Ketoconazole HRA
1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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This medicinal product is subject to additional monitoring. This will allow quick identification of new 
safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 
4.8 for how to report adverse reactions. 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Ketoconazole HRA 200 mg tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each tablet contains 200 mg ketoconazole. 
 
Excipient with known effect:  
Each tablet contains 19 mg of lactose (as monohydrate). 
 

For the full list of excipients, see section 6.1. 

 
 
3. PHARMACEUTICAL FORM 
 
Tablet. 
 
Off-white to light cream, round, 10 mm diameter, biconvex. 

 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Ketoconazole HRA is indicated for the treatment of endogenous Cushing’s syndrome in adults and adolescents 
above the age of 12 years. 
 
4.2 Posology and method of administration 
 
Treatment should be initiated and supervised by physicians experienced in endocrinology or internal medicine 
and having the appropriate facilities for monitoring of biochemical responses since the dose must be adjusted 
to meet the patient’s therapeutic need, based on the normalisation of cortisol levels. 
 
Posology 
 
Initiation 
The recommended dose at initiation in adults and adolescents is 400-600 mg/day taken orally in two or three 
divided 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 normalise 
urinary 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/or 
plasma cortisol levels are above the normal range, as long as the dose is tolerated by the patient; 



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

- When the effective dose of ketoconazole  is established, monitoring of urinary free cortisol and/or 
plasma 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 of 
ketoconazole should be decreased by at least 200 mg/day or the treatment should be temporarily 
discontinued 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 decrease 
where a change in the therapeutic strategy (e.g. surgery) is desired.  
 

Monitoring of liver function 
 
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 their 

doctor 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 immediately 
and liver function tests should be performed. 

 
Due to the known hepatotoxicity of ketoconazole, the treatment must not be initiated in patients with liver 
enzymes 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, should 

be performed at frequent intervals:  
 

o weekly for one month after initiation of the treatment 
o then monthly for 6 months 
o 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 frequent 
monitoring of liver function tests should be performed and the daily dose should be decreased by at least 
200 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 hepatic 
toxicity. 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 a 
dose increase after the first six months of treatment, monitoring of liver enzymes should be repeated on a 
weekly 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 by 

200 mg and concomitant corticosteroid replacement therapy should be added (see section 4.4). 
 
Special populations 
 
Elderly patients  



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Data on the use of ketoconazole in patients older than 65 years are limited, but there is no evidence to suggest 
that specific dose adjustment is required in these patients (see section 5.2). 
 
Renal impairment  
Although data are limited, the pharmacokinetics of ketoconazole are not significantly different in patients with 
renal failure compared to healthy subjects, and no specific dose adjustment is recommended in this population.  
 
Hepatic impairment  
Ketoconazole is contraindicated in patients with acute or chronic hepatic impairment (see sections 4.3, 4.4 and 
5.3). The treatment must not be initiated in patients with liver enzymes levels above 2 times the upper 
limit of normal 
 
Paediatric population 
The safety and efficacy of Ketoconazole HRA 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 can 
be made. 
 
Method of administration 
 
Oral use.  
 
4.3 Contraindications 
 
- 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 upper 

limit 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 in 

potentially life-threatening adverse reactions (see section 4.5): 

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 (eg 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; 



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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. 
 
4.4 Special warnings and precautions for use 
 
Monitoring of liver function 
 
Liver enzymes should be monitored in all patients receiving ketoconazole. Due to the risk of serious hepatic 
toxicity, 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 the 
treatment under conditions of a relative cortisol deficiency due to an increased glucocorticoid demand (e.g. in 
case of stress, surgery, or infection); and/or in case of ketoconazole overtreatment (for the patients treated with 
a block-only regimen); or if there is insufficient glucocorticoid replacement therapy (for the patients treated 
with a block-and-replace regimen). Serum or plasma and/or salivary cortisol and/or urinary free cortisol levels 
should be monitored, within one week following ketoconazole initiation as a minimum, and then periodically 
thereafter. When urinary free/serum/ plasma cortisol levels are normalised or close to target and the effective 
dose of ketoconazole is established, monitoring can be undertaken every 3 to 6 months (see section 4.2 for 
dose 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, hyperkalaemia 
and/or hypoglycaemia). 
 
If clinical symptoms are suggestive of adrenal insufficiency, cortisol levels should be measured and 
ketoconazole should be temporarily discontinued or the dose reduced and if necessary corticosteroid 
substitution 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 replacement 
therapy dose under conditions of stress (see section 4.2). In addition, they should receive an emergency card 
and 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. 



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In case of co-administration of an medicinal product known to increase QTc interval (see section 4.5), ECG 
monitoring is recommended. 
 
Contraception 
 
Women must be provided with comprehensive information on pregnancy prevention. As a minimum 
requirement, 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. aluminium 
hydroxide) should not be administered for at least 2 hours after the intake of ketoconazole. In patients with 
achlorhydria, 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 then 
ketoconazole 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 should 
be 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 section 
4.5). 

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 not 
recommended depending on the observed or expected effect with ketoconazole (i.e. resulting in augmentation 
of the plasma concentration, AUC, Cmax of the drugs) and the known therapeutic margins of the drugs. Some 
combinations may lead to an increased risk of ventricular tachyarrhythmias, including occurrences of torsade 
de 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 QT 
prolongation 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’s 
syndrome remission, including after treatment with ketoconazole. Patients with Cushing's syndrome and 
coexisting inflammatory/autoimmune disorders should be supervised after normalisation of cortisol levels on 
ketoconazole. 
 



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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 congenital lactase deficiency, galactosaemia or glucose-galactose intolerance must not be given 
this medicine unless strictly necessary. 
 
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 (eg dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine 
(methylergonovine) due to an increased risk of ergotism and other serious vasospastic adverse 
reactionsevents 
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.  



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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 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 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 
therapeutic area 

Expected effect on drug levels Recommendation for co-
administration 

Analgesic opioid   
Methadone  
 

Potential ↑ in plasma concentrations of 
methadone  

Contraindicated due to the increased 
risk of serious cardiovascular events 
including QT prolongation and 
torsade de pointes, or respiratory or 
CNS depression (see section 4.3). 

Buprenorphine IV and 
sublingual 

Buprenorphine: 
AUC: ↑ 1.5-fold 
Cmax: ↑1.7-fold 

Careful monitoring. 
The buprenorphine dose should be 
adjusted. 

Alfentanil, fentanyl 
 

Potential ↑in plasma concentrations of 
alfentanil and fentanyl  

Careful monitoring of adverse 
reactions (respiratory depression, 
sedation) is recommended. It may be 
necessary to lower the dose of 
alfentanil and fentanyl. 

Oxycodone 
 

↑in plasma concentrations of oxycodone 
have been observed 
 

Careful monitoring. 
The oxycodone dose may be 
adjusted. 

Antiarrhythmics   
Disopyramide  
Quinidine 
 
Dronedarone 
 
 

Potential ↑in plasma concentrations of 
disopyramide and quinidine  
 
Repeated doses of 200 mg ketoconazole 
daily resulted in a 17-fold increase in 
dronedarone exposure 

Contraindicated due to the risk of 
serious cardiovascular events 
including QT prolongation (see 
section 4.3).  



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Medicinal product by 
therapeutic area 

Expected effect on drug levels Recommendation for co-
administration 

Digoxin 
 

Potential ↑in plasma concentrations of 
digoxine 

Careful monitoring of digoxin levels 
is recommended.  

Anticoagulants and 
antiplatelet drugs 

  

Dabigatran 
 

Dabigatran: 
AUC: ↑ 2.6-fold  
Cmax: ↑2.5-fold 

Contraindicated due to an increased 
bleeding risk (see section 4.3). 

Rivaroxaban 
 

Rivaroxaban: 
AUC: ↑ 2.6-fold 
Cmax: ↑1.7-fold 

Not recommended due to an 
increased bleeding risk. 

Apixaban Apixaban 
AUC: ↑ 2-fold  
Cmax: ↑1.6-fold 

Not recommended due to an 
increased bleeding risk. 

Cilostazol 
 

Cilostazol: 
AUC: ↑ 2.2 fold  
 
The overall pharmacological activity of 
cilostazol increases 35% when co-
administered with ketoconazole. 

Careful monitoring 
A cilostazol dose of 50 mg twice 
daily is recommended in combination 
with ketoconazole. 

Warfarin and other 
coumarin-like drugs 

Potential ↑in plasma concentrations of 
warfarin  

Careful monitoring 
INR (international normalised ratio) 
monitoring recommended.  

