l MEDICINAL FORMS There can be variation in the licensing of
different medicines containing the same drug.
Powder for solution for infusion
▶ Kadcyla (Roche Products Ltd)
Trastuzumab emtansine 100 mg Kadcyla 100mg powder for
concentrate for solution for infusion vials | 1 vial P £1,641.01
Trastuzumab emtansine 160 mg Kadcyla 160mg powder for
concentrate for solution for infusion vials | 1 vial P £2,625.62
l DRUG ACTION Telotristat ethyl and its active metabolite
inhibit L-tryptophan hydroxylases TPH-1 and TPH-2
which reduces the production of serotonin, thereby
alleviating symptoms associated with carcinoid syndrome.
Carcinoid syndrome diarrhoea (specialist use only)
▶ Adult: 250 mg 3 times a day, review treatment if no
l INTERACTIONS → Appendix 1: telotristat ethyl
l PREGNANCY Manufacturer advises avoid—toxicity in
l BREAST FEEDING Manufacturer advises avoid—no
l HEPATIC IMPAIRMENT Manufacturer advises caution in
mild to moderate impairment; avoid in severe impairment
Dose adjustments Manufacturer advises consider dose
reduction to 250 mg twice daily in mild impairment and to
250 mg once daily in moderate impairment, according to
l RENAL IMPAIRMENT Manufacturer advises caution in
mild-to-moderate impairment; avoid in severe
impairment—no information available.
l MONITORING REQUIREMENTS Manufacturer advises
monitor liver function at initiation and during treatment
as clinically indicated—discontinue if liver injury
l PATIENT AND CARER ADVICE Manufacturer advises inform
patients to report any symptoms of depression or
l NATIONAL FUNDING/ACCESS DECISIONS
Scottish Medicines Consortium (SMC) decisions
The Scottish Medicines Consortium has advised (June 2018)
that telotristat ethyl (Xermelo ®) is accepted for restricted
use within NHS Scotland for the treatment of carcinoid
syndrome diarrhoea in adults who experience an average
of four or more bowel motions per day, despite receiving
somatostatin analogue therapy. This advice is contingent
upon the continuing availability of the patient access
scheme in NHS Scotland or a list price that is equivalent or
All Wales Medicines Strategy Group (AWMSG) decisions
The All Wales Medicines Strategy Group has advised (July
2018) that telotristat ethyl (Xermelo ®) is recommended as
an option for restricted use within NHS Wales for the
treatment of carcinoid syndrome diarrhoea in adults who
are inadequately controlled by somatostatin analogue
therapy and who experience an average of four or more
bowel movements a day. This recommendation applies
only in circumstances where the approved Wales Patient
Access Scheme (WPAS) is utilised or where the
list/contract price is equivalent or lower than the WPAS
l MEDICINAL FORMS There can be variation in the licensing of
different medicines containing the same drug.
CAUTIONARY AND ADVISORY LABELS 3, 21
Telotristat ethyl 250 mg Xermelo 250mg tablets | 90 tablet P £1,120.00
The chemotherapy of cancer is complex and should be
confined to specialists in oncology. Cytotoxic drugs have
both anti-cancer activity and the potential to damage
normal tissue; most cytotoxic drugs are teratogenic.
Chemotherapy may be given with a curative intent or it may
aim to prolong life or to palliate symptoms. In an increasing
number of cases chemotherapy may be combined with
radiotherapy or surgery or both as either neoadjuvant
treatment (initial chemotherapy aimed at shrinking the
primary tumour, thereby rendering local therapy less
destructive or more effective) or as adjuvant treatment
(which follows definitive treatment of the primary disease,
when the risk of subclinical metastatic disease is known to be
high). All cytotoxic drugs cause side-effects and a balance
has to be struck between likely benefit and acceptable
Combinations of cytotoxic drugs, as continuous or pulsed
cycles of treatment, are frequently more toxic than single
drugs but have the advantage in certain tumours of
enhanced response, reduced development of drug resistance
Cytotoxic drugs fall into a number of classes, each with
characteristic antitumour activity, sites of action, and
toxicity. A knowledge of sites of metabolism and excretion is
important because impaired drug handling as a result of
disease is not uncommon and may result in enhanced
Cytotoxic drug handling guidelines
. Trained personnel should reconstitute cytotoxics
. Reconstitution should be carried out in designated
. Protective clothing (including gloves, gowns, and masks)
. The eyes should be protected and means of first aid should
. Pregnant staff should avoid exposure to cytotoxic drugs
(all females of child-bearing age should be informed of the
. Use local procedures for dealing with spillages and safe
disposal of waste material, including syringes, containers,
. Staff exposure to cytotoxic drugs should be monitored
Immune system and malignant disease
A Health Service Circular (HSC 2008/001) provides guidance
on the introduction of safe practice in NHS Trusts where
intrathecal chemotherapy is administered; written local
guidance covering all aspects of national guidance should be
available. Support for training programmes is also available.
