Interactions : אינטראקציות

4.5 Interaction with other medicinal products and other forms of interaction

Concomitant therapy with medicinal products that are contraindicated during treatment with ketoconazole and resulting in potentially life-threatening adverse reactions: o CYP3A4 metabolised HMG-CoA reductase inhibitors (e.g. simvastatin, atorvastatin and lovastatin) due to an increased risk of skeletal muscle toxicity including rhabdomyolysis; o eplerenone due to an increased risk of hyperkalemia and hypotension; o substances that may have their plasma concentrations increased and have QT prolonging potential : methadone, disopyramide, quinidine, dronedarone, pimozide, sertindole, saquinavir (saquinavir/ritonavir 1000/100 mg bid), ranolazine, mizolastine, halofantrine;
o dabigatran due to an increased bleeding risk;
o triazolam, oral midazolam and alprazolam due to potential for prolonged or increased sedation and respiratory depression;
o ergot alkaloids (e.g. dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine) due to an increased risk of ergotism and other serious vasospastic adverse reactions o lurasidone;
o quetiapine due to an increased risk of toxicity;
o telithromycin and clarithromycin in patients with severe renal impairment due to an increased risk of hepatotoxicity and QT interval prolongation;
o felodipine, nisoldipine due to an increased risk of oedema and congestive heart failure; o colchicine in patients with renal impairment due to an increased risk of severe adverse reactions; o irinotecan due to an alteration of the metabolism of this medicinal product; o everolimus, sirolimus (also known as rapamycin) due to an increase of the plasma concentrations of these medicinal products;
o vardenafil in men older than 75-years due to increased risk of adverse reactions o paritaprevir/ombitasvir (ritonavir) due to increased risk of adverse reactions; o fesoterodine and solifenacin in patients with renal impairment;
o tolvaptan used for a specific disease called “syndrome of inappropriate antidiuretic hormone secretion”.

The list above is not an inclusive list of compounds that may interact with ketoconazole and result in potentially life-threatening reactions.


Medicinal products affecting the absorption of ketoconazole
Medicinal products affecting gastric acidity impair the absorption of ketoconazole (see section 4.4).
Effects of other medicinal products on the metabolism of ketoconazole Ketoconazole is mainly metabolised by cytochrome CYP3A4.
Enzyme-inducing medicinal products such as rifampicin, rifabutin, carbamazepine, isoniazid, nevirapine, mitotane and phenytoin may significantly reduce the bioavailability of ketoconazole. Use of ketoconazole with potent enzyme inducers is not recommended.
Potent inhibitors of CYP3A4 (e.g. antivirals such as ritonavir, ritonavir-boosted darunavir and ritonavir- boosted fosamprenavir) may increase the bioavailability of ketoconazole, these medicinal products should be used with caution when co-administered with ketoconazole and patients should be monitored closely for signs and symptoms of adrenal insufficiency. Ketoconazole dose should be adjusted accordingly.

Effects of ketoconazole on the metabolism of the other medicinal products - Ketoconazole is a potent inhibitor of CYP3A4 and can inhibit the metabolism of medicinal products metabolised by this enzyme. This can result in an increase and/or prolongation of their effects, including adverse reactions.
- In vitro data indicate that ketoconazole is an inhibitor of CYP1A2 and does not significantly inhibit CYP     2A6 and 2E1. At clinically relevant concentrations inhibition of CYP2B6, 2C9/C8, 2C19 and 2D6 by ketoconazole cannot be excluded.
-     Ketoconazole can inhibit the transport of medicinal products by P-gp, which may result in an increased plasma concentration of these medicinal products.
-     Ketoconazole inhibits BCRP (Breast Cancer Resistance Protein) in in vitro studies. Data of inhibition indicate that risk of interaction with BCRP substrates cannot be excluded at the systemic level with very high doses of ketoconazole. However, ketoconazole may be an inhibitor of BCRP at the intestinal level at clinically relevant concentrations. Considering the rapid absorption of ketoconazole, intake of BCRP substrates should be postponed for 2 hours after ketoconazole intake.

Table 1 Interactions and recommendations for co-administration.
Interactions between ketoconazole and other medicinal products are listed in the table below (increase is indicated as “↑”, decrease as “↓”, an no change as “↔”). The degrees of interaction mentioned below are not absolute values and may be dependent on the ketoconazole dose given, i.e. many results are reported following a ketoconazole dose of 200 mg and a stronger interaction may be expected at a higher dose and/or shorter dosing interval. The following list is not an inclusive list of interactions between ketoconazole and other medicinal products.

