osteoporosis . photosensitivity reaction .rheumatoid
arthritis aggravated . seizure . severe cutaneous adverse
reactions (SCARs). vasculitis . vertigo . vulvovaginal
disorders . haemorrhage . healing impaired . hepatic
disorders . increased risk of infection . lipoatrophy . local
arthritis aggravated . seizure . severe cutaneous adverse
reactions (SCARs). sterile abscess . vasculitis . vertigo . vulvovaginal disorders
▶ With oral use Azotaemia . brain oedema . cognitive
impairment. conjunctivitis . cough . dyspnoea . eosinophilia . gynaecomastia . hypotension . immune
disorders . pericarditis . proteinuria . psychosis .radiation
injuries .renal impairment.retinopathy . sensation
fracture .taste altered .telangiectasia . vision disorders
▶ With oral use Encephalopathy
SIDE-EFFECTS, FURTHER INFORMATION Give folic acid to
reduce side-effects. Folic acid decreases mucosal and
gastrointestinal side-effects of methotrexate and may
prevent hepatotoxicity; there is no evidence of a reduction
in haematological side-effects.
Withdraw treatment if ulcerative stomatitis develops—
may be first sign of gastro-intestinal toxicity.
Treatment with folinic acid (as calcium folinate) may be
l CONCEPTION AND CONTRACEPTION Manufacturer advises
effective contraception during and for at least 6 months
after treatment in men and women.
l PREGNANCY Avoid (teratogenic; fertility may be reduced
during therapy but this may be reversible).
l BREAST FEEDING Discontinue breast-feeding—present in
l HEPATIC IMPAIRMENT When used for malignancy, avoid in
severe hepatic impairment—consult local treatment
protocol for details. Avoid with hepatic impairment in
non-malignant conditions—dose-related toxicity.
l RENAL IMPAIRMENT Risk of nephrotoxicity at high doses.
l PRE-TREATMENT SCREENING Exclude pregnancy before
Patients should have full blood count and renal and liver
function tests before starting treatment.
▶ In view of reports of blood dyscrasias (including fatalities)
and liver cirrhosis with low-dose methotrexate patients
. have full blood count and renal and liver function tests
repeated every 1–2 weeks until therapy stabilised,
thereafter patients should be monitored every
. be advised to report all symptoms and signs suggestive
of infection, especially sore throat
▶ Local protocols for frequency of monitoring may vary.
▶ Treatment with folinic acid (as calcium folinate) may be
l PRESCRIBING AND DISPENSING INFORMATION Folinic acid
following methotrexate administration helps to prevent
methotrexate-induced mucositis and myelosuppression.
The licensed routes of administration for parenteral
preparations vary—further information can be found in
the product literature for the individual preparations.
l PATIENT AND CARER ADVICE Patients and their carers
should be warned to report immediately the onset of any
feature of blood disorders (e.g. sore throat, bruising, and
mouth ulcers), liver toxicity (e.g. nausea, vomiting,
abdominal discomfort and dark urine), and respiratory
effects (e.g. shortness of breath).
Patients should be advised to avoid self-medication with
over-the-counter aspirin or ibuprofen.
Patients should be counselled on the dose, treatment
booklet, and the use of NSAIDs.
Methotrexate treatment booklets Methotrexate treatment
booklets should be issued where appropriate.
In England, Wales, and Northern Ireland, they are
GP practices can obtain supplies through their Local
NHS Hospitals can order supplies from www.nhsforms.co.
uk or by emailing nhsforms@mmm.com.
