Tolsura

WARNING: CONGESTIVE HEART FAILURE and DRUG INTERACTIONS

• Congestive Heart Failure

  
  
  TOLSURA can cause or exacerbate congestive heart failure (CHF). When itraconazole was administered intravenously to healthy human volunteers and dogs, negative inotropic effects were seen. If signs or symptoms of congestive heart failure occur or worsen during administration of TOLSURA, reassess the benefit-risk of continuing treatment. (

  5.1 Congestive Heart Failure

  TOLSURA can cause or exacerbate congestive heart failure (CHF)

  [see Boxed Warningand Adverse Reactions (6.1)].

  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

  [see Adverse Reactions (6.2)]

  .

  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

  [see Contraindications (4.1), Drug Interactions (7.1)and Adverse Reactions (6.2)]

  ,

  6 ADVERSE REACTIONS

  The following clinically significant adverse reactions are described elsewhere in the labeling:

  • Congestive Heart Failure
    [see Warnings and Precautions (5.1)]
  • Hepatotoxicity
    [see Warnings and Precautions (5.2)]
  • Cardiac Dysrhythmias
    [see Warnings and Precautions (5.3)]
  • Pseudoaldosteronism
    [see Warnings and Precautions (5.4)]
  • Peripheral Neuropathy
    [see Warnings and Precautions (5.6)]
  • Hearing Loss
    [see Warnings and Precautions (5.7)]
  • Hypersensitivity Reactions
    [see Warnings and Precautions (5.8)]

  Most common adverse reactions (incidence ≥ 1%) are nausea, rash, vomiting, edema, headache, diarrhea, fatigue, fever, pruritus, hypertension, abnormal hepatic function, abdominal pain, dizziness, hypokalemia, anorexia, malaise, decreased libido, somnolence, albuminuria, impotence

  
  
  

  To report SUSPECTED ADVERSE REACTIONS, contact Mayne Pharma at 1-844-825-8500 or FDA at 1-800-FDA-1088 or

  www.fda.gov/medwatch

  .

  6.1 Clinical Trials Experience

  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.

  Adverse Reactions in the Treatment of Systemic Fungal Infections

  Safety data with itraconazole capsules were derived from 602 patients treated for systemic fungal disease in U.S. clinical trials who were immunocompromised or receiving multiple concomitant medications. Treatment was discontinued in 10.5% of patients due to adverse events. The median duration before discontinuation of therapy was 81 days (range: 2 to 776 days). Table 2 lists adverse reactions reported by at least 1% of patients.

  Table 2: Clinical Trials of Systemic Fungal Infections: Adverse Reactions Occurring with an Incidence of ≥1%

  Body System/Adverse Reaction	Incidence (%) (N=602)
  Gastrointestinal
  Nausea	11
  Vomiting	5
  Diarrhea	3
  Abdominal Pain	2
  Anorexia	1
  Body as a Whole
  Edema	4
  Fatigue	3
  Fever	3
  Malaise	1
  Skin and Appendages
  RashRash tends to occur more frequently in immunocompromised patients receiving immunosuppressive medications.	9
  Pruritus	3
  Central/Peripheral Nervous System
  Headache	4
  Dizziness	2
  Psychiatric
  Libido Decreased	1
  Somnolence	1
  Cardiovascular
  Hypertension	3
  Metabolic/Nutritional
  Hypokalemia	2
  Urinary System
  Albuminuria	1
  Liver and Biliary System
  Hepatic Function Abnormal	3
  Reproductive System, Male
  Impotence	1

  Adverse reactions reported at a rate of <1% included: constipation, gastritis, depression, insomnia, tinnitus, menstrual disorder, adrenal insufficiency, gynecomastia, and male breast pain.