Medicinal product by    Expected effect on drug levels             Recommendation for co- therapeutic area                                                   administration Analgesic opioid
Methadone               Potential ↑ in plasma concentrations of    Contraindicated due to the increased methadone                                  risk of serious cardiovascular events including QT prolongation and torsade de pointes, or respiratory or
CNS depression (see section 4.3).
Buprenorphine IV and    Buprenorphine:                             Careful monitoring.
sublingual              AUC: ↑ 1.5-fold                            The buprenorphine dose should be Cmax: ↑1.7-fold                            adjusted.
Alfentanil, fentanyl    Potential ↑in plasma concentrations of     Careful monitoring of adverse alfentanil and fentanyl                    reactions (respiratory depression, sedation) is recommended. It may be necessary to lower the dose of alfentanil and fentanyl.
Oxycodone               ↑in plasma concentrations of oxycodone     Careful monitoring.
have been observed                         The oxycodone dose may be adjusted.
Antiarrhythmics
Disopyramide            Potential ↑in plasma concentrations of     Contraindicated due to the risk of Quinidine               disopyramide and quinidine                 serious cardiovascular events including QT prolongation (see
Dronedarone             Repeated doses of 200 mg ketoconazole      section 4.3).
daily resulted in a 17-fold increase in dronedarone exposure
Digoxin                 Potential ↑in plasma concentrations of     Careful monitoring of digoxin levels digoxine                                   is recommended.
Anticoagulants and antiplatelet drugs
Dabigatran              Dabigatran:                                Contraindicated due to an increased AUC: ↑ 2.6-fold                            bleeding risk (see section 4.3).
Cmax: ↑2.5-fold
Rivaroxaban             Rivaroxaban:                               Not recommended due to an AUC: ↑ 2.6-fold                            increased bleeding risk.
Cmax: ↑1.7-fold
Apixaban                Apixaban                                   Not recommended due to an AUC: ↑ 2-fold                              increased bleeding risk.
Cmax: ↑1.6-fold
Cilostazol              Cilostazol:                                Careful monitoring Medicinal product by     Expected effect on drug levels            Recommendation for co- therapeutic area                                                   administration AUC: ↑ 2.2 fold                           A cilostazol dose of 50 mg twice daily is recommended in combination
The overall pharmacological activity of   with ketoconazole.
cilostazol increases 35% when co- administered with ketoconazole.
Warfarin and other       Potential ↑in plasma concentrations of    Careful monitoring coumarin-like drugs      warfarin                                  INR (international normalised ratio) monitoring recommended.
Edoxaban                 AUC: ↑ 1.8-fold                           Dose of edoxaban needs to be Cmax: ↑1.8-fold                           reduced when used concomitantly, please consult edoxaban SmPC.
Anticonvulsants
Carbamazepine            Potential ↑in plasma concentrations of    Not recommended.
Phenytoin                carbamazepine and phenytoin               (See also “Effects of other medicinal products on the metabolism of
Potential ↓ in plasma concentrations of   Ketoconazole HRA ”).
ketoconazole are expected.
(CYP3A enzyme induction)
Antidiabetics
Repaglinide              Repaglinide:                              Careful monitoring.
AUC: ↑ 1.2-fold                           Dose adjustement of repaglinide may Cmax: ↑ 1.2-fold                          be required.
Saxagliptin              Saxagliptin:                              Careful monitoring.
AUC: ↑ 2.5-fold                           Dose adjustment of saxagliptin may Cmax: ↑ 1.6-fold                          be required.
Associated with a decrease in corresponding values for the active metabolite
Tolbutamide              Tolbutamide:                              Careful monitoring.
AUC: ↑ 1.7-fold                           Dose adjustment of tolbutamide may be required.
Anti-infectives
Rifabutin                Potential ↑ in plasma concentrations of   Not recommended. (See also “Effects Rifampicin               rifabutine.                               of other medicinal products on the Isoniazid                Potential ↓ in plasma concentrations of   metabolism of Ketoconazole HRA ”) ketoconazole are expected.
(CYP3A4 enzyme induction)
Telithromycin            Telithromycine:                           Not recommended.
Clarithromycin           AUC: ↑ 2-fold                             Contraindicated in patients with Cmax: ↑1.5-fold                           severe renal impairment due to the Potential ↑in plasma concentrations of    risk of QT interval prolongation and clarithromycin                            serious hepatic adverse reactions (see section 4.3).
Isavuconazole            AUC: ↑ 5-fold                             Not recommended due to increased Cmax: ↑1.1-fold                           risk of isavuconazole adverse reactions, please consult isavuconazole SmPC
Praziquantel             ↑in plasma concentrations of              Careful monitoring.
praziquantel have been observed           Dose adjustment of praziquantel may be required.
Antimigraine Drugs
Ergots alkaloids such as Potential ↑in plasma concentrations of    Contraindicated due to the increased dihydroergotamine,       ergot alkaloids                           risk of ergotism and other serious ergometrine
Medicinal product by   Expected effect on drug levels           Recommendation for co- therapeutic area                                                administration (ergonovine),                                                   vasospastic adverse reactions (see ergotamine,                                                     section 4.3).
methylergometrine
(methylergonovine)
Eletriptan             Eletriptan:                              Not recommended.
AUC: ↑ 5.9-fold
Cmax: ↑ 2.7-fold


