Interactions : אינטראקציות

4.5    Interaction with other medicinal products and other forms of interaction

Itraconazole is mainly metabolised 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 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 co-administered with itraconazole. Upon co-administration, 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 
Medicinal products Per          Expected/Potential effect on itraconazole            Clinical comment Orale [PO] Single Dose          levels                                               (see above for additional unless otherwise stated)        (↑ = increase; ↔ = no change; ↓ = decrease)          info and also sections 4.3 and within class                                                                         4.4) Anti-bacterials for Systemic Use; Anti-mycobacterials
Although not studied directly, isoniazid is likely
Isoniazid                                                                            Not recommended to decrease the concentrations of 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
Itraconazole Cmax ↑ 90%, AUC ↑ 92%                   Use with caution BID



Antiepileptics
Although not studied directly, these drugs are
Carbamazepine, Phenobarbital      likely to decrease concentrations of             Not recommended itraconazole.
Itraconazole Cmax ↓ 83%, AUC ↓ 93%
Phenytoin PO 300 mg OD                                                             Not recommended Hydroxyitraconazole Cmax ↓ 84%, AUC ↓ 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 are
Ombitasvir/Paritaprevir/Ritona expected to increase the concentrations of       Contraindicated vir (with or without Dasabuvir) itraconazole.
Itraconazole Cmax ↓ 37%, AUC ↓ 39%;
Efavirenz 600 mg                                                                   Not recommended Hydroxyitraconazole Cmax ↓ 35%, AUC ↓ 37%
Nevirapine PO 200 mg OD           Itraconazole Cmax ↓ 38%, AUC ↓ 62%               Not recommended Cobicistat,
Darunavir (boosted),
Elvitegravir (ritonavir-
Although not studied directly, these drugs are boosted),
expected to increase the concentrations of       Use with caution
Fosamprenavir (ritonavir- itraconazole.
boosted),
Ritonavir,
Saquinavir (ritonavir-boosted)
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 (aluminium, calcium,
magnesium, or sodium bicarbonate),
H2-receptor antagonists (e.g.,
Itraconazole Cmax ↓, AUC ↓                         Use with caution cimetidine, ranitidine),
Proton pump inhibitors (e.g.,
lansoprazole, omeprazole,
rabeprazole)
Respiratory System: Other Respiratory System Products
Lumacaftor/Ivacaftor
Itraconazole concentration ↓                     Not recommended
PO 200/250 mg BID
Miscellaneous
Although not studied directly, St. John's Wort
St. John's Wort is likely to decrease the concentration of       Not recommended
(Hypericum perforatum) itraconazole.



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

Expected/Potential effect on drug
Medicinal products (PO Single                                                 Clinical comment levels
Dose unless otherwise stated)
(↑ = increase; ↔ = no change; ↓ =           (see above for additional info and within class decrease)                                   also sections 4.3 and 4.4) Analgesics; Anaesthetics

Ergot alkaloids (e.g.,            Although not studied directly,
dihydroergotamine, ergometrine,   itraconazole is likely to increase the      Contraindicated ergotamine, methylergometrine)    concentrations of these drugs.

Although not studied directly,
Eletriptan, Fentanyl              itraconazole is likely to increase the      Not recommended concentrations of these drugs.
Alfentanil,
Buprenorphine (IV and             Although not studied directly,
sublingual),                      itraconazole is likely to increase the      Use with caution Cannabinoids, Methadone,          concentrations of these drugs.
Sufentanil
Oxycodone PO: Cmax ↑ 45%, AUC ↑
Oxycodone PO 10 mg,                                                           Use with caution 2.4-fold
Oxycodone IV 0.1 mg/kg            Oxycodone IV: AUC ↑ 51%                     Use with caution Anti-bacterials for Systemic Use; Anti-mycobacterials; Antimycotics for Systemic Use Although not studied directly,
Isavuconazole                     itraconazole is likely to increase the      Contraindicated concentrations of isavuconazole.
Although     not     studied    directly,
Bedaquiline                       itraconazole is likely to increase the      Not recommended 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 delamanid.
Antiepileptics
Although not studied directly,
Carbamazepine                     itraconazole is likely to increase the      Not recommended concentrations of carbamazepine.
Anti-inflammatory and Antirheumatic Products
Meloxicam 15 mg                   Meloxicam Cmax ↓ 64%, AUC ↓ 37%             Use with caution Anthelmintics; Antiprotozoals
Although not studied directly,
Halofantrine                      itraconazole is likely to increase the      Contraindicated concentrations of halofantrine.
Although not studied directly,
Artemether-lumefantrine,
itraconazole is likely to increase the      Use with caution
Praziquantel concentrations of these drugs.
Quinine 300 mg                    Quinine Cmax ↔, AUC ↑ 96%                   Use with caution 