  Adverse Reactions Reported from Other Clinical Trials

  In addition, the following adverse reactions were reported in itraconazole-treated patients who participated in clinical trials:

  Hepatobiliary Disorders:

  hyperbilirubinemia;

  Cardiac Disorders:

  cardiac failure, left ventricular failure, tachycardia;

  General Disorders and Administration Site Conditions:

  face edema, chest pain, chills;

  Hepatobiliary Disorders:

  hepatic failure, jaundice;

  Investigations:

  alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, blood lactate dehydrogenase increased, blood urea increased, gammaglutamyltransferase increased, urine analysis abnormal;

  Metabolism and Nutrition Disorders:

  hyperglycemia, hyperkalemia, hypomagnesemia;

  Psychiatric Disorders:

  confusional state;

  Renal and Urinary Disorders:

  renal impairment;

  Respiratory, Thoracic and Mediastinal Disorders:

  dysphonia, cough;

  Skin and Subcutaneous Tissue Disorders:

  hyperhidrosis;

  Vascular Disorders:

  hypotension

  6.2 Postmarketing Experience

  Adverse reactions that have been identified during post-marketing experience with itraconazole are listed in Table 3. 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 3: 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 blurred vision and diplopia
  Ear and Labyrinth Disorders:	Transientor permanent hearing loss
  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

  ).
• Drug Interactions
  • Co-administration of certain drugs that are metabolized by human CYP3A4 enzymes are contraindicated with TOLSURA because plasma concentrations of such drugs are increased. (

    4.1 Drug Interactions

    • Co-administration of certain drugs that are metabolized by human CYP3A4 substrates are contraindicated with TOLSURA because plasma concentrations of such drugs are increased, which may also increase or prolong both the pharmacologic effects and/or adverse reactions to these drugs
      [see Warnings and Precaution (5.5)and Drug Interactions (7.1)]
      .
    • Co-administration with colchicine, fesoterodine and solifenacin is contraindicated in subjects with varying degrees of renal or hepatic impairment.
    • 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 Drug Interactions (7.1)]
      .
    • Increased plasma concentrations of some of these drugs due to co-administration of TOLSURA can lead to QT prolongation and ventricular tachyarrhythmias including occurrences of
      torsade de pointes
      , a potentially fatal arrhythmia
      [
      see
      Drug Interactions (7.1)]
      .

    ,

    5.5 Drug Interaction Potential

    Itraconazole has a potential for clinically important drug interactions

    [see Drug Interactions (7.1, 7.2)]

    . 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.

    [see Boxed Warning, Contraindications (4.1)and Drug Interactions (7.1, 7.2)].

    ,

    7.1 Effect of TOLSURA 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. Table 4 lists examples of drugs that may have their concentrations affected by itraconazole, 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.

    Although many of the clinical drug interactions in Table 4 are based on information with a similar azole antifungal, ketoconazole, these interactions are expected to occur with itraconazole.

    Table 4: Drug Interactions with TOLSURA that Affect Concomitant Drug Concentrations