Antineoplastics
Irinotecan             Irinotecan:                              Contraindicated due to an alteration AUC: ↑ 2.1-fold                          of the metabolism of this medicinal product (see section 4.3).
Sunitinib              Sunitinib                                Not recommended due to the risk of Dasatinib              AUC: ↑ 1.5-fold                          increased exposure to these medicinal Lapatinib              Cmax: ↑ 1.5-fold                         products and QT prolongation.
Nilotinib              Lapatinib:
Erlotinib              AUC: ↑ 3.6-fold
Dabrafenib             Nilotinib:
Cabozantinib           AUC: ↑ 3.0-fold
Erlotinib:
AUC: ↑ 1.9-fold
Cmax: ↑ 1.7-fold
Dasatinib
↑in plasma concentrations of
Dasatinib have been observed
Dabrafenib
AUC: ↑ 1.7-fold
Cmax: ↑ 1.3-fold
Cabozantinib
AUC: ↑ 1.4-fold
Cmax: ↔
Ibrutinib              Ibrutinib:                               Not recommended as it may increase AUC: ↑ 24-fold                           ibrutinib-related toxicity.
Cmax: ↑ 29-fold
Crizotinib             Crizotinib                               Not recommended due to the risk of AUC: ↑ 3.2-fold                          QT interval prolongation and serious Cmax: ↑ 1.4-fold                         hepatic adverse reactions.

Monitoring of QT-prolongation if used concomitantly.
Bortezomib             Bortezomib:                              Careful monitoring.
Busulfan               AUC: ↑ 1.4-fold                          Dose adjustment of each medicinal Docetaxel              Imatinib:                                product may be required.
Imatinib               AUC: ↑ 1.4-fold
Cabazitaxel            Cmax: ↑ 1.3-fold
↑in plasma concentrations of docetaxel have been observed
Potential ↑in plasma concentrations of busulfan
Cabazitaxel
AUC: ↑ 1.3-fold
Paclitaxel             Paclitaxel:                              Careful monitoring.
Dose adjustment of paclitaxel
Medicinal product by    Expected effect on drug levels          Recommendation for co- therapeutic area                                                administration No change in plasma concentration were may be required.
shown with paclitaxel concentrate. No studies were performed with albumin bound nanoparticules.
Vincristine, vinblastine Potential ↑in plasma concentrations of Careful monitoring as it may cause (vinca alkaloids)        vinca alkaloids.                       an earlier onset and/or an increased severity of side-effects.
Antipsychotics,
Anxiolytics and
Hypnotics
Triazolam                AUC: ↑ have been observed              Contraindicated due to the risk of Alprazolam               Cmax: ↑ have been observed             potentially prolonged or increased Midazolam oral                                                  sedation and respiratory depression (see section 4.3).
Lurasidone               Lurasidone:                            Contraindicated due to the increased AUC: ↑ 9 fold                          risk of adverse reactions (see section Cmax: ↑ 6 fold                         4.3).
Pimozide                 Potential ↑in plasma concentrations of Contraindicated due to the risk of pimozide.                              serious cardiovascular events including QT prolongation (see section 4.3).
Sertindole               Potential ↑in plasma concentrations of Contraindicated due to the risk of QT sertindole.                            prolongation (see section 4.3).
Quetiapine               Quetiapine:                            Contraindicated as it may increase AUC: ↑ 6.2-fold                        quetiapine-related toxicity (see Cmax: ↑ 3.4-fold                       section 4.3).
Haloperidol              Potential ↑in plasma concentrations of Not recommended due to the haloperidol.                           increased risk of QT prolongation and extrapyramidal symptoms. It may be necessary to reduce haloperidol dosage.
Reboxetine               Reboxetine:                            Not recommended because of AUC: ↑ 1.5-fold of both enantiomers    reboxetine narrow’s therapeutic margin.
Midazolam IV             Midazolam:                             Careful monitoring.
AUC: ↑ 1.6-fold                        Dose adjustment of midazolam IV may be required.
Buspirone                Potential ↑in plasma concentrations of Careful monitoring.
buspirone.                             Dose adjustement of buspirone may be required.
Aripiprazole             Aripiprazole                           Careful monitoring.
AUC: ↑ 1.6-fold                        Aripiprazole dose should be reduced Cmax: ↑ 1.4-fold                       to approximatively one-half of its prescribed dose.
Risperidone              Potential ↑in AUC of risperidone       Careful monitoring. Dose adjustment of risperidone may be required.
Antivirals products
Saquinavir               Saquinavir:                            Contraindicated due to the risk of QT (saquinavir/ritonavir    AUC: ↔                                 prolongation (see section 4.3).
1000/100 mg bid)         Cmax: ↔
Ketoconazole
AUC: ↑ 2.7-fold
Cmax:↑ 1.5-fold
Medicinal product by    Expected effect on drug levels             Recommendation for co- therapeutic area                                                   administration (CYP3A4 enzyme inhibition by ritonavir)
Paritaprevir:                              Contraindicated due to the increased AUC: ↑2.2-fold                             risk of adverse reactions (see section Cmax: ↑1.7-fold                            4.3).

