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MITOTANE ESTEVE is a brand name for Mitotane. The medicine, its uses, side effects and dosage are the same regardless of brand.
Verbatim from this product's MHRA label. Tap a section to expand.
Treatment should be initiated and followed by a suitably experienced specialist. g. at two-week intervals) until mitotane plasma levels reach the therapeutic window 14 – 20 mg/L. g. every week). A starting dose higher than 6 g/day is generally not recommended.
Dose adjustments, monitoring and discontinuation 2 Dose adjustment is aimed to reach a therapeutic window (mitotane plasma levels 14 - 20 mg/L) which ensures optimal use of Mitotane Esteve with acceptable safety. 1). Mitotane plasma levels higher than 20 mg/L may be associated with severe undesirable effects, including neurological toxicity, and offer no further benefit in terms of efficacy, therefore this threshold should not be exceeded.
Mitotane plasma levels should therefore be monitored in order to adjust the Mitotane Esteve dose and to avoid reaching toxic levels. For further information on the sample testing please contact the Marketing Authorisation Holder or its local representative (see section 7).
Dosing should be individually adjusted based on mitotane plasma levels monitoring and clinical tolerance until mitotane plasma levels reach the therapeutic window 14 - 20 mg/L. The target plasma concentration is usually reached within a period of 3 to 5 months.
g. every two weeks), until the optimal maintenance dose is reached. g. every week) when a high starting dose has been used. It should be taken into account that dose adjustments do not produce immediate changes in plasma levels of mitotane (see section 0).
g. monthly) once the maintenance dose has been reached. g. every two months) of mitotane plasma levels is also necessary after interruption of treatment. Treatment can be resumed when mitotane plasma levels range between 14 - 20 mg/L. Due to the prolonged half-life, significant serum concentrations may persist for weeks after cessation of therapy.
If serious adverse reactions occur, such as neurotoxicity, treatment with mitotane may need to be temporarily interrupted. In case of mild toxicity, the dose should be reduced until the maximum tolerated dose is attained. Treatment with Mitotane Esteve should be continued as long as clinical benefits are observed.
If no clinical benefits are observed after 3 months at optimal dose, treatment should be permanently discontinued. Special populations Paediatric population The experience in children is limited. The paediatric posology of mitotane has not been well characterised but appears equivalent to that of adults after correction for body surface area.
5 g/m2/day in children and adolescents with the objective of reaching 4 g/m2/day. Mitotane plasma levels should be monitored as for adults, with particular attention when plasma levels reach 10 mg/L as a quick increase in plasma levels may be observed.
Dose may be reduced after 2 or 3 months according to the mitotane plasma levels or in case of serious toxicity. Hepatic impairment There is no experience in the use of mitotane in patients with hepatic impairment, so data are insufficient to give a dose recommendation in this group.
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 Adverse reaction System Organ Class Very common Common Not Known Infections and infestations Opportunistic infection Blood and lymphatic Leukopenia Anaemia 7 system disorders Bleeding time prolonged Thrombocytopenia Immune system disorders Hypersensitivity reactions Endocrine disorders Adrenal insufficiency Thyroid disorder Hypogonadism (in males) Metabolism and nutrition disorders Decreased appetite Hypercholesterolemia Hypertriglyceridaemia Hypouricaemia Psychiatric disorders Confusional state Nervous system disorders Ataxia Paraesthesia Vertigo Somnolence Mental impairment Polyneuropathy Movement disorder Dizziness Headache Balance disorder Eye disorders Maculopathy Retinal toxicity Diplopia Lenticular opacities Visual impairment Vision blurred Vascular disorders Hypertension Orthostatic hypotension Flushing Gastrointestinal disorders Mucosal inflammation Vomiting Diarrhoea Nausea Epigastric discomfort Salivary hypersecretion Dysgeusia Dyspepsia Hepatobiliary disorders Elevated liver enzymes Autoimmune hepatitis Liver injury (hepatocellular/cholestatic /mixed) Skin and subcutaneous tissue disorders Skin rash Pruritus Muscoloskeletal and connective tissue disorders Muscular weakness Renal and urinary disorders Cystitis haemorrhagic Haematuria Proteinuria Reproductive system and breast disorders Gynaecomastia Ovarian macrocysts General disorders and administration site conditions Asthenia Hyperpyrexia Generalised aching Investigations Blood cholesterol increased Blood triglycerides increased Blood uric acid decreased Blood androstenedione decreased (in females) Blood testosterone decreased (in females) Sex hormone binding globulin increased Blood testosterone free decreased (in males) Corticosteroid binding globulin increased 8 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.
Before the initiation of the treatment:
Large metastatic masses should be surgically removed as far as possible before starting mitotane treatment, in order to minimise the risk of infarction and haemorrhage in the tumour due to a rapid cytotoxic effect of mitotane.
Risk of adrenal insufficiency:
All patients with non functional tumour and 75% of patients with functional tumour show signs of adrenal insufficiency. Therefore, steroid replacement may be necessary in these patients. Since mitotane increases plasma levels of steroid binding proteins, free cortisol and corticotropin (ACTH) determinations are necessary for optimal dosing of steroid substitution (see section Error!
). Glucocorticoid insufficiency is more frequent, but mineralocorticoid insufficiency may also be associated and the steroid substitution may need to be adapted accordingly.