Copies, and further information may be obtained from:
It is also available from the Department of Health website
Safe systems for cytotoxic medicines
NHS cancer networks have been established across the UK to
bring together all stakeholders in all sectors of care, to work
collaboratively to plan and deliver high quality cancer
services for a given population. NHS cancer networks have
websites containing information on local chemotherapy
. cytotoxic drugs for the treatment of cancer should be given
as part of a wider pathway of care coordinated by a
. cytotoxic drugs should be prescribed, dispensed, and
administered only in the context of a written protocol or
. injectable cytotoxic drugs should only be dispensed if they
are prepared for administration
. oral cytotoxic medicines should be dispensed with clear
Cytotoxic drugs: important safety information
Risk of incorrect dosing of oral anti-cancer medicines
The National Patient Safety Agency has advised (January
2008) that the prescribing and use of oral cytotoxic
medicines should be carried out to the same standard as
. non-specialists who prescribe or administer on-going oral
cytotoxic medication should have access to written
protocols and treatment plans, including guidance on the
monitoring and treatment of toxicity;
. staff dispensing oral cytotoxic medicines should confirm
that the prescribed dose is appropriate for the patient.
Patients should have written information that includes
details of the intended oral anti-cancer regimen, the
treatment plan, and arrangements for monitoring, taken
from the original protocol from the initiating hospital.
Staff dispensing oral cytotoxic medicines should also have
access to this information, and to advice from an
experienced cancer pharmacist in the initiating hospital.
Doses of cytotoxic drugs are determined using a variety of
further adjusted following consideration of a patient’s
neutrophil count, renal and hepatic function, and history of
previous adverse effects to the cytotoxic drug. Doses may
also differ depending on whether a drug is used alone or in
Because of the complexity of dosage regimens in the
treatment of malignant disease, dose statements have been
omitted from some of the drug entries in this chapter.
However, even where dose statements have been provided,
detailed specialist literature, individual hospital
chemotherapy protocols, or local cancer networks should be
consulted before prescribing, dispensing, or administering
Prescriptions should not be repeated except on the
Side-effects common to most cytotoxic drugs are discussed
below whilst side-effects characteristic of a particular drug or
class of drugs (e.g. neurotoxicity with vinca alkaloids) are
mentioned in the appropriate sections. Manufacturers’
side-effects associated with individual drugs and specific
Many side-effects of cytotoxic drugs often do not occur at
the time of administration, but days or weeks later. It is
therefore important that patients and healthcare
professionals can identify symptoms that cause concern and
can contact an expert for advice. Toxicities should be
accurately recorded using a recognised scoring system such
as the Common Toxicity Criteria for Adverse Events (CTCAE)
developed by the National Cancer Institute.
Extravasation of intravenous drugs
A number of cytotoxic drugs will cause severe local tissue
necrosis if leakage into the extravascular compartment
occurs. To reduce the risk of extravasation injury it is
recommended that cytotoxic drugs are administered by
appropriately trained staff. See information on the
prevention and management of extravasation injury.
A sore mouth is a common complication of cancer
chemotherapy; it is most often associated with fluorouracil
p. 910, methotrexate p. 913, and the anthracyclines. It is best
to prevent the complication. Good oral hygiene (rinsing the
mouth frequently and effective brushing of the teeth with a
soft brush 2–3 times daily) is probably beneficial. For
fluorouracil p. 910, sucking ice chips during short infusions
Once a sore mouth has developed, treatment is much less
effective. Saline mouthwashes should be used but there is no
Tumour lysis syndrome occurs secondary to spontaneous or
treatment-related rapid destruction of malignant cells.
Patients at risk of tumour lysis syndrome include those with
non-Hodgkin’s lymphoma (especially if high grade and bulky
disease), Burkitt’s lymphoma, acute lymphoblastic
leukaemia and acute myeloid leukaemia (particularly if high
white blood cell counts or bulky disease), and occasionally
those with solid tumours. Pre-existing hyperuricaemia,
dehydration, and renal impairment are also predisposing
factors. Features include hyperkalaemia, hyperuricaemia
(see below), and hyperphosphataemia with hypocalcaemia;
renal damage and arrhythmias can follow. Early
identification of patients at risk, and initiation of
prophylaxis or therapy for tumour lysis syndrome, is
Hyperuricaemia, which may be present in high-grade
lymphoma and leukaemia, can be markedly worsened by
chemotherapy and is associated with acute renal failure.
Allopurinol p. 1121 should be started 24 hours before
treating such tumours and patients should be adequately
hydrated. The dose of mercaptopurine p. 912 or azathioprine
p. 836 should be reduced if allopurinol needs to be given
concomitantly. Febuxostat p. 1121 may also be used and
should be started 2 days before cytotoxic therapy is initiated.
