LYSODREN 500mg tablets medication leaflet

Lysodren 500 mg tablets

Each tablet contains 500 mg of mitotane.

For the full list of excipients, see section 6.1.

Tablet

White, biconvex, round, scored tablets.

They are bisected on one side and impressed 'BL' over 'L1' on the other side.

Symptomatic treatment of advanced (unresectable, metastatic or relapsed) adrenocortical carcinoma(ACC).

The effect of Lysodren on non functional adrenocortical carcinoma is not established.

Treatment should be initiated and followed by a suitably experienced specialist.

Treatment in adults should be started with 2 - 3 g mitotane per day and increased progressively (e.g. attwo-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 dosesbetween 4 - 6 g per day could be necessary and daily dose increased more rapidly (e.g. every week). Astarting dose higher than 6 g/day is generally not recommended.

Dose adjustments, monitoring and discontinuation

Dose adjustment is aimed to reach a therapeutic window (mitotane plasma levels 14 - 20 mg/L) whichensures optimal use of Lysodren with acceptable safety. There are some data suggesting that amitotane plasma level above 14 mg/L may result in enhanced efficacy (see section 5.1). Mitotaneplasma levels higher than 20 mg/L may be associated with severe undesirable effects, includingneurological toxicity, and offer no further benefit in terms of efficacy, therefore this threshold shouldnot be exceeded. Mitotane plasma levels should therefore be monitored in order to adjust the Lysodrendose and to avoid reaching toxic levels. For further information on the sample testing please contactthe Marketing Authorisation Holder or its local representative (see section 7).

Dosing should be individually adjusted based on mitotane plasma levels monitoring and clinicaltolerance until mitotane plasma levels reach the therapeutic window 14 - 20 mg/L. The target plasmaconcentration 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 doseadjustments do not produce immediate changes in plasma levels of mitotane (see section 4.4). Inaddition, 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 afterinterruption of treatment. Treatment can be resumed when mitotane plasma levels range between14 - 20 mg/L. Due to the prolonged half-life, significant serum concentrations may persist for weeksafter cessation of therapy.

If serious adverse reactions occur, such as neurotoxicity, treatment with mitotane may need to betemporarily interrupted. In case of mild toxicity, the dose should be reduced until the maximumtolerated dose is attained.

Treatment with Lysodren should be continued as long as clinical benefits are observed. If no clinicalbenefits are observed after 3 months at optimal dose, treatment should be permanently discontinued.

The experience in children is limited.

The paediatric posology of mitotane has not been well characterised but appears equivalent to that ofadults after correction for body surface area.

Treatment should be initiated at 1.5 to 3.5 g/m2/day in children and adolescents with the objective ofreaching 4 g/m2/day. Mitotane plasma levels should be monitored as for adults, with particularattention 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 serioustoxicity.

There is no experience in the use of mitotane in patients with hepatic impairment, so data areinsufficient to give a dose recommendation in this group. Since mitotane is mainly metabolisedthrough the liver, mitotane plasma levels are expected to increase if liver function is impaired. The useof mitotane in patients with severe hepatic impairment is not recommended. In patients with mild tomoderate hepatic impairment, caution should be exercised and monitoring of liver function should beperformed. Monitoring of mitotane plasma levels is specially recommended in these patients (seesection 4.4).

There is no experience in the use of mitotane in patients with renal impairment, so data are insufficientto give a dose recommendation in this group. The use of mitotane in patients with severe renalimpairment is not recommended and, in cases of mild to moderate renal impairment, caution should beexercised. Monitoring of mitotane plasma levels is specially recommended in these patients (seesection 4.4).

Elderly patients (≥ 65 years old)

There is no experience on the use of mitotane in elderly patients, so data are insufficient to give a doserecommendation in this group. Caution should be exercised and frequent monitoring of mitotaneplasma levels is especially recommended in these patients.

The total daily dose may be divided in two or three doses according to patient’s convenience. Tabletsshould be taken with a glass of water during meals containing fat-rich food (see section 4.5). Patientsshould be advised not to use any tablets showing signs of deterioration, and caregivers to weardisposable gloves when handling the tablets.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Lactation (see section 4.6).

Concomitant use with spironolactone (see section 4.5).

