Interactions : אינטראקציות

4.5. Interaction with other medicinal products and other forms of interaction

Itraconazole is mainly metabolized through CYP3A4. Other substances that either share this metabolic pathway or modify CYP3A4 activity may influence the pharmacokinetics of itraconazole. Itraconazole is a strong CYP3A4 inhibitor and a P-glycoprotein inhibitor and Breast Cancer Resistance Protein (BCRP) inhibitor.
Itraconazole may modify the pharmacokinetics of other substances that share this metabolic or these protein transporter pathways.
Examples of drugs that may impact on the plasma concentration of itraconazole are presented by drug class in Table 1 below. Examples of drugs that may have their plasma concentrations impacted by itraconazole are presented in Table 2 below. Due to the number of interactions, the potential changes in safety or efficacy of the interacting drugs are not included. Please refer to the prescribing information of the interacting drug for more information.

The interactions described in these tables are categorised as contraindicated, not recommended or to be used with caution with itraconazole taking into account the extent of the concentration increase and the safety profile of the interacting drug (see also sections 4.3 and 4.4 for further information). The interaction potential of the listed drugs was evaluated based on human pharmacokinetic studies with itraconazole, and/or human pharmacokinetic studies with other strong CYP3A4 inhibitors (e.g. ketoconazole) and/or in vitro data:

•    ‘Contraindicated’: Under no circumstances is the drug to be co-administered with itraconazole, and up to two weeks after discontinuation of treatment with itraconazole.
•    ‘Not recommended’: The use of the drug should be avoided during and up to two weeks after discontinuation of treatment with itraconazole, unless the benefits outweigh the potentially increased risks of side effects. If co-administration cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged effects or side effects of the concomitantly administered drug is recommended, and its dosage be reduced or interrupted as deemed necessary. When appropriate, it is recommended that plasma concentrations of the co administered drug be measured.
•    ‘Use with caution’: Careful monitoring is recommended when the drug is coadministered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of the interacting drug, and its dosage be reduced as deemed necessary.
When appropriate, it is recommended that plasma concentrations of the co administered drug be measured.

The interactions listed in these tables have been characterised in studies that were performed with recommended doses of itraconazole. However, the extent of interaction may be dependent on the dose of itraconazole administered. A stronger interaction may occur at a higher dose or with a shorter dosing interval. Extrapolation of the findings with other dosing scenarios or different drugs should be done with caution.
Once treatment is stopped, itraconazole plasma concentrations decrease to an almost undetectable concentration within 7 to 14 days, depending on the dose and duration of treatment. In patients with hepatic cirrhosis or in subjects receiving CYP3A4 inhibitors, the decline in plasma concentrations may be even more gradual. This is particularly important when initiating therapy with drugs whose metabolism is affected by itraconazole. (See section 5.2)
Table 1: Examples of drugs that may impact the plasma concentration of itraconazole, presented by drug class

Expected/Potential effect on
Clinical comment
Examples of medicinal products (Per Orale [PO] Single   itraconazole levels (see above for additional info
Dose unless otherwise stated) within class              (↑ = increase;   = no change;   = and also sections 4.3 and 4.4) decrease)

Antibacterials for Systemic Use; Antimycobacterials

                                                            Although not studied directly, isoniazid is
Isoniazid                                                   likely to decrease the concentrations of    Not recommended itraconazole.

Rifampicin PO 600 mg OD                                     Itraconazole AUC                           Not recommended 
Rifabutin PO 300 mg OD                                      Itraconazole Cmax   71%, AUC      74%      Not recommended 

Ciprofloxacin PO 500 mg BID                                 Itraconazole Cmax ↑ 53%, AUC ↑ 82%         Use with caution 

Erythromycin 1 g                                            Itraconazole Cmax ↑ 44%, AUC ↑ 36%         Use with caution 

Clarithromycin PO 500 mg BID                                Itraconazole Cmax ↑ 90%, AUC ↑ 92%         Use with caution 
Antiepileptics

Although not studied directly, these drugs
Carbamazepine, Phenobarbital                                are likely to decrease concentrations of   Not recommended itraconazole.


