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Hydroxycarbamide 22-Mar-2018

(Hydroxyurea)

l INDICATIONS AND DOSE

Polycythaemia vera (specialist use only)

▶ BY MOUTH

▶ Adult: Initially 15–20 mg/kg daily, adjusted according

to response, for information on dose adjustment based

on haematocrit and platelet count—consult product

literature; usual dose 500–1000 mg daily, dosage

should be based on actual or ideal body weight,

whichever is less

Essential thrombocythaemia (specialist use only)

▶ BY MOUTH

▶ Adult: Initially 15 mg/kg daily, adjusted according to

response, for information on dose adjustment based on

platelet count and white cell count—consult product

literature, dosage should be based on actual or ideal

body weight, whichever is less

Chronic myeloid leukaemia (specialist use only)

▶ BY MOUTH

▶ Adult: Initially 40 mg/kg daily, then reduced to

20 mg/kg daily, adjusted according to response, for

information on dose adjustment based on white cell

count—consult product literature, dosage should be

based on actual or ideal body weight, whichever is less

HYDREA ®

Chronic myeloid leukaemia (specialist use only)| Cancer of

the cervix (specialist use only)

▶ BY MOUTH

▶ Adult: 20–30 mg/kg daily, alternatively 80 mg/kg every

3 days, for information on dose adjustment based on

platelet count, white cell count and actual or ideal body

weight—consult product literature

SIKLOS ®

Sickle-cell disease [prevention of recurrent vaso-occlusive

crises] (initiated by a specialist)

▶ BY MOUTH

▶ Adult: Initially 15 mg/kg daily, increased in steps of

2.5–5 mg/kg daily, dose to be increased every 12 weeks

according to response; usual dose 15–30 mg/kg daily;

maximum 35 mg/kg per day

IMPORTANT SAFETY INFORMATION

RISKS OF INCORRECT DOSING OF ORAL ANTI-CANCER MEDICINES

See Cytotoxic drugs p. 888.

l CAUTIONS Leg ulcers (review treatment if cutaneous

vasculitic ulcerations develop)

l INTERACTIONS → Appendix 1: hydroxycarbamide

l SIDE-EFFECTS

▶ Common or very common Alopecia . anaemia . appetite

decreased . asthenia . bone marrow failure . chills . constipation . cutaneous vasculitis . dermatomyositis . diarrhoea . disorientation . dizziness . drowsiness . dyspnoea . dysuria .fever. gastrointestinal discomfort. hallucination . headache . hepatic disorders . leucopenia . malaise . melaena . mucositis . nail disorder. nausea . pancreatitis . peripheral neuropathy . pulmonary oedema . respiratory disorders . seizure . skin cancer. skin reactions . skin ulcer. sperm abnormalities . stomatitis . thrombocytopenia . vomiting

▶ Rare or very rare Gangrene

l CONCEPTION AND CONTRACEPTION Manufacturer advises

effective contraception before and during treatment.

l PREGNANCY Avoid (teratogenic in animal studies). See

also Pregnancy and reproductive function in Cytotoxic drugs

p. 888.

l BREAST FEEDING Discontinue breast-feeding.

l HEPATIC IMPAIRMENT Manufacturer advises caution in

mild to moderate impairment; avoid in severe impairment

(unless used for malignant conditions).

l RENAL IMPAIRMENT In sickle-cell disease, avoid if eGFR

less than 30 mL/minute/1.73 m2

. Use with caution in

malignant disease.

Dose adjustments In sickle-cell disease, reduce initial dose

by 50% if eGFR less than 60 mL/minute/1.73 m2

.

l MONITORING REQUIREMENTS

▶ Monitor renal and hepatic function before and during

treatment.

▶ Monitor full blood count before treatment, and repeatedly

throughout use; in sickle-cell disease monitor every

2 weeks for the first 2 months and then every 2 months

thereafter (or every 2 weeks if on maximum dose).

▶ Patients receiving long-term therapy for malignant disease

should be monitored for secondary malignancies.

l PATIENT AND CARER ADVICE Patients receiving long-term

therapy with hydroxycarbamide should be advised to

protect skin from sun exposure.

l MEDICINAL FORMS There can be variation in the licensing of

different medicines containing the same drug. Forms available

from special-order manufacturers include: capsule, oral

suspension, oral solution

Tablet

▶ Siklos (Nordic Pharma Ltd)

Hydroxycarbamide 100 mg Siklos 100mg tablets | 60 tablet P £100.00 DT = £100.00

Hydroxycarbamide 1 gram Siklos 1000mg tablets | 30 tablet P £500.00 DT = £500.00

Capsule

▶ Hydroxycarbamide (Non-proprietary)

Hydroxycarbamide 500 mg Hydroxycarbamide 500mg capsules | 100 capsule P £86.00 DT = £12.14