    Concomitant Drug Within Class		Prevention or Management
    Drug Interactions with TOLSURA 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 TOLSURA treatment.
    Analgesics
    Methadone		Contraindicated during and 2 weeks after TOLSURA treatment.
    Fentanyl		Not recommended during and 2 weeks after TOLSURA 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 TOLSURA 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 TOLSURA not recommended for more than 2 weeks at any time during bedaquiline treatment.
    Rifabutin		Not recommended 2 weeks before, during, and 2 weeks after TOLSURA treatment. See also Table 5.
    Clarithromycin		Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. See also Table 5.
    Trimetrexate		Monitor for adverse reactions. Concomitant drug dose reduction may be necessary.
    Anticoagulants and Antiplatelets
    Ticagrelor		Contraindicated during and 2 weeks after TOLSURA treatment.
    Apixaban Rivaroxaban Vorapaxar		Not recommended during and 2 weeks after TOLSURA 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 TOLSURA treatment. See also Table 5.
    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 TOLSURA 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 TOLSURA treatment.
    Eletriptan		Monitor for adverse reactions. Concomitant drug dose reduction may be necessary
    Antineoplastics
    Irinotecan		Contraindicated during and 2 weeks after TOLSURA treatment.
    Axitinib Bosutinib Cabazitaxel Cabozantinib Ceritinib Cobimetinib Crizotinib Dabrafenib Dasatinib	Docetaxel Ibrutinib Lapatinib Nilotinib Olaparib Pazopanib Sunitinib Trabectedin Trastuzumab-­emtansine Vinca alkaloids	Not recommended during and 2 weeks after TOLSURA treatment.
    Bortezomib Brentuximab-vedotin Busulfan Erlotinib Gefitinib Idelalisib Imatinib Ixabepilone	Nintedanib Panobinostat Ponatinib Ruxolitinib Sonidegib Vandetanib	Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. For Idelalisib, see also Table 5.
    Antipsychotics, Anxiolytics and Hypnotics
    Alprazolam Aripiprazole Buspirone 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 TOLSURA treatment.
    Antivirals
    Simeprevir		Not recommended during and 2 weeks after TOLSURA treatment.
    Daclatasvir Indinavir Maraviroc		Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. For indinavir, see also Table 5.
    Cobicistat Elvitegravir (ritonavir-boosted) Ritonavir Saquinavir (unboosted)		Monitor for adverse reactions. See also Table 5.
    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 TOLSURA treatment.
    Diltiazem Other dihydropyridines Verapamil		Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. For diltiazem, see also Table 5.
    Cardiovascular Drugs, Miscellaneous
    Ivabradine Ranolazine		Contraindicated during and 2 weeks after TOLSURA treatment.
    Aliskiren Riociguat Sildenafil (for pulmonary hypertension) Tadalafil (for pulmonary hypertension)		Not recommended during and 2 weeks after TOLSURA treatment. For sildenafil and tadalafil, see also Urologic Drugsbelow.
    Bosentan Guanfacine		Monitor for adverse reactions. Concomitant drug dose reduction may be necessary.
    Contraceptives
    Dienogest Ulipristal		Monitor for adverse reactions.
    Diuretics
    Eplerenone		Contraindicated during and 2 weeks after TOLSURA treatment.
    Gastrointestinal Drugs
    Naloxegol		Contraindicated during and 2 weeks after TOLSURA treatment.
    Aprepitant Loperamide		Monitor for adverse reactions. Concomitant drug dose reduction may be necessary.
    Netupitant		Monitor for adverse reactions.
    Immunosuppressants
    Everolimus Sirolimus Temsirolimus (IV)		Not recommended during and 2 weeks after TOLSURA treatment.
    Budesonide (inhalation) Budesonide (noninhalation) 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 TOLSURA treatment.
    Atorvastatin		Monitor for drug adverse reactions. Concomitant drug dose reduction may be necessary.
    Respiratory Drugs
    Salmeterol		Not recommended during and 2 weeks after TOLSURA 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 TOLSURA treatment.
    Fesoterodine		Patients with moderate to severe renal or hepatic impairment : Contraindicated during and 2 weeks after TOLSURA 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 TOLSURA treatment. Other patients : Monitor for adverse reactions. Concomitant drug dose reduction may be necessary.
    Darifenacin Vardenafil		Not recommended during and 2 weeks after TOLSURA 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 TOLSURA treatment. Other patients : Not recommended during and 2 weeks after TOLSURA treatment.
    Eliglustat		CYP2D6 EMsEMs: 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 TOLSURA 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 TOLSURA treatment.
    Alitretinoin (oral) Cabergoline Cannabinoids Cinacalcet Ivacaftor		Monitor for adverse reactions. Concomitant drug dose reduction may be necessary.
    Vasopressin Receptor Antagonists
    Conivaptan Tolvaptan		Not recommended during and 2 weeks after TOLSURA treatment.
    Drug Interactions with TOLSURA that Decrease Concomitant Drug Concentrations and May Reduce Efficacy of the Concomitant Drug
    Antineoplastics
    Regorafenib		Not recommended during and 2 weeks after TOLSURA treatment.
    Gastrointestinal Drugs
    Saccharomyces boulardii		Not recommended during and 2 weeks after TOLSURA treatment.
    Nonsteroidal Anti-Inflammatory Drugs
    Meloxicam		Concomitant drug dose increase may be necessary.

    )
  • Co-administration with colchicine, fesoterodine and solifenacin is contraindicated in subjects with varying degrees of renal or hepatic impairment. (

    4.1 Drug Interactions

    • Co-administration of certain drugs that are metabolized by human CYP3A4 substrates are contraindicated with TOLSURA because plasma concentrations of such drugs are increased, which may also increase or prolong both the pharmacologic effects and/or adverse reactions to these drugs
      [see Warnings and Precaution (5.5)and Drug Interactions (7.1)]
      .
    • Co-administration with colchicine, fesoterodine and solifenacin is contraindicated in subjects with varying degrees of renal or hepatic impairment.
    • 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 Drug Interactions (7.1)]
      .
    • Increased plasma concentrations of some of these drugs due to co-administration of TOLSURA can lead to QT prolongation and ventricular tachyarrhythmias including occurrences of
      torsade de pointes
      , a potentially fatal arrhythmia
      [
      see
      Drug Interactions (7.1)]
      .