Rasburicase p. 942, a recombinant urate oxidase, is
licensed for hyperuricaemia in patients with haematological
malignancy. It rapidly reduces plasma-uric acid
BNF 78 Cytotoxic responsive malignancy 889
Immune system and malignant disease
concentration and may be of particular value in preventing
complications following treatment of leukaemias or bulky
All cytotoxic drugs except vincristine sulfate p. 929 and
bleomycin p. 919 cause bone-marrow suppression. This
commonly occurs 7 to 10 days after administration, but is
delayed for certain drugs, such as carmustine p. 893,
lomustine p. 897, and melphalan p. 897. Peripheral blood
counts must be checked before each treatment, and doses
should be reduced or therapy delayed if bone-marrow has
Cytotoxic drugs may be contra-indicated in patients with
acute infection; any infection should be treated before, or
when starting, cytotoxic drugs.
Fever in a neutropenic patient (neutrophil count less than
/litre) requires immediate broad-spectrum
antibacterial therapy. Appropriate bacteriological
investigations should be conducted as soon as possible.
Patients taking cytotoxic drugs who have signs or symptoms
of infection should be advised to seek prompt medical
attention. All patients should initially be investigated and
treated under the supervision of the appropriate oncology or
In selected patients, the duration and the severity of
neutropenia can be reduced by the use of recombinant
human granulocyte-colony stimulating factors.
Symptomatic anaemia is usually treated with red blood cell
transfusions. For guidance on the use of erythropoietins in
patients with cancer, see MHRA/CHM advice and NICE
Reversible hair loss is a common complication, although it
varies in degree between drugs and individual patients. No
pharmacological methods of preventing this are available.
Venous thromboembolism can be a complication of cancer
itself, but chemotherapy increases the risk.
Cytotoxic drugs: effect on pregnancy and
Most cytotoxic drugs are teratogenic and should not be
administered during pregnancy, especially during the first
trimester. Considerable caution is necessary if a pregnant
woman presents with cancer requiring chemotherapy, and
specialist advice should always be sought.
Exclude pregnancy before treatment with cytotoxic drugs.
Contraceptive advice should be given before cytotoxic
therapy begins- women of childbearing age should use
effective contraception during and after treatment.
Regimens that do not contain an alkylating drug or
procarbazine may have less effect on fertility, but those with
an alkylating drug or procarbazine carry the risk of causing
permanent male sterility (there is no effect on potency).
Pretreatment counselling and consideration of sperm
storage may be appropriate. Women are less severely
affected, though the span of reproductive life may be
shortened by the onset of a premature menopause. No
increase in fetal abnormalities or abortion rate has been
recorded in patients who remain fertile after cytotoxic
Cytotoxic drugs: nausea and vomiting
Nausea and vomiting cause considerable distress to many
patients who receive chemotherapy and to a lesser extent
abdominal radiotherapy, and may lead to refusal of further
treatment; prophylaxis of nausea and vomiting is therefore
extremely important. Symptoms may be acute (occurring
within 24 hours of treatment), delayed (first occurring more
than 24 hours after treatment), or anticipatory (occurring
prior to subsequent doses). Delayed and anticipatory
symptoms are more difficult to control than acute symptoms
and require different management.
Patients vary in their susceptibility to drug-induced
nausea and vomiting; those affected more often include
women, patients under 50 years of age, anxious patients, and
those who experience motion sickness. Susceptibility also
increases with repeated exposure to the cytotoxic drug.
Drugs may be divided according to their emetogenic
potential and some examples are given below, but the
symptoms vary according to the dose, to other drugs
administered and to the individual’s susceptibility to
Mildly emetogenic treatment—fluorouracil, etoposide
p. 923, methotrexate p. 913 (less than 100 mg/m2
in children), the vinca alkaloids, and abdominal
Moderately emetogenic treatment—the taxanes, doxorubicin
hydrochloride p. 901, intermediate and low doses of
cyclophosphamide p. 894, mitoxantrone p. 903, and high
doses of methotrexate (0.1– 1.2 g/m2
Highly emetogenic treatment— cisplatin p. 921, dacarbazine
p. 895, and high doses of cyclophosphamide.
For patients at low risk of emesis, pretreatment with
dexamethasone p. 675 or lorazepam p. 339 may be used.
For patients at high risk of emesis, a 5HT3-receptor
antagonist, usually given by mouth in combination with
dexamethasone and the neurokinin receptor antagonist
aprepitant p. 433 is effective.
Prevention of delayed symptoms
For delayed symptoms associated with moderately
emetogenic chemotherapy, a combination of
dexamethasone and 5HT3-receptor antagonist is effective;
for highly emetogenic chemotherapy, a combination of
dexamethasone and aprepitant is effective. Rolapitant p. 434
and metoclopramide hydrochloride p. 432 are also licensed
for delayed chemotherapy-induced nausea and vomiting.