▶ Droxia (Imported (United States))

Hydroxycarbamide 300 mg Droxia 300mg capsules | 60 capsule P s

▶ Hydrea (Bristol-Myers Squibb Pharmaceuticals Ltd)

Hydroxycarbamide 500 mg Hydrea 500mg capsules | 100 capsule P £10.47 DT = £12.14

Mitotane

l DRUG ACTION Mitotane selectively inhibits the activity of

the adrenal cortex, necessitating corticosteroid

replacement therapy.

l INDICATIONS AND DOSE

Symptomatic treatment of advanced or inoperable

adrenocortical carcinoma

▶ BY MOUTH

▶ Adult: Initially 2–3 g daily in 2–3 divided doses

adjusted according to plasma-concentration

monitoring, in severe illness initial dose can be

increased up to 6 g daily, reduce dose or interrupt

treatment if signs of toxicity, discontinue if inadequate

response after 3 months

IMPORTANT SAFETY INFORMATION

RISKS OF INCORRECT DOSING OF ORAL ANTI-CANCER MEDICINES

See Cytotoxic drugs p. 888.

l CAUTIONS Avoid in Acute porphyrias p. 1058 .risk of

accumulation in overweight patients

l INTERACTIONS → Appendix 1: mitotane

l SIDE-EFFECTS

▶ Common or very common Adrenal insufficiency . anaemia . appetite decreased . asthenia . cognitive impairment. confusion . diarrhoea . dizziness . drowsiness . dyslipidaemia . gastrointestinal discomfort.

BNF 78 Cytotoxic responsive malignancy 935

Immune system and malignant disease

8

gynaecomastia . headache . hepatic disorders . leucopenia . movement disorders . mucositis . muscle weakness . nausea . paraesthesia . polyneuropathy .rash .thrombocytopenia . vertigo . vomiting

▶ Frequency not known Encephalopathy . eye disorders . flushing . fungal infection . generalised pain . growth

retardation . haemorrhage . hyperpyrexia . hypersalivation . hypertension . hypothyroidism . hypouricaemia . lens

opacity . neuro-psychological retardation . ovarian cyst. postural hypotension . proteinuria .taste altered .thyroid

disorder. vision disorders

l CONCEPTION AND CONTRACEPTION Contraceptive advice

required, see Pregnancy and reproductive function in

Cytotoxic drugs p. 888.

l PREGNANCY Manufacturer advises avoid. See also

Pregnancy and reproductive function in Cytotoxic drugs

p. 888.

l BREAST FEEDING Discontinue breast-feeding.

l HEPATIC IMPAIRMENT Manufacturer advises caution in

mild to moderate impairment; avoid in severe impairment

(limited information available).

Monitoring In mild to moderate hepatic impairment,

monitoring of plasma-mitotane concentration is

recommended.

l RENAL IMPAIRMENT Manufacturer advises caution in mild

to moderate impairment. Avoid in severe impairment.

Monitoring In mild to moderate renal impairment,

monitoring of plasma-mitotane concentration is

recommended.

l MONITORING REQUIREMENTS

▶ Plasma-mitotane concentration for optimum response

14–20 mg/litre.

▶ Monitor plasma-mitotane concentration—consult product

literature.

l PRESCRIBING AND DISPENSING INFORMATION

Corticosteroid replacement therapy Corticosteroid

replacement therapy is necessary with treatment with

mitotane. The dose of glucocorticoid should be increased

in case of shock, trauma, or infection.

l PATIENT AND CARER ADVICE Patients should be warned to

contact doctor immediately if injury, infection, or illness

occurs (because of risk of acute adrenal insufficiency).

Driving and skilled tasks Central nervous system toxicity

may affect performance of skilled tasks (e.g. driving).

l MEDICINAL FORMS There can be variation in the licensing of

different medicines containing the same drug.

Tablet

CAUTIONARY AND ADVISORY LABELS 2, 10, 21

▶ Lysodren (HRA Pharma UK Ltd)

Mitotane 500 mg Lysodren 500mg tablets | 100 tablet P £590.97

Panobinostat 01-Feb-2017

l DRUG ACTION Panobinostat is a histone deacetylase

inhibitor, which promotes cell-cycle arrest and apoptosis

of tumour cells via multiple pathways.

