Adverse reactions : תופעות לוואי

4.8 Undesirable effects

Safety data are based on literature (mainly retrospective studies). More than 80 % of patients treated with mitotane have shown at least one type of undesirable effect. Adverse reactions listed below are classified according to frequency and 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 1: Frequency of adverse reactions

System Organ                                      Adverse reaction
Class              Very common                      Common               Not Known Infections and                                                           Opportunistic infection infestations
Blood and          Leukopoenia               Anaemia lymphatic          Bleeding time             Thrombocytopenia system disorders   prolonged
Immune system                                                            Hypersensitivity reactions disorders

Endocrine          Adrenal insufficiency                                 Thyroid disorder disorders                                                                Hypogonadism (in males) Metabolism and     Decreased appetite                                    Hypouricaemia nutrition          Hypercholesterolemia disorders          Hypertriglyceridaemia
Psychiatric        Confusional state disorders
Nervous system     Ataxia                    Mental impairment           Balance disorder disorders          Parasthesia               Polyneuropathy
Vertigo                   Movement disorder
Somnolence                Dizziness
Headache
Eye disorders                                                            Maculopathy Retinal toxicity
Diplopia
Lenticular opacities
Visual impairment
Vision blurred
Vascular                                                                 Hypertension disorders                                                                Orthostatic hypotension Flushing
Gastrointestinal   Mucosal inflammation                                  Salivary hypersecretion disorders          Vomiting                                              Dysgeusia Diarrhoea                                             Dyspepsia
Nausea
Epigastric discomfort
Hepatobiliary      Elevated liver            Autoimmune hepatitis        Liver injury disorders          enzymes                                               (hepatocellular/cholestatic /mixed)
Skin and           Skin rash                                             Pruritus subcutaneous tissue disorders
Muscoloskeletal    Muscular weakness and connective tissue disorders
Renal and                                                                Cystitis haemorrhagic urinary                                                                  Haematuria disorders                                                                Proteinuria Reproductive       Gynaecomastia                                         Ovarian macrocysts system and breast disorders
General            Asthenia                                              Hyperpyrexia disorders and                                                            Generalised aching administration site conditions
Investigations     Blood cholesterol                                     Blood uric acid decreased increased                                             Blood androstenedione Blood triglycerides                                   decreased (in females) increased                                             Blood testosterone decreased (in females)
Sex hormone binding globulin increased
Blood testosterone free decreased (in males)
Corticosteroid binding globulin increased
Thyroxin binding globulin increased


Description of selected adverse reactions
Gastrointestinal disorders are the most frequently reported (10 to 100 % of patients) and are reversible when the dose is reduced. Some of these effects (anorexia) may constitute the hallmark of initial central nervous system impairment.

Nervous system undesirable effects occur in approximately 40 % of patients. Other undesirable central nervous effects have been reported in literature such as memory defects, aggressiveness, central vestibular syndrome, dysarthria, or Parkinson syndrome. Serious undesirable effects appear linked to the cumulative exposure to mitotane and are most likely to occur when mitotane plasma levels are at 20 mg/L or above. At high doses and after prolonged utilization, brain function impairment can occur. Nervous system undesirable effects appear reversible after cessation of mitotane treatment and decrease in plasma levels (see section 4.4).

Skin rashes which have been reported in 5 to 25 % of patients do not seem to be dose related.

Leukopoenia has been reported in 8 to 12 % of patients. Prolonged bleeding time appears a frequent finding (90 %): although the exact mechanism of such an effect is unknown and its relation with mitotane or with the underlying disease is uncertain, it should be taken into account when surgery is considered.
The activity of liver enzymes (gamma-GT, aminotransferase, alkaline phosphatase) is commonly increased. Liver enzymes levels usually normalize when the mitotane dose is decreased or temporarily interrupted or discontinued. However, autoimmune hepatitis has been reported in 7 % of patients with no other information on mechanism. Very rare serious cases of liver injury (acute hepatic failure and hepatic encephalopathy) have been observed.
Hypogonadism: Hypogonadism in males (with symptoms such as gynaecomastia, libido decreased, erectile dysfunction, fertility disorders) has been described.

Premenopausal women
Non-malignant ovarian macrocysts (with symptoms such as pelvic pain, vaginal bleeding, menstrual disorders or asymptomatic) have been described.

Paediatric population
Neuro-psychological retardation may be observed during mitotane treatment. In such cases, thyroid function should be investigated in order to identify a possible thyroid impairment linked to mitotane treatment. Hypothyroidism and growth retardation may be also observed.
One case of encephalopathy has been observed in a paediatric patient five months after initiation of the treatment; this case was considered to be related to an increased mitotane plasma level of 34.5 mg/L. After six months mitotane plasma levels were undetectable and the patient recovered clinically.
Oestrogenic-like effects (such as gynaecomastia in male patients and breast development and/or vaginal bleeding in female patients) have been observed.

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 online form https://sideeffects.health.gov.il/