    ,

    7.1 Effect of TOLSURA 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. Table 4 lists examples of drugs that may have their concentrations affected by itraconazole, 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.

    Although many of the clinical drug interactions in Table 4 are based on information with a similar azole antifungal, ketoconazole, these interactions are expected to occur with itraconazole.

    Table 4: Drug Interactions with TOLSURA that Affect Concomitant Drug Concentrations

    Concomitant Drug Within Class		Prevention or Management
    Drug Interactions with TOLSURA 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 TOLSURA treatment.
    Analgesics
    Methadone		Contraindicated during and 2 weeks after TOLSURA treatment.
    Fentanyl		Not recommended during and 2 weeks after TOLSURA 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 TOLSURA 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 TOLSURA not recommended for more than 2 weeks at any time during bedaquiline treatment.
    Rifabutin		Not recommended 2 weeks before, during, and 2 weeks after TOLSURA treatment. See also Table 5.
    Clarithromycin		Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. See also Table 5.
    Trimetrexate		Monitor for adverse reactions. Concomitant drug dose reduction may be necessary.
    Anticoagulants and Antiplatelets
    Ticagrelor		Contraindicated during and 2 weeks after TOLSURA treatment.
    Apixaban Rivaroxaban Vorapaxar		Not recommended during and 2 weeks after TOLSURA 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 TOLSURA treatment. See also Table 5.
    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 TOLSURA 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 TOLSURA treatment.
    Eletriptan		Monitor for adverse reactions. Concomitant drug dose reduction may be necessary
    Antineoplastics
    Irinotecan		Contraindicated during and 2 weeks after TOLSURA treatment.
    Axitinib Bosutinib Cabazitaxel Cabozantinib Ceritinib Cobimetinib Crizotinib Dabrafenib Dasatinib	Docetaxel Ibrutinib Lapatinib Nilotinib Olaparib Pazopanib Sunitinib Trabectedin Trastuzumab-­emtansine Vinca alkaloids	Not recommended during and 2 weeks after TOLSURA treatment.
    Bortezomib Brentuximab-vedotin Busulfan Erlotinib Gefitinib Idelalisib Imatinib Ixabepilone	Nintedanib Panobinostat Ponatinib Ruxolitinib Sonidegib Vandetanib	Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. For Idelalisib, see also Table 5.
    Antipsychotics, Anxiolytics and Hypnotics
    Alprazolam Aripiprazole Buspirone 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 TOLSURA treatment.
    Antivirals
    Simeprevir		Not recommended during and 2 weeks after TOLSURA treatment.
    Daclatasvir Indinavir Maraviroc		Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. For indinavir, see also Table 5.
    Cobicistat Elvitegravir (ritonavir-boosted) Ritonavir Saquinavir (unboosted)		Monitor for adverse reactions. See also Table 5.
    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 TOLSURA treatment.
    Diltiazem Other dihydropyridines Verapamil		Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. For diltiazem, see also Table 5.
    Cardiovascular Drugs, Miscellaneous
    Ivabradine Ranolazine		Contraindicated during and 2 weeks after TOLSURA treatment.
    Aliskiren Riociguat Sildenafil (for pulmonary hypertension) Tadalafil (for pulmonary hypertension)		Not recommended during and 2 weeks after TOLSURA treatment. For sildenafil and tadalafil, see also Urologic Drugsbelow.
    Bosentan Guanfacine		Monitor for adverse reactions. Concomitant drug dose reduction may be necessary.
    Contraceptives
    Dienogest Ulipristal		Monitor for adverse reactions.
    Diuretics
    Eplerenone		Contraindicated during and 2 weeks after TOLSURA treatment.
    Gastrointestinal Drugs
    Naloxegol		Contraindicated during and 2 weeks after TOLSURA treatment.
    Aprepitant Loperamide		Monitor for adverse reactions. Concomitant drug dose reduction may be necessary.
    Netupitant		Monitor for adverse reactions.
    Immunosuppressants
    Everolimus Sirolimus Temsirolimus (IV)		Not recommended during and 2 weeks after TOLSURA treatment.
    Budesonide (inhalation) Budesonide (noninhalation) 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 TOLSURA treatment.
    Atorvastatin		Monitor for drug adverse reactions. Concomitant drug dose reduction may be necessary.
    Respiratory Drugs
    Salmeterol		Not recommended during and 2 weeks after TOLSURA 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 TOLSURA treatment.
    Fesoterodine		Patients with moderate to severe renal or hepatic impairment : Contraindicated during and 2 weeks after TOLSURA 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 TOLSURA treatment. Other patients : Monitor for adverse reactions. Concomitant drug dose reduction may be necessary.
    Darifenacin Vardenafil		Not recommended during and 2 weeks after TOLSURA 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 TOLSURA treatment. Other patients : Not recommended during and 2 weeks after TOLSURA treatment.
    Eliglustat		CYP2D6 EMsEMs: 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 TOLSURA 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 TOLSURA treatment.
    Alitretinoin (oral) Cabergoline Cannabinoids Cinacalcet Ivacaftor		Monitor for adverse reactions. Concomitant drug dose reduction may be necessary.
    Vasopressin Receptor Antagonists
    Conivaptan Tolvaptan		Not recommended during and 2 weeks after TOLSURA treatment.
    Drug Interactions with TOLSURA that Decrease Concomitant Drug Concentrations and May Reduce Efficacy of the Concomitant Drug
    Antineoplastics
    Regorafenib		Not recommended during and 2 weeks after TOLSURA treatment.
    Gastrointestinal Drugs
    Saccharomyces boulardii		Not recommended during and 2 weeks after TOLSURA treatment.
    Nonsteroidal Anti-Inflammatory Drugs
    Meloxicam		Concomitant drug dose increase may be necessary.