l INDICATIONS AND DOSE

Treatment of relapsed or refractory multiple myeloma (in

combination with bortezomib and dexamethasone), in

patients who have received at least two prior regimens,

including bortezomib and an immunomodulatory agent

▶ BY MOUTH

▶ Adult 18–74 years: 20 mg once daily, on days 1, 3, 5, 8,

10 and 12 of a 21-day cycle for 8 cycles. Patients with

clinical benefit should continue treatment for 8

additional cycles; total duration 16 cycles (48 weeks),

for doses of dexamethasone and bortezomib, or dose

adjustment due to side-effects—consult product

literature

▶ Adult 75 years and over: 20 mg once daily, on days 1, 3,

5, 8, 10 and 12 of a 21-day cycle for 8 cycles. Patients

with clinical benefit should continue treatment for 8

additional cycles; total duration 16 cycles (48 weeks),

alternatively initially 15 mg once daily, on days 1, 3, 5,

8, 10 and 12 of a 21-day cycle for 1 cycle, increased if

tolerated to 20 mg once daily, on days 1, 3, 5, 8, 10 and

12 of a 21-day cycle for 7 subsequent cycles, patients

with clinical benefit should continue treatment for 8

additional cycles; total duration 16 cycles (48 weeks),

lower dose may be used for the first cycle depending on

patient’s condition and co-morbidities, for doses of

dexamethasone and bortezomib, or dose adjustment

due to side-effects—consult product literature

DOSE ADJUSTMENTS DUE TO INTERACTIONS

▶ Manufacturer advises reduce dose to 10 mg with

concurrent use of potent inhibitors of CYP3A4; if the

potent inhibitor of CYP3A4 is to be continued, consider

increasing the dose to 15 mg if tolerated.

▶ Manufacturer advises avoid potent inhibitors of

CYP3A4 if possible in patients taking a reduced

panobinostat dose due to side-effects, or in those with

hepatic impairment.

IMPORTANT SAFETY INFORMATION

RISKS OF INCORRECT DOSING OF ORAL ANTI-CANCER MEDICINES

See Cytotoxic drugs p. 888.

l CAUTIONS Coagulation disorders . elderly . QT-interval

prolongation .risk factors for QT-interval prolongation

CAUTIONS, FURTHER INFORMATION

▶ Risk factors for QT-interval prolongation Patients at risk of

developing QT-interval prolongation include those with

long QT syndrome, or uncontrolled or significant cardiac

disease.

l INTERACTIONS → Appendix 1: panobinostat

l SIDE-EFFECTS

▶ Common or very common Anaemia . antibiotic associated

colitis . appetite decreased . arrhythmias . asthenia . cheilitis . chills . cough . decreased leucocytes . diarrhoea . dizziness . dry mouth . dyspnoea . electrolyte imbalance . fever. fluid imbalance . gastrointestinal discomfort. gastrointestinal disorders . haemorrhage . headache . hepatic disorders . hyperbilirubinaemia . hyperglycaemia . hypertension . hyperuricaemia . hypoalbuminaemia . hypotension . hypothyroidism . increased risk of infection . insomnia . intracranial haemorrhage . joint swelling . malaise . nausea . neutropenia . palpitations . pancytopenia . peripheral oedema . QT interval prolongation .renal

failure .respiratory disorders . sepsis . skin reactions . syncope .taste altered .thrombocytopenia .tremor. urinary incontinence . vomiting . weight decreased

▶ Uncommon Haemorrhagic shock . myocardial infarction

SIDE-EFFECTS, FURTHER INFORMATION Side-effects are

reported when used in combination with bortezomib and

dexamethasone.

Gastro-intestinal disorders Manufacturer advises that

patients are treated with anti-diarrhoeals, or any

additional treatment, in accordance with local treatment

guidelines at the first sign of abdominal cramping or onset

of diarrhoea.

l CONCEPTION AND CONTRACEPTION Manufacturer advises

exclude pregnancy before starting treatment in women of

child-bearing potential, and ensure highly effective

contraception used during treatment and for 3 months

after last dose. Women using hormonal contraceptives

should also use a barrier method of contraception. Highly

effective contraception also required for men and their

936 Cytotoxic responsive malignancy BNF 78

Immune system and malignant disease

8

female partners during treatment and for 6 months after

last dose.

l PREGNANCY Manufacturer advises avoid unless potential

benefit outweighs risk—toxicity in animal studies. See also

Pregnancy and reproductive function in Cytotoxic drugs

p. 888.

l BREAST FEEDING Manufacturer advises avoid—no

information available.

l HEPATIC IMPAIRMENT Manufacturer advises frequent

monitoring of hepatic function in mild and moderate

impairment, particularly during the dose escalation phase;

avoid in severe impairment—no information available.

Dose adjustments Manufacturer advises reduce initial dose

to 15 mg during the first treatment cycle in mild

impairment—dose may be increased to 20 mg based on

patient tolerability; reduce initial dose to 10 mg during the

first treatment cycle in moderate impairment—dose may

be increased to 15 mg based on patient tolerability.

l MONITORING REQUIREMENTS

▶ Manufacturer advises monitor full blood count before

treatment, then frequently during treatment; reduce dose

or interrupt treatment if thrombocytopenia or neutropenia

occur—consult product literature.