Itraconazole Cmax   83%, AUC      93%
Phenytoin PO 300 mg OD                                      Hydroxyitraconazole Cmax     84%, AUC      Not recommended 95%


Antineoplastics Agents
Although not studied directly, idelalisib is
Idelalisib                                                  likely to increase the concentrations of     Use with caution itraconazole.

Antivirals for Systemic Use

Although not studied directly, these drugs
Ombitasvir/Paritaprevir/Ritonavir (with or without are expected to increase the               Contraindicated
Dasabuvir) concentrations of itraconazole.

Itraconazole Cmax   37%, AUC      39%;
Efavirenz 600 mg                                            Hydroxyitraconazole Cmax     35%, AUC      Not recommended 37%


Nevirapine PO 200 mg OD                                     Itraconazole Cmax   38%, AUC 62%           Not recommended 

Cobicistat, Darunavir (boosted), Elvitegravir (ritonavir-   Although not studied directly, these drugs boosted), Fosamprenavir (ritonavir- boosted), Ritonavir,    are expected to increase the               Use with caution Saquinavir (ritonavir-boosted)                              concentrations of itraconazole.


Indinavir PO 800 mg TID                                  Itraconazole concentration ↑                  Use with caution 
Calcium Channel Blockers

Although not studied directly, diltiazem is
Diltiazem                                                likely to increase the concentration of     Use with caution itraconazole.

Drugs for Acid Related Disorders

Antacids (aluminum, calcium, magnesium, or sodium bicarbonate), H2-receptor antagonists (eg, cimetidine,
Itraconazole Cmax , AUC                       Use with caution ranitidine), Proton pump inhibitors (eg, lansoprazole,
omeprazole, rabeprazole)
Respiratory System: Other Respiratory System Products

Lumacaftor/Ivacaftor PO 200/250 mg BID                   Itraconazole concentration                    Not recommended 
Miscellaneous

St. John's Wort                                          Although not studied directly, St. John's Wort is likely to decrease the                Not recommended
(Hypericum perforatum)                                   concentration of itraconazole.


Table 2 Examples of drugs that may have their plasma concentrations impacted by itraconazole, presented by drug class

Expected/Potential effect on drugs
Clinical comment
Examples of medicinal products (PO Single Dose unless levels
(see above for additional info otherwise stated) within class                        (↑ = increase;  = no change; = and also sections 4.3 and 4.4) decrease)

Analgesics; Anaesthetics

Although not studied directly,              Contraindicated
Ergot alkaloids (eg, dihydroergotamine, ergometrine,
itraconazole is likely to increase the ergotamine, methylergometrine) concentrations of these drugs.
Although not studied directly,
Eletriptan, Fentanyl                                     itraconazole is likely to increase the      Not recommended concentrations of these drugs.

Although not studied directly,
Alfentanil, Buprenorphine (IV and sublingual),
itraconazole is likely to increase the      Use with caution
Cannabinoids, Methadone, Sufentanil concentrations of these drugs.

Oxycodone PO 10 mg,                                      Oxycodone PO: Cmax ↑ 45%, AUC ↑             Use with caution 2.4-fold
Oxycodone IV 0.1 mg/kg                                   Oxycodone IV: AUC ↑ 51%                     Use with caution 
Antibacterials for Systemic Use; Antimycobacterials; Antimycotics for Systemic Use 

Although not studied directly,
Isavuconazole                                  itraconazole is likely to increase the   Contraindicated concentrations of isavuconazole.

Not recommended
Although not studied directly,
Bedaquiline                                    itraconazole is likely to increase the concentrations of bedaquiline.

Rifabutin concentration ↑ (extent
Rifabutin PO 300 mg OD                                                                  Not recommended unknown)

Clarithromycin PO 500 mg BID                   Clarithromycin concentration ↑           Use with caution 
Although not studied directly,
Delamanid                                      itraconazole is likely to increase the   Use with caution concentrations of delaminid.