    )
  • Co-administration with eliglustat is contraindicated in poor or intermediate metabolizers of CYP2D6 and in subjects taking strong or moderate CYP2D6 inhibitors. (

    4.1 Drug Interactions

    • Co-administration of certain drugs that are metabolized by human CYP3A4 substrates are contraindicated with TOLSURA because plasma concentrations of such drugs are increased, which may also increase or prolong both the pharmacologic effects and/or adverse reactions to these drugs
      [see Warnings and Precaution (5.5)and Drug Interactions (7.1)]
      .
    • Co-administration with colchicine, fesoterodine and solifenacin is contraindicated in subjects with varying degrees of renal or hepatic impairment.
    • 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 Drug Interactions (7.1)]
      .
    • Increased plasma concentrations of some of these drugs due to co-administration of TOLSURA can lead to QT prolongation and ventricular tachyarrhythmias including occurrences of
      torsade de pointes
      , a potentially fatal arrhythmia
      [
      see
      Drug Interactions (7.1)]
      .

    ,

    7.1 Effect of TOLSURA 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. Table 4 lists examples of drugs that may have their concentrations affected by itraconazole, 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.

    Although many of the clinical drug interactions in Table 4 are based on information with a similar azole antifungal, ketoconazole, these interactions are expected to occur with itraconazole.

    Table 4: Drug Interactions with TOLSURA that Affect Concomitant Drug Concentrations