Edoxaban AUC: ↑ 1.8-fold  
Cmax: ↑ 1.8-fold 

Dose of edoxaban needs to be 
reduced when used concomitantly, 
please consult edoxaban SmPC. 

Anticonvulsants   
Carbamazepine 
Phenytoin 
 

Potential ↑in plasma concentrations of 
carbamazepine and phenytoin 
 
Potential ↓ in plasma concentrations of 
ketoconazole are expected. 
(CYP3A enzyme induction) 

Not recommended. 
(See also “Effects of other medicinal 
products on the metabolism of 
Ketoconazole HRA ”). 

Antidiabetics   
Repaglinide 
 

Repaglinide: 
AUC: ↑ 1.2-fold 
Cmax: ↑ 1.2-fold  

Careful monitoring. 
Dose adjustement of repaglinide may 
be required. 

Saxagliptin Saxagliptin: 
AUC: ↑ 2.5-fold 
Cmax: ↑ 1.6-fold  
Associated with a decrease in 
corresponding values for the active 
metabolite 

Careful monitoring. 
Dose adjustment of saxagliptin may 
be required. 
 

Tolbutamide Tolbutamide: 
AUC: ↑ 1.7-fold 

Careful monitoring. 
Dose adjustment of tolbutamide may 
be required. 

Anti-infectives   
Rifabutin 
Rifampicin 
Isoniazid  

Potential ↑ in plasma concentrations of 
rifabutine. 
Potencial ↓ in plasma concentrations of 
ketoconazole are expected. 
(CYP3A4 enzyme induction) 

Not recommended. (See also “Effects 
of other medicinal products on the 
metabolism of Ketoconazole HRA ”) 



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Medicinal product by 
therapeutic area 

Expected effect on drug levels Recommendation for co-
administration 

Telithromycin 
Clarithromycin 
 
 

Telithromycine: 
AUC: ↑ 2-fold 
Cmax: ↑1.5-fold 
Potential ↑in plasma concentrations of 
clarithromycin 
 

Not recommended. 
Contraindicated in patients with 
severe renal impairment due to the 
risk of QT interval prolongation and 
serious hepatic adverse reactions (see 
section 4.3). 

Isavuconazole AUC: ↑ 5-fold  
Cmax: ↑ 1.1 -fold 

Not recommended due to increased 
risk of isavuconazole adverse 
reactions, please consult 
isavuconazole SmPC 

Praziquantel 
 

↑in plasma concentrations of 
praziquantel have been observed 

Careful monitoring. 
Dose adjustment of praziquantel 
may be required.  

Antimigraine Drugs   
Ergots alkaloids such as 
dihydroergotamine, 
ergometrine 
(ergonovine), 
ergotamine, 
methylergometrine 
(methylergonovine) 

Potential ↑in plasma concentrations of 
ergot alkaloids 

Contraindicated due to the increased 
risk of ergotism and other serious 
vasospastic adverse reactions (see 
section 4.3). 

Eletriptan 
 

Eletriptan: 
AUC: ↑ 5.9-fold 
Cmax: ↑ 2.7-fold 

Not recommended. 
 

Antineoplastics   
Irinotecan  
 

Irinotecan: 
AUC: ↑ 2.1-fold  

Contraindicated due to an alteration 
of the metabolism of this medicinal 
product (see section 4.3). 

Sunitinib 
Dasatinib 
Lapatinib 
Nilotinib 
Erlotinib 
Dabrafenib 
Cabozantinib 
 
 
 

Sunitinib 
AUC: ↑ 1.5-fold  
Cmax: ↑ 1.5-fold 
Lapatinib: 
AUC: ↑ 3.6-fold 
Nilotinib: 
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: ↔ 

Not recommended due to the risk of 
increased exposure to these medicinal 
products and QT prolongation. 

Ibrutinib Ibrutinib:  
AUC: ↑ 24-fold  
Cmax: ↑ 29-fold  

Not recommended as it may increase 
ibrutinib-related toxicity.  
 



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Medicinal product by 
therapeutic area 

Expected effect on drug levels Recommendation for co-
administration 

Crizotinib Crizotinib  
AUC: ↑ 3.2-fold  
Cmax: ↑ 1.4-fold  

Not recommended due to the risk of 
QT interval prolongation and serious 
hepatic adverse reactions. 
 
Monitoring of QT-prolongation if 
used concomitantly.  

Bortezomib 
Busulfan 
Docetaxel 
Imatinib 
Cabazitaxel 
 

Bortezomib: 
AUC: ↑ 1.4-fold 
Imatinib: 
AUC: ↑ 1.4-fold 
Cmax: ↑ 1.3-fold 
↑in plasma concentrations of 
docetaxel have been observed 
Potential ↑in plasma concentrations of 
busulfan 
Cabazitaxel 
AUC: ↑ 1.3-fold 

Careful monitoring. 
Dose adjustment of each medicinal 
product may be required. 
 

Paclitaxel  
 

Paclitaxel: 
No change in plasma concentration were 
shown with paclitaxel concentrate. No 
studies were performed with albumin 
bound nanoparticules. 

Careful monitoring. 
Dose adjustment of paclitaxel  
may be required. 
 

Vincristine, vinblastine 
(vinca alkaloids) 

Potential ↑in plasma concentrations of 
vinca alkaloids. 

Careful monitoring as it may cause 
an earlier onset and/or an increased 
severity of side-effects. 

Antipsychotics, 
Anxiolytics and 
Hypnotics 

  

Triazolam 
Alprazolam 
Midazolam oral 

AUC: ↑ have been observed 
Cmax: ↑ have been observed 

Contraindicated due to the risk of 
potentially prolonged or increased 
sedation and respiratory depression 
(see section 4.3). 

Lurasidone 
 

Lurasidone: 
AUC: ↑ 9 fold 
Cmax: ↑ 6 fold 

Contraindicated due to the increased 
risk of adverse reactions (see section 
4.3). 

Pimozide 
 

Potential ↑in plasma concentrations of 
pimozide.  

Contraindicated due to the risk of 
serious cardiovascular events 
including QT prolongation (see 
section 4.3). 

Sertindole 
 

Potential ↑in plasma concentrations of 
sertindole.  

Contraindicated due to the risk of QT 
prolongation (see section 4.3). 

Quetiapine 
 

Quetiapine: 
AUC: ↑ 6.2-fold  
Cmax: ↑ 3.4-fold  

Contraindicated as it may increase 
quetiapine-related toxicity (see 
section 4.3). 

Haloperidol  Potential ↑in plasma concentrations of 
haloperidol. 
 

Not recommended due to the 
increased risk of QT prolongation 
and extrapyramidal symptoms. It 
may be necessary to reduce 
haloperidol dosage. 

Reboxetine 
 

Reboxetine: 
AUC: ↑ 1.5-fold of both enantiomers 

Not recommended because of 
reboxetine narrow’s therapeutic 
margin. 

Midazolam IV 
 

Midazolam: 
AUC: ↑ 1.6-fold 
 

Careful monitoring. 
Dose adjustment of midazolam IV 
may be required. 



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Medicinal product by 
therapeutic area 

Expected effect on drug levels Recommendation for co-
administration 

Buspirone 
 

Potential ↑in plasma concentrations of 
buspirone. 

Careful monitoring. 
Dose adjustement of buspirone 
may be required. 

Aripiprazole Aripiprazole 
AUC: ↑ 1.6-fold  
Cmax: ↑ 1.4-fold  

Careful monitoring. 
Aripiprazole dose should be reduced 
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/ritonavir 
1000/100 mg bid) 
 

Saquinavir:  
AUC: ↔  
Cmax: ↔ 
Ketoconazole 
AUC: ↑ 2.7-fold  
Cmax:↑ 1.5-fold  
(CYP3A4 enzyme inhibition by 
ritonavir) 

Contraindicated due to the risk of QT 
prolongation (see section 4.3). 

Paritaprevir/Ombitasvir 
(ritonavir) 

Paritaprevir: 
AUC: ↑2.2-fold 
Cmax: ↑1.7-fold 
 
Ombitasvir: 
AUC: ↑1.3-fold 
Cmax: ↔ 
 
Ketoconazole: 
AUC: ↑2.1-fold 
Cmax: ↑1.1-fold 
t1/2: ↑ 4-fold 
 

Contraindicated due to the increased 
risk of adverse reactions (see section 
4.3). 

Nevirapine 
 

Ketoconazole:  
AUC: ↓0.28-fold 
Cmax: ↓0.56-fold 
Nevirapine: plasma levels: ↑1.15-1.28-
fold compared to historical controls 
 
(CYP3A enzyme induction) 

Not recommended  

Maraviroc 
 

Maraviroc: 
AUC: ↑ 5-fold 
Cmax: ↑ 3.4-fold 

Careful monitoring. Maraviroc dose 
should be decreased to 150 mg twice 
daily. 

