KETOCONAZOLE HRA 200mg tablets medication leaflet

Ketoconazole Esteve 200 mg tablets

Each tablet contains 200 mg ketoconazole.

Each tablet contains 19 mg of lactose (as monohydrate).

For the full list of excipients, see section 6.1.

Tablet.

Off-white to light cream, round, 10 mm diameter, biconvex.

Ketoconazole Esteve is indicated for the treatment of endogenous Cushing’s syndrome in adults andadolescents above the age of 12 years.

Treatment should be initiated and supervised by physicians experienced in endocrinology or internal medicineand having the appropriate facilities for monitoring of biochemical responses since the dose must be adjustedto meet the patient’s therapeutic need, based on the normalisation of cortisol levels.

The recommended dose at initiation in adults and adolescents is 400-600 mg/day taken orally in two or threedivided doses and this dose can be increased rapidly to 800-1,200 mg/day in two or three divided doses.

At treatment initiation, 24-hour urinary free cortisol should be controlled every few days/weeks.

Adjustment of the posology

Ketoconazole daily dose should be periodically adjusted on an individual basis with the aim to normaliseurinary free cortisol and/or plasma cortisol levels.

- A dose increase of 200 mg/day every 7 to 28 days may be considered if urinary free cortisol and/orplasma cortisol levels are above the normal range, as long as the dose is tolerated by the patient;

- A maintenance dose from 400 mg/day to a maximal dose of 1,200 mg/day taken orally in 2 to 3 divideddoses may be required to restore normal cortisol levels. In most of the publications the maintenancedose varied between 600 mg/day and 800 mg/day;

- When the effective dose of ketoconazole is established, monitoring of urinary free cortisol and/orplasma cortisol levels may be performed every 3 to 6 months (see section 4.4);

- In the case of adrenal insufficiency and depending on the severity of the event, the dose ofketoconazole should be decreased by at least 200 mg/day or the treatment should be temporarilydiscontinued and/or a corticosteroid therapy should be added until the resolution of the event.

Ketoconazole can be reintroduced thereafter at a lower dose (see section 4.4);

- Treatment with ketoconazole can be stopped abruptly without a need for progressive dose decreasewhere a change in the therapeutic strategy (e.g. surgery) is desired.

Before starting the treatment, it is mandatory:

- to measure liver enzymes (ASAT, ALAT, gammaGT and alkaline phosphatase) and bilirubin

- to inform the patients about the risk of hepatotoxicity, including to stop the treatment and to contact theirdoctor immediately if they feel unwell or in the event of symptoms such as anorexia, nausea, vomiting,fatigue, jaundice, abdominal pain or dark urine. If these occur, treatment should be stopped immediatelyand liver function tests should be performed.

Due to the known hepatotoxicity of ketoconazole, the treatment must not be initiated in patients with liverenzymes levels above 2 times the upper limit of normal (see section 4.3).

During the treatment:

- close clinical follow-up should be undertaken

- measurement of liver enzymes (ASAT, ALAT, gamma GT and alkaline phosphatase) and bilirubin, shouldbe performed at frequent intervals:

o weekly for one month after initiation of the treatmento then monthly for 6 monthso weekly during one month whenever the dose was increased.

In the case of an increase in liver enzymes of less than 3 times the upper limit of normal, more frequentmonitoring of liver function tests should be performed and the daily dose should be decreased by at least200 mg.

In the case of an increase in liver enzymes equal to or greater than 3 times the upper limit of normal,ketoconazole should be stopped immediately and should not be reintroduced due to the risk of serious hepatictoxicity. Ketoconazole should be discontinued without any delay if clinical symptoms of hepatitis develop.

In case of long term treatment (more than 6 months):

Although hepatotoxicity is usually observed at treatment initiation and within the first six months of treatment,monitoring of liver enzymes should be done under medical criteria. As a precautionary measure, in case of adose increase after the first six months of treatment, monitoring of liver enzymes should be repeated on aweekly basis for one month.

Dosing regimens for maintenance therapy

Subsequent maintenance therapy can be administered in one of two ways:

- Block-only regimen: the maintenance dose of ketoconazole may be continued as described above;

- Block-and-replace regimen: the maintenance dose of ketoconazole should be further increased by200 mg and concomitant corticosteroid replacement therapy should be added (see section 4.4).

Data on the use of ketoconazole in patients older than 65 years are limited, but there is no evidence to suggestthat specific dose adjustment is required in these patients (see section 5.2).

Although data are limited, the pharmacokinetics of ketoconazole are not significantly different in patients withrenal failure compared to healthy subjects, and no specific dose adjustment is recommended in this population.

