Tolsura Prescribing Information
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 FailureTOLSURA 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 REACTIONSThe 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 orwww.fda.gov/medwatch.6.1 Clinical Trials ExperienceBecause 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 InfectionsSafety 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) GastrointestinalNausea 11 Vomiting 5 Diarrhea 3 Abdominal Pain 2 Anorexia 1 Body as a WholeEdema 4 Fatigue 3 Fever 3 Malaise 1 Skin and AppendagesRashRash tends to occur more frequently in immunocompromised patients receiving immunosuppressive medications. 9 Pruritus 3 Central/Peripheral Nervous SystemHeadache 4 Dizziness 2 PsychiatricLibido Decreased 1 Somnolence 1 CardiovascularHypertension 3 Metabolic/NutritionalHypokalemia 2 Urinary SystemAlbuminuria 1 Liver and Biliary SystemHepatic Function Abnormal 3 Reproductive System, MaleImpotence 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 TrialsIn 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:hypotension6.2 Postmarketing ExperienceAdverse 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 - Congestive Heart Failure
- 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 oftorsade de pointes, a potentially fatal arrhythmia[seeDrug Interactions (7.1)].
,5.5 Drug Interaction PotentialItraconazole 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 DrugsItraconazole 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 DrugAlpha BlockersAlfuzosin
Silodosin
TamsulosinNot recommended during and 2 weeks after TOLSURA treatment. AnalgesicsMethadone 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.
SufentanilMonitor for adverse reactions. Concomitant drug dose reduction may be necessary. AntiarrhythmicsDisopyramide
Dofetilide
Dronedarone
QuinidineContraindicated during and 2 weeks after TOLSURA treatment. Digoxin Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. AntibacterialsBedaquilineBased 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 AntiplateletsTicagrelor Contraindicated during and 2 weeks after TOLSURA treatment. Apixaban
Rivaroxaban
VorapaxarNot recommended during and 2 weeks after TOLSURA treatment. Cilostazol
Dabigatran
WarfarinMonitor for adverse reactions. Concomitant drug dose reduction may be necessary. AnticonvulsantsCarbamazepine Not recommended 2 weeks before, during, and 2 weeks after TOLSURA treatment. See also Table 5. Antidiabetic DrugsRepaglinide
SaxagliptinMonitor for adverse reactions. Concomitant drug dose reduction may be necessary. Antihelminthics, Antifungals and AntiprotozoalsIsavuconazonium Contraindicated during and 2 weeks after TOLSURA treatment. Praziquantel Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. Artemether-lumefantrine
QuinineMonitor for adverse reactions. Antimigraine DrugsErgot 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 AntineoplasticsIrinotecan Contraindicated during and 2 weeks after TOLSURA treatment. Axitinib
Bosutinib
Cabazitaxel
Cabozantinib
Ceritinib
Cobimetinib
Crizotinib
Dabrafenib
DasatinibDocetaxel
Ibrutinib
Lapatinib
Nilotinib
Olaparib
Pazopanib
Sunitinib
Trabectedin
Trastuzumab-emtansine
Vinca alkaloidsNot recommended during and 2 weeks after TOLSURA treatment. Bortezomib
Brentuximab-vedotin
Busulfan
Erlotinib
Gefitinib
Idelalisib
Imatinib
IxabepiloneNintedanib
Panobinostat
Ponatinib
Ruxolitinib
Sonidegib
VandetanibMonitor for adverse reactions. Concomitant drug dose reduction may be necessary. For Idelalisib, see also Table 5. Antipsychotics, Anxiolytics and HypnoticsAlprazolam
Aripiprazole
Buspirone
Diazepam
HaloperidolMidazolam (IV)
Quetiapine
Ramelteon
Risperidone
SuvorexantMonitor 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