Ombitasvir:
AUC: ↑1.3-fold
Paritaprevir/Ombitasvir
Cmax: ↔
(ritonavir)
Ketoconazole:
AUC: ↑2.1-fold
Cmax: ↑1.1-fold t1/2: ↑ 4-fold

Ketoconazole:                              Not recommended
AUC: ↓0.28-fold
Cmax: ↓0.56-fold
Nevirapine
Nevirapine: plasma levels: ↑1.15-1.28- fold compared to historical controls
(CYP3A enzyme induction)
Maraviroc               Maraviroc:                                 Careful monitoring. Maraviroc dose AUC: ↑ 5-fold                              should be decreased to 150 mg twice Cmax: ↑ 3.4-fold                           daily.
Indinavir               Indinavir (600mg TID):                     Careful monitoring. Dose reduction AUC= 0.8-fold                              of Indinavir to 600 mg every 8 hours Cmin: ↑ 1.3-fold                           should be considered.
(Relative to Indinavir 800 mg TID alone)
Ketoconazole:                              A dose reduction of ketoconazole AUC: ↑3.4-fold                             should be considered when co- Cmax: ↑1.6-fold                            administered with ritonavir dosed as an antiretroviral medicinal product or
Ritonavir
(CYP3A enzyme inhibition)                  as a pharmacokinetic enhancer. (See also “Effects of other medicinal products on the metabolism of
Ketoconazole HRA ”).
Beta Blockers
Nadolol                 ↑in plasma concentrations of nadolol       Careful monitoring. Dose adjustment have been observed                         of nadolol may be required.
Calcium Channel
Blockers
Felodipine              AUC: ↑ has been observed                   Contraindicated due to an increase Nisoldipine             Cmax: ↑ has been observed                  risk of edema and congestive heart failure (see section 4.3).
Other dihydropyridines Potential ↑in plasma concentrations of      Careful monitoring. Dose adjustment Verapamil              these drugs                                 of dihydropyridines and verapamil may be required.
Cardiovascular Drugs,
Miscellaneous
Ranolazine            Ranolazine:                                  Contraindicated due to the potential AUC: ↑ 3.0 to 3.9-fold                       for serious cardiovascular events including QT prolongation (see section 4.3).
Medicinal product by     Expected effect on drug levels           Recommendation for co- therapeutic area                                                  administration Bosentan                 Bosentan:                                Not recommended due to the AUC: ↑ 2-fold                            potential for hepatic toxicity (see Cmax: ↑ 2-fold                           section 4.3).
Aliskiren                Aliskiren:                               Careful monitoring.
AUC: ↑ 1.8-fold                          Dose adjustment of aliskiren may be required.
Diuretics
Eplerenone               Eplerenone:                              Contraindicated due to the increased AUC: ↑ 5.5-fold                          risk of hyperkalaemia and hypotension (see section 4.3).
Gastrointestinal Drugs
Aprepitant             Aprepitant:                                Careful monitoring.
AUC: ↑ 5-fold                              Dose adjustment of aprepitant may be required
Domperidone              Domperidone:                             Not recommended due to an AUC: ↑ 3.0 fold                          increased risk in QT prolongation.
Cmax: ↑ 3.0 fold
Naloxegol                Naloxegol                                Not recommended AUC ↑ 12.9 fold
Cmax ↑ 9.6 fold
Immunosuppressants
Everolimus               Everolimus:                              Contraindicated due to the large Sirolimus (rapamycin)    AUC: ↑ 15.3-fold                         increase in these medicinal products Cmax: ↑ 4.1-fold                         concentrations (see section 4.3).
Sirolimus (rapamycin):
AUC: ↑ 10.9-fold
Cmax: ↑ 4.4-fold
Temsirolimus             Temsirolimus:                            Not recommended unless necessary.
AUC: ↔                                   Careful monitoring and dose Cmax: ↔                                  adjustment of these medicinal Tacrolimus               Ciclesonide active metabolite:           products may be required.
Ciclosporine             AUC: ↑ 3.5-fold
Budesonide
Ciclesonide              Rest of drugs
↑in plasma concentrations of these drugs have been observed
Dexamethasone,           Potential ↑in plasma concentrations of   Careful monitoring.
fluticasone,             these drugs                              Dose adjustment of these medicinal methylprednisolone                                                products may be required.
Lipid Lowering Drugs
Lovastatin, simvastatin, Potential ↑in plasma concentrations of   Contraindicated due to an increased atorvastatin*            these drugs                              risk of skeletal muscle toxicity, including rhabdomyolysis (see section 4.3).
Respiratory Drugs
Salmeterol               Salmeterol                               Not recommended due to an AUC: ↑ 15-fold                           increased risk in QT prolongation.
Cmax: ↑ 1.4-fold
Urological Drugs
Fesoterodine             Fesoterodine active metabolite:          Not recommended due to an Tolterodine              AUC: ↑ 2.3-fold                          increased risk of QT prolongation.
Solifenacin              Cmax: ↑ 2.0-fold
Medicinal product by         Expected effect on drug levels                  Recommendation for co- therapeutic area                                                             administration Solifenacin:                                    Fesoterodine and solifenacin are AUC: ↑ 3.0-fold                                 contraindicated in patients with renal impairment (see section 4.3).
↑in plasma concentrations of tolterodine have been observed
Phosphodiesterase(PD
E5) inhibitors
Sildenafil           Tadalafil:                                              Not recommended due to the Tadalafil            AUC: ↑ 4-fold                                           increased risk of adverse reactions.
Vardenafil           Cmax: ↑ 1.2-fold
Vardenafil is contraindicated in men
Vardenafil:                                     older than 75 years old (see section AUC: ↑ 10-fold                                  4.3).
Cmax: ↑ 4-fold