Ketoconazole is contraindicated in patients with acute or chronic hepatic impairment (see sections pct. 4.3, pct. 4.4 and5.3). The treatment must not be initiated in patients with liver enzymes levels above 2 times the upperlimit of normal

The safety and efficacy of Ketoconazole Esteve in children aged less than 12 years have not been established.

Currently available data are described in sections 4.8, 5.1 and 5.2 but no recommendation on a posology canbe made.

Oral use.

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1;

- Hypersensitivity to any imidazole antifungal medicinal product;

- Acute or chronic liver disease and/or if pre-treatment liver enzymes levels are above 2 times the upperlimit of normal (see sections 4.2 and 4.4):

- Pregnancy (see section 4.6);

- Breastfeeding (see section 4.6);

- Congenital or documented acquired QTc prolongation ;

- Concomitant therapy with any of the following medicinal products which may interact and result inpotentially life-threatening adverse reactions (see section 4.5):

o CYP3A4 metabolised HMG-CoA reductase inhibitors (e.g. simvastatin, atorvastatin andlovastatin) 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 andrespiratory depression;o ergot alkaloids (eg dihydroergotamine, ergometrine (ergonovine), ergotamine andmethylergometrine (methylergonovine) due to an increased risk of ergotism and other seriousvasospastic 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 riskof 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 concentrationsof 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 hormonesecretion”.

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

Liver enzymes should be monitored in all patients receiving ketoconazole. Due to the risk of serious hepatictoxicity, close follow-up of patients is required (see section 4.2).

Monitoring of adrenal function

Adrenal function should be monitored at regular intervals since adrenal insuficiency can occur during thetreatment under conditions of a relative cortisol deficiency due to an increased glucocorticoid demand (e.g. incase of stress, surgery, or infection); and/or in case of ketoconazole overtreatment (for the patients treated witha block-only regimen); or if there is insufficient glucocorticoid replacement therapy (for the patients treatedwith a block-and-replace regimen). Serum or plasma and/or salivary cortisol and/or urinary free cortisol levelsshould be monitored, within one week following ketoconazole initiation as a minimum, and then periodicallythereafter. When urinary free/serum/ plasma cortisol levels are normalised or close to target and the effectivedose of ketoconazole is established, monitoring can be undertaken every 3 to 6 months (see section 4.2 fordose adjustment in case of adrenal insufficiency).

All patients should be monitored and informed about the signs and symptoms associated with hypocortisolism(e.g. weakness, fatigue, anorexia, nausea, vomiting, weight-loss, hypotension, hyponatraemia, hyperkalaemiaand/or hypoglycaemia).

If clinical symptoms are suggestive of adrenal insufficiency, cortisol levels should be measured andketoconazole should be temporarily discontinued or the dose reduced and if necessary corticosteroidsubstitution should be initiated. Ketoconazole can be resumed thereafter at a lower dose (see section 4.2).

Block and replace regimen

Patients treated with a block-and-replace regimen should be taught to adjust their glucocorticoid replacementtherapy dose under conditions of stress (see section 4.2). In addition, they should receive an emergency cardand be equipped with an emergency glucocorticoid set.

Monitoring of the QTc interval

Monitoring for an effect on the QTc interval is advisable. An ECG should be performed:

- Prior to the start of ketoconazole

- Within one week after the beginning of the treatment

- As clinically indicated thereafter.

In case of co-administration of an medicinal product known to increase QTc interval (see section 4.5), ECGmonitoring is recommended.

Women must be provided with comprehensive information on pregnancy prevention. As a minimumrequirement, women of childbearing potential must use an effective method of contraception (see section 4.6).

Decreased gastric acidity

Absorption is impaired when gastric acidity is decreased. Acid-neutralising medicines (e.g. aluminiumhydroxide) should not be administered for at least 2 hours after the intake of ketoconazole. In patients withachlorhydria, such as certain AIDS patients and patients on acid secretion suppressors (e.g. H2-antagonists,proton pump inhibitors), it is advised to administer ketoconazole with an acidic beverage e.g. cola beverage,orange juice.

If acid secretion suppressors are added to or removed from the concomitant medicinal products thenketoconazole dose should be adjusted according to cortisol levels.

Potential interaction with medicinal products

Ketoconazole has a high potential for clinically important medicinal products interactions.

Ketoconazole is mainly metabolised through CYP3A4. Coadministration of potent enzyme inducers of

CYP3A4 may decrease the bioavailibity of ketoconazole. A review of concomitant medicinal products shouldbe conducted when initiating ketoconazole treatment since ketoconazole is a known strong CYP3A4 inhibitor.

The SmPC for concomitantly used products must be consulted for the recommendations regarding co-administration with strong CYP3A4 inhibitors.

Ketoconazole is a potent inhibitor of CYP3A4: inhibition of CYP3A4 by ketoconazole can increase patients’exposure to a number of medicinal products which are metabolised through this enzymatic system (see section4.5).