TriazolamContraindicated during and 2 weeks after TOLSURA treatment. AntiviralsSimeprevir Not recommended during and 2 weeks after TOLSURA treatment. Daclatasvir
Indinavir
MaravirocMonitor 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 BlockersNadolol Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. Calcium Channel BlockersFelodipine
NisoldipineContraindicated during and 2 weeks after TOLSURA treatment. Diltiazem
Other dihydropyridines
VerapamilMonitor for adverse reactions. Concomitant drug dose reduction may be necessary. For diltiazem, see also Table 5. Cardiovascular Drugs, MiscellaneousIvabradine
RanolazineContraindicated 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
GuanfacineMonitor for adverse reactions. Concomitant drug dose reduction may be necessary. ContraceptivesDienogest
UlipristalMonitor for adverse reactions. DiureticsEplerenone Contraindicated during and 2 weeks after TOLSURA treatment. Gastrointestinal DrugsNaloxegol Contraindicated during and 2 weeks after TOLSURA treatment. Aprepitant
LoperamideMonitor for adverse reactions. Concomitant drug dose reduction may be necessary. Netupitant Monitor for adverse reactions. ImmunosuppressantsEverolimus
Sirolimus
Temsirolimus (IV)Not recommended during and 2 weeks after TOLSURA treatment. Budesonide (inhalation)
Budesonide (noninhalation)
Ciclesonide (inhalation)
Cyclosporine (IV)
Cyclosporine (non-IV)
DexamethasoneFluticasone (inhalation)
Fluticasone (nasal)
Methylprednisolone
Tacrolimus (IV)
Tacrolimus (oral)Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. Lipid-Lowering DrugsLomitapide
Lovastatin
SimvastatinContraindicated during and 2 weeks after TOLSURA treatment. Atorvastatin Monitor for drug adverse reactions. Concomitant drug dose reduction may be necessary. Respiratory DrugsSalmeterol Not recommended during and 2 weeks after TOLSURA treatment. SSRIs, Tricyclics and Related AntidepressantsVenlafaxine Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. Urologic DrugsAvanafil 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 necessarySolifenacin 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
VardenafilNot recommended during and 2 weeks after TOLSURA treatment. Dutasteride
Oxybutynin
Sildenafil (for erectile dysfunction)
Tadalafil (for erectile dysfunction and benign prostatic hyperplasia)
TolterodineMonitor for adverse reactions. Concomitant drug dose reduction may be necessary. For sildenafil and tadalafil, see also Cardiovascular Drugsabove. Miscellaneous Drugs and Other SubstancesColchicine 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 EMsnot 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
IvacaftorMonitor for adverse reactions. Concomitant drug dose reduction may be necessary. Vasopressin Receptor AntagonistsConivaptan
TolvaptanNot recommended during and 2 weeks after TOLSURA treatment. Drug Interactions with TOLSURA that Decrease Concomitant Drug Concentrations and May Reduce Efficacy of the Concomitant DrugAntineoplasticsRegorafenib Not recommended during and 2 weeks after TOLSURA treatment. Gastrointestinal DrugsSaccharomyces boulardiiNot recommended during and 2 weeks after TOLSURA treatment. Nonsteroidal Anti-Inflammatory DrugsMeloxicam Concomitant drug dose increase may be necessary. - 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
- 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 oftorsade de pointes, a potentially fatal arrhythmia[seeDrug Interactions (7.1)].
)7.1 Effect of TOLSURA on Other DrugsItraconazole 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 DrugAlpha BlockersAlfuzosin
Silodosin
TamsulosinNot recommended during and 2 weeks after TOLSURA treatment. AnalgesicsMethadone 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.
