Drugs List

Therapeutic Indications

Uses

Advanced adrenal cortical carcinoma: symptomatic treatment

Symptomatic treatment of advanced (unresectable, metastatic or relapsed) adrenal cortical carcinoma.

Administration

For oral administration with water, preferably taken during meals. The manufacturer advises taking mitotane with fatty foods to enhance mitotane absorption.

Contraindications

Breastfeeding
Pregnancy
Severe hepatic impairment
Severe renal impairment

Precautions and Warnings

Obesity
Patients over 65 years
Prolonged bleeding times
Hepatic impairment
Porphyria
Renal impairment

Corticosteroid cover required in adrenal insufficiency
Advise ability to drive/operate machinery may be affected by side effects
Drug interactions may occur months after treatment has stopped
Excise large metastases to reduce risk of haemorrhage/infarct prior to tx
Treatment to be initiated and supervised by a specialist
Consult local policy on the safe use of oral anti-cancer drugs
Staff: Not to be handled by pregnant staff
Take with food - particularly high fat food
Examine patients complaining of abdominal/pelvic pain for ovarian cysts
Monitor full blood count regularly
Monitor hepatic function regularly
Monitor plasma concentrations of this drug
Monitor thyroid function in children with neuro-psychological reactions
Periodic neurological examination
Advise patients to report gynaecological bleeding and/or pelvic pain
May affect results of some laboratory tests
Discontinue if an adequate response not achieved within 3 months
Discontinue if neurological toxicity occurs
Discontinue immediately following shock, trauma or infection
Advise patient not to take St John's wort concurrently
Female: Ensure adequate contraception during treatment
Advise patient to carry package insert at all times

Long term administration of high doses may lead to reversible brain damage. Make neurological and behavioural assessments at regular intervals.

Caution should be taken when treating overweight patients as accumulation in fatty tissues can lead to prolonged release. The possibility of persisting side effects, interactions and the need for contraception requires consideration. Mitotane plasma levels may increase despite constant dosage and close monitoring of plasma levels is advised in overweight patients (see Therapeutic drug monitoring )

All blood cells may be affected with mitotane treatment. Red blood cell, white blood cell and platelet counts should be monitored during mitotane treatment. Mitotane can prolong bleeding times and this should be taken into account when surgery is to be performed.

Some sources indicate mitotane as unsuitable for use in porphyria as it probably porphyrinogenic.

Children
Neuro-psychological reactions have been observed in children during mitotane treatment. In such cases, investigate thyroid function to determine if thyroid function is impaired.

Pregnancy and Lactation

Pregnancy

Mitotane is contraindicated during pregnancy.

Data on a limited number of exposed pregnancies indicate adverse reactions of mitotane on the health of the foetus including adrenal abnormalities. Although animal studies on mitotane have not been carried out, Dichlorodiphenyltrichloroethane (DDT) and other polychlorinated biphenyls show fertility, pregnancy and developmental effects, and due to its similarity in structure, mitotane may share these effects.

Women of childbearing potential must use effective contraception during treatment and after discontinuation of treatment for as long as mitotane plasma levels are detectable.

The prolonged elimination of mitotane from the body after discontinuation should be considered.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Mitotane is contraindicated during breastfeeding.

Due to its being particularly lipophilic, mitotane is likely to be excreted in the breast milk. At the time of writing, there are no reports on the use of mitotane during breastfeeding.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Side Effects

Abnormal vaginal bleeding
Aches
Adrenal suppression
Anaemia
Androstenedione decreased
Anorexia
Asthenia
Ataxia
Autoimmune hepatitis
Blurred vision
Cholestatic hepatitis
Confusion
Decrease in plasma testosterone (transient)
Diarrhoea
Diplopia
Dizziness
Dysgeusia
Dyspepsia
Elevation of liver enzymes
Epigastric discomfort
Flushing
Growth retardation (children)
Gynaecomastia
Haematuria
Haemorrhagic cystitis
Headache
Hepatic damage
Hypercholesterolaemia
Hyperpyrexia
Hypertension
Hypertriglyceridaemia
Hypothyroidism
Hypouricaemia
Impairment of mental skills
Lens opacities
Leucopenia
Loss of balance
Macular retinopathy
Movement disturbances
Mucositis
Myasthenia
Nausea
Neuropathy
Opportunistic mycoses
Ovarian macrocysts
Paraesthesia
Pelvic pain
Postural hypotension
Prolonged bleeding
Proteinuria
Rash
Retinal toxicity
Salivation changes
Serum uric acid disturbances
Sex hormone binding globulin increased
Sleepiness
Thrombocytopenia
Vertigo
Visual disturbances
Vomiting

Presentation

Tablets containing mitotane

Drugs List

Therapeutic Indications

Uses

Advanced adrenal cortical carcinoma: symptomatic treatment

Symptomatic treatment of advanced (unresectable, metastatic or relapsed) adrenal cortical carcinoma.

Dosage

Before mitotane is administered, all possible tumour tissues should be surgically removed from large metastatic masses.

Whilst the doses stated below are those recommended by the manufacturer, local cancer network protocols for the relevant indication should be consulted.

Adults

Children

Administration

For oral administration with water, preferably taken during meals. The manufacturer advises taking mitotane with fatty foods to enhance mitotane absorption.

Therapeutic Drug Monitoring

Monitoring plasma levels of mitotane should be done frequently (every 2 weeks) until optimal maintenance dose is reached. Monitoring should be done more frequently ( e.g. every week) when a high starting dose has been used. Thereafter, monthly assays should be taken due to tissue accumulation. Plasma levels above 20 mg/litre have been associated with neurotoxicity and so plasma levels should be maintained below this threshold. Weaker evidence suggests that plasma levels above 14 mg/litre may result in enhanced efficacy.