Before the initiation of the treatment: Large metastatic masses should be surgically removed as far aspossible before starting mitotane treatment, in order to minimise the risk of infarction andhaemorrhage 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 withfunctional tumour show signs of adrenal insufficiency. Therefore, steroid replacement may benecessary in these patients. Since mitotane increases plasma levels of steroid binding proteins, freecortisol and corticotropin (ACTH) determinations are necessary for optimal dosing of steroidsubstitution (see section 4.8). Glucocorticoid insufficiency is more frequent, but mineralocorticoidinsufficiency may also be associated and the steroid substitution may need to be adapted accordingly.

Shock, severe trauma or infection: Mitotane should be temporarily discontinued immediatelyfollowing shock, severe trauma or infection, since adrenal suppression is its prime action. Exogenoussteroids should be administered in such circumstances, since the depressed adrenal gland may notimmediately start to secrete steroids. Because of an increased risk of acute adrenocorticalinsufficiency, patients should be instructed to contact their physician immediately if injury, infection,or any other concomitant illness occurs. Patients should carry with them the Lysodren Patient Cardprovided with the package leaflet indicating that they are prone to adrenal insufficiency and that, incase of emergency care, adequate precautionary measures should be taken.

Monitoring of plasma levels: Mitotane plasma levels should be monitored in order to adjust themitotane dose, particularly if high starting doses are considered necessary. Dose adjustments may benecessary to achieve the desired therapeutic levels in the window between 14 - 20 mg/L and avoidspecific adverse reactions (see section 4.2). For further information on the sample testing pleasecontact the Marketing Authorisation Holder or its local representative (see section 7).

Hepatic or renal impairment: There are insufficient data to support the use of mitotane in patients withsevere hepatic or renal impairment. In patients with mild or moderate hepatic or renal impairment,caution should be exercised and monitoring of mitotane plasma levels is particularly recommended(see section 4.2).

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 isnecessary 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, Lysodren treatment should be interrupted.

Treatment can be resumed at physician’s discretion depending on the severity of the event as well asthe patient's clinical condition.

Metabolism and nutrition disorders: Regardless of Lysodren dosage, triglycerides should bemonitored 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 Lysodren may beconsidered 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 prolongedhalf-life and potential accumulation of mitotane. Consequently, despite a constant dose, mitotanelevels may increase. Therefore, monitoring of mitotane plasma levels (e.g. every two months) is alsonecessary after interruption of treatment, as prolonged release of mitotane can occur. Caution andclose monitoring of mitotane plasma levels are highly recommended when treating overweightpatients and patients with recent weight loss.

Central nervous system disorders: Long-term continuous administration of high doses of mitotanemay lead to reversible brain damage and impairment of function. Behavioural and neurologicalassessments should be made at regular intervals, especially when mitotane plasma levels exceed20 mg/L (see section 4.8).

Blood and lymphatic system disorders: All blood cells can be affected with mitotane treatment.

Leukopenia (including neutropenia), anemia and thrombocytopenia have been reported frequentlyduring mitotane treatment (see section 4.8). Red blood cell, white blood cell and platelet counts shouldbe monitored during mitotane treatment.

Bleeding time: Prolonged bleeding time has been reported in patients treated with mitotane. In somepatients, in vitro bleeding time may be normal but with pathologic adenosine diphosphate (ADP)-induced platelet aggregation. This should be taken into account when surgery is considered (seesection 4.8).

Warfarin and coumarin-like anticoagulants: When administering mitotane to patients on coumarin-like anticoagulants, patients should be closely monitored for a change in anticoagulant doserequirements (see section 4.5).

Substances metabolised through cytochrome P450 and particularly cytochrome 3A4: Mitotane is ahepatic enzyme inducer and it should be used with caution in case of concomitant use of medicinalproducts influenced by hepatic metabolism (see section 4.5).

Premenopausal women: Non-malignant ovarian macrocysts, often bilateral and multiple, have beenobserved with higher incidence in this population. The ovarian macrocysts may be symptomatic (e.g.,pelvic pain or discomfort, vaginal bleeding or menstrual disorders) or asymptomatic. Isolated cases ofcomplicated cysts have been reported (adnexal torsion and haemorrhagic cyst rupture). Improvementafter mitotane discontinuation has been observed. Women should be urged to seek medical advice ifthey experience gynaecological symptoms such as bleeding and/or pelvic pain. Periodic ovarianultrasound monitoring is recommended in premenopausal women treated with mitotane.

