KETOCONAZOLE HRA

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; - 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.

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.

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. 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.

4). 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.

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 Esteve in children aged less than 12 years have not been established.

2 but no recommendation on a posology can be made. Method of administration Oral use.

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.

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. 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 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. 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).

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 Esteve 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 […]

Monitoring of liver function Liver enzymes should be monitored in all patients receiving ketoconazole. 2). 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. 2 for dose adjustment in case of adrenal insufficiency).

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.

2). 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), ECG monitoring is recommended. Contraception Women must be provided with comprehensive information on pregnancy prevention. 6). Decreased gastric acidity Absorption is impaired when gastric acidity is decreased. g. aluminium hydroxide) should not be administered for at least 2 hours after the intake of ketoconazole.

g. 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. 5). 5). e. resulting in augmentation of the plasma concentration, AUC, Cmax of the drugs) and the known therapeutic margins of the drugs.

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.

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.

5). Warning regarding excipients This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucosegalactose malabsorption should not take this medicine.

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; 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.