching to alternative therapy (see CLINICAL PHARMACOLOGY: Special Populations ). Hearing Loss: Transient or permanent hearing loss has been reported in patients receiving treatment with itraconazole.

Several of these reports included concurrent administration of quinidine which is contraindicated (see BOXED WARNING: Drug Interactions, CONTRAINDICATIONS: Drug Interactions and PRECAUTIONS: Drug Interactions ). The hearing loss usually resolves when treatment is stopped, but can persist in some patients. Information for Patients: Only itraconazole oral solution has been demonstrated effective for oral and/or esophageal candidiasis.

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

Taking itraconazole oral solution under fasted conditions improves the systemic availability of itraconazole. Instruct patients to take itraconazole oral solution without food, if possible. Itraconazole oral solution should not be used interchangeably with itraconazole capsules.

Instruct patients about the signs and symptoms of congestive heart failure, and if these signs or symptoms occur during itraconazole administration, they should discontinue itraconazole and contact their healthcare provider immediately. Instruct patients to stop itraconazole treatment immediately and contact their healthcare provider if any signs and symptoms suggestive of liver dysfunction develop. Such signs and symptoms may include unusual fatigue, anorexia, nausea and/or vomiting, jaundice, dark urine, or pale stools.

Instruct patients to contact their physician before taking any concomitant medications with itraconazole to ensure there are no potential drug interactions. Instruct patients that hearing loss can occur with the use of itraconazole. The hearing loss usually resolves when treatment is stopped, but can persist in some patients.

Advise patients to discontinue therapy and inform their physicians if any hearing loss symptoms occur. Instruct patients that dizziness or blurred/double vision can sometimes occur with itraconazole. Advise patients that if they experience these events, they should not drive or use machines.

Drug Interactions: Effect of Itraconazole on Other Drugs Itraconazole and its major metabolite, hydroxy-itraconazole, are potent CYP3A4 inhibitors. Itraconazole is an inhibitor of the drug transporters P-glycoprotein and breast cancer resistance protein (BCRP). Consequently, itraconazole has the potential to interact with many concomitant drugs resulting in either increased or sometimes decreased concentrations of the concomitant drugs.

Increased concentrations may increase the risk of adverse reactions associated with the concomitant drug which can be severe or life-threatening in some cases (e.g., QT prolongation, torsade de pointes, respiratory depression, hepatic adverse reactions, hypersensitivity reactions, myelosuppression, hypotension, seizures, angioedema, atrial fibrillation, bradycardia, priapism). Reduced con… [Excerpted — this section continues on DailyMed.]