Paediatric population: In children and adolescents, neuro-psychological retardation can be observedduring mitotane treatment. In such cases, thyroid function should be investigated in order to identify apossible thyroid impairment linked to mitotane treatment.

Spironolactone: Mitotane must not be given in combination with spironolactone, since this activesubstance may block the action of mitotane (see section 4.3).

Warfarin and coumarin-like anticoagulants: Mitotane has been reported to accelerate the metabolismof warfarin through hepatic microsomal enzyme induction, leading to an increase in dose requirementsfor warfarin. Therefore, patients should be closely monitored for a change in anticoagulant doserequirements when mitotane is administered to patients on coumarin-like anticoagulants.

Substances metabolised through cytochrome P450: Mitotane has been shown to have an inductiveeffect on cytochrome P450 enzymes. Therefore, the plasma concentrations of the substancesmetabolised via cytochrome P450 may be modified. In the absence of information on the specific

P450 isoenzymes involved, caution should be taken when co-prescribing active substancesmetabolised by this route such as, among others, anticonvulsants, rifabutin, rifampicin, griseofulvinand St. John’s wort (Hypericum perforatum). Particularly, mitotane has been shown to have aninductive effect on cytochrome 3A4. Therefore, the plasma concentrations of the substancesmetabolised via cytochrome 3A4 may be modified. Caution should be taken when co-prescribingactive substances metabolised by this pathway such as, among others, sunitinib, etoposide andmidazolam and dose should be adjusted as appropriate when coadministered with mitotane.

Enzyme induction is likely to persist after discontinuation of mitotane treatment.

Medicinal products active on central nervous system: Mitotane can cause central nervous systemundesirable effects at high concentrations (see section 4.8). Although no specific information onpharmacodynamic interactions in the central nervous system is available, this should be borne in mindwhen co-prescribing medicinal products with central nervous system depressant action.

Fat-rich food: Data with various mitotane formulations suggest that administration with fat-rich foodenhances absorption of mitotane.

Hormone binding protein: Mitotane has been shown to increase plasma levels of hormone bindingproteins (e.g. sex hormone-binding globulin (SHBG) and corticosteroid-binding globulin (CBG)). Thisshould be taken into account when interpreting the results of hormonal assays and may result ingynaecomastia.

Data, based on a limited number of exposed pregnancies, indicate abnormalities on the adrenals of thefoetus after exposure to mitotane. Mitotane has been detected in foetal cord blood. Pregnant womenshould be advised of a potential risk to the foetus. Animal reproduction studies have not beenconducted with mitotane. Animal studies with similar substances have shown reproductive toxicity(see section 5.3). Lysodren is not recommended during pregnancy and in women of childbearingpotential not using contraception.

Women of childbearing potential must use an effective contraception during treatment and afterdiscontinuation of treatment as long as mitotane plasma levels are detectable, which may requireseveral months. The prolonged elimination of mitotane from the body after discontinuation of

Lysodren should be considered (see section 5.2).

Due to the lipophilic nature of mitotane, it is likely to be excreted in breast milk. Because of thepotential for serious adverse reactions in the breastfed infant, breast-feeding is contraindicated whiletaking mitotane (see section 4.3) and after treatment discontinuation as long as mitotane plasma levelsare detectable.

Lysodren has a major influence on the ability to drive and use machines. Ambulatory patients shouldbe warned not to drive or use machines.

Safety data are based on literature (mainly retrospective studies). More than 80 % of patients treatedwith mitotane have shown at least one type of undesirable effect. Adverse reactions listed below areclassified according to frequency and system organ class. Frequency groupings are defined accordingto 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 beestimated from the available data). Within each frequency grouping, undesirable effects are presentedin order of decreasing seriousness.