▶ Manufacturer advises monitor ECG before treatment and

repeat periodically before each treatment cycle; QTcF

should be <480 milliseconds before treatment initiation—

consult product literature.

▶ Manufacturer advises monitor electrolytes before

treatment and periodically as clinically indicated,

especially in patients with diarrhoea; monitor thyroid and

pituitary function (free T4 and TSH) as clinically indicated;

monitor hepatic function before treatment and regularly

during treatment as clinically indicated.

▶ Manufacturer advises monitor patients over 65 years more

frequently, especially for thrombocytopenia and gastrointestinal toxicity.

l PATIENT AND CARER ADVICE Manufacturer advises that

patients and their carers should be told to seek medical

advice if severe gastro-intestinal toxicity occurs.

Missed doses Manufacturer advises if a dose is missed, it

can be taken up to 12 hours after the specified dose time.

Driving and skilled tasks Dizziness may affect performance

of skilled tasks (e.g. driving).

l NATIONAL FUNDING/ACCESS DECISIONS

NICE decisions

▶ Panobinostat for treating multiple myeloma after at least

2 previous treatments (January 2016) NICE TA380

Panobinostat, in combination with bortezomib and

dexamethasone, is recommended as an option for treating

relapsed or refractory multiple myeloma in patients who

have received at least 2 prior regimens including

bortezomib and an immunomodulatory agent when the

manufacturer provides panobinostat with the discount

agreed in the patient access scheme.

www.nice.org.uk/TA380

l MEDICINAL FORMS There can be variation in the licensing of

different medicines containing the same drug.

Capsule

CAUTIONARY AND ADVISORY LABELS 25

▶ Farydak (Novartis Pharmaceuticals UK Ltd) A

Panobinostat (as Panobinostat lactate anhydrous)

10 mg Farydak 10mg capsules | 6 capsule P £3,492.00

Panobinostat (as Panobinostat lactate anhydrous) 15 mg Farydak

15mg capsules | 6 capsule P £3,492.00

Panobinostat (as Panobinostat lactate anhydrous)

20 mg Farydak 20mg capsules | 6 capsule P £4,656.00

Pegaspargase 16-Mar-2017

l DRUG ACTION Pegaspargase breaks down the amino acid

L-asparagine, thereby interfering with the growth of

malignant cells, which are unable to synthesise Lasparagine.

l INDICATIONS AND DOSE

Acute lymphoblastic leukaemia (in combination with

other antineoplastic drugs) (specialist use only)

▶ BY INTRAMUSCULAR INJECTION, OR BY INTRAVENOUS INFUSION

▶ Adult 18–21 years: 2500 units/m2 every 14 days

▶ Adult 22 years and over: 2000 units/m2 every 14 days

l CONTRA-INDICATIONS History of pancreatitis . history of

serious haemorrhagic event with previous L-asparaginase

therapy . history of serious thrombosis with previous Lasparaginase therapy

l CAUTIONS Concomitant use of other hepatotoxic drugs

(particularly in pre-existing hepatic impairment)—monitor

hepatic function . diabetes (may raise blood glucose). hypersensitivity reactions . marked decrease of leukocyte

count at start of treatment is possible—may be associated

with significant rise in serum uric acid and development of

uric acid nephropathy

CAUTIONS, FURTHER INFORMATION

▶ Hypersensitivity reactions Serious hypersensitivity reactions,

including life-threatening anaphylaxis, can occur—

pegaspargase should only be administered when

appropriately trained staff and resuscitation facilities are

immediately available; manufacturer advises patients

should be closely monitored for signs of hypersensitivity

during treatment and for an hour after administration. In

the event of a hypersensitivity reaction, treatment should

be stopped immediately and appropriate management

initiated.

l INTERACTIONS → Appendix 1: pegaspargase

l SIDE-EFFECTS

▶ Common or very common Abdominal pain . bone marrow

depression . diarrhoea . hyperglycaemia . hypersensitivity . hypoxia . pain in extremity . pancreatitis (discontinue if

suspected and do not restart if confirmed). peripheral

neuropathy .rash . seizure . stomatitis . syncope . thrombosis (discontinue). vomiting

▶ Rare or very rare Acute kidney injury . posterior reversible

encephalopathy syndrome (PRES).tremor

▶ Frequency not known Confusion . diabetic ketoacidosis . drowsiness . hepatobiliary disorder. hyperammonaemia

(monitor if symptoms present).toxic epidermal necrolysis

SIDE-EFFECTS, FURTHER INFORMATION There have been

rare reports of cholestasis, icterus, hepatic cell necrosis

and hepatic failure with fatal outcome in patients

receiving pegaspargase.

l CONCEPTION AND CONTRACEPTION Manufacturer advises

effective contraception in men and women of childbearing potential during treatment and for at least

6 months after discontinuing treatment; pegaspargase

may reduce effectiveness of oral contraceptives—

additional precautions (e.g. barrier method) are required,

see also Pregnancy and reproductive function in Cytotoxic

drugs p. 888.

l PREGNANCY Manufacturer advises avoid unless essential.