In Scotland, treatment booklets can be obtained by
emailing stockorders.dppas@theapsgroup.com or by fax
These booklets include advice for adults taking oral
methotrexate for inflammatory conditions, and a section
for recording results of blood tests and dosage
l MEDICINAL FORMS There can be variation in the licensing of
different medicines containing the same drug. Forms available
from special-order manufacturers include: oral suspension, oral
solution, solution for injection
▶ Methotrexate (Non-proprietary)
Methotrexate 10 mg Methotrexate 10mg tablets | 100 tablet P £55.74 DT = £46.66
Methotrexate 2.5 mg Maxtrex 2.5mg tablets | 24 tablet P £2.39
Methotrexate 10 mg Maxtrex 10mg tablets | 100 tablet P £45.16 DT = £46.66
▶ Methotrexate (Non-proprietary)
Methotrexate (as Methotrexate sodium) 2.5 mg per
1 ml Methotrexate 5mg/2ml solution for injection vials | 5 vial P £36.00 (Hospital only)
914 Cytotoxic responsive malignancy BNF 78
Immune system and malignant disease
Methotrexate (as Methotrexate sodium) 25 mg per
Methotrexate 200mg/8ml solution for injection vials | 1 vial P £10.02
Methotrexate (as Methotrexate sodium) 100 mg per
1 ml Methotrexate 1g/10ml solution for injection vials | 1 vial P £85.00 (Hospital only)
▶ Methofill (Accord Healthcare Ltd)
Methotrexate 50 mg per 1 ml Methofill 12.5mg/0.25ml solution for
injection pre-filled injector | 1 pre-filled disposable injection P £14.34 DT = £14.35
Methofill 22.5mg/0.45ml solution for injection pre-filled injector |
1 pre-filled disposable injection P £16.10 DT = £16.11
Methofill 17.5mg/0.35ml solution for injection pre-filled injector |
1 pre-filled disposable injection P £15.24 DT = £15.25
Methotrexate 50 mg per 1 ml Metoject PEN 30mg/0.6ml solution for
injection pre-filled pen | 1 pre-filled disposable injection P £16.56
▶ Nordimet (Nordic Pharma Ltd)
Methotrexate 25 mg per 1 ml Nordimet 15mg/0.6ml solution for
injection pre-filled pens | 1 pre-filled disposable injection P £14.92 DT = £14.92
Nordimet 25mg/1ml solution for injection pre-filled pens | 1 pre-filled
disposable injection P £16.64 DT = £16.64
Methotrexate (as Methotrexate sodium) 25 mg per 1 ml Zlatal
17.5mg/0.7ml solution for injection pre-filled syringes | 1 pre-filled
disposable injection P £15.75 DT = £15.75
Zlatal 25mg/1ml solution for injection pre-filled syringes | 1 pre-filled
disposable injection P £16.64 DT = £16.64
▶ Methotrexate (Non-proprietary)
Methotrexate (as Methotrexate sodium) 25 mg per
1 ml Methotrexate 5g/200ml solution for infusion vials | 1 vial P £200.57
Methotrexate (as Methotrexate sodium) 100 mg per
1 ml Methotrexate 5g/50ml solution for infusion vials | 1 vial P £400.00 (Hospital only)
▶ Methotrexate (Non-proprietary)
Methotrexate (as Methotrexate sodium) 2 mg per
▶ Jylamvo (Intrapharm Laboratories Ltd)
Methotrexate (as Methotrexate sodium) 2 mg per 1 ml Jylamvo
2mg/ml oral solution sugar-free | 60 ml P £112.50
T-cell acute lymphoblastic leukaemia and T-cell
lymphoblastic lymphoma in patients who have relapsed
or who are refractory after receiving at least two
▶ Adult: (consult local protocol)
l CAUTIONS Previous or concurrent craniospinal irradiation
(increased risk of neurotoxicity). previous or concurrent
intrathecal chemotherapy (increased risk of neurotoxicity)
l INTERACTIONS → Appendix 1: nelarabine
risk of infection . leucopenia . memory loss . movement
▶ Rare or very rare Rhabdomyolysis
▶ Frequency not known Progressive multifocal
SIDE-EFFECTS, FURTHER INFORMATION If neurotoxicity
occurs, treatment should be discontinued.
l CONCEPTION AND CONTRACEPTION Manufacturer advises
effective contraception during and for at least 3 months
after treatment in men and women.
l PREGNANCY Avoid (toxicity in animal studies). See also
Pregnancy and reproductive function in Cytotoxic drugs
l BREAST FEEDING Discontinue breast-feeding.
▶ Neurotoxicity Close monitoring for neurological events is
strongly recommended—discontinue if neurotoxicty
BNF 78 Cytotoxic responsive malignancy 915
Immune system and malignant disease
Driving and skilled tasks Drowsiness may affect
performance of skilled tasks (e.g. cycling or driving).
l NATIONAL FUNDING/ACCESS DECISIONS
Scottish Medicines Consortium (SMC) decisions
The Scottish Medicines Consortium has advised (March
2008) that the use of nelarabine (Atriance ®) within NHS
Scotland is restricted to bridging treatment before stem
l MEDICINAL FORMS There can be variation in the licensing of
different medicines containing the same drug.