Prevention of anticipatory symptoms
Good symptom control is the best way to prevent
anticipatory symptoms. Lorazepam can be helpful for its
amnesic, sedative, and anxiolytic effects.
Treatment of cytotoxic-induced side-effects
Anthracycline-induced cardiotoxicity
Local guidelines for the management of extravasation
should be followed or specialist advice sought.
See further information on the prevention and
management of extravasation injury.
Chemotherapy-induced mucositis and myelosuppression
Folinic acid p. 941 (given as calcium folinate) is used to
counteract the folate-antagonist action of methotrexate
p. 913 and thus speed recovery from methotrexate-induced
mucositis or myelosuppression (‘folinic acid rescue’).
Folinic acid is also used in the management of
methotrexate overdose, together with other measures to
maintain fluid and electrolyte balance, and to manage
Folinic acid does not counteract the antibacterial activity
of folate antagonists such as trimethoprim p. 574.
When folinic acid and fluorouracil p. 910 are used together
in metastatic colorectal cancer the response-rate improves
compared to that with fluorouracil alone.
The calcium salt of levofolinic acid p. 942, a single isomer
of folinic acid, is also used for rescue therapy following
methotrexate administration, for cases of methotrexate
overdose, and for use with fluorouracil for colorectal cancer.
890 Cytotoxic responsive malignancy BNF 78
Immune system and malignant disease
The dose of calcium levofolinate is generally half that of
The disodium salts of folinic acid and levofolinic acid are
also used for rescue therapy following methotrexate therapy,
and for use with fluorouracil for colorectal cancer.
Haemorrhagic cystitis is a common manifestation of
urothelial toxicity which occurs with the oxazaphosphorines,
cyclophosphamide p. 894 and ifosfamide p. 896; it is caused
by the metabolite acrolein. Mesna p. 940 reacts specifically
with this metabolite in the urinary tract, preventing toxicity.
Mesna is used routinely (preferably by mouth) in patients
receiving ifosfamide, and in patients receiving
cyclophosphamide by the intravenous route at a high dose
(e.g. more than 2 g) or in those who experienced urothelial
toxicity when given cyclophosphamide previously.
Anthracyclines and other cytotoxic antibiotics
Drugs in this group are widely used. Many cytotoxic
antibiotics act as radiomimetics and simultaneous use of
radiotherapy should be avoided because it may markedly
increased toxicity. Daunorubicin p. 900, doxorubicin
hydrochloride p. 901, epirubicin hydrochloride p. 902 and
idarubicin hydrochloride p. 903 are anthracycline antibiotics.
Mitoxantrone p. 903 is an anthracycline derivative.
Doxorubicin hydrochloride is available as both
conventional and liposomal formulations. The different
formulations vary in their licensed indications,
pharmacokinetics, dosage and administration, and are not
interchangeable. Conventional doxorubicin hydrochloride is
solid tumours including breast cancer.
Epirubicin hydrochloride is structurally related to
doxorubicin hydrochloride and can be used to treat breast
Idarubicin hydrochloride has general properties similar to
those of doxorubicin hydrochloride; it is mostly used in the
treatment of haematological malignancies.
Daunorubicin also has general properties similar to those
Mitoxantrone is structurally related to doxorubicin
Pixantrone p. 904 is licensed as monotherapy for the
as a fifth-line or greater chemotherapy in refractory patients
Bleomycin p. 919 is given intravenously or intramuscularly
to treat metastatic germ cell cancer and, in some regimens,
Dactinomycin is principally used to treat paediatric
cancers. Its side-effects are similar to those of doxorubicin,
except that cardiac toxicity is not a problem.
Mitomycin p. 919 can be given intravenously to treat
gastro-intestinal and breast cancers, and by bladder
instillation for superficial bladder tumours. It causes delayed
The vinca alkaloids, vinblastine sulfate p. 929, vincristine
sulfate p. 929, and vindesine sulfate p. 930, are used to treat
a variety of cancers including leukaemias, lymphomas, and
some solid tumours. Vinorelbine p. 931 is a semi-synthetic
vinca alkaloid. See also, role of vinorelbine in the treatment
Antimetabolites are incorporated into new nuclear material
or combine irreversibly with cellular enzymes, preventing
Extensive experience is available with these drugs, which are
among the most widely used in cancer chemotherapy. They
act by damaging DNA, thus interfering with cell replication.
Cyclophosphamide is used mainly in combination with
other agents for treating a wide range of malignancies,
including some leukaemias, lymphomas, and solid tumours.
It is given by mouth or intravenously; it is inactive until
Ifosfamide is related to cyclophosphamide and is given
Melphalan p. 897 is licensed for the treatment of multiple
myeloma, polycythaemia vera, childhood neuroblastoma,
advanced ovarian adenocarcinoma, and advanced breast
cancer. However, in practice, melphalan is rarely used for
ovarian adenocarcinoma; it is no longer used for advanced
breast cancer. Melphalan is also licensed for regional arterial
perfusion in localised malignant melanoma of the
extremities and localised soft-tissue sarcoma of the
Lomustine p. 897 is a lipid-soluble nitrosourea and the
drug is given at intervals of 4 to 6 weeks.