Note that dose readjustments do not produce immediate changes in the plasma level of mitotane as it has a long half-life.

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 are between 14 to 20 mg/litre.

Contraindications

Breastfeeding
Pregnancy
Severe hepatic impairment
Severe renal impairment

Precautions and Warnings

Obesity
Patients over 65 years
Prolonged bleeding times
Hepatic impairment
Porphyria
Renal impairment

Corticosteroid cover required in adrenal insufficiency
Advise ability to drive/operate machinery may be affected by side effects
Drug interactions may occur months after treatment has stopped
Excise large metastases to reduce risk of haemorrhage/infarct prior to tx
Treatment to be initiated and supervised by a specialist
Consult local policy on the safe use of oral anti-cancer drugs
Staff: Not to be handled by pregnant staff
Take with food - particularly high fat food
Examine patients complaining of abdominal/pelvic pain for ovarian cysts
Monitor full blood count regularly
Monitor hepatic function regularly
Monitor plasma concentrations of this drug
Monitor thyroid function in children with neuro-psychological reactions
Periodic neurological examination
Advise patients to report gynaecological bleeding and/or pelvic pain
May affect results of some laboratory tests
Discontinue if an adequate response not achieved within 3 months
Discontinue if neurological toxicity occurs
Discontinue immediately following shock, trauma or infection
Advise patient not to take St John's wort concurrently
Female: Ensure adequate contraception during treatment
Advise patient to carry package insert at all times

Long term administration of high doses may lead to reversible brain damage. Make neurological and behavioural assessments at regular intervals.

Caution should be taken when treating overweight patients as accumulation in fatty tissues can lead to prolonged release. The possibility of persisting side effects, interactions and the need for contraception requires consideration. Mitotane plasma levels may increase despite constant dosage and close monitoring of plasma levels is advised in overweight patients (see Therapeutic drug monitoring )

All blood cells may be affected with mitotane treatment. Red blood cell, white blood cell and platelet counts should be monitored during mitotane treatment. Mitotane can prolong bleeding times and this should be taken into account when surgery is to be performed.

Some sources indicate mitotane as unsuitable for use in porphyria as it probably porphyrinogenic.

Children
Neuro-psychological reactions have been observed in children during mitotane treatment. In such cases, investigate thyroid function to determine if thyroid function is impaired.

Pregnancy and Lactation

Pregnancy

Mitotane is contraindicated during pregnancy.

Data on a limited number of exposed pregnancies indicate adverse reactions of mitotane on the health of the foetus including adrenal abnormalities. Although animal studies on mitotane have not been carried out, Dichlorodiphenyltrichloroethane (DDT) and other polychlorinated biphenyls show fertility, pregnancy and developmental effects, and due to its similarity in structure, mitotane may share these effects.

Women of childbearing potential must use effective contraception during treatment and after discontinuation of treatment for as long as mitotane plasma levels are detectable.

The prolonged elimination of mitotane from the body after discontinuation should be considered.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Mitotane is contraindicated during breastfeeding.

Due to its being particularly lipophilic, mitotane is likely to be excreted in the breast milk. At the time of writing, there are no reports on the use of mitotane during breastfeeding.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Side Effects

Abnormal vaginal bleeding
Aches
Adrenal suppression
Anaemia
Androstenedione decreased
Anorexia
Asthenia
Ataxia
Autoimmune hepatitis
Blurred vision
Cholestatic hepatitis
Confusion
Decrease in plasma testosterone (transient)
Diarrhoea
Diplopia
Dizziness
Dysgeusia
Dyspepsia
Elevation of liver enzymes
Epigastric discomfort
Flushing
Growth retardation (children)
Gynaecomastia
Haematuria
Haemorrhagic cystitis
Headache
Hepatic damage
Hypercholesterolaemia
Hyperpyrexia
Hypertension
Hypertriglyceridaemia
Hypothyroidism
Hypouricaemia
Impairment of mental skills
Lens opacities
Leucopenia
Loss of balance
Macular retinopathy
Movement disturbances
Mucositis
Myasthenia
Nausea
Neuropathy
Opportunistic mycoses
Ovarian macrocysts
Paraesthesia
Pelvic pain
Postural hypotension
Prolonged bleeding
Proteinuria
Rash
Retinal toxicity
Salivation changes
Serum uric acid disturbances
Sex hormone binding globulin increased
Sleepiness
Thrombocytopenia
Vertigo
Visual disturbances
Vomiting

Effects on Laboratory Tests

Mitotane may interfere with the results of hormonal assays as it has been known to increase plasma hormone binding proteins.

Overdosage

It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.

The following number will direct the caller to the relevant local centre (0844) 892 0111

Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Further Information

Last Full Review Date: June 2016

Reference Sources

British National Formulary, 64th Edition (2012) Pharmaceutical Press, London.

BNF for Children (2012-2013) Pharmaceutical Press, London.

Joint Formulary Committee. British National Formulary(online) London: BMJ Group and Pharmaceutical Press Accessed on 17 June 2016.

Paediatric Formulary Committee. BNF for Children (online) London: BMJ Group, Pharmaceutical Press, and RCPCH Publications Accessed on 17 June 2016.

Summary of Product Characteristics, Lysodren 500mg tablets. Laboratoire HRA Pharma. Revised April 2016.

The Norwegian Porphyria Centre (NAPOS).
Available at: https://www.drugs-porphyria.org
Last revised: 07 February 2011
Last accessed: 17 June 2016