SufentanilMonitor for adverse reactions. Concomitant drug dose reduction may be necessary. AntiarrhythmicsDisopyramide
Dofetilide
Dronedarone
QuinidineContraindicated during and 2 weeks after TOLSURA treatment. Digoxin Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. AntibacterialsBedaquilineBased 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 AntiplateletsTicagrelor Contraindicated during and 2 weeks after TOLSURA treatment. Apixaban
Rivaroxaban
VorapaxarNot recommended during and 2 weeks after TOLSURA treatment. Cilostazol
Dabigatran
WarfarinMonitor for adverse reactions. Concomitant drug dose reduction may be necessary. AnticonvulsantsCarbamazepine Not recommended 2 weeks before, during, and 2 weeks after TOLSURA treatment. See also Table 5. Antidiabetic DrugsRepaglinide
SaxagliptinMonitor for adverse reactions. Concomitant drug dose reduction may be necessary. Antihelminthics, Antifungals and AntiprotozoalsIsavuconazonium Contraindicated during and 2 weeks after TOLSURA treatment. Praziquantel Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. Artemether-lumefantrine
QuinineMonitor for adverse reactions. Antimigraine DrugsErgot 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 AntineoplasticsIrinotecan Contraindicated during and 2 weeks after TOLSURA treatment. Axitinib
Bosutinib
Cabazitaxel
Cabozantinib
Ceritinib
Cobimetinib
Crizotinib
Dabrafenib
DasatinibDocetaxel
Ibrutinib
Lapatinib
Nilotinib
Olaparib
Pazopanib
Sunitinib
Trabectedin
Trastuzumab-emtansine
Vinca alkaloidsNot recommended during and 2 weeks after TOLSURA treatment. Bortezomib
Brentuximab-vedotin
Busulfan
Erlotinib
Gefitinib
Idelalisib
Imatinib
IxabepiloneNintedanib
Panobinostat
Ponatinib
Ruxolitinib
Sonidegib
VandetanibMonitor for adverse reactions. Concomitant drug dose reduction may be necessary. For Idelalisib, see also Table 5. Antipsychotics, Anxiolytics and HypnoticsAlprazolam
Aripiprazole
Buspirone
Diazepam
HaloperidolMidazolam (IV)
Quetiapine
Ramelteon
Risperidone
SuvorexantMonitor 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
TriazolamContraindicated during and 2 weeks after TOLSURA treatment. AntiviralsSimeprevir Not recommended during and 2 weeks after TOLSURA treatment. Daclatasvir
Indinavir
MaravirocMonitor 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 BlockersNadolol Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. Calcium Channel BlockersFelodipine
NisoldipineContraindicated during and 2 weeks after TOLSURA treatment. Diltiazem
Other dihydropyridines
VerapamilMonitor for adverse reactions. Concomitant drug dose reduction may be necessary. For diltiazem, see also Table 5. Cardiovascular Drugs, MiscellaneousIvabradine
RanolazineContraindicated 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
GuanfacineMonitor for adverse reactions. Concomitant drug dose reduction may be necessary. ContraceptivesDienogest
UlipristalMonitor for adverse reactions. DiureticsEplerenone Contraindicated during and 2 weeks after TOLSURA treatment. Gastrointestinal DrugsNaloxegol Contraindicated during and 2 weeks after TOLSURA treatment. Aprepitant
LoperamideMonitor for adverse reactions. Concomitant drug dose reduction may be necessary. Netupitant Monitor for adverse reactions. ImmunosuppressantsEverolimus
Sirolimus
Temsirolimus (IV)Not recommended during and 2 weeks after TOLSURA treatment. Budesonide (inhalation)
Budesonide (noninhalation)
Ciclesonide (inhalation)
Cyclosporine (IV)
Cyclosporine (non-IV)
DexamethasoneFluticasone (inhalation)
Fluticasone (nasal)
Methylprednisolone
Tacrolimus (IV)
Tacrolimus (oral)Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. Lipid-Lowering DrugsLomitapide
Lovastatin
SimvastatinContraindicated during and 2 weeks after TOLSURA treatment. Atorvastatin Monitor for drug adverse reactions. Concomitant drug dose reduction may be necessary. Respiratory DrugsSalmeterol Not recommended during and 2 weeks after TOLSURA treatment. SSRIs, Tricyclics and Related AntidepressantsVenlafaxine Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. Urologic DrugsAvanafil 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 necessarySolifenacin 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
VardenafilNot recommended during and 2 weeks after TOLSURA treatment. Dutasteride
Oxybutynin
Sildenafil (for erectile dysfunction)
Tadalafil (for erectile dysfunction and benign prostatic hyperplasia)
TolterodineMonitor for adverse reactions. Concomitant drug dose reduction may be necessary. For sildenafil and tadalafil, see also Cardiovascular Drugsabove. Miscellaneous Drugs and Other SubstancesColchicine 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 EMsnot 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
IvacaftorMonitor for adverse reactions. Concomitant drug dose reduction may be necessary. Vasopressin Receptor AntagonistsConivaptan
TolvaptanNot recommended during and 2 weeks after TOLSURA treatment. Drug Interactions with TOLSURA that Decrease Concomitant Drug Concentrations and May Reduce Efficacy of the Concomitant DrugAntineoplasticsRegorafenib Not recommended during and 2 weeks after TOLSURA treatment. Gastrointestinal DrugsSaccharomyces boulardiiNot recommended during and 2 weeks after TOLSURA treatment. Nonsteroidal Anti-Inflammatory DrugsMeloxicam Concomitant drug dose increase may be necessary. - 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
- 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 oftorsade de pointes, a potentially fatal arrhythmia[seeDrug Interactions (7.1)].