Carmustine p. 893 has similar activity to lomustine; it is
given to patients with multiple myeloma, non-Hodgkin’s
lymphomas, and brain tumours. Carmustine implants are
licensed for intralesional use in adults for the treatment of
recurrent glioblastoma multiforme as an adjunct to surgery.
Carmustine implants are also licensed for high-grade
malignant glioma as adjunctive treatment to surgery and
Estramustine phosphate p. 896 is a combination of an
oestrogen and chlormethine used predominantly in prostate
cancer. It is given by mouth and has both an antimitotic
effect and (by reducing testosterone concentration) a
Mitobronitol is occasionally used to treat chronic myeloid
leukaemia; it is available on a named-patient basis from
specialist importing companies.
ANTINEOPLASTIC DRUGS › ALKYLATING AGENTS
Bendamustine hydrochloride 05-Jun-2018
Treatment of chronic lymphocytic leukaemia | Treatment
of non-Hodgkin’s lymphoma | Treatment of multiple
▶ Adult: (consult local protocol)
MHRA/CHM ADVICE: BENDAMUSTINE (LEVACT ®): INCREASED
MORTALITY OBSERVED IN RECENT CLINICAL STUDIES IN OFFLABEL USE; MONITOR FOR OPPORTUNISTIC INFECTIONS,
HEPATITIS B REACTIVATION (JULY 2017)
Recent clinical trials have shown increased mortality
when bendamustine was used in combination
treatments outside its approved indications. In addition,
a recent European review of post-marketing data has
suggested that the risk of opportunistic infections for all
patients receiving bendamustine treatment may be
greater than previously recognised.
The MHRA recommends monitoring patients for
opportunistic infections as well as cardiac, neurological,
and respiratory adverse events; known carriers of
hepatitis B virus (HBV) should be monitored for signs
and symptoms of active HBV infection. Patients should
be advised to report promptly new signs of infection;
consider discontinuing bendamustine if there are signs
BNF 78 Cytotoxic responsive malignancy 891
Immune system and malignant disease
l CONTRA-INDICATIONS Jaundice . low leucocyte count. low
platelet count. major surgery less than 30 days before start
of treatment. severe bone marrow suppression
l CAUTIONS Cardiac disorders—monitor serum potassium
l INTERACTIONS → Appendix 1: alkylating agents
system disorder. paraesthesia . peripheral neuropathy . sepsis .taste altered
▶ Frequency not known Extravasation necrosis . hepatic
failure . necrosis .renal failure . severe cutaneous adverse
SIDE-EFFECTS, FURTHER INFORMATION Secondary
malignancy Use of bendamustine is associated with an
increased incidence of acute leukaemias.
Infections Serious and fatal infections are reported,
including opportunistic infections such as Pneumocystis
jirovecii pneumonia (PJP), varicella zoster virus (VZV) and
cytomegalovirus (CMV)—manufacturer advises
monitoring for respiratory signs and symptoms
throughout treatment; patients should be advised to
report new signs of infection, including fever or
respiratory symptoms, promptly. Reactivation of hepatitis
B is reported in patients who are chronic carriers of the
virus—manufacturer advises monitoring for signs and
symptoms of active hepatitis B during treatment and for
several months after stopping treatment.
l CONCEPTION AND CONTRACEPTION Effective
contraception is required during treatment in men or
women, and for 6 months after treatment in men. See also
Pregnancy and reproductive function in Cytotoxic drugs
l PREGNANCY Avoid (teratogenic and mutagenic in animal
studies). See also Pregnancy and reproductive function in
l BREAST FEEDING Discontinue breast-feeding.
l HEPATIC IMPAIRMENT Manufacturer advises avoid in
severe impairment—no information available.
Dose adjustments Manufacturer advises reduce dose by
l RENAL IMPAIRMENT No information available on use in
patients with creatinine clearance less than 10 mL/minute.
l NATIONAL FUNDING/ACCESS DECISIONS
▶ Bendamustine for the first-line treatment of chronic
lymphocytic leukaemia (February 2011) NICE TA216
stage B or C) in patients for whom fludarabine
combination chemotherapy is not appropriate.
www.nice.org.uk/guidance/TA216
▶ Obinutuzumab with bendamustine for treating follicular
lymphoma refractory to rituximab (August 2017) NICE TA472
Bendamustine in combination with obinutuzumab
followed by obinutuzumab maintenance, is recommended
for use within the Cancer Drugs Fund as an option for
treating adults with follicular lymphoma that did not
respond or progressed during or up to 6 months after
treatment with rituximab or a rituximab-containing
regimen, only if the conditions in the managed access
agreement for obinutuzumab are followed.
www.nice.org.uk/guidance/TA472
Scottish Medicines Consortium (SMC) decisions
The Scottish Medicines Consortium has advised (April 2011)
that bendamustine (Levact ®) is accepted for use within
NHS Scotland for first-line treatment of chronic
lymphocytic leukaemia (Binet stage B or C) in patients for
whom fludarabine combination chemotherapy is not
l MEDICINAL FORMS There can be variation in the licensing of
different medicines containing the same drug.