    Concomitant Drug Within Class		Prevention or Management
    Drug Interactions with TOLSURA 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 TOLSURA treatment.
    Analgesics
    Methadone		Contraindicated during and 2 weeks after TOLSURA treatment.
    Fentanyl		Not recommended during and 2 weeks after TOLSURA 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 TOLSURA 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 TOLSURA not recommended for more than 2 weeks at any time during bedaquiline treatment.
    Rifabutin		Not recommended 2 weeks before, during, and 2 weeks after TOLSURA treatment. See also Table 5.
    Clarithromycin		Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. See also Table 5.
    Trimetrexate		Monitor for adverse reactions. Concomitant drug dose reduction may be necessary.
    Anticoagulants and Antiplatelets
    Ticagrelor		Contraindicated during and 2 weeks after TOLSURA treatment.
    Apixaban Rivaroxaban Vorapaxar		Not recommended during and 2 weeks after TOLSURA 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 TOLSURA treatment. See also Table 5.
    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 TOLSURA 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 TOLSURA treatment.
    Eletriptan		Monitor for adverse reactions. Concomitant drug dose reduction may be necessary
    Antineoplastics
    Irinotecan		Contraindicated during and 2 weeks after TOLSURA treatment.
    Axitinib Bosutinib Cabazitaxel Cabozantinib Ceritinib Cobimetinib Crizotinib Dabrafenib Dasatinib	Docetaxel Ibrutinib Lapatinib Nilotinib Olaparib Pazopanib Sunitinib Trabectedin Trastuzumab-­emtansine Vinca alkaloids	Not recommended during and 2 weeks after TOLSURA treatment.
    Bortezomib Brentuximab-vedotin Busulfan Erlotinib Gefitinib Idelalisib Imatinib Ixabepilone	Nintedanib Panobinostat Ponatinib Ruxolitinib Sonidegib Vandetanib	Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. For Idelalisib, see also Table 5.
    Antipsychotics, Anxiolytics and Hypnotics
    Alprazolam Aripiprazole Buspirone 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 TOLSURA treatment.
    Antivirals
    Simeprevir		Not recommended during and 2 weeks after TOLSURA treatment.
    Daclatasvir Indinavir Maraviroc		Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. For indinavir, see also Table 5.
    Cobicistat Elvitegravir (ritonavir-boosted) Ritonavir Saquinavir (unboosted)		Monitor for adverse reactions. See also Table 5.
    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 TOLSURA treatment.
    Diltiazem Other dihydropyridines Verapamil		Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. For diltiazem, see also Table 5.
    Cardiovascular Drugs, Miscellaneous
    Ivabradine Ranolazine		Contraindicated during and 2 weeks after TOLSURA treatment.
    Aliskiren Riociguat Sildenafil (for pulmonary hypertension) Tadalafil (for pulmonary hypertension)		Not recommended during and 2 weeks after TOLSURA treatment. For sildenafil and tadalafil, see also Urologic Drugsbelow.
    Bosentan Guanfacine		Monitor for adverse reactions. Concomitant drug dose reduction may be necessary.
    Contraceptives
    Dienogest Ulipristal		Monitor for adverse reactions.
    Diuretics
    Eplerenone		Contraindicated during and 2 weeks after TOLSURA treatment.
    Gastrointestinal Drugs
    Naloxegol		Contraindicated during and 2 weeks after TOLSURA treatment.
    Aprepitant Loperamide		Monitor for adverse reactions. Concomitant drug dose reduction may be necessary.
    Netupitant		Monitor for adverse reactions.
    Immunosuppressants
    Everolimus Sirolimus Temsirolimus (IV)		Not recommended during and 2 weeks after TOLSURA treatment.
    Budesonide (inhalation) Budesonide (noninhalation) 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 TOLSURA treatment.
    Atorvastatin		Monitor for drug adverse reactions. Concomitant drug dose reduction may be necessary.
    Respiratory Drugs
    Salmeterol		Not recommended during and 2 weeks after TOLSURA 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 TOLSURA treatment.
    Fesoterodine		Patients with moderate to severe renal or hepatic impairment : Contraindicated during and 2 weeks after TOLSURA 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 TOLSURA treatment. Other patients : Monitor for adverse reactions. Concomitant drug dose reduction may be necessary.
    Darifenacin Vardenafil		Not recommended during and 2 weeks after TOLSURA 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 TOLSURA treatment. Other patients : Not recommended during and 2 weeks after TOLSURA treatment.
    Eliglustat		CYP2D6 EMsEMs: 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 TOLSURA 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 TOLSURA treatment.
    Alitretinoin (oral) Cabergoline Cannabinoids Cinacalcet Ivacaftor		Monitor for adverse reactions. Concomitant drug dose reduction may be necessary.
    Vasopressin Receptor Antagonists
    Conivaptan Tolvaptan		Not recommended during and 2 weeks after TOLSURA treatment.
    Drug Interactions with TOLSURA that Decrease Concomitant Drug Concentrations and May Reduce Efficacy of the Concomitant Drug
    Antineoplastics
    Regorafenib		Not recommended during and 2 weeks after TOLSURA treatment.
    Gastrointestinal Drugs
    Saccharomyces boulardii		Not recommended during and 2 weeks after TOLSURA treatment.
    Nonsteroidal Anti-Inflammatory Drugs
    Meloxicam		Concomitant drug dose increase may be necessary.