Ketoconazole is also a potent inhibitor of P-gp: inhibition of P-gp by ketoconazole can increase patients’exposure to medicinal products which are P-gp substrates (see section 4.5).

CYP3A4-metabolised and/or P-gp substrates known to prolong the QT interval may be contraindicated or notrecommended depending on the observed or expected effect with ketoconazole (i.e. resulting in augmentationof the plasma concentration, AUC, Cmax of the drugs) and the known therapeutic margins of the drugs. Somecombinations may lead to an increased risk of ventricular tachyarrhythmias, including occurrences of torsadede pointes, a potentially fatal arrhythmia (see Table 1 Interactions and recommendations for co-administration,section 4.5).

Use with hepatotoxic medicinal products

Co-administration of ketoconazole and other medicinal products known to have potentially hepatotoxic effect(eg paracetamol) is not recommended since the combination may lead to increased risk of liver damage.

Use with pasireotide

Co-administration of ketoconazole and pasireotide is not recommended since the combination can lead to QTprolongation in patients with known cardiac rhythm disorders (see section 4.5).

Coexisting inflammatory/autoimmune disorders

Exacerbation or development of inflammatory/autoimmune disorders has been described after Cushing’ssyndrome remission, including after treatment with ketoconazole. Patients with Cushing's syndrome andcoexisting inflammatory/autoimmune disorders should be supervised after normalisation of cortisol levels onketoconazole.

Alcohol

Patients should be advised against alcohol consumption while on treatment (see section 4.5).

Warning regarding excipients

This medicinal product contains lactose.

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucosegalactosemalabsorption should not take this medicine.

Concomitant therapy with medicinal products that are contraindicated during treatment with ketoconazoleand 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/ritonavir1000/100 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 andrespiratory depression;o ergot alkaloids (eg dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine(methylergonovine) due to an increased risk of ergotism and other serious vasospastic adversereactionseventso 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 ofhepatotoxicity 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 ofthese medicinal products;o vardenafil in men older than 75-years due to increased risk of adverse reactionso 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 hormonesecretion”.

The list above is not an inclusive list of compounds that may interact with ketoconazole and result inpotentially 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 withpotent 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 beused with caution when co-administered with ketoconazole and patients should be monitored closely for signsand symptoms of adrenal insuficiency. 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 productsmetabolised by this enzyme. This can result in an increase and/or prolongation of their effects, includingadverse reactions.

- In vitro data indicate that ketoconazole is an inhibitor of CYP1A2 and does not significantly inhibit CYP2A6 and 2E1. At clinically relevant concentrations inhibition of CYP2B6, 2C9/C8, 2C19 and 2D6 byketoconazole cannot be excluded.

- Ketoconazole can inhibit the transport of medicinal products by P-gp, which may result in an increasedplasma concentration of these medicinal products.

- Ketoconazole inhibits BCRP (Breast Cancer Resistance Protein) in in vitro studies. Data of inhibitionindicate that risk of interaction with BCRP substrates cannot be excluded at the systemic level with veryhigh doses of ketoconazole. However, ketoconazole may be an inhibitor of BCRP at the intestinal level atclinically relevant concentrations. Considering the rapid absorption of ketoconazole, intake of BCRPsubstrates 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 isindicated as “↑”, decrease as “↓”, an no change as “↔”). The degrees of interaction mentioned below are notabsolute values and may be dependent on the ketoconazole dose given, i.e. many results are reported followinga ketoconazole dose of 200 mg and a stronger interaction may be expected at a higher dose and/or shorterdosing interval. The following list is not an inclusive list of interactions between ketoconazole and othermedicinal 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 increasedmethadone risk of serious cardiovascular eventsincluding QT prolongation andtorsade 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 adversealfentanil and fentanyl reactions (respiratory depression,sedation) is recommended. It may benecessary to lower the dose ofalfentanil and fentanyl.

Oxycodone ↑in plasma concentrations of oxycodone Careful monitoring.have been observed The oxycodone dose may beadjusted.

Antiarrhythmics

Disopyramide Potential ↑in plasma concentrations of Contraindicated due to the risk of

Quinidine disopyramide and quinidine serious cardiovascular eventsincluding QT prolongation (see

Dronedarone Repeated doses of 200 mg ketoconazole section 4.3).daily resulted in a 17-fold increase indronedarone exposure

Medicinal product by Expected effect on drug levels Recommendation for co-therapeutic area administration

Digoxin Potential ↑in plasma concentrations of Careful monitoring of digoxin levelsdigoxine is recommended.

