Adverse reactions : תופעות לוואי

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.

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 disorders           Not known                          Photophobia Respiratory,            Not known                          Epistaxis thoracic and mediastinal disorders
Gastrointestinal        Common                             Nausea, abdominal pain, vomiting, disorders                                                  diarrhoea
Not known                          Dyspepsia, flatulence, tongue discoloration, dry mouth, dysgeusia
Hepatobiliary           Very common                        Liver function tests abnormal disorders
Rare                               Serious hepatotoxicity, including jaundice, hepatitis, hepatic necrosis, hepatic cirrhosis,
hepatic failure including cases necessitating transplantation or resulting in death. (see
4.4 Special warnings and special precautions for use)
Skin and                Common                             Pruritus, rash subcutaneous tissue disorders
Uncommon                           Urticaria, alopecia
Not known                          Photosensitivity, erythema multiforme, dermatitis, erythema, xeroderma
Musculoskeletal and     Not known                          Myalgia, arthralgia connective tissue disorder
Reproductive system     Not known                          Menstrual disorder, azoospermia, erectile and breast disorders                                       dysfunction, gynaecomastia General disorders       Uncommon                           Asthenia and administration site conditions
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.
Any suspected adverse events should be reported to the Ministry of Health according to the national regulation by using an online form https://sideeffects.health.gov.il/.