Indinavir 
 

Indinavir (600mg TID): 
AUC= 0.8-fold  
Cmin: ↑ 1.3-fold  
(Relative to Indinavir 800 mg TID alone)  

Careful monitoring. Dose reduction 
of indinavir to 600 mg every 8 hours 
should be considered.  

Ritonavir 

Ketoconazole:  
AUC: ↑3.4-fold 
Cmax: ↑1.6-fold 
 
(CYP3A enzyme inhibition) 

A dose reduction of ketoconazole 
should be considered when co-
administered with ritonavir dosed as 
an antiretroviral medicinal product or 
as a pharmacokinetic enhancer. (See 
also “Effects of other medicinal 
products on the metabolism of 
ketoconazole HRA ”). 



13 

Medicinal product by 
therapeutic area 

Expected effect on drug levels Recommendation for co-
administration 

Beta Blockers   
Nadolol 
 

↑in plasma concentrations of nadolol 
have been observed 

Careful monitoring. Dose adjustment 
of nadolol may be required. 

Calcium Channel 
Blockers 

  

Felodipine 
Nisoldipine 
 

AUC: ↑ has been observed  
Cmax: ↑ has been observed  
 

Contraindicated due to an increase 
risk of edema and congestive heart 
failure (see section 4.3). 

Other dihydropyridines 
Verapamil 

Potential ↑in plasma concentrations of 
these drugs 

Careful monitoring. Dose adjustment 
of dihydropyridines and verapamil 
may be required. 

Cardiovascular Drugs, 
Miscellaneous 

  

Ranolazine 
 

Ranolazine: 
AUC: ↑ 3.0 to 3.9-fold 

Contraindicated due to the potential 
for serious cardiovascular events 
including QT prolongation (see 
section 4.3). 

Bosentan 
 

Bosentan: 
AUC: ↑ 2-fold 
Cmax: ↑ 2-fold 

Not recommended due to the 
potential for hepatic toxicity (see 
section 4.3). 

Aliskiren 
 

Aliskiren: 
AUC: ↑ 1.8-fold  
 

Careful monitoring. 
Dose adjustment of aliskiren may be 
required. 

Diuretics   
Eplerenone 
 

Eplerenone: 
AUC: ↑ 5.5-fold  

Contraindicated due to the increased 
risk of hyperkalaemia and 
hypotension (see section 4.3). 

Gastrointestinal Drugs   
Aprepitant 
 

Aprepitant: 
AUC: ↑ 5-fold 

Careful monitoring. 
Dose adjustment of aprepitant 
may be required  

Domperidone 
 

Domperidone: 
AUC: ↑ 3.0 fold 
Cmax: ↑ 3.0 fold 

Not recommended due to an 
increased risk in QT prolongation. 

Naloxegol Naloxegol  
AUC ↑ 12.9 fold  
Cmax ↑ 9.6 fold 

Not recommended 

Immunosuppressants   
Everolimus 
Sirolimus (rapamycin)  
 

Everolimus: 
AUC: ↑ 15.3-fold  
Cmax: ↑ 4.1-fold  
Sirolimus (rapamycin): 
AUC: ↑ 10.9-fold 
Cmax: ↑ 4.4-fold 

Contraindicated due to the large 
increase in these medicinal products 
concentrations (see section 4.3). 

Temsirolimus 
 
 
Tacrolimus 
Ciclosporine 
Budesonide 
Ciclesonide  

Temsirolimus: 
AUC: ↔ 
Cmax: ↔ 
Ciclesonide active metabolite:  
AUC: ↑ 3.5-fold 
 
Rest of drugs 
↑in plasma concentrations of 
these drugs have been observed 

Not recommended unless necessary. 
Careful monitoring and dose 
adjustment of these medicinal 
products may be required. 



14 

Medicinal product by 
therapeutic area 

Expected effect on drug levels Recommendation for co-
administration 

Dexamethasone, 
fluticasone, 
methylprednisolone 

Potential ↑in plasma concentrations of 
these drugs 
 

Careful monitoring. 
Dose adjustment of these medicinal 
products may be required. 

Lipid Lowering Drugs   
Lovastatin, simvastatin, 
atorvastatin* 
 

Potential ↑in plasma concentrations of 
these drugs 
 

Contraindicated due to an increased 
risk of skeletal muscle toxicity, 
including rhabdomyolysis (see 
section 4.3). 

Respiratory Drugs    
Salmeterol  Salmeterol  

AUC: ↑ 15-fold 
Cmax: ↑ 1.4-fold 

Not recommended due to an 
increased risk in QT prolongation. 

Urological Drugs   
Fesoterodine 
Tolterodine 
Solifenacin 
 

Fesoterodine active metabolite: 
AUC: ↑ 2.3-fold 
Cmax: ↑ 2.0-fold  
 
Solifenacin: 
AUC: ↑ 3.0-fold 
 
↑in plasma concentrations of tolterodine 
have been observed 

Not recommended due to an 
increased risk of QT prolongation. 
Fesoterodine and solifenacin are 
contraindicated in patients with renal 
impairment (see section 4.3). 

Phosphodiesterase(PD
E5) inhibitors  

  

Sildenafil 
Tadalafil 
Vardenafil  

Tadalafil: 
AUC: ↑ 4-fold 
Cmax: ↑ 1.2-fold 
 
Vardenafil: 
AUC: ↑ 10-fold 
Cmax: ↑ 4-fold 
 
Potential ↑in plasma concentrations of 
sildenafil 

Not recommended due to the 
increased risk of adverse reactions. 
 
Vardenafil is contraindicated in men 
older than 75 years old (see section 
4.3). 

Other   
Tolvaptan  
 

↑in plasma concentrations of tolvaptan 
have been observed  

Contraindicated due to an increase in 
the plasma concentrations (see 
section 4.3). 

Mizolastine 
Halofantrine 

Potential ↑in plasma concentrations of 
these drugs 

Contraindicated due to the potential 
for serious cardiovascular events 
including QT prolongation (see 
section 4.3). 

Colchicine  
  

↑in plasma concentrations of colchicine 
have been observed 
 

Not recommended due to a potential 
increase in colchicine-related 
toxicity. 
Contraindicated in patients with renal 
impairment (see section 4.3). 

Cinacalcet  
 

Cinacalcet  
AUC: ↑ 2 fold 
Cmax: ↑ 2 fold 

Careful monitoring. 
Dose adjustment of cinacalcet may 
be required. 

Ebastine 
 

↑in plasma concentrations of ebastine 
have been observed 

Not recommended due to an 
increased risk in QT prolongation. 

 



15 

* 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). 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
There are no or limited amount of data from the use of Ketoconazole HRA in pregnant women. Studies in 
animal have shown reproductive toxicity (see section 5.3). Preclinical data show that ketoconazole crosses the 
placenta and is teratogenic. Ketoconazole is contraindicated during pregnancy and it should not be used in 
women of childbearing potential not using an effective method of contraception (see section 4.3). 
 
Breast-feeding 
 
Since ketoconazole is excreted in the milk, mothers who are under treatment must not breast-feed whilst being 
treated with Ketoconazole HRA (see section 4.3). 
 
Fertility 
 
Studies in animals have shown effects on male and female reproductive parameters (see section 5.3). 
 
4.7 Effects on ability to drive and use machines 
 
Ketoconazole has a moderate influence in the ability to drive and use machines Patients should be warned 
about the potential for dizziness and somnolence (see section 4.8) and should be advised not to drive or operate 
machines if any of these symptoms occur. 
 
4.8 Undesirable effects 
 
Summary of the safety profile  
 
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 also 
result in cholestatic injury or a mixed pattern of toxicity. ASAT, ALAT, gammaGT, bilirubin and alkaline 
phosphatase should be monitored at frequent intervals during treatment (see sections 4.2 and 4.4). 
 
Tabulated list of adverse reactions  
 
The safety of ketoconazole has been evaluated based on published literature and use of ketoconazole as an 
antifungal treatment. 
 



