Sporanox

• SPORANOX
  
  ^®(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. If signs or symptoms of congestive heart failure occur during administration of SPORANOX
  
  ^®Capsules, discontinue administration.
  
  
• When itraconazole was administered intravenously to dogs and healthy human volunteers, negative inotropic effects were seen. (See
  
  

  CONTRAINDICATIONS

  Congestive Heart Failure

  SPORANOX^®(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 SPORANOX^®. 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 InteractionsSection 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.

  SPORANOX^®should not be administered for the treatment of onychomycosis to pregnant patients or to women contemplating pregnancy.

  SPORANOX^®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 SPORANOX^®to patients with hypersensitivity to other azoles.

  ,
  
  

  WARNINGS

  Hepatic Effects

  SPORANOX^®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 SPORANOX^®use or reinstitution of treatment with SPORANOX^®is strongly discouraged unless there is a serious or life-threatening situation where the expected benefit exceeds the risk. (See PRECAUTIONS: Information for Patientsand 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 SPORANOX^®and/or other CYP3A4 inhibitors. Concomitant administration of these drugs with SPORANOX^®is contraindicated. (See BOXED WARNING, CONTRAINDICATIONS, and PRECAUTIONS: Drug Interactions.)

  Cardiac Disease

  SPORANOX^®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.

  SPORANOX^®Capsules should not be used for other indications 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 SPORANOX^®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 SPORANOX^®Capsules, discontinue 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.

  SPORANOX^®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 SPORANOX^®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 CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, PRECAUTIONS: Drug Interactions, and ADVERSE REACTIONS: Postmarketing Experiencefor 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 SPORANOX^®, substitution with an appropriate antifungal drug that is not associated with pseudoaldosteronism, or use of aldosterone receptor antagonists.

  Interaction Potential

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

  Interchangeability

  SPORANOX^®(itraconazole) Capsules and SPORANOX^®Oral Solution should not be used interchangeably. This is because drug exposure is greater with the Oral Solution than with the Capsules when the same dose of drug is given. In addition, the topical effects of mucosal exposure may be different between the two formulations. Only the Oral Solution has been demonstrated effective for oral and/or esophageal candidiasis.

  ,
  
  

  Drug Interactions

  Effect of SPORANOX^®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, SPORANOX^®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 SPORANOX^®.

  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 SPORANOX^®.

  Table 1: Drug Interactions with SPORANOX^®that Affect Concomitant Drug Concentrations