ELECTROLYTES: May contain Sodium
▶ Atriance (Novartis Pharmaceuticals UK Ltd) A
Nelarabine 5 mg per 1 ml Atriance 250mg/50ml solution for infusion
l DRUG ACTION Pemetrexed inhibits thymidylate
transferase and other folate-dependent enzymes.
Treatment of unresectable malignant pleural
mesothelioma which has not previously been treated
with chemotherapy (in combination with cisplatin)|
First-line treatment of locally advanced or metastatic
non-small cell lung cancer other than predominantly
squamous cell histology (in combination with cisplatin)|
Second-line treatment of locally advanced or metastatic
non-small cell lung cancer other than predominantly
squamous cell histology (monotherapy)| Maintenance
treatment in locally advanced or metastatic non-small
cell lung cancer other than predominantly squamous cell
histology that has not progressed immediately following
platinum-based chemotherapy (monotherapy)
▶ Adult: (consult local protocol)
product literature). prophylactic vitamin B12
supplementation required (consult product literature)
l INTERACTIONS → Appendix 1: pemetrexed
l CONCEPTION AND CONTRACEPTION Manufacturer advises
effective contraception during treatment. Men must avoid
fathering a child during and for 6 months after treatment.
l PREGNANCY Avoid (toxicity in animal studies). See also
Pregnancy and reproductive function in Cytotoxic drugs
l BREAST FEEDING Discontinue breast-feeding.
l RENAL IMPAIRMENT Manufacturer advises avoid if
creatinine clearance less than 45 mL/minute—no
l NATIONAL FUNDING/ACCESS DECISIONS
▶ Pemetrexed for the treatment of non-small cell lung cancer
Pemetrexed is not recommended for the treatment of
locally advanced or metastatic non-small cell lung cancer
which has previously been treated with chemotherapy.
▶ Pemetrexed for the first-line treatment of non-small cell lung
cancer (September 2009) NICE TA181
Pemetrexed, in combination with cisplatin, is an option for
the first-line treatment of locally advanced or metastatic
non-small cell lung cancer only if the histology of the
tumour has been confirmed as adenocarcinoma or largecell carcinoma.
▶ Pemetrexed for the maintenance treatment of non-small-cell
lung cancer (updated August 2017) NICE TA190
Pemetrexed is recommended as an option for the
maintenance treatment of locally advanced or metastatic
non-small cell lung cancer other than predominantly
squamous cell histology if disease has not progressed
immediately following platinum-based chemotherapy in
combination with gemcitabine, paclitaxel or docetaxel.
www.nice.org.uk/guidance/TA190
Pemetrexed is recommended as an option for the
maintenance treatment of locally advanced or metastatic
non-squamous non-small cell lung cancer in patients
. their disease has not progressed immediately after
4 cycles of pemetrexed and cisplatin induction therapy
. their Eastern Cooperative Oncology Group performance
status is 0 or 1 at the start of maintenance treatment,
. the company provides the drug according to the terms of
the commercial access agreement as agreed with NHS
Patients whose treatment was started within the NHS
before this guidance was published should have the option
to continue treatment, without change to their funding
arrangements, until they and their clinician consider it
▶ Pemetrexed for the treatment of malignant pleural
mesothelioma (January 2008) NICE TA135
Pemetrexed is an option for the treatment of malignant
pleural mesothelioma only in patients who have a WHO
performance status of 0 or 1 [WHO performance status is a
measure of the ability to perform ordinary tasks], who are
considered to have advanced disease and for whom
surgical resection is considered inappropriate.
Scottish Medicines Consortium (SMC) decisions
The Scottish Medicines Consortium has advised (September
2008) that pemetrexed (Alimta ®) is accepted for restricted
cell lung cancer other than predominantly squamous cell
histology. It is restricted for use in patients with good
performance status who would otherwise be eligible for
The Scottish Medicines Consortium has advised (February
2010) that pemetrexed (Alimta ®) is accepted for restricted
use within NHS Scotland in combination with cisplatin for
the first-line treatment of locally advanced or metastatic
non-small cell lung cancer other than predominantly
squamous cell histology. It is restricted to patients in
whom histology has been confirmed as adenocarcinoma or
l MEDICINAL FORMS There can be variation in the licensing of
different medicines containing the same drug.