)7.1 Effect of TOLSURA on Other DrugsItraconazole 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 DrugAlpha BlockersAlfuzosin
Silodosin
TamsulosinNot recommended during and 2 weeks after TOLSURA treatment. AnalgesicsMethadone 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.
SufentanilMonitor for adverse reactions. Concomitant drug dose reduction may be necessary. AntiarrhythmicsDisopyramide
Dofetilide
Dronedarone
QuinidineContraindicated during and 2 weeks after TOLSURA treatment. Digoxin Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. AntibacterialsBedaquilineBased 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 AntiplateletsTicagrelor Contraindicated during and 2 weeks after TOLSURA treatment. Apixaban
Rivaroxaban
VorapaxarNot recommended during and 2 weeks after TOLSURA treatment. Cilostazol
Dabigatran
WarfarinMonitor for adverse reactions. Concomitant drug dose reduction may be necessary. AnticonvulsantsCarbamazepine Not recommended 2 weeks before, during, and 2 weeks after TOLSURA treatment. See also Table 5. Antidiabetic DrugsRepaglinide
SaxagliptinMonitor for adverse reactions. Concomitant drug dose reduction may be necessary. Antihelminthics, Antifungals and AntiprotozoalsIsavuconazonium Contraindicated during and 2 weeks after TOLSURA treatment. Praziquantel Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. Artemether-lumefantrine
QuinineMonitor for adverse reactions. Antimigraine DrugsErgot 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 AntineoplasticsIrinotecan Contraindicated during and 2 weeks after TOLSURA treatment. Axitinib
Bosutinib
Cabazitaxel
Cabozantinib
Ceritinib
Cobimetinib
Crizotinib
Dabrafenib
DasatinibDocetaxel
Ibrutinib
Lapatinib
Nilotinib
Olaparib
Pazopanib
Sunitinib
Trabectedin
Trastuzumab-emtansine
Vinca alkaloidsNot recommended during and 2 weeks after TOLSURA treatment. Bortezomib
Brentuximab-vedotin
Busulfan
Erlotinib
Gefitinib
Idelalisib
Imatinib
IxabepiloneNintedanib
Panobinostat
Ponatinib
Ruxolitinib
Sonidegib
VandetanibMonitor for adverse reactions. Concomitant drug dose reduction may be necessary. For Idelalisib, see also Table 5. Antipsychotics, Anxiolytics and HypnoticsAlprazolam
Aripiprazole
Buspirone
Diazepam
HaloperidolMidazolam (IV)
Quetiapine
Ramelteon
Risperidone
SuvorexantMonitor 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
TriazolamContraindicated during and 2 weeks after TOLSURA treatment. AntiviralsSimeprevir Not recommended during and 2 weeks after TOLSURA treatment. Daclatasvir
Indinavir
MaravirocMonitor 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 BlockersNadolol Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. Calcium Channel BlockersFelodipine
NisoldipineContraindicated during and 2 weeks after TOLSURA treatment. Diltiazem
Other dihydropyridines
VerapamilMonitor for adverse reactions. Concomitant drug dose reduction may be necessary. For diltiazem, see also Table 5. Cardiovascular Drugs, MiscellaneousIvabradine
RanolazineContraindicated 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