Antihistamines for Systemic Use
Although not studied directly,
Astemizole, Mizolastine,
itraconazole is likely to increase the     Contraindicated
Terfenadine concentrations of these drugs.
Ebastine Cmax ↑ 2.5-fold, AUC ↑ 6.2-
Ebastine 20 mg                       fold                                       Not recommended Carebastine Cmax ↔, AUC ↑ 3.1-fold
Although not studied directly,
Bilastine, Rupatadine                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.
Axitinib, Bosutinib,
Cabazitaxel, Cabozantinib,           Although not studied directly,
Ceritinib, Crizotinib,               itraconazole is likely to increase the Dabrafenib, Dasatinib,               concentrations of these drugs except for Docetaxel, Everolimus,               cabazitaxel and regorafenib. No
Ibrutinib, Lapatinib,                statistically significant change in Not recommended
Nilotinib, Pazopanib,                cabazitaxel exposure, but a high Regorafenib, Sunitinib,              variability in the results was observed.
Temsirolimus, Trabectedin,           Regorafenib AUC is expected to
Trastuzumab emtansine,               decrease (by estimation of active Vinca alkaloids (e.g., vinflunine,   moiety) vinorelbine)
Cobimetinib Cmax ↑ 3.2-fold, AUC ↑
Cobimetinib 10 mg                                                               Not recommended 6.7-fold
Olaparib 100 mg                      Olaparib Cmax ↑ 40%, AUC ↑ 2.7-fold        Not recommended Alitretinoin (oral),
Bortezomib,
Brentuximab vedotin,                 Although not studied directly,
Erlotinib, Idelalisib,               itraconazole is likely to increase the     Use with caution Imatinib, Nintedanib,                concentrations of these drugs
Panobinostat, Ponatinib,
Ruxolitinib, Sonidegib,
Busulfan 1 mg/kg Q6h                 Busulfan Cmax ↑, AUC ↑                     Use with caution Gefitinib 250 mg                     Gefitinib 250 mg Cmax ↑, AUC ↑ 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, Rivaroxaban,
itraconazole is likely to increase the     Not recommended
Vorapaxar concentrations of these drugs.
Although not studied directly,
Cilostazol,
itraconazole is likely to increase the     Use with caution
Coumarins (e.g., warfarin) concentrations of these drugs
Antivirals for Systemic Use
Ombitasvir/Paritaprevir/Ritonavir    Itraconazole may increase paritaprevir Contraindicated
(with or without Dasabuvir)          concentrations.