16 

The adverse reactions listed below in table 2 are classified according to System Organ Class. Frequency 
groupings 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 in 
adults and adolescents patients 
 

System organ class Frequency Adverse reaction 
Blood and lymphatic 
system disorders 

Uncommon Thrombocytopenia 

Immune system 
disorders 

Uncommon Allergic conditions including anaphylactic 
shock, anaphylactoid reaction and 
anaphylactic reaction and angioedema 

Endocrine disorders Common Adrenal insufficiency 
Metabolism and 
nutrition disorders 

Not known 
 

Alcohol intolerance, anorexia, increased 
appetite 

Psychiatric 
disorders 

Not Known Insomnia, nervousness 

Nervous system 
disorders 

Uncommon Headache, dizziness, somnolence 

 Not known 
 

Intracranial pressure increased 
(papilloedema, fontanelle bulging), 
paraesthesia 

Eye disorders Not known Photophobia 
Respiratory, 
thoracic and 
mediastinal 
disorders 

Not known Epistaxis 

Gastrointestinal 
disorders  

Common Nausea, abdominal pain, vomiting, 
diarrhoea 

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

Hepatobiliary 
disorders 

Very common Liver function tests abnormal 

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

Skin and 
subcutaneous tissue 
disorders 

Common Pruritus, rash 

 Uncommon Urticaria, alopecia 
 Not known Photosensitivity, erythema multiforme, 

dermatitis, erythema, , xeroderma 
Musculoskeletal and 
connective tissue 
disorder 

Not known 
 

Myalgia, arthralgia 

Reproductive system 
and breast disorders    

Not known 
 

Menstrual disorder, azoospermia, erectile 
dysfunction, gynaecomastia 



17 

General disorders 
and administration 
site conditions 

Uncommon Asthenia 

 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 testosterone 

concentrations 
 
Description of selected adverse reactions 
 
Hepatotoxicity 
Serious hepatic toxicity caused by ketoconazole treatment is rare (1/15000). Acute hepatocellular injury has 
been primarily observed as has cholestatic injury or a mixed pattern of toxicity. Fatal cases have been reported 
particularly 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 months 
of treatment. Liver enzyme levels returned to normal within 2-12 weeks after a dose decrease or withdrawal 
of ketoconazole. Hepatotoxicity does not appear to be dose dependent. All potential associated factors of 
hepatotoxicity, and abnormal liver enzyme levels detected before ketoconazole initiation, should be taken into 
account before considering ketoconazole treatment. Ketoconazole should not be administered when liver 
enzymes are greater than 2 times the upper limit of normal or in association with other hepatotoxic medicinal 
products. Liver enzyme monitoring should be performed once weekly during the first month of treatment and 
then monthly for 6 months. In the case an increase of liver enzymes is detected which is less than 3 times the 
upper limit of normal, closer monitoring of liver function should be performed and the daily dose should be 
decreased by at least 200 mg. In the case of increase of liver enzymes levels above 3 times the upper limit of 
normal, Ketoconazole should be stopped immediately and should not be reintroduced because of the risk of 
serious hepatic toxicity. 
 
Adrenal insufficiency 
Adrenal insufficiency may occur in patients on ketoconazole without corticosteroid substitution (block-only 
regimen) 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 with 
hypocortisolism (e.g. weakness, fatigue, anorexia, nausea, vomiting, hypotension, hyperkalemia, 
hyponatraemia, hyperkalaemia or hypoglycaemia). Adrenal insufficiency may be detected by periodic clinical 
assessment and monitoring of plasma/serum or salivary cortisol levels. In case of adrenal insufficiency, 
Ketoconazole HRA treatment should be temporarily discontinued or the dose reduced and, if needed, a 
corticosteroid substitution therapy added.  
 
Paediatric population 
Frequency of hepatotoxicity could be higher in adolescents than in adults. In the literature, among 24 paediatric 
patients 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, fever 
anorexia, nausea and vomiting. Ketoconazole was stopped, but she deteriorated rapidly and died. A 17 years 
old girl was treated on ketoconazole 1,200 mg/day for an adrenal carcinoma with liver metastasis and had 
altered liver function tests at 22 days. After ketoconazole withdrawal, liver enzymes returned to normal levels 
within 3 weeks (section 5.1). 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows 
continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked 
to report any suspected adverse reactions via the national reporting system listed in Appendix V. 
 



18 

4.9. Overdose 
 
There is no known antidote to ketoconazole. The maximal dose that was used for treatment of Cushing’s 
syndrome is 1,600 mg/day. 
In the event of accidental overdose, treatment consists of supportive measures. Within the first hour after 
ingestion 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 the 
medicinal 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 and 
electrolyte balance should be monitored for a few days. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antimycotics for systemic use, imidazole derivatives, ATC code: J02AB02 
 
Mechanism of action 
 
Ketoconazole is a steroidogenesis inhibitor. Ketoconazole is an imidazole derivative that is a potent inhibitor 
of 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 of 
cortisol and aldosterone synthesis. Ketoconazole is also a potent inhibitor of androgens synthesis, inhibiting 
the 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 in 
patients with Cushing’s disease. 
 
Clinical efficacy 
 
The efficacy and safety of ketoconazole in the treatment of Cushing’s syndrome from all causes have been 
described through several published retrospective studies, chart reviews and case reports. Control of cortisol 
levels, either in serum/plasma or urine, was used to assess the efficacy of the treatment, along with the 
evaluation of clinical symptoms of Cushing’s syndrome. More than 800 patients have been treated with 
ketoconazole with variable treatment duration and modalities. About 200 patients were treated for more than 
6 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 rates 
varied between 43 and 80% depending on the studies and the criteria to define a response. About 75% of 
patients achieved a decrease of more than 50% of UFC levels on ketoconazole, compared to pre-treatment 
levels 
 
Combination therapy 
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 single 
active substance or in those requiring a dose reduction of at least one of the medicinal products to improve 
tolerance. 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 all 
causes 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 and 
reinforces the need for a long-term clinical and biochemical follow-up of these patients. If such a phenomenon 
occurs, a further dose increase may be required  to maintain cortisol levels within the normal range. 
 



19 

Use in Cushing’s disease 
Data from 535 patients with Cushing’s disease treated with ketoconazole, along with 13 individual case reports 
are 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 43 
patients (27.2%) had unchanged UFC levels. At the last follow-up, clinical signs were improved in 74/134 
patients (55.2%), hypertension in 36/90 patients (40), hypokalaemia in 10/26 patients (38.4%), and diabetes 
mellitus 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 with 
18 individual case reports. In a Canadian study, of the 12 assessable patients (out of 15), 10 showed a reduction 
in 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 even 
in 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 adrenocortical 
hyperplasia (NAH) treated with ketoconazole are available in the literature along with 17 individual case 
reports of patients with benign or malignant tumours or NAH and 2 paediatric cases of McCune Albright 
syndrome. Improvement of clinical symptoms was noted in most patients after initiation of treatment. However 
in patients with adrenal cortical carcinoma, improvement of hypercortisolism on ketoconazole was limited in 
some cases. 
 
Paediatric population 
 
Data on 24 paediatric patients with endogenous Cushing’s syndrome treated with ketoconazole are available 
in 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 and 
clinical improvement, including recovering of growth rate and gonadal function, normalisation of blood 
pressure, Cushing’s syndrome features and weight loss in most of the cases. The doses used in adolescents 
above 12 years old were similar to the doses used in adults’ patients with endogenous Cushing’s syndrome.  
 
5.2 Pharmacokinetic properties 
 
Absorption 
 
Ketoconazole is a weak dibasic active substance and thus requires acidity for dissolution and absorption. Mean 
peak plasma concentrations of approximately 3.5 μg/ml are reached within 1 to 2 hours, following oral 
administration 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 of 
1.7µg/mL to 15.6µg/mL were reported for total daily doses of 200 mg to 1,200 mg. 
 
Distribution 
 
In vitro, the plasma protein binding is about 99% mainly to the albumin fraction. Ketoconazole is widely 
distributed into tissues; however, only a negligible proportion of ketoconazole reaches the cerebral-spinal fluid. 
 
Biotransformation 
 
Ketoconazole is extensively metabolised to a large number of inactive metabolites. In vitro studies have shown 
that 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 induce 
its own metabolism. 



20 

 
Elimination 
 
Plasma elimination is biphasic with a half-life of 2 hours during the first 10 hours and 8 hours thereafter. The 
half-life of ketoconazole increases with dose and duration of treatment. At doses > 400 mg/day, half-lives of 
3 to 10 hours have been reported. About 13% of the dose is excreted in the urine, of which 2 to 4% is unchanged 
medicinal 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 5 
to 10 mg/kg/days, corresponding approximately to daily doses of 200-800 mg, are similar in paediatric and 
adult population. 
 
Renal impairment 
The pharmacokinetics of ketoconazole were not significantly different in patients with renal failure compared 
to healthy subjects.  
 
Elderly patients 
No formal evaluation of the effect of age on the pharmacokinetics of ketoconazole has been performed. There 
are 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 OCT2 
and to a lesser extent of OAT1 and BSEP. Inhibition of these different transporters at clinically relevant 
concentrations of ketoconazole cannot be excluded. 
 