Shock, severe trauma or infection:
Mitotane should be temporarily discontinued immediately following shock, severe trauma or infection, since adrenal suppression is its prime action. Exogenous steroids should be administered in such circumstances, since the depressed adrenal gland may not immediately start to secrete steroids.
Because of an increased risk of acute adrenocortical insufficiency, patients should be instructed to contact their physician immediately if injury, infection, or any other concomitant illness occurs.
Monitoring of plasma levels:
Mitotane plasma levels should be monitored in order to adjust the mitotane dose, particularly if high starting doses are considered necessary. 2). For further information on the sample testing please contact the Marketing Authorisation Holder or its local representative (see section 7).
1. 5) 4. CLINICAL PARTICULARS
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Since mitotane is mainly metabolised through the liver, mitotane plasma levels are expected to increase if liver function is impaired. The use of mitotane in patients with severe hepatic impairment is not recommended. In patients with mild to moderate hepatic impairment, caution should be exercised and monitoring of liver function should be performed.
Monitoring of mitotane plasma levels is specially recommended in these patients (see section 0). 3 Renal impairment There is no experience in the use of mitotane in patients with renal impairment, so data are insufficient to give a dose recommendation in this group.
The use of mitotane in patients with severe renal impairment is not recommended and, in cases of mild to moderate renal impairment, caution should be exercised. Monitoring of mitotane plasma levels is specially recommended in these patients (see section 0).
Elderly patients (≥ 65 years old) There is no experience on the use of mitotane in elderly patients, so data are insufficient to give a dose recommendation in this group. Caution should be exercised and frequent monitoring of mitotane plasma levels is especially recommended in these patients.
Method of administration The total daily dose may be divided in two or three doses according to patient’s convenience. Tablets should be taken with a glass of water during meals containing fat-rich food (see section Error! ). Patients should be advised not to use any tablets showing signs of deterioration, and caregivers to wear disposable gloves when handling the tablets.
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 Error! ). Skin rashes which have been reported in 5 to 25 % of patients do not seem to be dose related.
Leucopoenia 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. 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.
9 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. uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
6. CLINICAL PARTICULARS
4 Hepatic or renal impairment: There are insufficient data to support the use of mitotane in patients with severe hepatic or renal impairment. 2). Hepatotoxicity has been observed in patients treated with mitotane. Cases of liver damage (hepatocellular, cholestatic and mixed) and autoimmune hepatitis were observed.
Liver function tests (alanine transaminase [ALT], aspartate transaminase [AST], bilirubin, and alkaline phosphatase [ALP] levels) should be periodically monitored, especially during the first months of treatment or when it is necessary to increase the dose.
If AST and/or ALT are increased > 5 ULN, or ALP or bilirubin > 2 ULN, there is risk of liver injury/failure. In this case, Mitotane Esteve treatment should be interrupted. Treatment can be resumed at physician’s discretion depending on the severity of the event as well as the patient's clinical condition.
Metabolism and nutrition disorders:
Regardless of Mitotane Esteve dosage, triglycerides should be monitored regularly especially in patients with or at risk of dyslipidemia (such as metabolic syndrome, alcohol abuse, high fat diet…). Triglyceride-lowering therapy and discontinuation of Mitotane Esteve may be considered in case of severe hypertriglyceridemia as it is a potential cause of acute pancreatitis.
Mitotane tissue accumulation:
Fat tissue can act as a reservoir for mitotane, resulting in a prolonged half-life and potential accumulation of mitotane. Consequently, despite a constant dose, mitotane levels may increase. g. every two months) is also necessary after interruption of treatment, as prolonged release of mitotane can occur.
Caution and close monitoring of mitotane plasma levels are highly recommended when treating overweight patients and patients with recent weight loss.
Central nervous system disorders:
Long-term continuous administration of high doses of mitotane may lead to reversible brain damage and impairment of function. Behavioural and neurological assessments should be made at regular intervals, especially when mitotane plasma levels exceed 20 mg/L (see section Error!
).
Blood and lymphatic system disorders:
All blood cells can be affected with mitotane treatment. Leucopenia (including neutropenia), anemia and thrombocytopenia have been reported frequently during mitotane treatment (see section Error! ). Red blood cell, white blood cell and platelet counts should be monitored during mitotane treatment.
Bleeding time:
Prolonged bleeding time has been reported in patients treated with mitotane. In some patients, in vitro bleeding time may be normal but with pathologic adenosine diphosphate (ADP)- induced platelet aggregation. 8).
Warfarin and coumarin-like anticoagulants:
When administering mitotane to patients on coumarin- like anticoagulants, patients should be closely monitored for a change in anticoagulant dose requirements (see section Error! ).
Substances metabolised through cytochrome P450 and particularly cytochrome 3A4:
Mitotane is a hepatic enzyme inducer and it should be used with caution in case of concomitant use of medicinal products influenced by hepatic metabolism (see section Error! ).
Premenopausal women:
Non-malignant ovarian macrocysts, often bilateral and multiple, have been observed with higher incidence in this population. , pelvic pain or discomfort, vaginal bleeding or menstrual disorders) or asymptomatic. Isolated cases of complicated cysts have been reported (adnexal torsion and haemorrhagic cyst rupture).
Improvement after mitotane discontinuation has been observed. Women should be urged to seek medical advice if they experience gynaecological symptoms such as bleeding […]