KETOCONAZOLE HRA Tablet Ref.[8866] Active ingredients: Ketoconazole

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 800-1200 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 HRA 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 1200 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 HRA 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 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 HRA can be reintroduced thereafter at a lower dose (see section 4.4);
• Treatment with Ketoconazole HRA can be stopped abruptly without a need for progressive dose decrease where a change in the therapeutic strategy (eg 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:
  • 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 HRA should be stopped immediately and should not be reintroduced due to the risk of serious hepatic toxicity. Ketoconazole HRA 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 HRA may be continued as described above;
• Block-and-replace regimen: the maintenance dose of Ketoconazole HRA should be further increased by 200 mg and concomitant corticosteroid replacement therapy should be added (see section 4.4).

Special populations

Paediatric population

The safety and efficacy of Ketoconazole HRA in children aged less than 12 years have not been established. No recommendation on posology can be made for children under 12. The posology in adolescents above the age of 12 years is the same as in adults (see section 5.1 and 5.2).

Elderly patients

Data on the use of Ketoconazole HRA 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).

Patients with renal impairment

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

Patients with hepatic impairment

Ketoconazole is contraindicated in patients with acute or chronic hepatic impairment (see sections 4.3, 4.4 and 5.3).

Gender, weight and race

No formal evaluation has been conducted to investigate the potential differences in ketoconazole pharmacokinetics between males and females and data evaluating the effect of weight on pharmacokinetics of ketoconazole are very limited.

Method of administration

Oral use.

There is no known antidote to Ketoconazole HRA. The maximal dose that was used for treatment of Cushing’s syndrome is 1600 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 drug 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.

Shelf life: 3 years.

This medicinal product does not require any special storage conditions.

PVC/Alu blister of 10 tablets.

Pack sizes containing 6 blisters of 10 tablets.

No special requirements for disposal.

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