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

Cobicistat,
Elvitegravir (ritonavir-boosted),   Although not studied directly,
Glecaprevir/Pibrentasvir,           itraconazole is likely to increase the   Use with caution Maraviroc, Ritonavir,               concentrations of these drugs.
Saquinavir
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,
Eplerenone, Ivabradine,             Although not studied directly,
Lercanidipine, Nisoldipine,         itraconazole is likely to increase the   Contraindicated Ranolazine,                         concentrations of these drugs.
Sildenafil (pulmonary hypertension)
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
Riociguat,                          Although not studied directly,
Tadalafil (pulmonary                itraconazole is likely to increase the   Not recommended hypertension)                       concentrations of these drugs.
Bosentan, Diltiazem,
Guanfacine,
Although not studied directly,
Other Dihydropyridines (e.g.,
itraconazole is likely to increase the   Use with caution amlodipine, isradipine,
concentrations of bosentan.
nifedipine, nimodipine),
Verapamil
Digoxin 0.5 mg                    Digoxin Cmax ↑ 34%, AUC ↑ 68%         Use with caution Nadolol Cmax ↑ 4.7-fold, AUC ↑ 2.2-
Nadolol 30 mg                                                           Use with caution 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 ↑
Budesonide INH 1 mg SD              4.2-fold; Budesonide (other              Use with caution 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%,
Methylprednisolone 16 mg            AUC ↑ 3.9-fold                           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 0.25 mg                Repaglinide Cmax ↑ 47%, AUC ↑ 41%          Use with caution Although not studied directly,
Saxagliptin                        itraconazole is likely to increase the     Use with caution concentrations of saxagliptin.
Gastrointestinal Drugs, including Antidiarrheals, Intestinal Anti-inflammatory/Anti-infective 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, AUC ↑
Domperidone 20 mg                                                             Contraindicated 3.2-fold
Although not studied directly,
Aprepitant, Loperamide,
itraconazole is likely to increase the     Use with caution
Netupitant 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 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, AUC ↑
Simvastatin 40 mg                                                             Contraindicated 19-fold
Atorvastatin acid: Cmax ↔ to ↑2.5-fold,
Atorvastatin                                                                  Not recommended AUC ↑ 40% to 3-fold
Psychoanaleptics; Psycholeptics (e.g., antipsychotics, anxiolytics, and hypnotics) Although not studied directly,
Lurasidone, Pimozide,
itraconazole is likely to increase the     Contraindicated
Quetiapine, Sertindole concentrations of these drugs.
Midazolam (oral) Cmax ↑ 2.5 to 3.4-fold,
Midazolam (oral) 7.5 mg                                                       Contraindicated 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 3 mg                  Aripiprazole Cmax ↑ 19%, AUC ↑ 48%         Use with caution Brotizolam 0.5 mg                  Brotizolam Cmax ↔, AUC ↑ 2.6-fold          Use with caution Buspirone Cmax ↑ 13.4-fold, AUC ↑
Buspirone 10 mg                                                               Use with caution 19.2-fold


Midazolam (iv) 7.5 mg: concentration
↑;
Although not studied directly,
Midazolam (iv) 7.5 mg                                                            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 7.5 mg                     Zopiclone Cmax ↑ 30%, AUC ↑ 70%             Use with caution Cariprazine, Galantamine,            Although not studied directly,
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 fold                                             Not recommended
200/250 mg BID
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 Gynaecologicals Although not studied directly,
Cabergoline, Dienogest,
itraconazole is likely to increase the      Use with caution
Ulipristal concentrations of these drugs.
Urologicals
Although not studied directly,
Avanafil, Dapoxetine,
itraconazole is likely to increase the      Contraindicated
Darifenacin 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
Fesoterodine                                                                     Concomitant use should be avoided concentrations of the active metabolites,
Normal renal or hepatic function:
5-hydroxymethyl tolterodine.
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.

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

Although not studied directly,
Dutasteride, Imidafenacin,
itraconazole is likely to increase the      Use with caution
Sildenafil (erectile dysfunction) concentrations of these drugs.
Oxybutynin Cmax ↑ 2-fold, AUC ↑ 2- fold
Oxybutynin 5 mg                                                                  Use with caution N-desethyloxybutynin Cmax ↔, AUC ↔


Following transdermal administration:
Although not studied directly,
itraconazole is likely to increase the concentrations of oxybutynin following transdermal administration.
Miscellaneous Drugs and Other Substances
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
Although not directly studied,
a strong or moderate CYP2D6
Eliglustat                       itraconazole is expected to increase the inhibitor.
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.