GuanfacineMonitor for adverse reactions. Concomitant drug dose reduction may be necessary. ContraceptivesDienogest
UlipristalMonitor for adverse reactions. DiureticsEplerenone Contraindicated during and 2 weeks after TOLSURA treatment. Gastrointestinal DrugsNaloxegol Contraindicated during and 2 weeks after TOLSURA treatment. Aprepitant
LoperamideMonitor for adverse reactions. Concomitant drug dose reduction may be necessary. Netupitant Monitor for adverse reactions. ImmunosuppressantsEverolimus
Sirolimus
Temsirolimus (IV)Not recommended during and 2 weeks after TOLSURA treatment. Budesonide (inhalation)
Budesonide (noninhalation)
Ciclesonide (inhalation)
Cyclosporine (IV)
Cyclosporine (non-IV)
DexamethasoneFluticasone (inhalation)
Fluticasone (nasal)
Methylprednisolone
Tacrolimus (IV)
Tacrolimus (oral)Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. Lipid-Lowering DrugsLomitapide
Lovastatin
SimvastatinContraindicated during and 2 weeks after TOLSURA treatment. Atorvastatin Monitor for drug adverse reactions. Concomitant drug dose reduction may be necessary. Respiratory DrugsSalmeterol Not recommended during and 2 weeks after TOLSURA treatment. SSRIs, Tricyclics and Related AntidepressantsVenlafaxine Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. Urologic DrugsAvanafil 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 necessarySolifenacin 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
VardenafilNot recommended during and 2 weeks after TOLSURA treatment. Dutasteride
Oxybutynin
Sildenafil (for erectile dysfunction)
Tadalafil (for erectile dysfunction and benign prostatic hyperplasia)
TolterodineMonitor for adverse reactions. Concomitant drug dose reduction may be necessary. For sildenafil and tadalafil, see also Cardiovascular Drugsabove. Miscellaneous Drugs and Other SubstancesColchicine 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 EMsnot 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
IvacaftorMonitor for adverse reactions. Concomitant drug dose reduction may be necessary. Vasopressin Receptor AntagonistsConivaptan
TolvaptanNot recommended during and 2 weeks after TOLSURA treatment. Drug Interactions with TOLSURA that Decrease Concomitant Drug Concentrations and May Reduce Efficacy of the Concomitant DrugAntineoplasticsRegorafenib Not recommended during and 2 weeks after TOLSURA treatment. Gastrointestinal DrugsSaccharomyces boulardiiNot recommended during and 2 weeks after TOLSURA treatment. Nonsteroidal Anti-Inflammatory DrugsMeloxicam Concomitant drug dose increase may be necessary. - 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
- 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 oftorsade de pointes, a potentially fatal arrhythmia[seeDrug Interactions (7.1)].
,5.5 Drug Interaction PotentialItraconazole 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 DrugsItraconazole 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 DrugAlpha BlockersAlfuzosin
Silodosin
TamsulosinNot recommended during and 2 weeks after TOLSURA treatment. AnalgesicsMethadone 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.