Powder for solution for infusion
▶ Bendamustine hydrochloride (Non-proprietary)
Bendamustine hydrochloride 25 mg Bendamustine 25mg powder
for concentrate for solution for infusion vials | 1 vial P £6.85–
£65.98 | 5 vial P £312.53–£347.26 (Hospital only) | 20 vial P £1,241.14 (Hospital only)
Bendamustine hydrochloride 100 mg Bendamustine 100mg
▶ Levact (Napp Pharmaceuticals Ltd)
Bendamustine hydrochloride 25 mg Levact 25mg powder for
concentrate for solution for infusion vials | 5 vial P £347.26
Bendamustine hydrochloride 100 mg Levact 100mg powder for
concentrate for solution for infusion vials | 5 vial P £1,379.04
Chronic myeloid leukaemia, induction of remission
▶ Adult: 60 micrograms/kg daily (max. per dose 4 mg);
Conditioning treatment before haematopoietic progenitor
▶ BY MOUTH, OR BY INTRAVENOUS INFUSION
▶ Adult: (consult local protocol)
Conditioning treatment before haematopoietic progenitor
cell transplantation in patients who are candidates for a
reduced-intensity conditioning (RIC) regimen
▶ Adult: (consult local protocol)
DOSES AT EXTREMES OF BODY-WEIGHT
▶ Dose may need to be calculated based on body surface
area or adjusted ideal body weight in obese patients—
RISKS OF INCORRECT DOSING OF ORAL ANTI-CANCER MEDICINES
l CAUTIONS Avoid in Acute porphyrias p. 1058 . high dose
(antiepileptic prophylaxis required). history of seizures
(antiepileptic prophylaxis required). ineffective once in
blast crisis phase . previous progenitor cell transplant
892 Cytotoxic responsive malignancy BNF 78
Immune system and malignant disease
more cycles of chemotherapy (increased risk of hepatic
l INTERACTIONS → Appendix 1: alkylating agents
▶ Common or very common Alopecia . diarrhoea . hepatic
disorders . nausea .respiratory disorders . sinusoidal
obstruction syndrome . skin reactions .thrombocytopenia . vomiting
▶ Rare or very rare Cataract. eye disorders
disorders . ovarian and fallopian tube disorders .testicular
▶ With intravenous use Hypogonadism . ovarian failure . premature menopause . sepsis
SIDE-EFFECTS, FURTHER INFORMATION Lung toxicity
Discontinue if lung toxicity develops.
Secondary malignancy Use of busulfan is associated
with an increased incidence of secondary malignancy.
l CONCEPTION AND CONTRACEPTION Manufacturers advise
effective contraception during and for 6 months after
treatment in men or women. See also Pregnancy and
reproductive function in Cytotoxic drugs p. 888.
l PREGNANCY Avoid (teratogenic in animals). See also
Pregnancy and reproductive function in Cytotoxic drugs
l BREAST FEEDING Discontinue breast-feeding.
l HEPATIC IMPAIRMENT Manufacturer advises caution.
Monitoring In patients with hepatic impairment,
manufacturer advises regular liver function tests—consult
▶ Monitor cardiac and liver function.
▶ Frequent blood tests are necessary because excessive
myelosuppression may result in irreversible bone-marrow
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
Busulfan 2 mg Busulfan 2mg tablets | 25 tablet P £69.02 DT =
Busulfan 6 mg per 1 ml Busulfan 60mg/10ml concentrate for
solution for infusion vials | 8 vial P £1,529.50–£2,054.80 (Hospital
Busulfan 6 mg per 1 ml Busilvex 60mg/10ml concentrate for
solution for infusion ampoules | 8 ampoule P £1,610.00 (Hospital
Multiple myeloma | Non-Hodgkin’s lymphomas | Brain
▶ Adult: (consult product literature)
Recurrent glioblastoma multiforme as an adjunct to
surgery | High-grade malignant glioma as adjunctive
treatment to surgery and radiotherapy
▶ BY INTRALESIONAL IMPLANTATION
▶ Adult: (consult product literature)
l CAUTIONS Avoid in Acute porphyrias p. 1058
l INTERACTIONS → Appendix 1: alkylating agents
thrombosis . eye pain . faecal incontinence .fever. gait
disorder.rash . sensation abnormal . sepsis . speech
impairment. stupor.thinking abnormal . thrombocytopenia .tremor. urinary incontinence . vision
doses). hepatotoxicity . myelodysplastic syndrome
(following long term use). ocular toxicity .respiratory
disorders .retinal haemorrhage . stomatitis
▶ When used by implant Cerebral infarction . intracranial
▶ With intravenous use Gynaecomastia . nephrotoxicity
(cumulative). peripheral vascular disease (with high doses)
▶ With intravenous use Infertility . myalgia
SIDE-EFFECTS, FURTHER INFORMATION Pulmonary
toxicity Lung infiltration, pulmonary fibrosis,
pneumonitis, and interstitial lung disease have been
BNF 78 Cytotoxic responsive malignancy 893
Immune system and malignant disease
reported, some of which have been fatal. These appear to
be dose-related, cumulative, and may be delayed.
