COMMON TRADE NAME(S): TOMUDEX(r) (notice of compliance,1 September 1996; patent expires2 July 2008)

CLASSIFICATION:

Special pediatric considerations are noted when applicable, otherwise adult provisions apply.

MECHANISM OF ACTION:

Raltitrexed is a quinazoline folate analogue that selectively inhibits thymidylate synthase (TS).3 Thymidylate synthase is a key enzyme in the de novo synthesis of thymidine triphosphate (TTP), a nucleotide required exclusively for deoxyribonucleic acid (DNA) synthesis. Inhibition of TS leads to DNA fragmentation and cell death.3 Intracellular retention of polyglutamated forms of raltitrexed leads to prolonged inhibitory effects.4 This permits a convenient dosing schedule of a single IV injection once every 3 weeks.5 Raltitrexed is a radiation-sensitizing agent.6 It is cell cycle phase-specific (S-phase).7

PHARMACOKINETICS:

SPECIAL PRECAUTIONS:

Contraindicated in patients with severe renal impairment, severe hepatic impairment3 and/or clinically significant cardiac arrhythmias requiring drug therapy.15

Carcinogenicity:

Mutagenicity: Not mutagenic in Ames test or in mammalian in vitro mutation test. Raltitrexed is clastogenic in human lymphocytes in vitro and mammalian bone marrow in vivo.3

Fertility: 3

animal studies showed impairment of male fertility. Fertility returned to normal three months after dosing ceased.

Pregnancy: 3

In pregnant rats, raltitrexed caused embryolethality and fetal abnormalities. If either partner is receiving raltitrexed, pregnancy should be excluded before treatment is commenced and avoided during and for at least 6 months after treatment.

Breastfeeding 3

SIDE EFFECTS:

ORGAN SITE	SIDE EFFECT	ONSET
Dose-limiting side effects are in bold, italics I = immediate (onset in hours to days); E = early (days to weeks); D = delayed (weeks to months); L = late (months to years)
blood/bone marrow febrile neutropenia	anemia (12-19%)		E	D
	leukocytopenia (18-23%) nadir in the first or second week, recovery by the third week		E
	thrombocytopenia (4%) nadir in the first or second week, recovery by the third week		E
cardiovascular (arrhythmia)	cardiac rhythm abnormalities (3%)		E
cardiovascular (general)	cardiac function abnormalities (2%)		E
cardiovascular (general)	edema (3-5%)		E
constitutional symptoms	asthenia (29-42%)		E	D
	fever (20%)	I
	malaise (2%)		E	D
	sweating (2-3%)		E
	weight loss (3-5%)		E	D
dermatology/skin	extravasation hazard: none 3

ORGAN SITE	SIDE EFFECT	ONSET
Dose-limiting side effects are in bold, italics I = immediate (onset in hours to days); E = early (days to weeks); D = delayed (weeks to months); L = late (months to years)
	alopecia (4-5%)		E	D
	pruritus (2%)		E
	rash (13%)		E
	desquamation (rare)		E
gastrointestinal	emetogenic potential: low moderate 3
	anorexia (18-24%)		E
	constipation (6%)		E
	dehydration (3-4%)		E
	diarrhea (30-34%)		E
	dyspepsia (2-6%)		E
	mouth ulceration (2%)		E
	nausea (47-54%)	I	E
	stomatitis (9%)		E
	taste disturbance (2-3%)		E
	vomiting (29-32%)	I	E
hepatic	fatal liver failure (rare) 16			D
	transient increase of alkaline phosphatase (2%)		E
	transient increase of ALT (12-15%)		E
	transient increase of AST (14-19%)		E
infection	sepsis (2-3%)		E
musculoskeletal	arthralgia (2%)		E
	cellulitis (2-3%)		E
	hypertonia (2%)		E
ocular/visual	conjunctivitis (2%)		E
pain	abdominal pain (6-8%)		E
	headache (2-3%)		E
	pain (2-3%)		E
pulmonary	cough (2%)		E
syndromes	flu-like symptoms (5-11%)	I	E

Adapted from reference 3 unless specified otherwise.

Drug-related deaths in clinical trials:

A similar incidence of drug-related death was found with single agent raltitrexed compared to the combination of fluorouracil plus leucovorin regimens in phase III trials in advanced colorectal cancer. There were 26 deaths in 684 raltitrexed patients (3.5%). However, 17 of these deaths were in patients who did not receive appropriate dosage modifications following toxicity/impaired renal function during a

previous cycle of raltitrexed.4 More recently, the drug manufacturer prematurely stopped the Pan European Trial in Adjuvant Colon Cancer-1 (PETACC-1). The interim safety review found that the number of drug-related deaths in the raltitrexed group (17 of 911 patients, 1.9%) was double that in the fluorouracil plus leucovorin group (7 of 927 patients, 0.8%). Eleven of the 17 drug-related deaths in the raltitrexed group were linked with serious deviations from the dose modification instructions in the protocol.17 Health care providers are cautioned to follow dose modifications for impaired renal function.3 BCCA Cancer Drug Manual(c) 2001 Page 3 of 7 Raltitrexed

Fatal liver failure:

Transient increases of hepatic transaminases are generally considered to be of no clinical significance. Recently, acute fatal liver failure has been reported in two patients. In both patients, toxicity occurred after repeated administration and was not preceded by a transient increase in transaminases during earlier cycles. Histologic findings showed acute necrosis of approximately 50% of the liver without concurrent changes suggestive of

preexisting chronic conditions.16

Nausea and vomiting 18

typically occurs after 2-3 days, rather than immediately after treatment. Most symptoms are managed with antiemetics such as oral metoclopramide.