▶ Pemetrexed (Non-proprietary)
Pemetrexed (as Pemetrexed ditrometamol) 25 mg per
1 ml Pemetrexed 100mg/4ml concentrate for solution for infusion
Pemetrexed 500mg/20ml concentrate for solution for infusion vials |
Pemetrexed 1000mg/40ml concentrate for solution for infusion vials
916 Cytotoxic responsive malignancy BNF 78
Immune system and malignant disease
Powder for solution for infusion
ELECTROLYTES: May contain Sodium
▶ Pemetrexed (Non-proprietary)
Pemetrexed (as Pemetrexed disodium) 100 mg Pemetrexed
Pemetrexed (as Pemetrexed disodium) 500 mg Pemetrexed
▶ Alimta (Eli Lilly and Company Ltd)
Pemetrexed (as Pemetrexed disodium) 100 mg Alimta 100mg
powder for concentrate for solution for infusion vials | 1 vial P £160.00 (Hospital only)
Pemetrexed (as Pemetrexed disodium) 500 mg Alimta 500mg
powder for concentrate for solution for infusion vials | 1 vial P £800.00 (Hospital only)
Tegafur with gimeracil and oteracil
l DRUG ACTION Tegafur is a prodrug of fluorouracil.
Gimeracil inhibits the degradation of fluorouracil and
oteracil decreases the activity of fluorouracil in normal
Treatment of advanced gastric cancer when used in
▶ Adult: (consult local protocol)
RISKS OF INCORRECT DOSING OF ORAL ANTI-CANCER MEDICINES
l CONTRA-INDICATIONS Dihydropyrimidine dehydrogenase
l INTERACTIONS → Appendix 1: tegafur
▶ Uncommon Aerophagia . allergic rhinitis . alopecia . angina
pectoris . anxiety . aphasia . arrhythmias . ascites . breast
of infection . joint disorders . limb discomfort. loss of
impairment. seizure . sensation abnormal . sepsis . sexual
cutaneous adverse reactions (SCARs)
l CONCEPTION AND CONTRACEPTION Manufacturer advises
effective contraception during and for up to 6 months after
l PREGNANCY Avoid. See also Pregnancy and reproductive
function in Cytotoxic drugs p. 888.
l BREAST FEEDING Discontinue breast-feeding.
l RENAL IMPAIRMENT Manufacturer advises avoid if
creatinine clearance less than 30 mL/minute.
Dose adjustments Reduce dose if creatinine clearance
30–50 mL/minute—consult product literature.
l NATIONAL FUNDING/ACCESS DECISIONS
Scottish Medicines Consortium (SMC) decisions
The Scottish Medicines Consortium has advised (September
2012) that tegafur with gimeracil and oteracil (Teysuno ®) is
accepted for restricted use within NHS Scotland for the
treatment of advanced gastric cancer, when given in
combination with cisplatin, in patients who are unsuitable
for an anthracycline, fluorouracil, and platinum triplet
l MEDICINAL FORMS There can be variation in the licensing of
different medicines containing the same drug.
CAUTIONARY AND ADVISORY LABELS 23
Gimeracil 4.35 mg, Oteracil (as Oteracil potassium) 11.8 mg,
Tegafur 15 mg Teysuno 15mg/4.35mg/11.8mg capsules | 126 capsule P £279.72
Gimeracil 5.8 mg, Oteracil (as Oteracil potassium) 15.8 mg,
Tegafur 20 mg Teysuno 20mg/5.8mg/15.8mg capsules | 84 capsule P £248.40
Acute leukaemia | Chronic myeloid leukaemia
▶ Adult: 100–200 mg/m2 daily, can be given at various
stages of treatment in short-term cycles
RISKS OF INCORRECT DOSING OF ORAL ANTI-CANCER MEDICINES
l CONTRA-INDICATIONS Absent thiopurine
l CAUTIONS Thiopurine methyltransferase status
▶ Thiopurine methyltransferase The enzyme thiopurine
methyltransferase (TPMT) metabolises thiopurine drugs
(azathioprine, mercaptopurine, tioguanine); the risk of
myelosuppression is increased in patients with reduced
activity of the enzyme, particularly for the few individuals
in whom TPMT activity is undetectable. Patients with
absent TPMT activity should not receive thiopurine drugs;
those with reduced TPMT activity may be treated under
▶ Long-term therapy Long-term therapy is no longer
recommended because of the high risk of liver toxicity.