Hepatotoxicity Hepatotoxicity has been reported to
occur with high doses, and may be delayed up to 60 days
after administration; usually reversible.
l CONCEPTION AND CONTRACEPTION Manufacturer advises
effective contraception during treatment in men or
women. See also Pregnancy and reproductive function in
l PREGNANCY Avoid (teratogenic and embryotoxic in
animals). See also Pregnancy and reproductive function in
l BREAST FEEDING Discontinue breast-feeding.
l NATIONAL FUNDING/ACCESS DECISIONS
▶ Carmustine implants and temozolomide for the treatment of
newly diagnosed high-grade glioma (June 2007) NICE TA121
Carmustine implants are an option for the treatment of
newly diagnosed high-grade (Grade 3 or 4) glioma only for
patients in whom at least 90% of the tumour has been
resected. Carmustine implants should only be used within
www.nice.org.uk/guidance/ta121
l MEDICINAL FORMS There can be variation in the licensing of
different medicines containing the same drug.
Carmustine 7.7 mg Gliadel 7.7mg implant | 8 device P £5,203.00
Some lymphomas and chronic leukaemias (used either
alone or in combination therapy)
▶ Adult: (consult local protocol)
RISKS OF INCORRECT DOSING OF ORAL ANTI-CANCER MEDICINES
l CAUTIONS Children with nephrotic syndrome (increased
seizure risk). history of epilepsy (increased seizure risk)
l INTERACTIONS → Appendix 1: alkylating agents
neuropathy .respiratory disorders . severe cutaneous
adverse reactions (SCARs).tremor
▶ Frequency not known Amenorrhoea . azoospermia
SIDE-EFFECTS, FURTHER INFORMATION Secondary
malignancy Use of chlorambucil is associated with an
increased incidence of acute leukaemia, particularly with
Skin reactions Manufacturer advises assessing
continued use if rash occurs—has been reported to
progress to Stevens-Johnson syndrome and toxic
l CONCEPTION AND CONTRACEPTION Contraceptive advice
required, see Pregnancy and reproductive function in
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 caution—
monitor for signs and symptoms of toxicity.
Dose adjustments Manufacturer advises consider dose
reduction in severe impairment—limited information
l NATIONAL FUNDING/ACCESS DECISIONS
▶ Obinutuzumab in combination with chlorambucil for
untreated chronic lymphocytic leukaemia (June 2015)
Obinutuzumab, in combination with chlorambucil, is an
option for untreated chronic lymphocytic leukaemia in
patients who have comorbidities that make full-dose
fludarabine-based therapy unsuitable for them, only if:
. bendamustine-based therapy is not suitable, and
. the manufacturer provides obinutuzumab with the
discount agreed in the patient access scheme.
Patients currently receiving obinutuzumab that is not
recommended according to the above criteria should have
the option to continue treatment until they and their NHS
clinician consider it appropriate to stop.
www.nice.org.uk/guidance/ta343
▶ Ofatumumab in combination with chlorambucil or
bendamustine for untreated chronic lymphocytic leukaemia
Ofatumumab in combination with chlorambucil is an
option for untreated chronic lymphocytic leukaemia only
. the patient is ineligible for fludarabine-based therapy,
. bendamustine is not suitable, and
. the manufacturer provides ofatumumab with the
discount agreed in the patient access scheme.
Patients currently receiving ofatumumab that is not
recommended according to the above criteria should have
the option to continue treatment until they and their NHS
clinician consider it appropriate to stop.
www.nice.org.uk/guidance/ta344
l MEDICINAL FORMS There can be variation in the licensing of
different medicines containing the same drug.
▶ Chlorambucil (Non-proprietary)
Chlorambucil 2 mg Chlorambucil 2mg tablets | 25 tablet P £42.87 DT = £42.87
Rheumatoid arthritis with severe systemic manifestations
Severe systemic rheumatoid arthritis | Other connective
tissue diseases (especially with active vasculitis)
▶ Adult: 0.5–1 g every 2 weeks, then reduced to 0.5–1 g
every month, frequency adjusted according to clinical
response and haematological monitoring. To be given
Used, mainly in combination with other agents for
treating a wide range of malignancies, including some
leukaemias, lymphomas, and solid tumours
▶ BY MOUTH, OR BY INTRAVENOUS INFUSION
▶ Adult: (consult local protocol)
894 Cytotoxic responsive malignancy BNF 78
Immune system and malignant disease
l UNLICENSED USE Not licensed for rheumatoid arthritis
with severe systemic manifestations.