    )
  • Increased plasma concentrations of some of these drugs can lead to QT prolongation and ventricular tachyarrhythmias including occurrences of torsades de pointes, a potentially fatal arrhythmia. (

    4.1 Drug Interactions

    • Co-administration of certain drugs that are metabolized by human CYP3A4 substrates are contraindicated with TOLSURA because plasma concentrations of such drugs are increased, which may also increase or prolong both the pharmacologic effects and/or adverse reactions to these drugs
      [see Warnings and Precaution (5.5)and Drug Interactions (7.1)]
      .
    • Co-administration with colchicine, fesoterodine and solifenacin is contraindicated in subjects with varying degrees of renal or hepatic impairment.
    • 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 Drug Interactions (7.1)]
      .
    • Increased plasma concentrations of some of these drugs due to co-administration of TOLSURA can lead to QT prolongation and ventricular tachyarrhythmias including occurrences of
      torsade de pointes
      , a potentially fatal arrhythmia
      [
      see
      Drug Interactions (7.1)]
      .

    ,

    5.5 Drug Interaction Potential

    Itraconazole has a potential for clinically important drug interactions

    [see Drug Interactions (7.1, 7.2)]

    . 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.

    [see Boxed Warning, Contraindications (4.1)and Drug Interactions (7.1, 7.2)].

    ,

    7.1 Effect of TOLSURA 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. Table 4 lists examples of drugs that may have their concentrations affected by itraconazole, 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.

    Although many of the clinical drug interactions in Table 4 are based on information with a similar azole antifungal, ketoconazole, these interactions are expected to occur with itraconazole.

    Table 4: Drug Interactions with TOLSURA that Affect Concomitant Drug Concentrations