See also Pregnancy and reproductive function in Cytotoxic

drugs p. 888.

l BREAST FEEDING Manufacturer advises avoid—no

information available.

l HEPATIC IMPAIRMENT Manufacturer advises avoid in

severe impairment.

l MONITORING REQUIREMENTS

▶ Manufacturer advises trough serum asparaginase activity

levels may be measured before the next administration of

BNF 78 Cytotoxic responsive malignancy 937

Immune system and malignant disease

8

pegaspargase; consider switching to a different

asparaginase preparation if target levels not reached—seek

expert advice.

▶ Manufacturer advises monitor plasma and urine glucose

levels during treatment; monitor coagulation profile at

baseline and periodically during and after treatment

(particularly with concomitant use of other drugs that

inhibit coagulation); monitor serum amylase.

l DIRECTIONS FOR ADMINISTRATION Manufacturer advises

for intramuscular injection, volumes over 3 mL must be

divided between more than one site.

l HANDLING AND STORAGE Manufacturer advises store in a

refrigerator between 2–8°C.

l PATIENT AND CARER ADVICE

Pancreatitis Manufacturer advises patients and carers

should be told how to recognise signs and symptoms of

pancreatitis and advised to seek medical attention if

symptoms such as persistent, severe abdominal pain

develop.

Driving and skilled tasks Manufacturer advises patients and

carers should be counselled on the effects on driving and

performance of skilled tasks—increased risk of confusion

and somnolence.

l NATIONAL FUNDING/ACCESS DECISIONS

NICE decisions

▶ Pegaspargase for treating acute lymphoblastic leukaemia

(September 2016) NICE TA408

Pegaspargase, as part of antineoplastic combination

therapy, is recommended as an option for treating acute

lymphoblastic leukaemia only in patients with untreated

newly diagnosed disease.

Patients whose treatment was started within the NHS

before this guidance was published may continue

treatment until they and their clinician consider it

appropriate to stop.

www.nice.org.uk/guidance/ta408

Scottish Medicines Consortium (SMC) decisions

The Scottish Medicines Consortium has advised (October

2016) that pegaspargase (Oncaspar ®) is accepted for use

within NHS Scotland as a component of antineoplastic

combination therapy in acute lymphoblastic leukaemia.

l MEDICINAL FORMS There can be variation in the licensing of

different medicines containing the same drug.

Solution for injection

▶ Oncaspar (Servier Laboratories Ltd) A

Pegaspargase 750 unit per 1 ml Oncaspar 3,750units/5ml solution

for injection vials | 1 vial P £1,296.19

Procarbazine

l DRUG ACTION Procarbazine is a mild monoamine-oxidase

inhibitor.

l INDICATIONS AND DOSE

Hodgkin’s lymphoma

▶ BY MOUTH

▶ Adult: (consult local protocol)

IMPORTANT SAFETY INFORMATION

RISKS OF INCORRECT DOSING OF ORAL ANTI-CANCER MEDICINES

See Cytotoxic drugs p. 888.

l CONTRA-INDICATIONS Pre-existing severe leucopenia . pre-existing severe thrombocytopenia

l CAUTIONS Cardiovascular disease . cerebrovascular disease . epilepsy . phaeochromocytoma . procarbazine is a mild

monoamineoxidase inhibitor (dietary restriction is rarely

considered necessary)

l INTERACTIONS → Appendix 1: procarbazine

l SIDE-EFFECTS

▶ Common or very common Appetite decreased

▶ Frequency not known Azoospermia . hepatic disorders . infection . lethargy . leucopenia . nausea . neutropenia . ovarian failure . pneumonitis . skin reactions . thrombocytopenia . vomiting

l CONCEPTION AND CONTRACEPTION Contraceptive advice

required, see Pregnancy and reproductive function in

Cytotoxic drugs p. 888.

l PREGNANCY Avoid (teratogenic in animal studies and

isolated reports in humans). See also Pregnancy and

reproductive function in Cytotoxic drugs p. 888.

l BREAST FEEDING Discontinue breast-feeding.

l HEPATIC IMPAIRMENT Manufacturer advises caution in

mild to moderate impairment; avoid in severe impairment.

l RENAL IMPAIRMENT Caution in mild to moderate

impairment. Avoid in severe impairment.

l MEDICINAL FORMS There can be variation in the licensing of

different medicines containing the same drug.

