Summary of Product Characteristics Updated 09-May-2016 | HRA Pharma UK and Ireland Limited
PosologyTreatment in adults should be started with 2 - 3 g mitotane per day and increased progressively (e.g. at two-week intervals) until mitotane plasma levels reach the therapeutic window 14 20 mg/l. If it is urgent to control Cushing's symptoms in highly symptomatic patients, higher starting doses between 4 - 6 g per day could be necessary and daily dose increased more rapidly (e.g. every week). A starting dose higher than 6 g/day is generally not recommended.
Dose adjustments, monitoring and discontinuationDose adjustment is aimed to reach a therapeutic window (mitotane plasma levels 14 - 20 mg/l) which ensures optimal use of Lysodren with acceptable safety. Indeed, neurologic toxicity has been associated with levels above 20 mg/l and therefore this threshold should not be reached. There are some data suggesting that mitotane plasma above 14 mg/l may result in enhanced efficacy (see section 5.1).Mitotane plasma levels higher than 20 mg/l may be associated with severe undesirable effects and offer no further benefit in terms of efficacy. Mitotane plasma levels should therefore be monitored in order to adjust the Lysodren 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.Mitotane plasma levels should be assessed after each dose adjustment and at frequent intervals (e.g. every two weeks), until the optimal maintenance dose is reached. Monitoring should be more frequent (e.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 4.4). In addition, because of tissue accumulation, mitotane plasma levels should be monitored regularly (e.g. monthly) once the maintenance dose has been reached.Regular monitoring (e.g. every two months) of mitotane plasma levels is also necessary after interruption of treatment. Treatment can be resumed when mitotane plasma levels will be ranged 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 Lysodren 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.
Paediatric patientsThe 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.Treatment should be initiated at 1.5 to 3.5 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 impairmentThere 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. 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 4.4).
Renal impairmentThere 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 4.4).
Older patients (≥ 65 years old)There is no experience on the use of mitotane in older 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 administrationThe 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 4.5). Patients should be advised not to use any tablets showing signs of deterioration, and caregivers to wear disposable gloves when handling the tablets.
PregnancyData on a limited number of exposed pregnancies indicate abnormalities on the adrenals of the foetus after exposure to mitotane. Animal reproduction studies have not been conducted with mitotane. Animal studies with similar substances have shown reproductive toxicity (see section 5.3). Lysodren should be given to pregnant women only if clearly needed and if the clinical benefit clearly outweighs any potential risk to the foetus.Women of childbearing potential must use an effective contraception during treatment and after discontinuation of treatment as long as mitotane plasma levels are detectable. The prolonged elimination of mitotane from the body after discontinuation of Lysodren should be considered.
Breast-feedingDue to the lipophilic nature of mitotane, it is likely to be excreted in breast milk. Breast-feeding is contraindicated while taking mitotane (see section 4.3) and after treatment discontinuation as long as mitotane plasma levels are detectable.
|System Organ Class||Very common||Common||Not Known|
|Investigations||Elevated liver enzymes Plasma cholesterol increased Plasma triglycerides increased||Blood uric acid decreasedBlood androstenedione decreased (in females)Blood testosterone decreased (in females) Sex hormone binding globulin increasedBlood free testosterone decreased (in males)|
|Blood and lymphatic system disorders||Leucopoenia Bleeding time prolonged||Anaemia Thrombocytopenia|
|Nervous system disorders||Ataxia Paresthesia Vertigo Sleepiness||Mental impairment Polyneuropathy Movement disorder Dizziness Headache||Balance disorders|
|Eye disorders||Maculopathy Retinal toxicity Diplopia Lens opacity Visual impairment Vision blurred|
|Gastrointestinal disorders||Mucositis Vomiting Diarrhoea Nausea Epigastric discomfort||Salivary hypersecretion Dysgeusia Dyspepsia|
|Renal and urinary disorders||Haemorrhagic cystitis Haematuria Proteinuria|
|Skin and subcutaneous tissue disorders||Skin rash|
|Muscoloskeletal and connective tissue disorders||Myasthenia|
|Endocrine disorders||Adrenal insufficiency||Thyroid impairment|
|Metabolism and nutrition disorders||Anorexia Hypercholesterolemia Hypertriglyceridaemia||Hypouricaemia|
|Infections and infestations||Opportunistic mycosis|
|Vascular disorders||Hypertension Orthostatic hypotension Flushing|
|General disorders and administration site conditions||Asthenia||Hyperpyrexia Generalised aching|
|Hepatobiliary disorders||Autoimmune hepatitis||Liver damage (hepatocellular/cholestatic/mixed)|
|Reproductive system and breast disorders||Gynaecomastia||Ovarian macrocysts|
Description of selected adverse reactionsGastrointestinal 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.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. Autoimmune hepatitis has been reported in 7 % of patients with no other information on mechanism. Liver enzymes levels normalize when the mitotane dose is decreased. A case of cholestatic hepatitis has been reported. Therefore, the possibility of mitotane-induced liver damage cannot be excluded.Premenopausal women Non-malignant ovarian macrocysts (with symptoms such as pelvic pain, bleeding) have been described.