Antiepileptics

Although not studied directly,
Carbamazepine                                  itraconazole is likely to increase the   Not recommended concentrations of carbamazepine.

Anti-inflammatory and Antirheumatic Products

Meloxicam Cmax      64%, AUC
Meloxicam 15 mg                                                                         Use with caution 37%

Anthelmintics; Antiprotozoals

Although not studied directly,
Halofantrine                                   itraconazole is likely to increase the   Contraindicated concentrations of halofantrine.

Although not studied directly,
Artemether-lumefantrine, Praziquantel          itraconazole is likely to increase the   Use with caution concentrations of these drugs.

Quinine 300 mg                                 Quinine Cmax    , AUC ↑ 96%              Use with caution 
Antihistamines for Systemic Use
Although not studied directly,
Astemizole, Mizolastine, Terfenadine           itraconazole is likely to increase the   Contraindicated concentrations of these drugs.
Ebastine Cmax ↑ 2.5-fold, AUC ↑ 6.2- fold
Ebastine 20 mg                                                                          Not recommended Carabastine Cmax    , AUC ↑ 3.1- fold

Although not studied directly,
Bilastine, Rupatidine                          itraconazole is likely to increase the   Use with caution concentrations of these drugs.

Antineoplastic Agents

Although not studied directly,
itraconazole is likely to increase the
Irinotecan                                                                                            Contraindicated concentrations of irinotecan and its active metabolite.

Mobocertinib Cmax ↑↑ ↑ 3.8-
Mobocertinib                                                 fold, AUC ↑↑↑                            Contraindicated ↑ 8.4-fold


Contraindicated in patients with chronic lymphocytic leukaemia during dose
Although not studied
Venetoclax                                                                                            initiation/titration/rampup directly, itraconazole is phase of venetoclax.
likely to increase the
Otherwise, not concentrations of recommended unless venetoclax.
the benefits outweigh the risks. Refer to the venetoclax prescribing information.


Although not studied directly,
itraconazole is likely to increase the
Axitinib, Bosutinib, Cabazitaxel, Cabozantinib,            concentrations of these drugs except for Ceritinib, Crizotinib, Dabrafenib, Dasatinib, Docetaxel, cabazitaxel and regorafenib. No Everolimus, Glasdegib, Ibrutinib, Lapatinib, Nilotinib, statistically significant change in cabazitaxel exposure, but a high         Not recommended
Pazopanib, Regorafenib, Sunitinib, Temsirolimus,
Trabectedin, Trastuzumab emtansine, Vinca alkaloids (eg,  variability in the results was observed.
vinflunine, vinorelbine)                Regorafenib AUC is expected to decrease (by estimation of active moiety)

Entrectinib Cmax ↑ 73%,
Entrectinib                                                                                           Not recommended AUC ↑ 6.0 fold
Cobimetinib Cmax ↑ 3.2-fold, AUC
Cobimetinib 10 mg,                                           ↑6.7-fold                                Not recommended 
Olaparib 100 mg                                              Olaparib Cmax ↑ 40%, AUC ↑ 2.7- fold Not recommended Talazoparib Cmax ↑ 40%,
Talazoparib                                                                                           Not recommended AUC ↑ 56%

Alitretinoin (oral), Bortezomib, Brentuximab vedotin,        Although not studied directly, Erlotinib, Idelalisib, Imatinib, Nintedanib, Panobinostat,   itraconazole is likely to increase the   Use with caution Ponatinib, Ruxolitinib, Sonidegib, Tretinoin (Oral)          concentrations of these drugs 
Pemigatinib Cmax ↑ 17%,
Pemigatinib                                                                                           Use with caution AUC ↑ 91%↑



Busulfan 1 mg/kg Q6h                                         Busulfan Cmax ↑, AUC ↑                   Use with caution 
Gefitinib 250 mg Cmax ↑, AUC ↑
Gefitinib 250 mg                                             78%                                      Use with caution 

