Ketoconazole Esteve (previously Ketoconazole HRA) · 4.3 Contraindications · 1

HOS-097317 · has-adverse-reaction-information · PDF-Seite 15

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. 15 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 Uncommon Thrombocytopenia system disorders Immune system Uncommon Allergic conditions including anaphylactic disorders shock, anaphylactoid reaction and anaphylactic reaction and angioedema Endocrine disorders Common Adrenal insufficiency Metabolism and Not known Alcohol intolerance, anorexia, increased nutrition disorders appetite Psychiatric Not Known Insomnia, nervousness disorders Nervous system Uncommon Headache, dizziness, somnolence disorders Not known Intracranial pressure increased (papilloedema, fontanelle bulging), paraesthesia Eye diso

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HOS-097313 · has-contraindication-information · PDF-Seite 4

- 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; 4  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

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HOS-097312 · has-indication-information · PDF-Seite 2

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

HOS-097315 · has-interaction-information · PDF-Seite 7

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 i

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HOS-097316 · has-pregnancy-information · PDF-Seite 15

Pregnancy There are no or limited amount of data from the use of Ketoconazole Esteve 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 Esteve (see section 4.3). Fertility Studies in animals have shown effects on male and female reproductive parameters (see section 5.3).

HOS-097314 · has-warning-information · PDF-Seite 5

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

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