5.3 Preclinical safety data 
 
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 in 
rats and dogs. 

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

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

Ketoconazole was not genotoxic in vitro and in vivo. However, the genotoxic potential was not properly 
determined 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 higher 
in male rats and dogs produced sperm abnormalities and decreased fertility in rats. Ketoconazole at doses up 
to 40 mg/kg had no effects on female fertility in the rat, whilst doses of 75 mg/kg and higher decreased the 
pregnancy rate and the number of implantation sites. Doses of 80 and 160 mg/kg inhibited ovulation in 
immature rats. Ketoconazole at doses of 40 mg/kg/day and higher produces evidence of embryotoxicity and 
teratogenicity in rats and rabbits. Observed teratogenic effects were mainly skeletal anomalies, including cleft 
palate, brachydactylia, ectrodactylia and syndactylia. Treatment of juvenile rats for 30 day beginning at 21 
days 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 the 
placenta. 

 



21 

 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Maize starch 
Lactose monohydrate 
Povidone  
Microcrystalline cellulose 
Silica colloidal 
Magnesium stearate 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container  
 
PVC/Alu blister of 10 tablets 
Pack sizes containing 60 tablets (6 blisters of 10 tablets).  
 
6.6 Special precautions for disposal 
 
No special requirements for disposal. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
7. MARKETING AUTHORISATION HOLDER 
 
HRA Pharma Rare Diseases  
200 avenue de Paris 
92320 CHATILLON 
France 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/14/965/001 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 19 November 2014 
Date of latest renewal: <DD month YYYY> 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu.  



22 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND 
USE 

 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 
 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE 
SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 
 
 



23 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 

Name and address of the manufacturer(s) responsible for batch release 

Centre Spécialités Pharmaceutiques 
76-78 avenue du Midi 
63800 Courron d‘Auvergne 
France 
 
 
Polfarmex S.A. 
ul. Jozefow 9 
99-300 Kutno 
Poland 
 
The printed package leaflet of the medicinal product must state the name and address of the manufacturer 
responsible for the release of the concerned batch. 

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION  
 

• Periodic safety update reports (PSURs) 

The requirements for submission of PSURsfor this medicinal product are set out in the list of Union 
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent 
updates published on the European medicines web-portal. 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE 

OF THE MEDICINAL PRODUCT 
 
• Risk management plan (RMP) 
 

The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities and 
interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation and any 
agreed subsequent updates of the RMP. 

An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 

• Whenever the risk management system is modified, especially as the result of new information 
being received that may lead to a significant change to the benefit/risk profile or as the result of an 
important (pharmacovigilance or risk minimisation) milestone being reached. 

 

 



24 

• Obligation to conduct post-authorisation measures  
 

The MAH shall complete, within the stated timeframe, the below measures: 

 
Description Due date 
Post Authorisation safety study (PASS): Multi-country, observational registry to 
collect clinical information on patients with Cushing Syndrome patients exposed with 
Ketoconazole (preferably using the existing European Registry on Cushing’s 
syndrome (ERCUSYN) registry where feasible ), to assess drug utilization patterns 
and to document the safety (eg hepatotoxicity, QT prolongation) and effectiveness of 
ketoconazole 

Yearly 
submission  

 
 
 
 
  



25 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



26 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
  



27 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Ketoconazole HRA 200 mg tablets 
ketoconazole  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 200 mg of ketoconazole. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. 
See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
60 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF 

THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 
 



28 

 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
HRA Pharma Rare Diseases  
200 avenue de Paris 
92320 CHATILLON 
France 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/14/965/001 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Ketoconazole HRA 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC  
SN  
NN  
 
  



29 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Ketoconazole HRA 200 mg tablets 
ketoconazole  
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
HRA Pharma Rare Diseases  
 
 
3. EXPIRY DATE 
 
EXP  
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 
 
  



30 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
B. PACKAGE LEAFLET 



31 

Package leaflet: Information for the patient 
 

Ketoconazole HRA 200 mg tablets 
ketoconazole  

 
This medicine is subject to additional monitoring. This will allow quick identification of new safety 

information. You can help by reporting any side effects you may get. See the end of section 4 for how to 
report side effects. 
 
Read all of this leaflet carefully before you start taking this medicine because it contains important 
information for you. 
- Keep this leaflet. You may need to read it again.  
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if 

their signs of illness are the same as yours.  
- If you get any side effects, talk to your doctor, or pharmacist. This includes any possible side effects 

not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Ketoconazole HRA is and what it is used for  
2. What you need to know before you take Ketoconazole HRA  
3. How to take Ketoconazole HRA  
4. Possible side effects  
5. How to store Ketoconazole HRA  
6. Contents of the pack and other information 
 
 
1. What Ketoconazole HRA is and what it is used for 
 
Ketoconazole HRA is a medicine that contains the active substance ketoconazole. It is used to treat endogenous 
Cushing’s syndrome (when the body produces an excess of cortisol) in adults and adolescents above the age 
of 12 years. 
 
Cushing’s syndrome is caused by overproduction of a hormone called cortisol which is produced by the adrenal 
glands. Ketoconazole HRA is able to block the activity of the enzymes responsible for the synthesis of cortisol 
and consequently is able to decrease the over-production of cortisol by your body and to improve the symptoms 
of Cushing’s syndrome. 
 
 
2. What you need to know before you take Ketoconazole HRA 
 
Do not take Ketoconazole HRA 
 
- if you are allergic to ketoconazole and/or to any imidazole antifungal medicine, or to any of the other 

ingredients of this medicine (listed in section 6) 

- if you have liver problems 
- if you are pregnant  
- if you are breastfeeding 
- if you have a history of an irregular heart beat 
- if you are taking any of the following medicines: 

- certain medicines for lowering blood cholesterol: simvastatin, atorvastatin, lovastatin  
- certain heart medicines: epleronone, dronedarone, disopyramide, felodipine, nisoldipine, 

ranolazine  



32 

- certain medicines used for the treatment of the paludism: quinidine, halofantrine 
- certain medicines  used for severe mental health disorders and severe depression: pimozide, 

sertindole, lurasidone, quetiapine 
- certain medicines used for the allergies: mizolastine  
- dabigatran – medicine used to prevent the formation of blood clots  
- certain medicines to help to sleep and for anxiety: triazolam, alprazolam, midazolam (taken by 

mouth) 
- certain medicines used for migraine attacks: dihydroergotamine, ergometrine (ergonovine) 

ergotamine and methylergometrine (methylergonovine)  
- certain medicines used in cancers: irinotecan, everolimus  
- sirolimus: used to prevent your body from rejecting a kidney transplant 
- tolvaptan used for a specific disease called “syndrome of inappropriate antidiuretic hormone 

secretion” 
- vardenafil in men older than 75 years – medicine to treat erectile dysfunction in adults men 
- certain medicines for HIV: saquinavir/ritonavir, saquinavir 
- certain medicines to treat long-term (chronic) hepatitis C (an infectious disease that affects the 

liver, caused by the hepatitis C virus): Paritaprevir/Ombitasvir (ritonavir) 
- methadone: medicine to treat dependence to drugs 
- In patients with renal disorders: 

 colchicine: medicine to treat gout 
 fesoterodine and solifenacin: medicines to treat the symptoms of an overactive bladder 
 telithromycin and clarithromycin: medicine used to treat infections 

 
Do not take Ketoconazole HRA if any of the above applies to you. If you are not sure, talk to your doctor or 
pharmacist before taking Ketoconazole HRA. 

 
Warnings and precautions  
 
Talk to your doctor or pharmacist before taking Ketoconazole HRA. 
 
Liver disease 
Speak with your doctor if you have a history of liver disease. You should know that your liver enzyme tests 
will be regularly monitored before starting the treatment, once weekly during the first month after 
Ketoconazole HRA initiation and then monthly for 6 months due to the risk of serious hepatic toxicity. They 
will be checked again after that in case your doctor increases your daily ketoconazole dose. You should stop 
your treatment and contact your doctor immediately if you feel unwell or experience symptoms such as 
lack of appetite, nausea, vomiting, fatigue, jaundice, abdominal pain or dark urine.  
 
Specific dosing regimen  
If you take concomitant glucocorticoid replacement therapy with your Ketoconazole HRA treatment, your 
doctor should inform you how to adapt your glucocorticoid replacement therapy dose if you are under stress 
or have surgery or an infection. In addition, you should receive an emergency card and should be equipped 
with an emergency glucocorticoid set. 
 