  Examples of Concomitant Drugs Within Class		Prevention or Management
  Drug Interactions with SPORANOX ® 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 SPORANOX®treatment.
  Analgesics
  Methadone		Contraindicated during and 2 weeks after SPORANOX®treatment.
  Fentanyl		Not recommended during and 2 weeks after SPORANOX®treatment.
  Alfentanil Buprenorphine (IV and sublingual) OxycodoneBased 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 SPORANOX®treatment.
  Digoxin		Monitor for adverse reactions. Concomitant drug dose reduction may be necessary.
  Antibacterials
  BedaquilineBased on 400 mg bedaquiline once daily for 2 weeks.		Concomitant SPORANOX®not recommended for more than 2 weeks at any time during bedaquiline treatment.
  Rifabutin		Not recommended 2 weeks before, during, and 2 weeks after SPORANOX®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 SPORANOX®treatment.
  Apixaban Rivaroxaban Vorapaxar		Not recommended during and 2 weeks after SPORANOX®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 SPORANOX®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 SPORANOX®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 SPORANOX®treatment.
  Eletriptan		Monitor for adverse reactions. Concomitant drug dose reduction may be necessary.
  Antineoplastics
  Irinotecan		Contraindicated during and 2 weeks after SPORANOX®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 SPORANOX®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 SPORANOX®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 SPORANOX®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 SPORANOX®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 SPORANOX®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 SPORANOX®treatment.
  Aliskiren Riociguat Sildenafil (for pulmonary hypertension) Tadalafil (for pulmonary hypertension)		Not recommended during and 2 weeks after SPORANOX®treatment. For sildenafil and tadalafil, see also Urologic Drugsbelow.
  Bosentan Guanfacine		Monitor for adverse reactions. Concomitant drug dose reduction may be necessary.
  ContraceptivesCYP3A4 inhibitors (including itraconazole) may increase systemic contraceptive hormone concentrations.
  Dienogest Ulipristal		Monitor for adverse reactions.
  Diuretics
  Eplerenone Finerenone		Contraindicated during and 2 weeks after SPORANOX®treatment.
  Gastrointestinal Drugs
  Cisapride Naloxegol		Contraindicated during and 2 weeks after SPORANOX®treatment.
  Aprepitant Loperamide		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 SPORANOX®treatment.
  Everolimus Sirolimus Temsirolimus (IV)		Not recommended during and 2 weeks after SPORANOX®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 SPORANOX®treatment.
  Atorvastatin		Monitor for drug adverse reactions. Concomitant drug dose reduction may be necessary.
  Respiratory Drugs
  Salmeterol		Not recommended during and 2 weeks after SPORANOX®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 SPORANOX®treatment.
  Fesoterodine		Patients with moderate to severe renal or hepatic impairment : Contraindicated during and 2 weeks after SPORANOX®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 SPORANOX®treatment. Other patients : Monitor for adverse reactions. Concomitant drug dose reduction may be necessary.
  Darifenacin Vardenafil		Not recommended during and 2 weeks after SPORANOX®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 Drugsabove.
  Miscellaneous Drugs and Other Substances
  Colchicine		Patients with renal or hepatic impairment: Contraindicated during and 2 weeks after SPORANOX®treatment. Other patients : Not recommended during and 2 weeks after SPORANOX®treatment.
  Eliglustat		CYP2D6 EMsEMs: extensive metabolizers; IMs: intermediate metabolizers, PMs: poor metabolizerstaking a strong or moderate CYP2D6 inhibitor, CYP2D6 IMs , or CYP2D6 PMs : Contraindicated during and 2 weeks after SPORANOX®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 SPORANOX®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 SPORANOX®treatment.
  Drug Interactions with SPORANOX®that Decrease Concomitant Drug Concentrations and May Reduce Efficacy of the Concomitant Drug
  Antineoplastics
  Regorafenib		Not recommended during and 2 weeks after SPORANOX®treatment.
  Gastrointestinal Drugs
  Saccharomyces boulardii		Not recommended during and 2 weeks after SPORANOX®treatment.
  Nonsteroidal Anti-Inflammatory Drugs
  Meloxicam		Concomitant drug dose increase may be necessary.

  Effect of Other Drugs on SPORANOX^®

  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 SPORANOX^®resulting in either increased or sometimes decreased concentrations of SPORANOX^®. Increased concentrations may increase the risk of adverse reactions associated with SPORANOX^®. Decreased concentrations may reduce SPORANOX^®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 SPORANOX^®.

  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 SPORANOX^®.

  Table 2: Drug Interactions with Other Drugs that Affect SPORANOX^®Concentrations

  Examples of Concomitant Drugs Within Class	Prevention or Management
  Drug Interactions with Other Drugs that Increase SPORANOX ® Concentrations and May Increase Risk of Adverse Reactions Associated with SPORANOX®
  Antibacterials
  CiprofloxacinBased on clinical drug interaction information with itraconazole. Erythromycin Clarithromycin	Monitor for adverse reactions. SPORANOX®dose reduction may be necessary.
  Antineoplastics
  Idelalisib	Monitor for adverse reactions. SPORANOX®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. SPORANOX®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. SPORANOX®dose reduction may be necessary. See also Table 1.
  Drug Interactions with Other Drugs that Decrease SPORANOX®Concentrations and May Reduce Efficacy of SPORANOX®
  Antibacterials
  Isoniazid Rifampicin	Not recommended 2 weeks before and during SPORANOX®treatment.
  Rifabutin	Not recommended 2 weeks before, during, and 2 weeks after SPORANOX®treatment. See also Table 1.
  Anticonvulsants
  Phenobarbital Phenytoin	Not recommended 2 weeks before and during SPORANOX®treatment.
  Carbamazepine	Not recommended 2 weeks before, during, and 2 weeks after SPORANOX®treatment. See also Table 1.
  Antivirals
  Efavirenz Nevirapine	Not recommended 2 weeks before and during SPORANOX®treatment.
  Gastrointestinal Drugs
  Drugs that reduce gastric acidity e.g. acid neutralizing medicines such as aluminum hydroxide, or acid secretion suppressors such as H2- 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 SPORANOX®capsules.
  Miscellaneous Drugs and Other Substances
  Lumacaftor/Ivacaftor	Not recommended 2 weeks before, during, and 2 weeks after SPORANOX®treatment.