Capsule

CAUTIONARY AND ADVISORY LABELS 4

▶ Procarbazine (Non-proprietary)

Procarbazine (as Procarbazine hydrochloride)

50 mg Procarbazine 50mg capsules | 50 capsule P £411.35–

£452.48 DT = £431.92

Raltitrexed

l DRUG ACTION Raltitrexed is a thymidylate synthase

inhibitor.

l INDICATIONS AND DOSE

Palliation of advanced colorectal cancer when fluorouracil

and folinic acid cannot be used

▶ BY INTRAVENOUS INFUSION

▶ Adult: (consult local protocol)

l INTERACTIONS → Appendix 1: raltitrexed

l SIDE-EFFECTS

▶ Common or very common Alopecia . anaemia . appetite

decreased . arthralgia . asthenia . cellulitis . conjunctivitis . constipation . dehydration . diarrhoea . fever. gastrointestinal discomfort. headache . hyperbilirubinaemia . hyperhidrosis . influenza like illness . leucopenia . malaise . mucositis . muscle cramps . muscle

tone increased . nausea . neutropenia . oral disorders . pain . peripheral oedema . sepsis . skin reactions .taste altered . thrombocytopenia . vomiting . weight decreased

▶ Frequency not known Gastrointestinal haemorrhage

l CONCEPTION AND CONTRACEPTION Ensure effective

contraception during and for at least 6 months after

treatment in men or women.

l PREGNANCY See Pregnancy and reproductive function in

Cytotoxic drugs p. 888.

l BREAST FEEDING Discontinue breast-feeding.

l HEPATIC IMPAIRMENT Manufacture advises caution in

mild to moderate impairment; avoid in severe impairment,

jaundice or decompensated disease (no information

available).

l RENAL IMPAIRMENT Avoid if creatinine clearance less than

25 mL/minute.

Dose adjustments Reduce dose and increase dosing

interval if creatinine clearance less than 65 mL/minute

(consult product literature).

938 Cytotoxic responsive malignancy BNF 78

Immune system and malignant disease

8

l NATIONAL FUNDING/ACCESS DECISIONS

NICE decisions

▶ Irinotecan, oxaliplatin, and raltitrexed for advanced colorectal

cancer (August 2005) NICE TA93

Raltitrexed is not recommended for the treatment of

advanced colorectal cancer. Its use should be confined to

clinical studies.

www.nice.org.uk/TA93

l MEDICINAL FORMS There can be variation in the licensing of

different medicines containing the same drug.

Powder for solution for infusion

▶ Tomudex (Pfizer Ltd)

Raltitrexed 2 mg Tomudex 2mg powder for solution for infusion vials

| 1 vial P £148.75 (Hospital only)

RETINOID AND RELATED DRUGS

Bexarotene 27-Apr-2019

l DRUG ACTION Bexarotene is an agonist at the retinoid X

receptor, which is involved in the regulation of cell

differentiation and proliferation. Bexarotene can cause

regression of cutaneous T-cell lymphoma.

l INDICATIONS AND DOSE

Skin manifestations of cutaneous T-cell lymphoma

refractory to previous systemic treatment

▶ BY MOUTH

▶ Adult: Initially 300 mg/m2 once daily, adjusted

according to response, to be taken with a meal

IMPORTANT SAFETY INFORMATION

RISKS OF INCORRECT DOSING OF ORAL ANTI-CANCER MEDICINES

See Cytotoxic drugs p. 888.

l CONTRA-INDICATIONS History of pancreatitis . hypervitaminosis A. uncontrolled hyperlipidaemia . uncontrolled hypothyroidism

l CAUTIONS Avoid in Acute porphyrias p. 1058 . hyperlipidaemia . hypothyroidism

l INTERACTIONS → Appendix 1: retinoids

l SIDE-EFFECTS

▶ Common or very common Alopecia . anaemia . appetite

decreased . arthralgia . asthenia . chills . constipation . deafness . diarrhoea . dizziness . dry eye . dry mouth . dyslipidaemia . eye disorders . gastrointestinal discomfort. gastrointestinal disorders . headaches . hyperhidrosis . hypersensitivity . hypoproteinaemia . hypothyroidism . increased risk of infection . insomnia . leucopenia . lymphadenopathy . muscle complaints . nausea . oedema . oral disorders . pain . pseudolymphoma . sensation

abnormal . skin nodule . skin reactions . skin ulcer.thyroid

disorder. vomiting . weight changes

▶ Uncommon Albuminuria . anxiety . arrhythmias . ataxia . blood disorder. cataract. coagulation disorder. depression . ear disorder. eosinophilia . eye inflammation .fever. gout . haemorrhage . hair disorder. hepatic failure . hyperbilirubinaemia . hypertension . hyperthyroidism . increased leucocytes . mucous membrane disorder. muscle

weakness . nail disorder. neoplasms . nerve disorders . pancreatitis .renal impairment. serous drainage . thrombocytopenia .thrombocytosis . varicose veins . vasodilation . vertigo . vision disorders