Adrenal function 
Your adrenal function will be monitored at regular intervals as this is the standard care in the follow-up of 
Cushing’s syndrome therapy and since adrenal insuficiency can occur during the treatment. You should contact 
your doctor immediately if you have symptoms such as weakness, fatigue, lack of appetite, nausea, vomiting 
or low blood pressure.  
 
Heart disease 
Ketoconazole HRA can change how your heart beats – this can be serious. Contact your doctor immediately, 
if you get palpitations or an irregular heartbeat during treatment.  
 
 
 



33 

Coexisting inflammatory/autoimmune disorders 
Tell your doctor if you suffer from an autoimmune disorder, you will be closely supervised. 
 
 
Children and adolescents 
This medicine is not recommended for children under 12 years due to the lack of data in these patients. 
 
Other medicinal products and Ketoconazole HRA 
Tell your doctor or phamacist if you are taking, have recently taken or might take any other medicines. There 
are some medicines that must not be taken with Ketoconazole HRA (see section 2). Ask your doctor or 
pharmacist for more information if you are taking Ketoconazole HRA with other medicines. 
 
Medicines that can interact with Ketoconazole HRA include: 

- pasireotide, another drug used to treat a subset of the Cushing’s syndrome because it can lead to severe 
side effects in patients suffering from cardiac disorders 

-  medicines taken by mouth that prevent blood clots from forming: rivaroxaban, apixaban, edoxaban, 
cilostazol, warfarin and others coumarin like 

- HIV medicines such as maraviroc, indinavir, nevirapine, ritonavir 
- certain medicines used for cancer such as vinca alkaloids, busulfan, docetaxel, erlotinib, imatinib, dasatinib, 

sunitinib, lapatinib, nilotinib, bortezomib, paclitaxel, vincristine, vinblastine, cabozantinib, dabrafenib, 
cabazitaxel, crizotinib, ibrutinib 

- certain medicines used to treat infections: rifabutin, telithromycin, rifampicin, isoniazide, clarithromycin, 
isavuconazole 

- certain antidiabetics: repaglinide, saxagliptin, tolbutamide 
- certain medicines used for mental disorders: buspirone, aripipazole, haloperidol, reboxetine, risperidone 
- certain heart medicines – verapamil, digoxin, nadolol, aliskiren 
- certain anticonvulsivants: carbamazepine, phenitoin  
- certain glucocorticoids – such as budesonide, fluticasone, dexamethasone, methylprednisolone, ciclesonide 
- certain stong painkillers (narcotics) – such as alfentanyl, fentanyl, buprenorphine (injection and sublingual), 

oxycodone 
- certain medicines used for nausea and vomiting: domperidone, aprepitant 
- naloxegol (medicine for treatment of constipation specifically caused by strong pain medicines) 
- solifenacin, fesoterodine in patients with renal impairment 
- others: sildenafil, , tolterodine, mitotane, praziquantel, eletriptan, , salmeterol, bosentan, midazolam (by 

injection), tadalafil, vardenafil, temsirolimus, cinalcacet, tacrolimus, ebastine, ciclosporine, colchicine 
 
You should not take antacids (eg aluminium hydroxide) or other medicines for acid indigestion for at least 2 
hours after the intake of Ketoconazole HRA (see section Warning and Precautions). 
 
Ketoconazole HRA with alcohol 
No alcohol should be consumed during treatment with ketoconazole.  
 
Pregnancy, breast-feeding and fertility 
Do not take this medicinal product during pregnancy. If you think you may be pregnant or are planning to have 
a baby, ask your doctor for advice before taking this medicine.  
Do not breastfeed your baby if you are taking Ketoconazole HRA. 
 
Driving and using machines 
Dizziness or somnolence have been reported during treatement with Ketoconazole HRA. Do not drive or 
operate machines if you experience these symptoms. 
 
Ketoconazole HRA contains lactose 
If you have been told by your doctor that you have intolerance to some sugars, contact your doctor before 
taking this medicinal product. 
 
 



34 

3. How to take Ketoconazole HRA  
 
Initiation and follow up of the treatment must be supervised by specialists in endocrinology.  
 
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you 
are not sure. 
 
Your doctor will test your blood before you start the treatment and regularly during the treatment to detect any 
possible abnormalities and also to measure the levels of cortisol. The dose will be adapted to your condition 
with the aim to restore normal cortisol levels. 
 
The recommended initial dose is usually 600 mg per day taken orally (3 tablets per day in 3 divided times). A 
daily dose from 400 mg per day (2 tablets) to 1,200 mg per day (6 tablets) taken orally in 2 to 3 divided doses 
may be required to restore your normal cortisol levels.  
 
If you take more Ketoconazole HRA than you should 
If you have taken more than the prescribed dose of Ketoconazole HRA, you must contact your doctor 
immediately. 
 
If you forget to take Ketoconazole HRA 
Do not take a double dose to make up for a forgotten dose. If you forget to take one dose, take this dose as 
soon as you remember. Then go on with regular schedule as prescribed. Do not change the prescribed dose 
yourself. 
 
If you stop taking Ketoconazole HRA 
If you interrupt your treatment with Ketoconazole HRA your cortisol level may increase again and your 
symptoms may come back. Therefore, do not stop taking Ketoconazole HRA unless your doctor tells you. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Some side effects may be serious. Liver problems can rarely happen (may affect up to 1 in 1,000 people).  
Stop taking Ketoconazole HRA and tell your doctor straight away if you experience any of the following: 
- long-lasting severe headache or blurred vision  
- severe lack of appetite (anorexia) 
- weight loss 
- nausea or vomiting 
- unusual tiredness or fever 
- stomach pain 
- muscle weakness 
- yellowing of the skin or whites of the eyes 
- unusually dark urine or pale stools  
 
Adrenal insufficiency is common and can be a serious side effect. Ketoconazole HRA may temporarily lower 
the amount of hormones produced by your adrenal gland (cortisol) to below the normal range, but your doctor 
will correct this using appropriate hormone medicines or by adjusting the dose of Ketoconazole HRA. You 
should contact your doctor immediately if you have symptoms such as weakness, fatigue, loss of appetite, 
nausea, vomiting, low blood pressure. 
 
 
Very common side effects (may affect more than 1 in 10 people): 
 

• An elevated levels of liver enzymes in your blood  



35 

 
Common side effects (may affect up to 1 in 10 people): 
 

• Nausea 
• Abdominal pain 
• Vomiting 

• Diarrhoea 
• Skin reactions (pruritus, rash) 

 
Uncommon side effects (may affect up to 1 in 100 people): 
 

• Allergic reactions which can, rarely, be 
serious 

• Change in laboratory markers 
• Platelet count decreased 
• Headache 

• Dizziness 
• Sleepiness 
• Skin reactions (urticaria) 
• Hair loss 
• Fatigue 

 
 
Very rare side effects (may affect up to 1 in 10,000 people): 
 

• Pyrexia (fever) 
 

Side effects with frequency not known (frequency cannot be estimated from the available data): 
 

• Insomnia 
• Nervousness 
• Intolerance to alcohol 
• Loss of appetite or increased appetite 
• Headache 
• Sensation of tingling or pricking 
• Aversion to light 
• Bleeding from the nose 
• Dyspepsia (impaired digestion) 
• Flatulence 
• Tongue discoloration 
• Dry mouth 
• Distortion of the sense of taste 
• Skin redness, drying, itching 

• Photosensitivity (increase in the reaction to 
sunlight: redness, itching rash) 

• Myalgia (muscle pain) 
• Arthralgia (joint pain) 
• Menstrual disorders 
• Azoospermia (no sperm count) 
• Erectile dysfunction 
• Gynaecomastia (enlargement in breast 

tissues in male) 
• Oedema peripheral (dropsy in extremities) 
• Malaise 
• Hot flush 
• Transient decrease of testosterone, a male 

hormone (androgen) made by the body, 
mostly produced in the testes 

 
Reporting of side effects 
If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet. 
You can also report side effects directly via the national reporting system listed in Appendix V. By reporting 
side effects you can help provide more information on the safety of this medicine. 
 
 
5. How to store Ketoconazole HRA  
 
- Keep this medicine out of the sight and reach of children. 
- Do not use this medicine after the expiry date which is stated on the carton and on the blister after EXP. 

The expiry date refers to the last day of that month. 
- This medicine does not require any special storage conditions  
- Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 

throw away medicines you no longer use. These measures will help protect the environment. 
 