Antithrombotic Agents
Although not studied directly,
Dabigatran, Ticagrelor                                       itraconazole is likely to increase the   Contraindicated concentrations of these drugs.
Although not studied directly,
Apixaban, Edoxaban, Rivaroxaban, Vorapaxar                   itraconazole is likely to increase the   Not recommended concentrations of these drugs.
Although not studied directly,
Cilostazol, Coumarins (eg, warfarin)                         itraconazole is likely to increase the   Use with caution concentrations of these drugs
Antivirals for Systemic Use

Ombitasvir/Paritaprevir/Ritonavir (with or without           Itraconazole may increase paritaprevir Contraindicated
Dasabuvir)                                                   concentrations.

Although not studied directly,
Elbasvir/Grazoprevir, , Tenofovir alefenamide fumarate itraconazole is likely to increase the   Not recommended
(TAF), Tenofovir disoproxil fumarate (TDF) concentrations of these drugs.

Although not studied directly,
Cobicistat, Elvitegravir (ritonavir-boosted),
itraconazole is likely to increase the   Use with caution
Glecaprevir/Pibrentasvir, Maraviroc, Ritonavir, Saquinavir concentrations of these drugs.
Indinavir PO 800 mg TID                                      Indinavir Cmax    , AUC ↑                Use with caution 
Cardiovascular System (Agents Acting on the Renin-Angiotensin System; Antihypertensives; Beta Blocking Agents; Calcium Channel Blockers; Cardiac Therapy; Diuretics)

Bepridil, Disopyramide, Dofetilide, Dronedarone,             Although not studied directly, Eplerenone, Ivabradine, Lercanidipine, Nisoldipine,          itraconazole is likely to increase the   Contraindicated Ranolazine, Sildenafil (pulmonary hypertension)              concentrations of these drugs.
Although not studied directly, itraconazole is
Finerenone                                                                                            Contraindicated likely to increase the concentrations of these drugs
Aliskiren Cmax ↑ 5.8-fold, AUC ↑ 6.5-
Aliskiren 150 mg,                                                                                     Contraindicated fold


Quinidine 100 mg                                             Quinidine Cmax ↑ 59%, AUC ↑ 2.4- fold Contraindicated 
Felodipine Cmax ↑ 7.8-fold, AUC ↑ 6.3-
Felodipine 5 mg                                                                                     Not recommended fold


Although not studied directly,
Riociguat, Tadalafil (pulmonary hypertension)                itraconazole is likely to increase the   Not recommended concentrations of these drugs.

Bosentan, Diltiazem, Guanafacine, Other Dihydropyridines Although not studied directly, (eg, amlodipine, isradipine, nifedipine, nimodipine),    itraconazole is likely to increase the      Use with caution Verapamil                                                concentrations of bosentan.

Digoxin 0.5 mg                                              Digoxin Cmax ↑ 34%, AUC ↑68%             Use with caution 
Nadolol Cmax ↑ 4.7-fold, AUC ↑
Nadolol 30 mg                                                                                        Use with caution 2.2-fold

Corticosteroids for Systemic Use; Drugs for Obstructive Airway Diseases 
Although not studied directly,
itraconazole is likely to increase the
Ciclesonide, Salmeterol                                                                              Not recommended concentrations of salmeterol and the active metabolite of ciclesonide.


Budesonide INH Cmax ↑ 65%, AUC ↑
4.2-fold;
Budesonide INH 1 mg SD,                                                                              Use with caution Budesonide (other formulations) concentration ↑

Dexamethasone IV: Cmax       , AUC ↑
Dexamethasone IV 5 mg                                       3.3-fold
Use with caution
Dexamethasone PO 4.5 mg                                     Dexamethasone PO: Cmax ↑ 69%, AUC ↑ 3.7-fold

Fluticasone INH 1 mg BID,                                   Fluticasone INH concentration ↑          Use with caution 
Methylprednisolone PO Cmax ↑ 92%,
AUC ↑ 3.9-fold
Methylprednisolone 16 mg,                                                                            Use with caution Methylprednisolone IV AUC ↑ 2.6- fold

Although not studied directly,
itraconazole is likely to increase the
Fluticasone nasal                                                                                   Use with caution concentrations of nasally- administered fluticasone.