Potential ↑in plasma concentrations of sildenafil
Other
Tolvaptan                    ↑in plasma concentrations of tolvaptan          Contraindicated due to an increase in have been observed                              the plasma concentrations (see section 4.3).
Mizolastine                  Potential ↑in plasma concentrations of          Contraindicated due to the potential Halofantrine                 these drugs                                     for serious cardiovascular events including QT prolongation (see section 4.3).
Colchicine                   ↑in plasma concentrations of colchicine         Not recommended due to a potential have been observed                              increase in colchicine-related toxicity.
Contraindicated in patients with renal impairment (see section 4.3).
Cinacalcet                   Cinacalcet                                      Careful monitoring.
AUC: ↑ 2 fold                                   Dose adjustment of cinacalcet Cmax: ↑ 2 fold                                  may be required.
Ebastine                     ↑in plasma concentrations of ebastine           Not recommended due to an have been observed                              increased risk in QT prolongation.

* Rosuvastatin is not a CYP 3A4 substrate. ketoconazole did not produce any change in rosuvastatin pharmacokinetics, therefore, co-administration of ketoconazole and rosuvastatin is unlikely to increase the risk of toxicity of rosuvastatin.
Other statins that are not CYP3A4 substrates (pravastatin and fluvastatin) can be co-administered with ketoconazole.

Other interactions

Exceptional cases of a disulfiram-like reaction have been reported when ketoconazole was co-administered with alcohol, characterised by flushing, rash, peripheral oedema, nausea and headache, have been reported.
All symptoms resolved completely within a few hours.

Co-administration of ketoconazole and pasireotide is not recommended since the combination can lead to a QT prolongation in patients with known cardiac rhythm disorders.

There is no evidence to suggest that there is an interaction between ketoconazole and other steroidogenesis inhibitors (i.e. metyrapone).