 



36 

6. Contents of the pack and other information 
 
What Ketoconazole HRA contains  
- The active substance is ketoconazole. Each tablet contains 200 milligram ketoconazole 
- The other ingredients are maize starch, lactose monohydrate (see section 2), povidone, 

microcrystalline cellulose, silica colloidal, magnesium stearate 
 
What Ketoconazole HRA looks like and contents of the pack 
Ketoconazole HRA is available in packs containing 60 tablets. 
 
Marketing Authorisation Holder  
HRA Pharma Rare Diseases  
200 avenue de Paris 
92320 CHATILLON 
France 
Tel : + 33 1 40 33 93 14 
 
Manufacturer 
Centre Spécialités Pharmaceutiques 
76-78 avenue du Midi 
63800 Courron d‘Auvergne 
France 
 
 
Polfarmex S.A. 
ul. Józefów 9, 
99-300 Kutno 
Poland 
 
 
This leaflet was last revised in. 
 
 
Other sources of information 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. There are also links to other websites about rare diseases and treatments.  
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION 
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET
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{'Title': '2. what you need to know before you take ketoconazole hra', 'Section_Content': 'do not take ketoconazole hra - if you are allergic to ketoconazole and/or to any imidazole antifungal medicine, or to any of the other ingredients of this medicine (listed in section 6) - if you have liver problems - if you are pregnant - if you are breastfeeding - if you have a history of an irregular heart beat - if you are taking any of the following medicines: - certain medicines for lowering blood cholesterol: simvastatin, atorvastatin, lovastatin - certain heart medicines: epleronone, dronedarone, disopyramide, felodipine, nisoldipine, ranolazine 32 - certain medicines used for the treatment of the paludism: quinidine, halofantrine - certain medicines used for severe mental health disorders and severe depression: pimozide, sertindole, lurasidone, quetiapine - certain medicines used for the allergies: mizolastine - dabigatran medicine used to prevent the formation of blood clots - certain medicines to help to sleep and for anxiety: triazolam, alprazolam, midazolam (taken by mouth) - certain medicines used for migraine attacks: dihydroergotamine, ergometrine (ergonovine) ergotamine and methylergometrine (methylergonovine) - certain medicines used in cancers: irinotecan, everolimus - sirolimus: used to prevent your body from rejecting a kidney transplant - tolvaptan used for a specific disease called "syndrome of inappropriate antidiuretic hormone secretion" - vardenafil in men older than 75 years medicine to treat erectile dysfunction in adults men - certain medicines for hiv: saquinavir/ritonavir, saquinavir - certain medicines to treat long-term (chronic) hepatitis c (an infectious disease that affects the liver, caused by the hepatitis c virus): paritaprevir/ombitasvir (ritonavir) - methadone: medicine to treat dependence to drugs - in patients with renal disorders: colchicine: medicine to treat gout fesoterodine and solifenacin: medicines to treat the symptoms of an overactive bladder telithromycin and clarithromycin: medicine used to treat infections do not take ketoconazole hra if any of the above applies to you. if you are not sure, talk to your doctor or pharmacist before taking ketoconazole hra. warnings and precautions talk to your doctor or pharmacist before taking ketoconazole hra. liver disease speak with your doctor if you have a history of liver disease. you should know that your liver enzyme tests will be regularly monitored before starting the treatment, once weekly during the first month after ketoconazole hra initiation and then monthly for 6 months due to the risk of serious hepatic toxicity. they will be checked again after that in case your doctor increases your daily ketoconazole dose. you should stop your treatment and contact your doctor immediately if you feel unwell or experience symptoms such as lack of appetite, nausea, vomiting, fatigue, jaundice, abdominal pain or dark urine. specific dosing regimen if you take concomitant glucocorticoid replacement therapy with your ketoconazole hra treatment, your doctor should inform you how to adapt your glucocorticoid replacement therapy dose if you are under stress or have surgery or an infection. in addition, you should receive an emergency card and should be equipped with an emergency glucocorticoid set. adrenal function your adrenal function will be monitored at regular intervals as this is the standard care in the follow-up of cushing\'s syndrome therapy and since adrenal insuficiency can occur during the treatment. you should contact your doctor immediately if you have symptoms such as weakness, fatigue, lack of appetite, nausea, vomiting or low blood pressure. heart disease ketoconazole hra can change how your heart beats this can be serious. contact your doctor immediately, if you get palpitations or an irregular heartbeat during treatment. coexisting inflammatory/autoimmune disorders tell your doctor if you suffer from an autoimmune disorder, you will be closely supervised. children and adolescents this medicine is not recommended for children under 12 years due to the lack of data in these patients. other medicinal products and ketoconazole hra tell your doctor or phamacist if you are taking, have recently taken or might take any other medicines. there are some medicines that must not be taken with ketoconazole hra (see section 2). ask your doctor or pharmacist for more information if you are taking ketoconazole hra with other medicines. medicines that can interact with ketoconazole hra include: - pasireotide, another drug used to treat a subset of the cushing\'s syndrome because it can lead to severe side effects in patients suffering from cardiac disorders - medicines taken by mouth that prevent blood clots from forming: rivaroxaban, apixaban, edoxaban, cilostazol, warfarin and others coumarin like - hiv medicines such as maraviroc, indinavir, nevirapine, ritonavir - certain medicines used for cancer such as vinca alkaloids, busulfan, docetaxel, erlotinib, imatinib, dasatinib, sunitinib, lapatinib, nilotinib, bortezomib, paclitaxel, vincristine, vinblastine, cabozantinib, dabrafenib, cabazitaxel, crizotinib, ibrutinib - certain medicines used to treat infections: rifabutin, telithromycin, rifampicin, isoniazide, clarithromycin, isavuconazole - certain antidiabetics: repaglinide, saxagliptin, tolbutamide - certain medicines used for mental disorders: buspirone, aripipazole, haloperidol, reboxetine, risperidone - certain heart medicines verapamil, digoxin, nadolol, aliskiren - certain anticonvulsivants: carbamazepine, phenitoin - certain glucocorticoids such as budesonide, fluticasone, dexamethasone, methylprednisolone, ciclesonide - certain stong painkillers (narcotics) such as alfentanyl, fentanyl, buprenorphine (injection and sublingual), oxycodone - certain medicines used for nausea and vomiting: domperidone, aprepitant - naloxegol (medicine for treatment of constipation specifically caused by strong pain medicines) - solifenacin, fesoterodine in patients with renal impairment - others: sildenafil, , tolterodine, mitotane, praziquantel, eletriptan, , salmeterol, bosentan, midazolam (by injection), tadalafil, vardenafil, temsirolimus, cinalcacet, tacrolimus, ebastine, ciclosporine, colchicine you should not take antacids (eg aluminium hydroxide) or other medicines for acid indigestion for at least 2 hours after the intake of ketoconazole hra (see section warning and precautions). ketoconazole hra with alcohol no alcohol should be consumed during treatment with ketoconazole. pregnancy, breast-feeding and fertility do not take this medicinal product during pregnancy. if you think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. do not breastfeed your baby if you are taking ketoconazole hra. driving and using machines dizziness or somnolence have been reported during treatement with ketoconazole hra. do not drive or operate machines if you experience these symptoms. ketoconazole hra contains lactose if you have been told by your doctor that you have intolerance to some sugars, contact your doctor before taking this medicinal product.', 'Entity_Recognition': [{'Text': 'ketoconazole hra', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'ketoconazole hra', 'Type': 'TREATMENT', 'BeginOffset': 12, 'EndOffset': 28}, {'Text': 'allergic', 'Type': 'PROBLEM', 'BeginOffset': 42, 'EndOffset': 50}, {'Id': 10, 'BeginOffset': 54, 'EndOffset': 66, 'Score': 0.9986407160758972, 'Text': 'ketoconazole', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'any imidazole antifungal medicine', 'Type': 'TREATMENT', 'BeginOffset': 77, 'EndOffset': 110}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 150, 'EndOffset': 163}, {'Text': '6', 'Type': 'NUMBER', 'BeginOffset': 183, 'EndOffset': 184}, {'Id': 58, 'BeginOffset': 200, 'EndOffset': 214, 'Score': 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{'Title': '3. how to take ketoconazole hra', 'Section_Content': 'initiation and follow up of