▶ Frequency not known Burping . chest pain . confusion . cough aggravated . dehydration . drowsiness . dysphagia . dyspnoea . emotional lability . hypercalcaemia . hyperuricaemia . libido decreased . muscle tone increased . pelvic pain . peripheral vascular disease .red blood cell

abnormality .taste altered .thirst.tinnitus . white blood

cell abnormalities

l ALLERGY AND CROSS-SENSITIVITY Caution—

hypersensitivity to retinoids.

l CONCEPTION AND CONTRACEPTION Manufacturer advises

effective contraception during and for at least 1 month

after treatment in men and women.

l PREGNANCY Avoid. See also Pregnancy and reproductive

function in Cytotoxic drugs p. 888.

l BREAST FEEDING Discontinue breast-feeding.

l HEPATIC IMPAIRMENT Manufacturer advises avoid in

hepatic insufficiency.

l NATIONAL FUNDING/ACCESS DECISIONS

Scottish Medicines Consortium (SMC) decisions

SMC No. 14/02

The Scottish Medicines Consortium has advised (November

2002) that bexarotene (Targretin ®) is recommended for

restricted use as a second-line treatment for patients with

advanced (stages IIb or III) cutaneous T-cell lymphoma

who have proved refractory both to local skin directed

therapy and to at least one systemic therapy.

l MEDICINAL FORMS There can be variation in the licensing of

different medicines containing the same drug.

Capsule

▶ Targretin (Eisai Ltd)

Bexarotene 75 mg Targretin 75mg capsules | 100 capsule P £937.50

Tretinoin

l INDICATIONS AND DOSE

Induction of remission in acute promyelocytic leukaemia

(used in previously untreated patients as well as in those

who have relapsed after standard chemotherapy or who

are refractory to it)

▶ BY MOUTH

▶ Adult: 45 mg/m2 daily in 2 divided doses maximum

duration of treatment is 90 days, consult product

literature for details of concomitant chemotherapy

l CAUTIONS Increased risk of thromboembolism during first

month of treatment

l INTERACTIONS → Appendix 1: retinoids

l SIDE-EFFECTS

▶ Common or very common Abdominal pain . alopecia . anxiety . appetite decreased . arrhythmia . asthma . bone

pain . cheilitis . chest pain . chills . confusion . constipation . depression . diarrhoea . dizziness . dry mouth . flushing . headache . hearing impairment. hyperhidrosis . insomnia . intracranial pressure increased . malaise . nasal dryness . nausea . pancreatitis . paraesthesia .respiratory disorders . skin reactions . visual impairment. vomiting

▶ Frequency not known Embolism and thrombosis . erythema

nodosum . genital ulceration . hepatotoxicity . hypercalcaemia . increased leucocytes . myocardial

infarction . myositis . necrotising fasciitis . QT interval

prolongation . stroke .thrombocytosis . vasculitis

SIDE-EFFECTS, FURTHER INFORMATION Retinoic acid

syndrome Fever, dyspnoea, acute respiratory distress,

pulmonary infiltrates, pleural effusion, hyperleucocytosis,

hypotension, oedema, weight gain, hepatic, renal and

multi-organ failure requires immediate treatment—

consult product literature.

l CONCEPTION AND CONTRACEPTION Effective

contraception must be used for at least 1 month before

oral treatment, during treatment and for at least 1 month

after stopping (oral progestogen-only contraceptives not

considered effective).

l PREGNANCY Teratogenic. See Pregnancy and reproductive

function in Cytotoxic drugs p. 888.

l BREAST FEEDING Avoid (discontinue breast-feeding).

BNF 78 Cytotoxic responsive malignancy 939

Immune system and malignant disease

8

l HEPATIC IMPAIRMENT Manufacturer advises caution.

Dose adjustments Manufacturer advises dose reduction to

25 mg/m2

.

l RENAL IMPAIRMENT

Dose adjustments Reduce dose to 25 mg/m2

.

l MONITORING REQUIREMENTS Monitor haematological and

coagulation profile, liver function, serum calcium and

plasma lipids before and during treatment.

l PRESCRIBING AND DISPENSING INFORMATION Tretinoin is

the acid form of vitamin A.

l MEDICINAL FORMS There can be variation in the licensing of

different medicines containing the same drug.

