Cytotoxic drugs 461
8.1 Cytotoxic drugs 461
8 Malignant
disease
and immunosupp
ressio n
8.1 Cytotoxic drugs BNF 57
Chemotherapy-induced mucositis and
Injection , folinic acid (as calcium salt) 3 mg/mL, net
myelosuppression
price 1-mL amp = £4.00, 10-mL amp = £4.62; 7.5 mg/ Folinic acid (given as calcium folinate) is used to
mL, net price 2-mL amp = £7.80; 10 mg/mL, net price counteract the folate-antagonist action of methotrexate
5-mL vial = £19.41, 10-mL vial = £35.09, 30-mL vial = and thus speed recovery from methotrexate-induced
£94.69, 35-mL vial = £90.98 mucositis or myelosuppression (‘folinic acid rescue’).
Note Not all strengths and pack sizes are available from all manufacturers
Folinic acid is also used in the management of metho- Injection , powder for reconstitution, folinic acid (as trexate overdose, together with other measures to main-
calcium salt), net price 15-mg vial = £4.46; 30-mg vial tain fluid and electrolyte balance, and to manage pos-
sible renal failure. Folinic acid does not counteract the antibacterial activ-
CALCIUM LEVOFOLINATE
ity of folate antagonists such as trimethoprim.
(Calcium levoleucovorin) When folinic acid and fluorouracil are used together in
metastatic colorectal cancer the response-rate improves Indications see notes above compared to that with fluorouracil alone.
Cautions see Calcium Folinate n Side-effects see Calcium Folinate
The calcium salt of levofolinic acid, a single isomer of
Dose
essio Doses expressed as levofolinic acid
folinic acid, is also used for rescue therapy following
Note
methotrexate administration, for cases of methotrexate
overdose, and for use with fluorouracil for colorectal . Prevention of methotrexate-induced adverse effects, cancer. The dose of calcium levofolinate is generally half
(usually started 24 hours after beginning of metho- osuppr that of calcium folinate.
trexate infusion), by intramuscular injection , or by intravenous injection or by intravenous infusion ,
The disodium salt of folinic acid is also licensed for usually 7.5 mg every 6 hours for 10 doses immun rescue therapy following methotrexate therapy and for . Suspected methotrexate overdosage, by intravenous use with fluorouracil for colorectal cancer. injection or by intravenous infusion (at a max. rate
and Palifermin, a human keratinocyte growth factor, is of 160 mg/minute), initial dose at least 50% of the licensed for the management of oral mucositis in
dose of methotrexate; consult poisons information patients with haematological malignancies receiving
service (p. 27) for advice on continuing manage- myeloablative therapy with autologous haematopoietic
ment
disease stem-cell support. . Adjunct to fluorouracil in colorectal cancer, consult product literature
gnant
Isovorin c CALCIUM FOLINATE (Wyeth) TA
, levofolinic acid (as calcium salt) 10 mg/mL,
Mali
(Calcium leucovorin)
Injection net price 2.5-mL vial = £12.09, 5-mL vial = £26.00,
8 Indications see notes above
17.5-mL vial = £84.63 Cautions avoid simultaneous administration of methotrexate; not indicated for pernicious anaemia or other megaloblastic anaemias due to vitamin B
DISODIUM FOLINATE
deficiency; pregnancy (Appendix 4) and breast-feed- Indications see notes above ing (Appendix 5); interactions: Appendix 1 (folates)
Cautions see Calcium Folinate Important Intrathecal injection contra-indicated
Side-effects see Calcium Folinate Side-effects hypersensitivity reactions; rarely pyrexia
Dose
after parenteral use Dose
. As an antidote to methotrexate, see Calcium Folinate Note
. Adjunct to fluorouracil in colorectal cancer, consult Doses expressed as folinic acid
product literature . Prevention of methotrexate-induced adverse effects, usually started 24 hours after start of methotrexate c Sodiofolin (Medac) A
infusion, by intramuscular injection , or by intra- Injection , folinic acid (as disodium salt) 50 mg/mL, venous injection , or by intravenous infusion , 15 mg,
net price 2-mL vial = £35.09, 8-mL vial = £126.25, 18- repeated every 6 hours for 24 hours (may be con-
mL vial = £284.07 tinued by mouth); consult local treatment protocol
for further information
PALIFERMIN
. Suspected methotrexate overdosage, by intravenous injection or by intravenous infusion (at a max. rate
Indications see notes above of 160 mg/minute), initial dose equal to or exceed-
Cautions pregnancy (Appendix 4) ing dose of methotrexate; consult poisons informa-
Contra-indications breast-feeding tion service (p. 27) for advice on continuing man-
Side-effects taste disturbance, thickening and disco- agement
loration of tongue; fever; oedema; arthralgia; rash, . Adjunct to fluorouracil in colorectal cancer, consult
pruritus, erythema product literature
Dose Calcium Folinate (Non-proprietary) A . By intravenous injection , 60 micrograms/kg once
Tablets , scored, folinic acid (as calcium salt) 15 mg, daily for 3 doses (third dose given 24–48 hours net price 10-tab pack = £39.20, 30-tab pack = £85.74
before myeloablative therapy) then 3 further doses Brands include Refolinon
at least 24 hours after myeloablative therapy, start- Note Not all strengths and pack sizes are available from all
ing on same day as (but after) stem-cell infusion; manufacturers
CHILD not recommended
BNF 57
8.1.1 Alkylating drugs 463
Kepivance c (Amgen) TA fluid intake for 24–48 hours after intravenous injection, Injection , powder for reconstitution, palifermin, net
can prevent this complication. When high-dose therapy price 6.25-mg vial = £544.24
(e.g. more than 2 g intravenously) is used or when the patient is considered to be at high risk of cystitis (e.g.