  Pediatric Population

  Interaction studies have only been performed in adults.

  ,
  
  

  Postmarketing Experience

  Adverse drug reactions that have been first identified during postmarketing experience with SPORANOX^®(all formulations) are listed in the table 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 6: 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
  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, dyspnea
  Gastrointestinal Disorders:	Pancreatitis, dysgeusia
  Hepatobiliary Disorders:	Serious hepatotoxicity (including some cases of fatal acute liver failure), hepatitis
  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 SPORANOX^®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 SPORANOX^®has not been established. (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: Drug Interactionsfor more information.)

  , and
  
  

  Special Populations

  Renal Impairment

  Limited data are available on the use of oral itraconazole in patients with renal impairment. A pharmacokinetic study using a single 200 mg oral dose of itraconazole was conducted in three groups of patients with renal impairment (uremia: n=7; hemodialysis: n=7; and continuous ambulatory peritoneal dialysis: n=5). In uremic subjects with a mean creatinine clearance of 13 mL/min. × 1.73 m², the exposure, based on AUC, was slightly reduced compared with normal population parameters. This study did not demonstrate any significant effect of hemodialysis or continuous ambulatory peritoneal dialysis on the pharmacokinetics of itraconazole (T_max, C_max, and AUC_0–8h). Plasma concentration-versus-time profiles showed wide intersubject variation in all three groups. After a single intravenous dose, the mean terminal half-lives of itraconazole in patients with mild (defined in this study as CrCl 50–79 mL/min), moderate (defined in this study as CrCl 20–49 mL/min), and severe renal impairment (defined in this study as CrCl <20 mL/min) were similar to that in healthy subjects (range of means 42–49 hours vs 48 hours in renally impaired patients and healthy subjects, respectively). Overall exposure to itraconazole, based on AUC, was decreased in patients with moderate and severe renal impairment by approximately 30% and 40%, respectively, as compared with subjects with normal renal function. Data are not available in renally impaired patients during long-term use of itraconazole. Dialysis has no effect on the half-life or clearance of itraconazole or hydroxy-itraconazole. (See PRECAUTIONSand DOSAGE AND ADMINISTRATION.)

  Hepatic Impairment

  Itraconazole is predominantly metabolized in the liver. A pharmacokinetic study was conducted in 6 healthy and 12 cirrhotic subjects who were administered a single 100 mg dose of itraconazole as capsule. A statistically significant reduction in mean C_max(47%) and a twofold increase in the elimination half-life (37±17 hours vs. 16±5 hours) of itraconazole were noted in cirrhotic subjects compared with healthy subjects. However, overall exposure to itraconazole, based on AUC, was similar in cirrhotic patients and in healthy subjects. Data are not available in cirrhotic patients during long-term use of itraconazole. (See CONTRAINDICATIONS, PRECAUTIONS: Drug Interactionsand DOSAGE AND ADMINISTRATION.)

  Decreased Cardiac Contractility

  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. If signs or symptoms of congestive heart failure appear during administration of SPORANOX^®Capsules, SPORANOX^®should be discontinued. (See BOXED WARNING, CONTRAINDICATIONS, WARNINGS, PRECAUTIONS: Drug Interactionsand ADVERSE REACTIONS: Postmarketing Experiencefor more information.)

  for more information.)
  
  

SPORANOX
^®(itraconazole) Capsules are indicated for the treatment of the following fungal infections in

• 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.

SPORANOX
^®Capsules are also indicated for the treatment of the following fungal infections in

• 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

SPORANOX
^®(itraconazole) Capsules should be taken with a full meal to ensure maximal absorption. SPORANOX
^®(itraconazole) Capsules must be swallowed whole.

SPORANOX
^®Capsules is a different preparation than SPORANOX
^®Oral Solution and should not be used interchangeably.

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.

SPORANOX
^® 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 SPORANOX
^® use should be reassessed. (See

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, SPORANOX
^® 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 SPORANOX
^®.

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 SPORANOX
^®.