KETOCONAZOLE HRA 200 mg

/ CTS

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 normalize 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. 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.
– In the case of adrenal insufficiency and depending on the severity of the event, the dose of Ketoconazole HRA 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.
– 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, gamma GT 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.
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:

• weekly for one month after initiation of the treatment
• then monthly for 6 months
• 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.
Special populations
Elderly patients
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.
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.
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 this drug in children aged less than 12 years have not been established.

Indicated for the treatment of endogenous Cushing’s syndrome in adults and adolescents above the age of 12 years.

Hypersensitivity to the active substance or to any of the excipients.
Hypersensitivity to any imidazole antifungal medication product;
Acute or chronic liver disease and/or if pre-treatment liver enzymes levels are above 2 times the upper limit of normal.
Pregnancy.
Breastfeeding.
Congenital or documented acquired QTc prolongation
Concomitant therapy with any of the following medicinal products: simvastatin, atorvastatin and lovastatin).
Concomitant therapy with eplerenone.
Concomitant therapy with: methadone, disopyramide, quinidine, dronedarone, pimozide, sertindole, saquinavir (saquinavir/ritonavir 1000/100 mg bid), ranolazine, mizolastine, halofantrine .
Concomitant therapy with dabigatran.
Concomitant therapy with triazolam, oral midazolam and alprazolam.
Concomitant therapy with ergot alkaloids (e.g. dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine).
Concomitant therapy with lurasidone.
Concomitant therapy with quetiapine.
Concomitant therapy with telithromycin and clarithromycin, felodipine, nisoldipine, colchicine,  irinotecan, everolimus, sirolimus.
Concomitant therapy with vardenafil in men older than 75-years.
Concomitant therapy with paritaprevir/ombitasvir (ritonavir).
Concomitant therapy with fesoterodine and solifenacin in patients with renal impairment
Concomitant therapy with tolvaptan.

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.
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.
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 HRA 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.
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.
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.
In case of co-administration of a medicinal product known to increase QTc interval, 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.
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.
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.).
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.
Use with hepatotoxic medicinal products
Co-administration of ketoconazole and other medicinal products known to have potentially hepatotoxic effect (e.g. 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.
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.
Alcohol
Patients should be advised against alcohol consumption while on treatment.
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.
See prescribing information for full details

Adrenal insufficiency, Nausea, abdominal pain, vomiting, diarrhea, Liver function tests abnormal, Pruritus, rash, Hepatic enzyme increased. See prescribing information for full details.

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

Pregnancy
There are no or limited amount of data from the use of Ketoconazole HRA in pregnant women. See prescribing information for full details.
Lactation
Since ketoconazole is excreted in the milk, mothers who are under treatment must not breast-feed whilst being treated with Ketoconazole. See prescribing information for full details.

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.