Urothelial toxicity
because of pelvic irradiation) mesna (given initially Haemorrhagic cystitis is a common manifestation of
intravenously then by mouth) can also help prevent urothelial toxicity which occurs with the oxazaphos-
cystitis—see under Urothelial Toxicity (section 8.1). phorines, cyclophosphamide and ifosfamide; it is caused
Ifosfamide is related to cyclophosphamide and is given by the metabolite acrolein. Mesna reacts specifically
intravenously; mesna (section 8.1) is routinely given with this metabolite in the urinary tract, preventing
with it to reduce urothelial toxicity. toxicity. Mesna is used routinely (preferably by mouth)
Chlorambucil is used to treat chronic lymphocytic in patients receiving ifosfamide, and in patients receiv-
leukaemia, non-Hodgkin’s lymphoma, Hodgkin’s dis- ing cyclophosphamide by the intravenous route at a
ease, and Waldenstrom’s macroglobulinaemia. It is high dose (e.g. more than 2 g) or in those who experi-
given by mouth. Side-effects, apart from bone-marrow enced urothelial toxicity when given cyclophosphamide
suppression, are uncommon. However, patients occa- previously.
sionally develop severe widespread rashes which can progress to Stevens-Johnson syndrome or to toxic epi-
dermal necrolysis. If a rash occurs further chlorambucil Indications
MESNA
is contra-indicated and cyclophosphamide is substi- see notes above
tuted.
Contra-indications hypersensitivity to thiol-contain- ing compounds
Melphalan is licensed for the treatment of multiple Side-effects nausea, vomiting, colic, diarrhoea, fati-
advanced ovarian adenocarcinoma, gue, headache, limb and joint pains, depression, irrit-
myeloma,
advanced breast cancer, childhood neuroblastoma, ability, rash, hypotension and tachycardia; rarely
and polycythaemia vera. Melphalan is also licensed for hypersensitivity reactions (more common in patients
regional arterial perfusion in localised malignant with auto-immune disorders)
melanoma of the extremities and localised soft-tissue Dose
sarcoma of the extremities. Interstitial pneumonitis and Note
life-threatening pulmonary fibrosis are associated with Doses calculated according to oxazaphosphorine (cyclophosphamide or ifosfamide) treatment—for details
melphalan.