Drugs Used in Diabetes

Repaglinide Cmax ↑ 47%, AUC ↑
Repaglinide 0.25 mg                                                                                  Use with caution 41%

Although not studied directly,
Saxagliptin                                                 itraconazole is likely to increase the   Use with caution concentrations of saxagliptin.

Gastrointestinal Drugs, including Antidiarrheals, Intestinal Antiinflammatory/Antiinfective Agents; Antiemetics and Antinauseants; Drugs for Constipation; Drugs for Functional Gastrointestinal Disorders 
Although not studied directly,
Cisapride, Naloxegol                                        itraconazole is likely to increase the   Contraindicated concentrations of these drugs.


                                                          Domperidone Cmax ↑ 2.7-fold,
Domperidone 20 mg                                                                                     Contraindicated AUC ↑ 3.2-fold

Use with caution
Although not studied directly,
Aprepitant, Loperamide, Netupitant                        itraconazole is likely to increase the concentrations of aprepitant.


Immunosuppressants

Although not studied directly,
Sirolimus (rapamycin)                                     itraconazole is likely to increase the      Not recommended concentrations of sirolimus.

Although not studied directly,
Cyclosporine, Tacrolimus                                  itraconazole is likely to increase the      Use with caution concentrations of cyclosporine.

Tacrolimus IV 0.03 mg/kg OD                               Tacrolimus IV concentration ↑               Use with caution Although not studied
Voclosporin                                                                                           Contraindicated directly, itraconazole is likely to increase the
Lipid Modifying Agents

Although not studied directly,
Lomitapide                                                itraconazole is likely to increase the      Contraindicated concentrations of lomitapide.

Lovastatin Cmax ↑ 14.5->20-fold,
AUC ↑ >14.8 - >20-fold
Lovastatin 40 mg,                                                                                     Contraindicated Lovastatin acid Cmax ↑ 11.5-13- fold,
AUC ↑ 15.4-20-fold

Simvastatin acid Cmax ↑ 17-fold,
Simvastatin 40 mg                                                                                     Contraindicated AUC ↑ 19-fold

Atorvastatin                                              Atorvastatin acid: Cmax     to ↑2.5 fold, Not recommended
AUC ↑ 40% to 3-fold

Psychoanaleptics; Psycholeptics (eg, antipsychotics, anxiolytics, and hypnotics) 
Although not studied directly,
Lurasidone, Pimozide, Quetiapine, Sertindole              itraconazole is likely to increase the      Contraindicated concentrations of these drugs.

Midazolam (oral) Cmax ↑ 2.5 to
Midazolam (oral) 7.5 mg                                                                               Contraindicated 3.4-fold, AUC ↑ 6.6 to 10.8-fold

Triazolam 0.25 mg                                         Triazolam Cmax ↑, AUC ↑                     Contraindicated 

Alprazolam 0.8 mg                                         Alprazolam Cmax      , AUC ↑ 2.8- fold      Use with caution 

                                                        Aripiprazole Cmax ↑ 19%, AUC ↑
Aripiprazole 3 mg                                                                                Use with caution 48%

Brotizolam Cmax     ,     AUC ↑ 2.6-
Brotizolam 0.5 mg                                                                                Use with caution fold

Buspirone Cmax ↑ 13.4-fold, AUC
Buspirone 10 mg                                                                                  Use with caution ↑ 19.2-fold

Midazolam (iv) 7.5 mg: concentration
↑;
Midazolam (iv) 7.5 mg                                   Although not studied directly,         Use with caution itraconazole is likely to increase the concentrations of midazolam following oromucosal administration.