RISKS OF INCORRECT DOSING OF ORAL ANTI-CANCER MEDICINES
l CONTRA-INDICATIONS Haemorrhagic cystitis
l CAUTIONS Avoid in Acute porphyrias p. 1058 . diabetes
mellitus . previous or concurrent mediastinal irradiation—
l INTERACTIONS → Appendix 1: alkylating agents
abnormalities . neutropenia . progressive multifocal
leukoencephalopathy (PML).reactivation of infections . sperm abnormalities .thrombocytopenia
▶ Frequency not known Abdominal pain . altered smell
sensation . arrhythmias . arthralgia . ascites . cardiac
▶ With intravenous use Infusion site necrosis . injection site
SIDE-EFFECTS, FURTHER INFORMATION Haemorrhagic
cystitis A urinary metabolite of cyclophosphamide,
acrolein, can cause haemorrhagic cystitis; this is a rare but
serious complication that may be prevented by increasing
fluid intake for 24–48 hours after intravenous injection.
Mesna can also help prevent cystitis when high-dose
therapy (e.g. more than 2 g intravenously) is used or when
the patient is considered to be at high risk of cystitis (e.g.
because of pelvic irradiation).
Secondary malignancy As with all cytotoxic therapy,
treatment with cyclophosphamide is associated with an
increased incidence of secondary malignancies.
l CONCEPTION AND CONTRACEPTION Manufacturer advises
effective contraception during and for at least 3 months
after treatment in men or women. See also Pregnancy and
reproductive function in Cytotoxic drugs p. 888.
l PREGNANCY Avoid. See also Pregnancy and reproductive
function in Cytotoxic drugs p. 888.
l BREAST FEEDING Discontinue breast-feeding during and
for 36 hours after stopping treatment.
l HEPATIC IMPAIRMENT Manufacturer advises caution (risk
of decreased cyclophosphamide activation and increased
risk of veno-occlusive liver disease).
Dose adjustments Manufacturer advises consider dose
adjustment in severe impairment—consult product
Dose adjustments Reduce dose if serum creatinine
concentration greater than 120 micromol/litre.
l DIRECTIONS FOR ADMINISTRATION
▶ With intravenous use For intravenous infusion
(cyclophosphamide injection; Baxter) give via drip tubing
in Glucose 5% or Sodium chloride 0.9%; reconstitute
500 mg with 25 mL sodium chloride 0.9%; reconstitute 1 g
with 50 mL sodium chloride 0.9%.
l MEDICINAL FORMS There can be variation in the licensing of
different medicines containing the same drug. Forms available
from special-order manufacturers include: tablet, oral
suspension, oral solution, solution for injection, solution for
CAUTIONARY AND ADVISORY LABELS 25, 27
▶ Cyclophosphamide (Non-proprietary)
Cyclophosphamide (as Cyclophosphamide monohydrate)
50 mg Cyclophosphamide 50mg tablets | 100 tablet P £139.00
▶ Cytoxan (Imported (United States))
Cyclophosphamide 25 mg Cytoxan 25mg tablets |
Powder for solution for injection
▶ Cyclophosphamide (Non-proprietary)
Cyclophosphamide (as Cyclophosphamide monohydrate)
500 mg Cyclophosphamide 500mg powder for solution for injection
vials | 1 vial P £9.66 (Hospital only) | 1 vial P £9.66
Cyclophosphamide (as Cyclophosphamide monohydrate)
Cyclophosphamide (as Cyclophosphamide monohydrate)
2 gram Cyclophosphamide 2g powder for solution for injection vials
| 1 vial P £34.12 (Hospital only)
Metastatic melanoma | Soft-tissue sarcomas (combination
therapy)| Hodgkin’s disease (combination therapy)
▶ BY INTRAVENOUS INFUSION, OR BY INTRAVENOUS INJECTION
▶ Adult: (consult local protocol)
l CAUTIONS Caution in handling—irritant to tissues
l INTERACTIONS → Appendix 1: alkylating agents
l CONCEPTION AND CONTRACEPTION Ensure effective
contraception during and for at least 6 months after
treatment in men or women. See also Pregnancy and
reproductive function in Cytotoxic drugs p. 888.
l PREGNANCY Avoid (carcinogenic and teratogenic in
animal studies). See also Pregnancy and reproductive
function in Cytotoxic drugs p. 888.
l BREAST FEEDING Discontinue breast-feeding.
l HEPATIC IMPAIRMENT Avoid in severe impairment.
BNF 78 Cytotoxic responsive malignancy 895
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