Capsule

CAUTIONARY AND ADVISORY LABELS 21, 25

▶ Tretinoin (Non-proprietary)

Tretinoin 10 mg Tretinoin 10mg capsules | 100 capsule P £300.00–£315.00 DT = £300.00

3.1 Cytotoxic drug-induced side

effects

ANTIDOTES AND CHELATORS › IRON CHELATORS

Dexrazoxane

l DRUG ACTION Dexrazoxane is an iron chelator.

l INDICATIONS AND DOSE

CARDIOXANE ®

Prevention of chronic cumulative cardiotoxicity caused by

doxorubicin or epirubicin treatment in advanced or

metastatic breast cancer patients who have received a

prior cumulative dose of 300 mg/m2 of doxorubicin or a

prior cumulative dose of 540 mg/m2 of epirubicin when

further anthracycline treatment is required

▶ BY INTRAVENOUS INFUSION

▶ Adult: Administer 10 times the doxorubicin-equivalent

dose or 10 times the epirubicin-equivalent dose, dose

to be given 30 minutes before anthracycline

administration

SAVENE ®

Anthracycline extravasation

▶ BY INTRAVENOUS INFUSION

▶ Adult: Initially 1 g/m2 daily (max. per dose 2 g) for

2 days, then 500 mg/m2 for 1 day, first dose to be given

as soon as possible and within 6 hours after injury

l CONTRA-INDICATIONS Children

l CAUTIONS Myelosuppression (effects may be additive to

those of chemotherapy)

CARDIOXANE ® Manufacturer advises caution in patients

with heart failure—no information available . manufacturer advises caution in patients with myocardial

infarction in previous 12 months—no information

available . manufacturer advises caution in patients with

symptomatic valvular heart disease—no information

available . manufacturer advises caution in patients with

uncontrolled angina—no information available

l INTERACTIONS → Appendix 1: iron chelators

l SIDE-EFFECTS

▶ Common or very common Alopecia . anaemia . appetite

decreased . asthenia . constipation . cough . diarrhoea . dizziness . drowsiness . dry mouth . dyspnoea . embolism

and thrombosis .fever. gastrointestinal discomfort. headache . increased risk of infection . leucopenia . myalgia . nail disorder. nausea . neutropenia . peripheral

neuropathy . peripheral oedema . post procedural infection . sensation abnormal . skin reactions . stomatitis . syncope .

tachycardia .thrombocytopenia .tremor. vaginal

haemorrhage . vomiting . weight decreased . wound

complications

▶ Uncommon Acute myeloid leukaemia . lymphoedema . sepsis .thirst. vertigo

▶ Frequency not known Anaphylactic reaction

l CONCEPTION AND CONTRACEPTION Ensure effective

contraception during and for at least 3 months after

treatment in men and women.

l PREGNANCY Avoid unless essential (toxicity in animal

studies).

l BREAST FEEDING Discontinue breast-feeding.

l HEPATIC IMPAIRMENT

CARDIOXANE ® Manufacturer advises caution (no

information available).

Dose adjustments Manufacturer advises if anthracycline

dose is reduced, reduce the Cardioxane ® dose by a similar

ratio.

SAVENE ® Manufacturer advises avoid (no information

available).

l RENAL IMPAIRMENT

CARDIOXANE ® DOSE ADJUSTMENTS Manufacturer

advises reduce dose by 50% if creatinine clearance less

than 40 mL/minute.

SAVENE ® Manufacturer advises avoid—risk of

accumulation.

l MONITORING REQUIREMENTS

▶ Monitor full blood count.

▶ Monitor for cardiac toxicity.

▶ Monitor liver function.

l DIRECTIONS FOR ADMINISTRATION Local coolants such as

ice packs should be removed at least 15 minutes before

administration.

CARDIOXANE ® For intravenous infusion, give

intermittently in Compound sodium lactate; reconstitute

each vial with 25 mL water for injections and dilute each

vial with 25–100 mL infusion fluid; give requisite dose over

15 minutes.

SAVENE ® For intravenous infusion, give intermittently in

diluent; reconstitute each 500-mg vial with 25 mL of

diluent; dilute requisite dose further in remaining diluent

and give over 1–2 hours into a large vein in an area other

than the one affected.

l MEDICINAL FORMS There can be variation in the licensing of

different medicines containing the same drug.

Powder for solution for infusion

▶ Cardioxane (Clinigen Healthcare Ltd)

Dexrazoxane 500 mg Cardioxane 500mg powder for solution for

infusion vials | 1 vial P £156.57

Powder and solvent for solution for infusion

ELECTROLYTES: May contain Potassium, sodium

▶ Savene (Clinigen Healthcare Ltd)

Dexrazoxane 500 mg Savene 500mg powder for concentrate and

solvent for solution for infusion vials | 10 vial P s

DETOXIFYING DRUGS › UROPROTECTIVE DRUGS

Mesna

l INDICATIONS AND DOSE

Cytotoxic induced urothelial toxicity

▶ BY MOUTH, OR BY INTRAVENOUS INJECTION

▶ Adult: Dose to be calculated according to

oxazaphosphorine (cyclophosphamide or ifosfamide)

treatment (consult product literature)

l SIDE-EFFECTS

▶ Common or very common Appetite decreased . arthralgia . asthenia . chest pain . chills . concentration impaired .

940 Cytotoxic responsive malignancy BNF 78

Immune system and malignant disease

8

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