consult product literature Busulfan (busulphan) is given by mouth to treat chronic . By mouth , dose is given 2 hours before oxazapho-
myeloid leukaemia. Busulfan given by mouth or intra- sphorine treatment and repeated 2 and 6 hours after
venously, followed by cyclophosphamide, is also treatment
licensed as conditioning treatment before haematopoie- . By intravenous injection , dose is given with oxaza-
tic stem-cell transplantation in adults and children. phosphorine treatment and repeated 4 and 8 hours
Frequent blood tests are necessary because excessive after treatment
myelosuppression may result in irreversible bone-mar-
c row aplasia. Rarely, progressive pulmonary fibrosis is
Uromitexan (Baxter) A associated with busulfan. Skin hyperpigmentation is a Tablets , f/c, mesna 400 mg, net price 10-tab pack =
Malignant
common side-effect of oral therapy. £23.20; 600 mg, 10-tab pack = £30.10
Injection , mesna 100 mg/mL. Net price 4-mL amp =
Lomustine is a lipid-soluble nitrosourea and is given by £1.95; 10-mL amp = £4.38
mouth. It is used mainly to treat Hodgkin’s disease Note For oral administration contents of ampoule are taken in a
resistant to conventional therapy, malignant melanoma flavoured drink such as orange juice or cola which may be stored
disease
and certain solid tumours. Bone-marrow toxicity is
in a refrigerator for up to 24 hours in a sealed container delayed, and the drug is therefore given at intervals of
4 to 6 weeks. Permanent bone-marrow damage can occur with prolonged use. Nausea and vomiting are
and
8.1.1 common and moderately severe. Alkylating drugs
Carmustine given intravenously has similar activity to
immunosupp
lomustine; it is given to patients with multiple myeloma, Extensive experience is available with these drugs,
non-Hodgkin’s lymphomas, and brain tumours. Cumu- which are among the most widely used in cancer
lative renal damage and delayed pulmonary fibrosis chemotherapy. They act by damaging DNA, thus inter-
may occur with intravenous use. Carmustine implants fering with cell replication. In addition to the side-effects
are licensed for intralesional use in adults for the treat- common to many cytotoxic drugs (section 8.1), there
ressio
are two problems associated with prolonged usage. ment of recurrent glioblastoma multiforme as an Firstly, gametogenesis is often severely affected (section
adjunct to surgery. Carmustine implants are also licensed for high-grade malignant glioma as adjunctive
8.1). Secondly, prolonged use of these drugs, particularly when combined with extensive irradiation, is associated
treatment to surgery and radiotherapy. with a marked increase in the incidence of acute non-
lymphocytic leukaemia. NICE guidance (carmustine implants and
temozolomide for the treatment of newly Cyclophosphamide
is used for the treatment of diagnosed high-grade glioma) chronic lymphocytic leukaemia, the lymphomas, soft-
See p. 476
tissue and osteogenic sarcoma, and solid tumours. It is
given by mouth or intravenously; it is inactive until metabolised by the liver. A urinary metabolite of cyclo-
Estramustine is a combination of an oestrogen and phosphamide, acrolein, can cause haemorrhagic cyst-
chlormethine used predominantly in prostate cancer. itis; this is a rare but serious complication; increased
It is given by mouth and has both an antimitotic effect
8.1.1 Alkylating drugs BNF 57 and (by reducing testosterone concentration) a hormo-
Dose
nal effect. . Hodgkin’s disease, used alone, 200 micrograms/kg Treosulfan is given by mouth or by intravenous or
daily for 4–8 weeks intraperitoneal administration and is used to treat
. Non-Hodgkin’s lymphoma, used alone, initially 100– ovarian cancer. Skin pigmentation is a common side-
200 micrograms/kg daily for 4–8 weeks then dose effect and allergic alveolitis, pulmonary fibrosis and
reduced or given intermittently haemorrhagic cystitis occur rarely.
. Chronic lymphocytic leukaemia, initially 150 micr- Thiotepa is usually used as an intracavitary drug for the
ograms/kg daily until leucocyte count sufficiently treatment of malignant effusions or bladder cancer
reduced; maintenance (started 4 weeks after end of (section 7.4.4). It is also occasionally used to treat breast
first course) 100 micrograms/kg daily cancer, but requires parenteral administration.
. Waldenstrom’s macroglobulinaemia, 6–12 mg daily Mitobronitol is occasionally used to treat chronic
until leucopenia occurs, then reduce to 2–8 mg daily myeloid leukaemia; it is available on a named-patient
Leukeran c (GSK) A basis from specialist importing companies, see p. 939.
Tablets , f/c, brown, chlorambucil 2 mg, net price 25- tab pack = £8.36
n BUSULFAN
(Busulphan) essio Indications see notes above
CYCLOPHOSPHAMIDE
Cautions see section 8.1 and notes above; monitor Indications see notes above; rheumatoid arthritis cardiac function; previous radiation therapy; avoid in
(section 10.1.3)
osuppr
acute porphyria (section 9.8.2); hepatic impairment Cautions see section 8.1 and notes above; hepatic (Appendix 2); interactions: Appendix 1 (busulfan)
impairment (Appendix 2); renal impairment (Appen- Contra-indications
immun dix 3); avoid in acute porphyria (section 9.8.2); pregnancy (Appendix 4); breast- feeding
interactions: Appendix 1 (cyclophosphamide) Side-effects see section 8.1 and notes above; also
and Contra-indications haemorrhagic cystitis; pregnancy hepatotoxicity (including hepatic veno-occlusive dis-