Risperidone and active metabolite
Risperidone 2-8 mg/day                                                                           Use with caution concentration ↑

Zopiclone Cmax ↑ 30%, AUC ↑
Zopiclone 7.5 mg                                                                                 Use with caution 70%

Although not studied directly,
Cariprazine, Galantamine, Haloperidol, Reboxetine,
itraconazole is likely to increase the   Use with caution
Venlafaxine concentrations of these drugs.

Respiratory System: Other Respiratory System Products
Ivacaftor Cmax ↑ 3.6-fold, AUC ↑ 4.3-
Lumacaftor/Ivacaftor PO 200/250 mg BID                  fold                                     Not recommended Lumacaftor Cmax         , AUC

Although not studied directly,
Ivacaftor                                               itraconazole is likely to increase the   Use with caution concentrations of ivacaftor.

Sex Hormones and Modulators of the Genital System; Other Gynecologicals 
Although not studied directly,
Cabergoline, Dienogest, Ulipristal                      itraconazole is likely to increase the   Use with caution concentrations of these drugs.

Urologicals

Although not studied directly,
Avanafil, Dapoxetine, Darifenacin                       itraconazole is likely to increase the   Contraindicated concentrations of these drugs.



                                                                                                        Moderate or severe renal or hepatic impairment:
Contraindicated
Although not studied directly,            Mild renal or hepatic impairment: itraconazole is likely to increase the    Concomitant use should be
Fesoterodine concentrations of the active metabolites, avoided
5-hydroxymethyl- tolterodine.             Normal renal or hepatic impairment: Use with caution with a maximum fesoterodine dose of 4 mg.

Severe renal impairment:
Contraindicated
Although not studied directly,           Moderate or severe hepatic
Solifenacin                                                    itraconazole is likely to increase the   impairment: Contraindicated concentrations of solifenacin.           Use with caution in all other patients with a maximum solifenacin dose of 5 mg.


Although not studied directly,           Contraindicated in patients older Vardenafil                                                     itraconazole is likely to increase the   than 75 years; otherwise not concentrations of vardenafil.            recommended.

Although not studied directly,
Alfuzosin, Silodosin, Tadalafil (erectile dysfunction and itraconazole is likely to increase the   Not recommended benign prostatic hyperplasia), Tamsulosin, Tolterodine concentrations of these drugs.

Although not studied directly,
Dutasteride, Imidafenacin, Sildenafil (erectile dysfunction)   itraconazole is likely to increase the   Use with caution concentrations of these drugs.
Oxybutynin Cmax ↑ 2-fold,                Use with caution
AUC ↑ 2-fold
N-desethyloxybutynin Cmax       , AUC

Following transdermal administration:
Although not studied directly,
Oxybutynin 5 mg                                                itraconazole is likely to increase the concentrations of oxybutynin following transdermal administration.



Miscellaneous Drugs and Other Substances



                                                                                                 Use with caution,
monitor for
Valbenazine Cmax (↑), AUC                valbenazine-related
Valbenazine                                                                                      adverse reactions, dose (↑↑)                                     reduction of valbenazine is necessary.

Although not studied directly,           Contraindicated in patients with Colchicine                                              itraconazole is likely to increase the   renal or hepatic impairment. Not concentrations of colchicine             recommended in other patients.

Contraindicated in CYP2D6 poor metabolisers (PM).
Contraindicated in CYP2D6 intermediate metabolisers (IMs) or extensive metabolisers (EMs) taking a strong or moderate
Although not directly studied,
CYP2D6 inibitor.
Eliglustat                                              itraconazole is expected to increase the concentrations of eliglustat.            Use with caution in CYP2D6 IMs and EMs.
In CYP2D6 EMs with mild hepatic impairment, an eliglustat dose of 84 mg/day should be considered.

Although not studied directly,
Cinacalcet                                              itraconazole is likely to increase the   Use with caution concentrations of cinacalcet.