Anticoagulants andantiplatelet 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

AUC: ↑ 2.2 fold A cilostazol dose of 50 mg twicedaily 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 monitoringcoumarin-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 medicinalproducts on the metabolism of

Potential ↓ in plasma concentrations of Ketoconazole Esteve ”).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 incorresponding values for the activemetabolite

Tolbutamide Tolbutamide: Careful monitoring.

AUC: ↑ 1.7-fold Dose adjustment of tolbutamide maybe required.

Anti-infectives

Rifabutin Potential ↑ in plasma concentrations of Not recommended. (See also “Effects

Rifampicin rifabutine. of other medicinal products on the

Isoniazid Potencial ↓ in plasma concentrations of metabolism of Ketoconazole Esteveketoconazole are expected. ”)(CYP3A4 enzyme induction)

Medicinal product by Expected effect on drug levels Recommendation for co-therapeutic area administration

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 andclarithromycin serious hepatic adverse reactions (seesection 4.3).

Isavuconazole AUC: ↑ 5-fold Not recommended due to increased

Cmax: ↑ 1.1 -fold risk of isavuconazole adversereactions, please consultisavuconazole SmPC

Praziquantel ↑in plasma concentrations of Careful monitoring.praziquantel have been observed Dose adjustment of praziquantelmay be required.

Antimigraine Drugs

Ergots alkaloids such as Potential ↑in plasma concentrations of Contraindicated due to the increaseddihydroergotamine, ergot alkaloids risk of ergotism and other seriousergometrine vasospastic adverse reactions (see(ergonovine), section 4.3).ergotamine,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 medicinalproduct (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

Medicinal product by Expected effect on drug levels Recommendation for co-therapeutic area administration

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 ifused 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 ofdocetaxel have been observed

Potential ↑in plasma concentrations ofbusulfan

Cabazitaxel

AUC: ↑ 1.3-fold

Paclitaxel Paclitaxel: Careful monitoring.

No change in plasma concentration were Dose adjustment of paclitaxelshown with paclitaxel concentrate. No may be required.studies were performed with albuminbound nanoparticules.

Vincristine, vinblastine Potential ↑in plasma concentrations of Careful monitoring as it may cause(vinca alkaloids) vinca alkaloids. an earlier onset and/or an increasedseverity 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 ofpimozide. serious cardiovascular eventsincluding QT prolongation (seesection 4.3).

Sertindole Potential ↑in plasma concentrations of Contraindicated due to the risk of QTsertindole. 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 thehaloperidol. increased risk of QT prolongationand extrapyramidal symptoms. Itmay be necessary to reducehaloperidol dosage.

Reboxetine Reboxetine: Not recommended because of

AUC: ↑ 1.5-fold of both enantiomers reboxetine narrow’s therapeuticmargin.

Midazolam IV Midazolam: Careful monitoring.

AUC: ↑ 1.6-fold Dose adjustment of midazolam IVmay be required.

Medicinal product by Expected effect on drug levels Recommendation for co-therapeutic area administration

Buspirone Potential ↑in plasma concentrations of Careful monitoring.buspirone. Dose adjustement of buspironemay be required.

Aripiprazole Aripiprazole Careful monitoring.

AUC: ↑ 1.6-fold Aripiprazole dose should be reduced

Cmax: ↑ 1.4-fold to approximatively one-half of itsprescribed dose.

Risperidone Potential ↑in AUC of risperidone: Careful monitoring. Dose adjustmentof 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(CYP3A4 enzyme inhibition byritonavir)

Paritaprevir: Contraindicated due to the increased

AUC: ↑2.2-fold risk of adverse reactions (see section

Cmax: ↑1.7-fold 4.3).

Ombitasvir:

Paritaprevir/Ombitasvir AUC: ↑1.3-fold(ritonavir) Cmax: ↔

Ketoconazole:

AUC: ↑2.1-fold

Cmax: ↑1.1-foldt1/2: ↑ 4-fold

Ketoconazole: Not recommended

AUC: ↓0.28-fold

Nevirapine Cmax: ↓0.56-fold

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

Ritonavir an antiretroviral medicinal product or(CYP3A enzyme inhibition) as a pharmacokinetic enhancer. (Seealso “Effects of other medicinalproducts on the metabolism ofketoconazole Esteve ”).

Medicinal product by Expected effect on drug levels Recommendation for co-therapeutic area administration

Beta Blockers

Nadolol ↑in plasma concentrations of nadolol Careful monitoring. Dose adjustmenthave 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 heartfailure (see section 4.3).

Other dihydropyridines Potential ↑in plasma concentrations of Careful monitoring. Dose adjustment

Verapamil these drugs of dihydropyridines and verapamilmay be required.

Cardiovascular Drugs,

Miscellaneous

Ranolazine Ranolazine: Contraindicated due to the potential

AUC: ↑ 3.0 to 3.9-fold for serious cardiovascular eventsincluding QT prolongation (seesection 4.3).