l INTERACTIONS → Appendix 1: tioguanine
BNF 78 Cytotoxic responsive malignancy 917
Immune system and malignant disease
▶ Frequency not known Photosensitivity reaction
l CONCEPTION AND CONTRACEPTION Ensure effective
contraception during treatment in men or women.
l PREGNANCY Avoid (teratogenicity reported when men
receiving tioguanine have fathered children). See also
Pregnancy and reproductive function in Cytotoxic drugs
l BREAST FEEDING Discontinue breast-feeding.
l HEPATIC IMPAIRMENT Manufacturer advises caution.
Dose adjustments Manufacturer advises consider dose
l PRE-TREATMENT SCREENING Consider measuring
thiopurine methyltransferase (TPMT) activity before
l MONITORING REQUIREMENTS Monitor liver function
weekly—discontinue if liver toxicity develops.
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
▶ Tioguanine (Non-proprietary)
Tioguanine 40 mg Tioguanine 40mg tablets | 25 tablet P £109.57
Trifluridine with tipiracil 06-Feb-2019
l DRUG ACTION Trifluridine is an antimetabolite that
interferes with cancer cell DNA synthesis and inhibits cell
proliferation; tipiracil is a TPase inhibitor that boosts
Metastatic colorectal cancer, in patients previously
treated with (or unsuitable for treatment with) available
therapies including fluoropyrimidine-, oxaliplatin-, and
irinotecan-based chemotherapies, or anti-vascular
endothelial growth factor (VEGF) agents, or antiepidermal growth factor receptor (EGFR) agents
▶ Adult: Initially 35 mg/m2 twice daily (max. per dose
80 mg), given on days 1 to 5 and days 8 to 12 of each
28-day cycle, consult product literature for further
information on dose adjustment
RISKS OF INCORRECT DOSING OF ORAL ANTI-CANCER MEDICINES
▶ Common or very common Alopecia . anaemia . appetite
decreased . asthenia . constipation . cough . decreased
prolongation .renal failure .rhinorrhoea . sensation
abnormal . sensation of pressure . septic shock (including
fatal cases). syncope . urinary disorder. vertigo . vision
l CONCEPTION AND CONTRACEPTION Manufacturer advises
effective contraception in women of child-bearing
potential and in men with a partner of child-bearing
potential, during treatment and for 6 months after
stopping treatment. Manufacturer also advises use of an
additional barrier method in women using hormonal
contraceptives—effect of trifluridine with tipiracil on
hormonal contraception unknown.
l PREGNANCY Manufacturer advises avoid unless
essential—reproductive toxicity in animal studies.
l BREAST FEEDING Manufacturer advises avoid—present in
l HEPATIC IMPAIRMENT Manufacturer advises avoid in
moderate to severe impairment (limited information
l RENAL IMPAIRMENT Manufacturer advises caution if eGFR
toxicities; manufacturer advises avoid if eGFR less than
l MONITORING REQUIREMENTS Manufacturer advises obtain
baseline blood cell counts before and during treatment;
monitor closely for myelosuppression. Manufacturer also
advises monitoring for proteinuria before and during
l NATIONAL FUNDING/ACCESS DECISIONS
▶ Trifluridine with tipiracil for previously treated metastatic
colorectal cancer (August 2016) NICE TA405
Trifluridine with tipiracil (Lonsurf ®) is recommended,
within its marketing authorisation, as an option for
treating metastatic colorectal cancer in adults, only when
provided by the manufacturer with the discount agreed in
www.nice.org.uk/guidance/ta405
Scottish Medicines Consortium (SMC) decisions
The Scottish Medicines Consortium has advised (February
2017) that trifluridine with tipiracil (Lonsurf ®) is accepted
for use within NHS Scotland for the treatment of adults
with metastatic colorectal cancer who have been
previously treated with, or are not considered candidates
for, available therapies including fluoropyrimidine-,
This advice is contingent upon the continuing
availability of the Patient Access Scheme in NHS Scotland
or a list price that is equivalent or lower.
918 Cytotoxic responsive malignancy BNF 78
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