    Concomitant Drug Within Class		Prevention or Management
    Drug Interactions with TOLSURA 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 TOLSURA treatment.
    Analgesics
    Methadone		Contraindicated during and 2 weeks after TOLSURA treatment.
    Fentanyl		Not recommended during and 2 weeks after TOLSURA 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 TOLSURA 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 TOLSURA not recommended for more than 2 weeks at any time during bedaquiline treatment.
    Rifabutin		Not recommended 2 weeks before, during, and 2 weeks after TOLSURA treatment. See also Table 5.
    Clarithromycin		Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. See also Table 5.
    Trimetrexate		Monitor for adverse reactions. Concomitant drug dose reduction may be necessary.
    Anticoagulants and Antiplatelets
    Ticagrelor		Contraindicated during and 2 weeks after TOLSURA treatment.
    Apixaban Rivaroxaban Vorapaxar		Not recommended during and 2 weeks after TOLSURA 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 TOLSURA treatment. See also Table 5.
    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 TOLSURA 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 TOLSURA treatment.
    Eletriptan		Monitor for adverse reactions. Concomitant drug dose reduction may be necessary
    Antineoplastics
    Irinotecan		Contraindicated during and 2 weeks after TOLSURA treatment.
    Axitinib Bosutinib Cabazitaxel Cabozantinib Ceritinib Cobimetinib Crizotinib Dabrafenib Dasatinib	Docetaxel Ibrutinib Lapatinib Nilotinib Olaparib Pazopanib Sunitinib Trabectedin Trastuzumab-­emtansine Vinca alkaloids	Not recommended during and 2 weeks after TOLSURA treatment.
    Bortezomib Brentuximab-vedotin Busulfan Erlotinib Gefitinib Idelalisib Imatinib Ixabepilone	Nintedanib Panobinostat Ponatinib Ruxolitinib Sonidegib Vandetanib	Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. For Idelalisib, see also Table 5.
    Antipsychotics, Anxiolytics and Hypnotics
    Alprazolam Aripiprazole Buspirone 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 TOLSURA treatment.
    Antivirals
    Simeprevir		Not recommended during and 2 weeks after TOLSURA treatment.
    Daclatasvir Indinavir Maraviroc		Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. For indinavir, see also Table 5.
    Cobicistat Elvitegravir (ritonavir-boosted) Ritonavir Saquinavir (unboosted)		Monitor for adverse reactions. See also Table 5.
    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 TOLSURA treatment.
    Diltiazem Other dihydropyridines Verapamil		Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. For diltiazem, see also Table 5.
    Cardiovascular Drugs, Miscellaneous
    Ivabradine Ranolazine		Contraindicated during and 2 weeks after TOLSURA treatment.
    Aliskiren Riociguat Sildenafil (for pulmonary hypertension) Tadalafil (for pulmonary hypertension)		Not recommended during and 2 weeks after TOLSURA treatment. For sildenafil and tadalafil, see also Urologic Drugsbelow.
    Bosentan Guanfacine		Monitor for adverse reactions. Concomitant drug dose reduction may be necessary.
    Contraceptives
    Dienogest Ulipristal		Monitor for adverse reactions.
    Diuretics
    Eplerenone		Contraindicated during and 2 weeks after TOLSURA treatment.
    Gastrointestinal Drugs
    Naloxegol		Contraindicated during and 2 weeks after TOLSURA treatment.
    Aprepitant Loperamide		Monitor for adverse reactions. Concomitant drug dose reduction may be necessary.
    Netupitant		Monitor for adverse reactions.
    Immunosuppressants
    Everolimus Sirolimus Temsirolimus (IV)		Not recommended during and 2 weeks after TOLSURA treatment.
    Budesonide (inhalation) Budesonide (noninhalation) 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 TOLSURA treatment.
    Atorvastatin		Monitor for drug adverse reactions. Concomitant drug dose reduction may be necessary.
    Respiratory Drugs
    Salmeterol		Not recommended during and 2 weeks after TOLSURA 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 TOLSURA treatment.
    Fesoterodine		Patients with moderate to severe renal or hepatic impairment : Contraindicated during and 2 weeks after TOLSURA 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 TOLSURA treatment. Other patients : Monitor for adverse reactions. Concomitant drug dose reduction may be necessary.
    Darifenacin Vardenafil		Not recommended during and 2 weeks after TOLSURA 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 TOLSURA treatment. Other patients : Not recommended during and 2 weeks after TOLSURA treatment.
    Eliglustat		CYP2D6 EMsEMs: 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 TOLSURA 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 TOLSURA treatment.
    Alitretinoin (oral) Cabergoline Cannabinoids Cinacalcet Ivacaftor		Monitor for adverse reactions. Concomitant drug dose reduction may be necessary.
    Vasopressin Receptor Antagonists
    Conivaptan Tolvaptan		Not recommended during and 2 weeks after TOLSURA treatment.
    Drug Interactions with TOLSURA that Decrease Concomitant Drug Concentrations and May Reduce Efficacy of the Concomitant Drug
    Antineoplastics
    Regorafenib		Not recommended during and 2 weeks after TOLSURA treatment.
    Gastrointestinal Drugs
    Saccharomyces boulardii		Not recommended during and 2 weeks after TOLSURA treatment.
    Nonsteroidal Anti-Inflammatory Drugs
    Meloxicam		Concomitant drug dose increase may be necessary.

    )

TOLSURA is 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, anti-fungal therapy should be adjusted accordingly

TOLSURA must be administered with food.

TOLSURA capsules must be swallowed whole. Do not chew, crush or break TOLSURA capsules.

Table 1 below describes the recommended dosage for TOLSURA.

TOLSURA (itraconazole capsules) is available in a size 1, hard gelatin capsules with light blue cap and white body, imprinted with "i-65" in black on the cap and containing 65 mg of itraconazole.

There are no data on exposure to itraconazole during pregnancy for the approved indications. Published epidemiologic studies of women exposed to short courses of treatment with itraconazole in the first trimester of pregnancy have reported no risk of major birth defects overall and inconclusive findings on the risk of miscarriage

In animal reproduction studies, itraconazole was found to cause a dose-related increase in maternal toxicity, embryotoxicity, and teratogenicity in rats at dosage levels of approximately (6-25 times the maximum recommended human dose [MRHD] of 390 mg/day based on mg/kg comparisons), and in mice at dosage levels of approximately 80 mg/kg/day (12 times the MRHD).

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.