the treatment must be supervised by specialists in endocrinology. always take this medicine exactly as your doctor has told you. check with your doctor or pharmacist if you are not sure. your doctor will test your blood before you start the treatment and regularly during the treatment to detect any possible abnormalities and also to measure the levels of cortisol. the dose will be adapted to your condition with the aim to restore normal cortisol levels. the recommended initial dose is usually 600 mg per day taken orally (3 tablets per day in 3 divided times). a daily dose from 400 mg per day (2 tablets) to 1,200 mg per day (6 tablets) taken orally in 2 to 3 divided doses may be required to restore your normal cortisol levels. if you take more ketoconazole hra than you should if you have taken more than the prescribed dose of ketoconazole hra, you must contact your doctor immediately. if you forget to take ketoconazole hra do not take a double dose to make up for a forgotten dose. if you forget to take one dose, take this dose as soon as you remember. then go on with regular schedule as prescribed. do not change the prescribed dose yourself. if you stop taking ketoconazole hra if you interrupt your treatment with ketoconazole hra your cortisol level may increase again and your symptoms may come back. therefore, do not stop taking ketoconazole hra unless your doctor tells you. if you have any further questions on the use of this medicine, ask your doctor or pharmacist.', 'Entity_Recognition': [{'Text': 'ketoconazole hra', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'the treatment', 'Type': 'TREATMENT', 'BeginOffset': 28, 'EndOffset': 41}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 106, 'EndOffset': 119}, {'Text': 'the treatment', 'Type': 'TREATMENT', 'BeginOffset': 265, 'EndOffset': 278}, {'Text': 'the treatment', 'Type': 'TREATMENT', 'BeginOffset': 300, 'EndOffset': 313}, {'Text': 'any possible abnormalities', 'Type': 'PROBLEM', 'BeginOffset': 324, 'EndOffset': 350}, {'Text': 'cortisol', 'Type': 'TEST', 'BeginOffset': 385, 'EndOffset': 393}, {'Id': 25, 'BeginOffset': 469, 'EndOffset': 484, 'Score': 0.5167319178581238, 'Text': 'cortisol levels', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': []}, {'Text': '600', 'Type': 'NUMBER', 'BeginOffset': 526, 'EndOffset': 529}, {'Text': '3', 'Type': 'NUMBER', 'BeginOffset': 555, 'EndOffset': 556}, {'Text': '3', 'Type': 'NUMBER', 'BeginOffset': 576, 'EndOffset': 577}, {'Text': '400', 'Type': 'NUMBER', 'BeginOffset': 612, 'EndOffset': 615}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 628, 'EndOffset': 629}, {'Text': '1,200', 'Type': 'NUMBER', 'BeginOffset': 642, 'EndOffset': 647}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 687, 'EndOffset': 688}, {'Text': '3', 'Type': 'NUMBER', 'BeginOffset': 692, 'EndOffset': 693}, {'Text': 'ketoconazole hra', 'Type': 'TREATMENT', 'BeginOffset': 781, 'EndOffset': 797}, {'Text': 'ketoconazole hra', 'Type': 'TREATMENT', 'BeginOffset': 865, 'EndOffset': 881}, {'Id': 27, 'BeginOffset': 912, 'EndOffset': 923, 'Score': 0.9999994039535522, 'Text': 'immediately', 'Category': 'TIME_EXPRESSION', 'Type': 'TIME_TO_MEDICATION_NAME', 'Traits': [], 'Attributes': [{'Type': 'GENERIC_NAME', 'Score': 0.9794329404830933, 'RelationshipScore': 0.8434128761291504, 'RelationshipType': 'OVERLAP', 'Id': 15, 'BeginOffset': 865, 'EndOffset': 877, 'Text': 'ketoconazole', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'ketoconazole hra', 'Type': 'TREATMENT', 'BeginOffset': 947, 'EndOffset': 963}, {'Text': 'a double dose', 'Type': 'TREATMENT', 'BeginOffset': 976, 'EndOffset': 989}, {'Text': 'ketoconazole hra', 'Type': 'TREATMENT', 'BeginOffset': 1206, 'EndOffset': 1222}, {'Text': 'your treatment', 'Type': 'TREATMENT', 'BeginOffset': 1240, 'EndOffset': 1254}, {'Id': 21, 'BeginOffset': 1260, 'EndOffset': 1272, 'Score': 0.9913062453269958, 'Text': 'ketoconazole', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'your cortisol level', 'Type': 'TEST', 'BeginOffset': 1277, 'EndOffset': 1296}, {'Text': 'your symptoms', 'Type': 'PROBLEM', 'BeginOffset': 1320, 'EndOffset': 1333}, {'Text': 'ketoconazole hra', 'Type': 'TREATMENT', 'BeginOffset': 1379, 'EndOffset': 1395}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 1474, 'EndOffset': 1487}]}
{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. some side effects may be serious. liver problems can rarely happen (may affect up to 1 in 1,000 people). stop taking ketoconazole hra and tell your doctor straight away if you experience any of the following: - long-lasting severe headache or blurred vision - severe lack of appetite (anorexia) - weight loss - nausea or vomiting - unusual tiredness or fever - stomach pain - muscle weakness - yellowing of the skin or whites of the eyes - unusually dark urine or pale stools adrenal insufficiency is common and can be a serious side effect. ketoconazole hra may temporarily lower the amount of hormones produced by your adrenal gland (cortisol) to below the normal range, but your doctor will correct this using appropriate hormone medicines or by adjusting the dose of ketoconazole hra. you should contact your doctor immediately if you have symptoms such as weakness, fatigue, loss of appetite, nausea, vomiting, low blood pressure. very common side effects (may affect more than 1 in 10 people): an elevated levels of liver enzymes in your blood 35 common side effects (may affect up to 1 in 10 people): nausea abdominal pain vomiting diarrhoea skin reactions (pruritus, rash) uncommon side effects (may affect up to 1 in 100 people): allergic reactions which can, rarely, be serious change in laboratory markers platelet count decreased headache dizziness sleepiness skin reactions (urticaria) hair loss fatigue very rare side effects (may affect up to 1 in 10,000 people): pyrexia (fever) side effects with frequency not known (frequency cannot be estimated from the available data): insomnia nervousness intolerance to alcohol loss of appetite or increased appetite headache sensation of tingling or pricking aversion to light bleeding from the nose dyspepsia (impaired digestion) flatulence tongue discoloration dry mouth distortion of 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{'Title': '5. how to store ketoconazole hra', 'Section_Content': '- keep this medicine out of the sight and reach of children. - do not use this medicine after the expiry date which is stated on the carton and on the blister after exp. the expiry date refers to the last day of that month. - this medicine does not require any special storage conditions - do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help protect the environment.', 'Entity_Recognition': None}
{'Title': '6. contents of the pack and other information', 'Section_Content': 'what ketoconazole hra contains - the active substance is ketoconazole. each tablet contains 200 milligram ketoconazole - the other ingredients are maize starch, lactose monohydrate (see section 2), povidone, microcrystalline cellulose, silica colloidal, magnesium stearate what ketoconazole hra looks like and contents of the pack ketoconazole hra is available in packs containing 60 tablets.', 'Entity_Recognition': [{'Text': 'ketoconazole hra', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'ketoconazole hra', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 21}, {'Id': 2, 'BeginOffset': 57, 'EndOffset': 69, 'Score': 0.9979071617126465, 'Text': 'ketoconazole', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.937858521938324, 'RelationshipScore': 0.9996383190155029, 'RelationshipType': 'FORM', 'Id': 3, 'BeginOffset': 76, 'EndOffset': 82, 'Text': 'tablet', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.8766047954559326, 'RelationshipScore': 0.945152223110199, 'RelationshipType': 'DOSAGE', 'Id': 4, 'BeginOffset': 92, 'EndOffset': 105, 'Text': '200 milligram', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '200 milligram ketoconazole', 'Type': 'TREATMENT', 'BeginOffset': 92, 'EndOffset': 118}, {'Text': 'maize starch', 'Type': 'TREATMENT', 'BeginOffset': 147, 'EndOffset': 159}, {'Id': 6, 'BeginOffset': 161, 'EndOffset': 180, 'Score': 0.6368082165718079, 'Text': 'lactose monohydrate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 7, 'BeginOffset': 198, 'EndOffset': 206, 'Score': 0.8323481678962708, 'Text': 'povidone', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 8, 'BeginOffset': 208, 'EndOffset': 234, 'Score': 0.9926907420158386, 'Text': 'microcrystalline cellulose', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 9, 'BeginOffset': 236, 'EndOffset': 252, 'Score': 0.9679063558578491, 'Text': 'silica colloidal', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 10, 'BeginOffset': 254, 'EndOffset': 272, 'Score': 0.9925740957260132, 'Text': 'magnesium stearate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'ketoconazole hra', 'Type': 'TREATMENT', 'BeginOffset': 278, 'EndOffset': 294}, {'Text': 'the pack ketoconazole hra', 'Type': 'TREATMENT', 'BeginOffset': 322, 'EndOffset': 347}, {'Text': '60', 'Type': 'NUMBER', 'BeginOffset': 381, 'EndOffset': 383}]}