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 berequired.

Eplerenone Eplerenone: Contraindicated due to the increased

AUC: ↑ 5.5-fold risk of hyperkalaemia andhypotension (see section 4.3).

Gastrointestinal Drugs

Aprepitant Aprepitant: Careful monitoring.

AUC: ↑ 5-fold Dose adjustment of aprepitantmay 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

Ciclesonide Rest of drugs↑in plasma concentrations ofthese drugs have been observed

Medicinal product by Expected effect on drug levels Recommendation for co-therapeutic area administration

Dexamethasone, Potential ↑in plasma concentrations of Careful monitoring.fluticasone, these drugs Dose adjustment of these medicinalmethylprednisolone products may be required.

Lipid Lowering Drugs

Lovastatin, simvastatin, Potential ↑in plasma concentrations of Contraindicated due to an increasedatorvastatin* these drugs risk of skeletal muscle toxicity,including rhabdomyolysis (seesection 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 Fesoterodine and solifenacin arecontraindicated in patients with renal

Solifenacin: impairment (see section 4.3).

AUC: ↑ 3.0-fold↑in plasma concentrations of tolterodinehave 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 ofsildenafil

Tolvaptan ↑in plasma concentrations of tolvaptan Contraindicated due to an increase inhave been observed the plasma concentrations (seesection 4.3).

Mizolastine Potential ↑in plasma concentrations of Contraindicated due to the potential

Halofantrine these drugs for serious cardiovascular eventsincluding QT prolongation (seesection 4.3).

Colchicine ↑in plasma concentrations of colchicine Not recommended due to a potentialhave been observed increase in colchicine-relatedtoxicity.

Contraindicated in patients with renalimpairment (see section 4.3).

Cinacalcet Cinacalcet Careful monitoring.

AUC: ↑ 2 fold Dose adjustment of cinacalcet may

Cmax: ↑ 2 fold be required.

Ebastine ↑in plasma concentrations of ebastine Not recommended due to anhave been observed increased risk in QT prolongation.

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

Exceptional cases of a disulfiram-like reaction have been reported when ketoconazole was co-administeredwith 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 steroidogenesisinhibitors (i.e. metyrapone).

There are no or limited amount of data from the use of Ketoconazole Esteve in pregnant women. Studies inanimal have shown reproductive toxicity (see section 5.3). Preclinical data show that ketoconazole crosses theplacenta and is teratogenic. Ketoconazole is contraindicated during pregnancy and it should not be used inwomen of childbearing potential not using an effective method of contraception (see section 4.3).

Since ketoconazole is excreted in the milk, mothers who are under treatment must not breast-feed whilst beingtreated with Ketoconazole Esteve (see section 4.3).

Studies in animals have shown effects on male and female reproductive parameters (see section 5.3).

Ketoconazole has a moderate influence on the ability to drive and use machines Patients should be warnedabout the potential for dizziness and somnolence (see section 4.8) and should be advised not to drive or operatemachines if any of these symptoms occur.

The most frequent adverse reactions are adrenal insufficiency, nausea, vomiting, abdominal pain, diarrhoea,pruritus, rash and the hepatic enzymes increased.

The most serious adverse reaction is hepatotoxicity, primarily as acute hepatocellular toxicity, but may alsoresult in cholestatic injury or a mixed pattern of toxicity. ASAT, ALAT, gammaGT, bilirubin and alkalinephosphatase should be monitored at frequent intervals during treatment (see sections 4.2 and 4.4).

The safety of ketoconazole has been evaluated based on published literature and use of ketoconazole as anantifungal treatment.

The adverse reactions listed below in table 2 are classified according to System Organ Class. Frequencygroupings are defined according to the following convention: very common (≥ 1/10), common (≥ 1/100 to <1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known:cannot be estimated from the available data.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 2: Incidence of adverse reactions and marked laboratory abnormalities reported in the literature inadults and adolescents patients

System organ class Frequency Adverse reaction

Blood and lymphatic Uncommon Thrombocytopeniasystem disorders

Immune system Uncommon Allergic conditions including anaphylacticdisorders shock, anaphylactoid reaction andanaphylactic reaction and angioedema

Endocrine disorders Common Adrenal insufficiency

Metabolism and Not known Alcohol intolerance, anorexia, increasednutrition disorders appetite

Psychiatric Not Known Insomnia, nervousnessdisorders

Nervous system Uncommon Headache, dizziness, somnolencedisorders

Not known Intracranial pressure increased(papilloedema, fontanelle bulging),paraesthesia

Eye disorders Not known Photophobia

Respiratory, Not known Epistaxisthoracic andmediastinaldisorders

Gastrointestinal Common Nausea, abdominal pain, vomiting,disorders diarrhoea

Not known Dyspepsia, flatulence, tongue discoloration,dry mouth, dysgeusia

Hepatobiliary Very common Liver function tests abnormaldisorders

Rare Serious hepatotoxicity, including jaundice,hepatitis, hepatic necrosis, hepatic cirrhosis,hepatic failure including cases necessitatingtransplantation or resulting in death.