Table 1: Frequency of adverse reactions

Adverse reaction

System Organ Class Very common Common Not Known

Infections and Opportunistic infectioninfestations

Blood and lymphatic Leukopenia Anaemiasystem disorders Bleeding time prolonged Thrombocytopenia

Immune system Hypersensitivity reactionsdisorders

Endocrine disorders Adrenal insufficiency Thyroid disorder

Hypogonadism (in males)

Metabolism and Decreased appetite Hypouricaemianutrition disorders Hypercholesterolemia

Hypertriglyceridaemia

Psychiatric disorders Confusional state

Nervous system Ataxia Mental impairment Balance disorderdisorders Paraesthesia Polyneuropathy

Vertigo Movement disorder

Somnolence Dizziness

Eye disorders Maculopathy

Retinal toxicity

Diplopia

Lenticular opacities

Visual impairment

Vision blurred

Vascular disorders Hypertension

Flushing

Gastrointestinal Mucosal inflammation Salivary hypersecretiondisorders Vomiting Dysgeusia

Diarrhoea Dyspepsia

Nausea

Epigastric discomfort

Hepatobiliary disorders Elevated liver enzymes Autoimmune hepatitis Liver injury(hepatocellular/cholestatic/mixed)

Skin and subcutaneous Skin rash Pruritustissue disorders

Muscoloskeletal and Muscular weaknessconnective tissuedisorders

Renal and urinary Cystitis haemorrhagicdisorders Haematuria

Proteinuria

Reproductive system Gynaecomastia Ovarian macrocystsand breast disorders

General disorders and Asthenia Hyperpyrexiaadministration site Generalised achingconditions

Investigations Blood cholesterol Blood uric acid decreasedincreased Blood androstenedione

Blood triglycerides decreased (in females)increased Blood testosteronedecreased (in females)

Sex hormone bindingglobulin increased

Blood testosterone freedecreased (in males)

Corticosteroid bindingglobulin increased

Thyroxin binding globulinincreased

Gastrointestinal disorders are the most frequently reported (10 to 100 % of patients) and are reversiblewhen the dose is reduced. Some of these effects (anorexia) may constitute the hallmark of initialcentral nervous system impairment.

Nervous system undesirable effects occur in approximately 40 % of patients. Other undesirable centralnervous effects have been reported in literature such as memory defects, aggressiveness, centralvestibular syndrome, dysarthria, or Parkinson syndrome. Serious undesirable effects appear linked tothe cumulative exposure to mitotane and are most likely to occur when mitotane plasma levels are at20 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 anddecrease 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 frequentfinding (90 %): although the exact mechanism of such an effect is unknown and its relation withmitotane or with the underlying disease is uncertain, it should be taken into account when surgery isconsidered.

The activity of liver enzymes (gamma-GT, aminotransferase, alkaline phosphatase) is commonlyincreased. Liver enzymes levels usually normalize when the mitotane dose is decreased or temporarilyinterrupted or discontinued. However, autoimmune hepatitis has been reported in 7 % of patients withno other information on mechanism. Very rare serious cases of liver injury (acute hepatic failure andhepatic encephalopathy) have been observed.

Hypogonadism: Hypogonadism in males (with symptoms such as gynaecomastia, libido decreased,erectile dysfunction, fertility disorders) has been described.

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

Neuro-psychological retardation may be observed during mitotane treatment. In such cases, thyroidfunction should be investigated in order to identify a possible thyroid impairment linked to mitotanetreatment. Hypothyroidism and growth retardation may be also observed. One case of encephalopathyhas been observed in a paediatric patient five months after initiation of the treatment; this case wasconsidered to be related to an increased mitotane plasma level of 34.5 mg/L. After six monthsmitotane plasma levels were undetectable and the patient recovered clinically.

Oestrogenic-like effects (such as gynaecomastia in male patients and breast development and/orvaginal bleeding in female patients) have been observed.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Mitotane overdose may lead to central nervous system impairment especially if mitotane plasma levelsare above 20 mg/L. No proven antidotes have been established for mitotane overdose. Temporaryinterruption of Lysodren should be considered. The patient should be followed closely, taking intoaccount that impairment is reversible, but given the long half-life and the lipophilic nature of mitotane,it may take weeks to return to normal. Other effects should be treated symptomatically. Because of itslipophilic nature, mitotane is not likely to be dialysable.

It is recommended to increase frequency of mitotane plasma level monitoring (e.g. every two weeks)in patients at risk of overdose (e.g. in case of renal or hepatic impairment, obese patients or patientswith a recent weight loss).

Pharmacotherapeutic group: Other antineoplastic agents, ATC code: L01XX23.