SufentanilMonitor for adverse reactions. Concomitant drug dose reduction may be necessary. AntiarrhythmicsDisopyramide
Dofetilide
Dronedarone
QuinidineContraindicated during and 2 weeks after TOLSURA treatment. Digoxin Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. AntibacterialsBedaquilineBased 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 AntiplateletsTicagrelor Contraindicated during and 2 weeks after TOLSURA treatment. Apixaban
Rivaroxaban
VorapaxarNot recommended during and 2 weeks after TOLSURA treatment. Cilostazol
Dabigatran
WarfarinMonitor for adverse reactions. Concomitant drug dose reduction may be necessary. AnticonvulsantsCarbamazepine Not recommended 2 weeks before, during, and 2 weeks after TOLSURA treatment. See also Table 5. Antidiabetic DrugsRepaglinide
SaxagliptinMonitor for adverse reactions. Concomitant drug dose reduction may be necessary. Antihelminthics, Antifungals and AntiprotozoalsIsavuconazonium Contraindicated during and 2 weeks after TOLSURA treatment. Praziquantel Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. Artemether-lumefantrine
QuinineMonitor for adverse reactions. Antimigraine DrugsErgot 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 AntineoplasticsIrinotecan Contraindicated during and 2 weeks after TOLSURA treatment. Axitinib
Bosutinib
Cabazitaxel
Cabozantinib
Ceritinib
Cobimetinib
Crizotinib
Dabrafenib
DasatinibDocetaxel
Ibrutinib
Lapatinib
Nilotinib
Olaparib
Pazopanib
Sunitinib
Trabectedin
Trastuzumab-emtansine
Vinca alkaloidsNot recommended during and 2 weeks after TOLSURA treatment. Bortezomib
Brentuximab-vedotin
Busulfan
Erlotinib
Gefitinib
Idelalisib
Imatinib
IxabepiloneNintedanib
Panobinostat
Ponatinib
Ruxolitinib
Sonidegib
VandetanibMonitor for adverse reactions. Concomitant drug dose reduction may be necessary. For Idelalisib, see also Table 5. Antipsychotics, Anxiolytics and HypnoticsAlprazolam
Aripiprazole
Buspirone
Diazepam
HaloperidolMidazolam (IV)
Quetiapine
Ramelteon
Risperidone
SuvorexantMonitor 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
TriazolamContraindicated during and 2 weeks after TOLSURA treatment. AntiviralsSimeprevir Not recommended during and 2 weeks after TOLSURA treatment. Daclatasvir
Indinavir
MaravirocMonitor 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 BlockersNadolol Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. Calcium Channel BlockersFelodipine
NisoldipineContraindicated during and 2 weeks after TOLSURA treatment. Diltiazem
Other dihydropyridines
VerapamilMonitor for adverse reactions. Concomitant drug dose reduction may be necessary. For diltiazem, see also Table 5. Cardiovascular Drugs, MiscellaneousIvabradine
RanolazineContraindicated 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
GuanfacineMonitor for adverse reactions. Concomitant drug dose reduction may be necessary. ContraceptivesDienogest
UlipristalMonitor for adverse reactions. DiureticsEplerenone Contraindicated during and 2 weeks after TOLSURA treatment. Gastrointestinal DrugsNaloxegol Contraindicated during and 2 weeks after TOLSURA treatment. Aprepitant
LoperamideMonitor for adverse reactions. Concomitant drug dose reduction may be necessary. Netupitant Monitor for adverse reactions. ImmunosuppressantsEverolimus
Sirolimus
Temsirolimus (IV)Not recommended during and 2 weeks after TOLSURA treatment. Budesonide (inhalation)
Budesonide (noninhalation)
Ciclesonide (inhalation)
Cyclosporine (IV)
Cyclosporine (non-IV)
DexamethasoneFluticasone (inhalation)
Fluticasone (nasal)
Methylprednisolone
Tacrolimus (IV)
Tacrolimus (oral)Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. Lipid-Lowering DrugsLomitapide
Lovastatin
SimvastatinContraindicated during and 2 weeks after TOLSURA treatment. Atorvastatin Monitor for drug adverse reactions. Concomitant drug dose reduction may be necessary. Respiratory DrugsSalmeterol Not recommended during and 2 weeks after TOLSURA treatment. SSRIs, Tricyclics and Related AntidepressantsVenlafaxine Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. Urologic DrugsAvanafil 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 necessarySolifenacin 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
VardenafilNot recommended during and 2 weeks after TOLSURA treatment. Dutasteride
Oxybutynin
Sildenafil (for erectile dysfunction)
Tadalafil (for erectile dysfunction and benign prostatic hyperplasia)