Skin and Common Pruritus, rashsubcutaneous tissuedisorders

Uncommon Urticaria, alopecia

Not known Photosensitivity, erythema multiforme,dermatitis, erythema, , xeroderma

Musculoskeletal and Not known Myalgia, arthralgiaconnective tissuedisorder

Reproductive system Not known Menstrual disorder, azoospermia, erectileand breast disorders dysfunction, gynaecomastia

General disorders Uncommon Astheniaand administrationsite conditions

Very rare Pyrexia

Not known Oedema peripheral, malaise, hot flush

Investigations Very common Hepatic enzyme increased

Uncommon Platelet count decreased

Not known Transient decrease of testosteroneconcentrations

Serious hepatic toxicity caused by ketoconazole treatment is rare (1/15000). Acute hepatocellular injury hasbeen primarily observed as has cholestatic injury or a mixed pattern of toxicity. Fatal cases have been reportedparticularly when treatment is continued despite liver enzyme elevation. Increases in liver enzymes (≤ 5N and> 5N) were observed in ~13.5 % and ~2.5% of patients respectively occurring mostly within the first 6 monthsof treatment. Liver enzyme levels returned to normal within 2-12 weeks after a dose decrease or withdrawalof ketoconazole. Hepatotoxicity does not appear to be dose dependent. All potential associated factors ofhepatotoxicity, and abnormal liver enzyme levels detected before ketoconazole initiation, should be taken intoaccount before considering ketoconazole treatment. Ketoconazole should not be administered when liverenzymes are greater than 2 times the upper limit of normal or in association with other hepatotoxic medicinalproducts. Liver enzyme monitoring should be performed once weekly during the first month of treatment andthen monthly for 6 months. In the case an increase of liver enzymes is detected which is less than 3 times theupper limit of normal, closer monitoring of liver function should be performed and the daily dose should bedecreased by at least 200 mg. In the case of increase of liver enzymes levels above 3 times the upper limit ofnormal, Ketoconazole should be stopped immediately and should not be reintroduced because of the risk ofserious hepatic toxicity.

Adrenal insufficiency may occur in patients on ketoconazole without corticosteroid substitution (block-onlyregimen) or if there is an insufficient glucocorticoid replacement therapy (for the patients treated with a block-and-replace regimen). Monitor and instruct patients on the signs and symptoms associated withhypocortisolism (e.g. weakness, fatigue, anorexia, nausea, vomiting, hypotension, hyperkalemia,hyponatraemia, hyperkalaemia or hypoglycaemia). Adrenal insufficiency may be detected by periodic clinicalassessment and monitoring of plasma/serum or salivary cortisol levels. In case of adrenal insufficiency,

Ketoconazole Esteve treatment should be temporarily discontinued or the dose reduced and, if needed, acorticosteroid substitution therapy added.

Frequency of hepatotoxicity could be higher in adolescents than in adults. In the literature, among 24 paediatricpatients treated with ketoconazole, two developed severe hepatoxicity. A 14 year-old girl who was treated for

Cushing’s disease with ketoconazole 200 mg twice daily presented one month later with jaundice, feveranorexia, nausea and vomiting. Ketoconazole was stopped, but she deteriorated rapidly and died. A 17 yearsold girl was treated on ketoconazole 1,200 mg/day for an adrenal carcinoma with liver metastasis and hadaltered liver function tests at 22 days. After ketoconazole withdrawal, liver enzymes returned to normal levelswithin 3 weeks (section 5.1).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allowscontinued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are askedto report any suspected adverse reactions via the national reporting system listed in Appendix V.

There is no known antidote to ketoconazole. The maximal dose that was used for treatment of Cushing’ssyndrome is 1,600 mg/day.

In the event of accidental overdose, treatment consists of supportive measures. Within the first hour afteringestion gastric lavage may be performed. Activated charcoal may be given if considered appropriate.

In the case of signs suggestive of an adrenal insufficiency, in addition to the general measures to eliminate themedicinal product and reduce its absorption, a 100 mg dose of hydrocortisone should be administered at once,together with saline and glucose infusions. Close surveillance will be necessary: blood pressure and fluid andelectrolyte balance should be monitored for a few days.