Mitotane is an adrenal cytotoxic active substance, although it can apparently also cause adrenalinhibition without cellular destruction. Its biochemical mechanism of action is unknown. Availabledata suggest that mitotane modifies the peripheral metabolism of steroids and that it also directlysuppresses the adrenal cortex. The administration of mitotane alters the extra-adrenal metabolism ofcortisol in humans, leading to a reduction in measurable 17-hydroxy corticosteroids, even thoughplasma levels of corticosteroids do not fall. Mitotane apparently causes increased formation of 6-beta-hydroxy cholesterol.

Mitotane has not been studied in a comprehensive clinical development program. Available clinicalinformation comes mainly from published data in patients with inoperable or metastatic adrenalcarcinoma. In terms of overall survival, four studies conclude that mitotane treatment does notincrease the survival rate whereas five find an increase in the survival rate. Among the latter, threestudies 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 ACTtrial, a randomized, prospective, controlled, open-label, multicenter, parallel-group study to comparethe efficacy of etoposide, doxorubicin and cisplatin plus mitotane (EDP/M) to that of streptozotocinplus mitotane (Sz/M) as first-line treatment in 304 patients. The analysis of patients who achievedmitotane 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 animprovement in disease control rate (62.9% versus 33.5%; p< 0. 0001). However, this result should becautiously taken since the examination of the mitotane effects was not the primary endpoint of thestudy.

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 substitutionhormonotherapy.

Clinical information comes mainly from a prospective trial (n= 24 patients) in children andadolescents aged at diagnosis from 5 months to 16 years (median age: 4 years) who had anunresectable primary tumour or who presented a tumour recurrence or a metastasic disease; most ofthe children (75%) presented with endocrine symptoms. Mitotane was given alone or combined withchemotherapy 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%.

In a study performed in 8 patients with adrenal carcinoma treated with 2 to 3 g daily of mitotane, ahighly significant correlation was found between plasma mitotane concentration and the total mitotanedose. The target plasma mitotane concentration (14 mg/L) was reached in all patients within 3 to 5months and the total mitotane dose ranged between 283 and 387 g (median value: 363 g). Thethreshold of 20 mg/L was reached for cumulative amounts of mitotane of approximately 500 g. Inanother study, 3 patients with adrenal carcinoma received Lysodren according to a precise protocolallowing 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 ordecreased in function of side effects and plasma mitotane levels. There was a positive linearcorrelation between the cumulative dose of Lysodren and the plasma levels of mitotane. In two of the3 patients, plasma levels of more than 14 mg/L were achieved within 15 days and in one of themlevels above 20 mg/L were achieved within approximately 30 days. In addition, in both studies, insome patients, the plasma mitotane levels continued to rise despite maintenance or a decrease of thedaily dose of mitotane.

Autopsy data from patients show that mitotane is found in most tissues of the body, with fat as theprimary site of storage.

Metabolism studies in man have identified the corresponding acid, 1,1-(o,p'-dichlorodiphenyl) aceticacid (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 hasbeen found in bile or in urine, where o,p’-DDA predominates, together with several of itshydroxylated metabolites. For induction with cytochrome P450, see section 4.5.

After 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, leadingto reported terminal plasma half-lives ranging from 18 to 159 days.

Non-clinical data on the general toxicity of mitotane is limited.

Reproductive toxicity studies have not been performed with mitotane. However,dichlorodiphenyltrichlorethane (DDT) and other polychlorinated biphenyl analogues are known tohave deleterious effects on fertility, pregnancy and development, and mitotane could be expected toshare these properties.

The genotoxic and carcinogenic potential of mitotane has not been investigated.

Maize starch

Microcrystalline cellulose (E 460)

Macrogol 3350

Silica colloidal anhydrous

Not applicable.

3 years.

After opening: 1 year.

Store in the original package.

Square opaque white HDPE bottle having a thread on the mouth containing 100 tablets.

Pack size of 1 bottle.

This medicinal product should not be handled by persons other than the patient and his/her caregivers,and especially not by pregnant women. Caregivers should wear disposable gloves when handling thetablets.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements for cytotoxic medicinal products.

Esteve Pharmaceuticals S.A.

Passeig de La Zona Franca 109 Planta 408038 Barcelona

Spain

EU/1/04/273/001

Date of first authorisation: 28 April 2004

Date of last renewal: 25 March 2009

Detailed information on this medicinal product is available on the website of the European Medicines

Agency (EMEA) https://www.emea.europa.eu/