TolterodineMonitor for adverse reactions. Concomitant drug dose reduction may be necessary. For sildenafil and tadalafil, see also Cardiovascular Drugsabove. Miscellaneous Drugs and Other SubstancesColchicine 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 EMsnot 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
IvacaftorMonitor for adverse reactions. Concomitant drug dose reduction may be necessary. Vasopressin Receptor AntagonistsConivaptan
TolvaptanNot recommended during and 2 weeks after TOLSURA treatment. Drug Interactions with TOLSURA that Decrease Concomitant Drug Concentrations and May Reduce Efficacy of the Concomitant DrugAntineoplasticsRegorafenib Not recommended during and 2 weeks after TOLSURA treatment. Gastrointestinal DrugsSaccharomyces boulardiiNot recommended during and 2 weeks after TOLSURA treatment. Nonsteroidal Anti-Inflammatory DrugsMeloxicam Concomitant drug dose increase may be necessary. - 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
Warnings and Precautions, Pseudoaldosteronism (5.4 PseudoaldosteronismPseudoaldosteronism, manifested by the onset of hypertension or worsening of hypertension, and abnormal laboratory findings (hypokalemia, low serum renin and aldosterone, and elevate 11-deoxycortisol), has been reported with itraconazole use in the postmarketing setting. Monitor blood pressure and potassium levels and manage as necessary. Management of pseudoaldosteronism may include discontinuation of TOLSURA, substitution with an appropriate antifungal drug that is not associated with pseudoaldosteronism, or use of aldosterone receptor antagonists. | 10/2024 |
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.
| Indications | Daily Dosing |
|---|---|
Treatment of Blastomycosis and Histoplasmosis | |
| Recommended dose | 130 mg (2 × 65 mg capsules) once daily If no obvious improvement, or there is evidence of progressive fungal disease, the dose should be increased in 65 mg increments to a maximum of 260 mg/day (130 mg (2 × 65 mg capsules) twice daily). Doses above 130 mg/day should be given in two divided doses. |
Treatment of Aspergillosis | |
| Recommended dose | 130 mg (2 × 65 mg capsules) once daily |
| 260 mg/day (130 mg (2 × 65 mg capsules) twice daily) | |
Treatment in Life-Threatening Situations | |
| Although clinical studies did not provide for a loading dose, it is recommended, based on pharmacokinetic data, that a loading dose should be used. | A loading dose of 130 mg (2 × 65 mg capsules) three times daily (390 mg/day) is recommended to be given for the first 3 days, followed by the appropriate recommended dosing based on indication. Treatment should be continued for a minimum of three months and until clinical parameters and laboratory tests indicate that the active fungal infection has subsided. An inadequate period of treatment may lead to recurrence of active infection. |
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
Published prospective and retrospective cohort studies of women exposed to short courses of treatment with itraconazole in the first trimester of pregnancy (sample size 198-687) have reported no increase in the rate of major birth defects. The most important methodological limitation of these studies is the short duration of exposure in pregnancy (mean duration 6.9 to 8.5 days), or the lack of information on treatment duration. The risk of prolonged exposure in pregnancy is not known.
Published prospective and retrospective cohort studies of pregnant women exposed to itraconazole (sample size 131-198) have reported inconsistent findings on the risk of miscarriage. Available data are inconclusive and limited by possible bias due to earlier enrollment and possible residual confounding in the exposed group compared to the unexposed group.
Itraconazole has been shown to cross the placenta in a rat model. In animal reproduction studies, itraconazole administration to rats and mice during organogenesis resulted in maternal toxicity, embryotoxicity and teratogenicity at and above 40 and 80 mg/kg respectively (doses equivalent to 6- and 12-times the MRHD of 390 mg/day, based on mg/kg comparisons). In rats, the teratogenicity consisted of major skeletal defects; in mice, it consisted of encephaloceles and/or macroglossia.
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.