Pharmacotherapeutic group: CORTICOSTEROIDS FOR SYSTEMIC USE, Anticorticosteroids, ATC code:

H02CA03

Ketoconazole is a steroidogenesis inhibitor. Ketoconazole is an imidazole derivative that is a potent inhibitorof cortisol synthesis resulting from its ability to inhibit several cytochrome P450 enzymes in the adrenal glands.

Ketoconazole inhibits primarily the activity of 17α-hydroxylase, but it also inhibits 11-hydroxylation steps,and at higher doses the cholesterol side-chain cleavage enzyme. Therefore, ketoconazole is an inhibitor ofcortisol and aldosterone synthesis. Ketoconazole is also a potent inhibitor of androgens synthesis, inhibitingthe activity of C17-20 lyase in the adrenals and also in Leydig cells.

Apart from adrenal blocking effect, ketoconazole may also have direct effects on corticotropic tumour cells inpatients with Cushing’s disease.

The efficacy and safety of ketoconazole in the treatment of Cushing’s syndrome from all causes have beendescribed through several published retrospective studies, chart reviews and case reports. Control of cortisollevels, either in serum/plasma or urine, was used to assess the efficacy of the treatment, along with theevaluation of clinical symptoms of Cushing’s syndrome. More than 800 patients have been treated withketoconazole with variable treatment duration and modalities. About 200 patients were treated for more than6 months and some of them were treated for several years.

Urinary free cortisol (UFC) levels were normalised in about 50% of patients on ketoconazole. Response ratesvaried between 43 and 80% depending on the studies and the criteria to define a response. About 75% ofpatients achieved a decrease of more than 50% of UFC levels on ketoconazole, compared to pre-treatmentlevels

Ketoconazole has been used both as sole medical therapy and in combination with other medicinal products,mainly with metyrapone, in patients with more severe disease or in those not completely responding to a singleactive substance or in those requiring a dose reduction of at least one of the medicinal products to improvetolerance. Ketoconazole has also been used with other therapies including surgery and pituitary radiation.

Overall, ketoconazole was shown to be an effective medicinal product for normalising cortisol levels in allcauses of Cushing’s syndrome and, if tolerated, ketoconazole treatment can be maintained for a long period.

Escape phenomenon

In approximately 10 to 15 % of ketoconazole treated patients, an 'escape phenomenon' is observed andreinforces the need for a long-term clinical and biochemical follow-up of these patients. If such a phenomenonoccurs, a further dose increase may be required to maintain cortisol levels within the normal range.

Use in Cushing’s disease

Data from 535 patients with Cushing’s disease treated with ketoconazole, along with 13 individual case reportsare available in the literature. In a retrospective study conducted in several French centres, 200 patients with

Cushing’s disease were followed between 1995 and 2012. At the last visit, 78 patients (49.3%) were controlled,37 patients (23.4%) had partial control with at least 50% decrease of UFC (without normalisation), and 43patients (27.2%) had unchanged UFC levels. At the last follow-up, clinical signs were improved in 74/134patients (55.2%), hypertension in 36/90 patients (40), hypokalaemia in 10/26 patients (38.4%), and diabetesmellitus in 23/39 patients (59%).

Use in ectopic Adrenocorticotropic Hormone (ACTH) syndrome

Data from 91 patients with the ectopic ACTH syndrome treated with ketoconazole were reviewed, along with18 individual case reports. In a Canadian study, of the 12 assessable patients (out of 15), 10 showed a reductionin urinary free cortisol levels, but only five had complete resolution on ketoconazole doses 400 to 1200 mg/day.

Clinical improvement in hypokalaemia, metabolic alkalosis, diabetes mellitus, and hypertension occurred evenin the absence of complete hormonal response.

Use in ACTH-independent Cushing’s syndrome

Data from 17 patients with adrenal tumours and from 2 patients with primary nodular adrenocorticalhyperplasia (NAH) treated with ketoconazole are available in the literature along with 17 individual casereports of patients with benign or malignant tumours or NAH and 2 paediatric cases of McCune Albrightsyndrome. Improvement of clinical symptoms was noted in most patients after initiation of treatment. Howeverin patients with adrenal cortical carcinoma, improvement of hypercortisolism on ketoconazole was limited insome cases.

Data on 24 paediatric patients with endogenous Cushing’s syndrome treated with ketoconazole are availablein the literature, among which 16 were aged over 12 years old and 8 were aged less than 12 years old.

Treatment with ketoconazole in paediatric patients allowed normalisation of urinary free cortisol levels andclinical improvement, including recovering of growth rate and gonadal function, normalisation of bloodpressure, Cushing’s syndrome features and weight loss in most of the cases. The doses used in adolescentsabove 12 years old were similar to the doses used in adults’ patients with endogenous Cushing’s syndrome.