Paediatric patientsNeuro-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.
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system (see details below).
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Mechanism of actionMitotane is an adrenal cytotoxic active substance, although it can apparently also cause adrenal inhibition without cellular destruction. Its biochemical mechanism of action is unknown. Available data suggest that mitotane modifies the peripheral metabolism of steroids and that it also directly suppresses the adrenal cortex. The administration of mitotane alters the extra-adrenal metabolism of cortisol in humans, leading to a reduction in measurable 17-hydroxy corticosteroids, even though plasma levels of corticosteroids do not fall. Mitotane apparently causes increased formation of 6-beta-hydroxy cholesterol.
Clinical efficacyMitotane has not been studied in a comprehensive clinical development program. Available clinical information comes mainly from published data in patients with inoperable or metastatic adrenal carcinoma. In terms of overall survival, four studies conclude that mitotane treatment does not increase the survival rate whereas five find an increase in the survival rate. Among the latter, three studies find such an increase only in patients in whom mitotane plasma is above 14 mg/l. Mitotane plasma levels and the possible relationship with its efficacy were studied in the FIRM ACT trial, a randomized, prospective, controlled, openlabel, multicenter, parallel-group study to compare the efficacy of etoposide, doxorubicin and cisplatin plus mitotane (EDP/M) to that of streptozotocin plus mitotane (Sz/M) as first-line treatment in 304 patients. The analysis of patients who achieved mitotane levels ≥ 14 mg/l at least once in 6 six months versus patients who mitotane levels were < 14 mg/l could suggest that patients with mitotane plasma levels ≥ 14 mg/l could have an improvement in disease control rate (62.9% versus 33.5%; p< 0. 0001). However, this result should be cautiously taken since the examination of the mitotane effects was not the primary endpoint of the study.In addition, mitotane induces a state of adrenal insufficiency which leads to the disappearance of Cushing syndrome in patients with secreting adrenal carcinoma and necessitates substitution hormonotherapy.
Paediatric patientsClinical information comes mainly from a prospective trial (n= 24 patients) in children and adolescents aged at diagnosis from 5 months to 16 years (median age: 4 years) who had an unresectable primary tumour or who presented a tumour recurrence or a metastasic disease; most of the children (75%) presented with endocrine symptoms. Mitotane was given alone or combined with chemotherapy with various agents. Overall, the disease-free interval was 7 months (2 to 16 months). There were recurrences in 40% of children; the survival rate at 5 years was 49%.
AbsorptionIn a study performed in 8 patients with adrenal carcinoma treated with 2 to 3 g daily of mitotane, a highly significant correlation was found between plasma mitotane concentration and the total mitotane dose. The target plasma mitotane concentration (14 mg/l) was reached in all patients within 3 to 5 months and the total mitotane dose ranged between 283 and 387 g (median value: 363 g). The threshold of 20 mg/l was reached for cumulative amounts of mitotane of approximately 500 g. In another study, 3 patients with adrenal carcinoma received Lysodren according to a precise protocol allowing fast introduction of a high dose if the product was well tolerated: 3 g (as 3 intakes) on day 1, 4.5 g on day 2, 6 g on day 3, 7.5 g on day 4 and 9 g on day 5. This dose of Lysodren was continued or decreased in function of side effects and plasma mitotane levels. There was a positive linear correlation between the cumulative dose of Lysodren and the plasma levels of mitotane. In two of the 3 patients, plasma levels of more than 14 mg/l were achieved within 15 days and in one of them levels above 20 mg/l were achieved within approximately 30 days. In addition, in both studies, in some patients, the plasma mitotane levels continued to rise despite maintenance or a decrease of the daily dose of mitotane.
DistributionAutopsy data from patients show that mitotane is found in most tissues of the body, with fat as the primary site of storage.
BiotransformationMetabolism studies in man have identified the corresponding acid, 1,1-(o,p'-dichlorodiphenyl) acetic acid (o,p'-DDA), as the major circulating metabolite, together with smaller quantities of the 1,1-(o,p'-dichlorodiphenyl)-2,2 dichloroethene (o,p'-DDE) analogue of mitotane. No unchanged mitotane has been found in bile or in urine, where o,p'-DDA predominates, together with several of its hydroxylated metabolites. For induction with cytochrome P450, see section 4.5.
EliminationAfter intravenous administration, 25% of the dose was excreted as metabolites within 24 hours. Following discontinuation of mitotane treatment, it is slowly released from storage sites in fat, leading to reported terminal plasma half-lives ranging from 18 to 159 days.
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