Ketoconazole is a weak dibasic active substance and thus requires acidity for dissolution and absorption. Meanpeak plasma concentrations of approximately 3.5 μg/ml are reached within 1 to 2 hours, following oraladministration of a single 200 mg dose taken with a meal.

Cmax and AUC increase more than proportionally with dose. At steady state, mean peak concentrations of1.7µg/mL to 15.6µg/mL were reported for total daily doses of 200 mg to 1,200 mg.

In vitro, the plasma protein binding is about 99% mainly to the albumin fraction. Ketoconazole is widelydistributed into tissues; however, only a negligible proportion of ketoconazole reaches the cerebral-spinal fluid.

Ketoconazole is extensively metabolised to a large number of inactive metabolites. In vitro studies have shownthat CYP3A4 is the major enzyme involved in the metabolism of ketoconazole.

The major identified metabolic pathways are oxidation and degradation of the imidazole and piperazine rings,oxidative O-dealkylation and aromatic hydroxylation.

Ketoconazole is a potent inhibitor of CYP3A4 and P-gp. Ketoconazole has not been demonstrated to induceits own metabolism.

Plasma elimination is biphasic with a half-life of 2 hours during the first 10 hours and 8 hours thereafter. Thehalf-life of ketoconazole increases with dose and duration of treatment. At doses > 400 mg/day, half-lives of3 to 10 hours have been reported. About 13% of the dose is excreted in the urine, of which 2 to 4% is unchangedmedicinal product. The major route of excretion is through the bile into the intestinal tract.

Special population

Paediatrics

Based on limited data, pharmacokinetics parameters (AUC, Cmax and half-life) of ketoconazole for doses of 5to 10 mg/kg/days, corresponding approximately to daily doses of 200-800 mg, are similar in paediatric andadult population.

The pharmacokinetics of ketoconazole were not significantly different in patients with renal failure comparedto healthy subjects.

No formal evaluation of the effect of age on the pharmacokinetics of ketoconazole has been performed. Thereare no data suggesting a need for a specific dose adjustment in this population.

In vitro data indicate that ketoconazole is a potent inhibitor of OATP1B1, OATP1B3, OAT3, OCT1 and OCT2and to a lesser extent of OAT1 and BSEP. Inhibition of these different transporters at clinically relevantconcentrations of ketoconazole cannot be excluded.

The toxicological profile of ketoconazole has been established from long term studies in rats and dogs.

Bone fragility and broken legs were reported in rats but were not observed in other species.

Consistent with the pharmacological action of ketaconazole, effects were observed on adrenal and gonads inrats and dogs.

Elevated liver enzymes and histological changes in the liver consisting in dose-related lipofuscin accumulationin hepatocytes were reported in rats and dogs after repeated administration of ketoconazole.

Electrophysiological studies have shown that ketoconazole inhibits the rapidly activating component of thecardiac delayed rectifier potassium current, prolongs the action potential duration, and may prolong the QTinterval. However no modifications of ECG were recorded in dogs at daily doses up to 40 mg/kg administeredfor 12 months.

Ketoconazole was not genotoxic in vitro and in vivo. However, the genotoxic potential was not properlydetermined for the proposed dosing regimen in the treatment of endogenous Cushing’s syndrome.

Ketoconazole is not carcinogenic.

In reproduction studies, ketoconazole impaired fertility in males and females. Doses of 25 mg/kg and higherin male rats and dogs produced sperm abnormalities and decreased fertility in rats. Ketoconazole at doses upto 40 mg/kg had no effects on female fertility in the rat, whilst doses of 75 mg/kg and higher decreased thepregnancy rate and the number of implantation sites. Doses of 80 and 160 mg/kg inhibited ovulation inimmature rats. Ketoconazole at doses of 40 mg/kg/day and higher produces evidence of embryotoxicity andteratogenicity in rats and rabbits. Observed teratogenic effects were mainly skeletal anomalies, including cleftpalate, brachydactylia, ectrodactylia and syndactylia. Treatment of juvenile rats for 30 day beginning at 21days of age delayed the puberty onset. Effects on human reproduction cannot be excluded.

Studies in pregnant rats and in guinea pigs with 3H-ketoconazole indicate that ketoconazole crosses theplacenta.

Maize starch

Lactose monohydrate

Povidone

Microcrystalline cellulose

Silica colloidal

Magnesium stearate

Not applicable.

3 years

This medicinal product does not require any special storage conditions.

PVC/Alu blister of 10 tablets

Pack sizes containing 60 tablets (6 blisters of 10 tablets).

No special requirements for disposal.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Esteve Pharmaceuticals S.A.

Passeig de La Zona Franca 109 Planta 408038 Barcelona

Spain

EU/1/14/965/001

Date of first authorisation: 19 November 2014

Date of latest renewal: 31 July 2019

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.