Cardiovascular system:

A number of cardiac rhythm or cardiac function abnormalities have been reported in clinical trials in advanced colorectal cancer. These included sinus tachycardia, supraventricular tachycardia, atrial fibrillation and congestive heart failure. The incidence of disorders of rhythm and function in patients treated with raltitrexed was 2.8% and 1.8% respectively, compared to 1.9% and 1.4% for patients on the comparator treatment (fluorouracil and leucovorin). A causal relationship could not be established since many of the abnormalities were concurrent with the

underlying conditions such as sepsis and dehydration and more than one third of the patients reported cardiovascular abnormalities prior to treatment.3 The safe use of raltitrexed in two patients with fluorouracil-associated cardiotoxicity has been reported. The authors speculated that the mechanism of fluorouracil cardiotoxicity is not due to the direct cytotoxic effect on DNA synthesis caused by thymidylate synthase inhibition.19 Use in elderly patients: Recent reports have concluded that raltitrexed is suitable for use in elderly patients. In 90 patients greater than 70 years of age with advanced colorectal cancer, severe toxicity was reported as nausea and vomiting 7%, diarrhea 3%, liver toxicity 6%, neutropenia 3% and anemia 2%. There were 3 drug-related deaths.20 In 51 patients greater than 70 years of age with metastatic colorectal cancer, severe toxicity was reported as increase in transaminases 20%, nausea/vomiting 8%, anemia 6%, diarrhea 10%, and infectious disease 2%. There were no drug- related deaths.21

Overdose: 3

For an overdose, consideration should be given to the administration of leucovorin. From clinical experience with other antifolates, leucovorin may be given at a dose of 25 mg/m2 IV every 6 hours.

INTERACTIONS:

SOLUTION PREPARATION AND COMPATIBILITY:

For basic information on solution preparation and compatibility, see Chemotherapy Chart in Appendix. Injection3

: 2 mg vial (as the disodium salt). Store at room temperature. Protect from light.

Reconstitute powder 3

Reconstituted solution for injection: 3

chemically stable for 24 hours at room temperature exposed to ambient light, however, it is recommended that raltitrexed be refrigerated to avoid bacterial contamination.

Diluted solution for infusion: 3

Dilute in 50-250 mL NS or D5W. Chemically stable for 24 hours at room temperature exposed to ambient light. If not used promptly, it is recommended that raltitrexed be refrigerated to avoid bacterial contamination.

Compatibility: 3

PARENTERAL ADMINISTRATION:

DOSAGE GUIDELINES:

Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease, response and concomitant therapy. Guidelines for dosing also include consideration of absolute neutrophil count (ANC). Dosage may be reduced, delayed or discontinued in patients with bone marrow depression due to cytotoxic/radiation therapy or in patients with other toxicities.

Intravenous: 3 week: 3 mg/m2 IV for one dose on day 1

once a dose reduction has been made, all subsequent doses should be given at the reduced dose level

modify according to protocol by which patient is being treated; if no guidelines

Dosage in renal failure3: For patients with abnormal serum creatinine, CrCl should be performed or calculated. For patients with normal serum creatinine but the serum creatinine may not correlate well with CrCl due to age or weight loss, CrCl should be performed or calculated.3 CrCl = N x (140 - Age) x weight (kg) serum creatinine (umol/L) where N = 1.04 for females and 1.23 for males

REFERENCES:

Cunningham D, Zalcberg JR, Rath U, et al. 'Tomudex' (ZD1694): results of a randomised trial in advanced colorectal cancer demonstrate efficacy and reduced mucositis and leucopenia. The 'Tomudex' Colorectal Cancer Study Group. Eur J Cancer 1995; 31A(12):1945-54.

James R, Price P, Valentini V. Raltitrexed (Tomudex) concomitant with radiotherapy as adjuvant treatment for patients with rectal cancer: preliminary results of phase I studies. Eur J Cancer 1999; 35(Suppl 1):S19-22.

Matsui SI, Arredondo MA, Wrzosek C, et al. DNA damage and p53 induction do not cause ZD1694-induced cell cycle arrest in human colon carcinoma cells. Cancer Res 1996; 56(20):4715-23.

Judson I, Maughan T, Beale P, et al. Effects of impaired renal function on the pharmacokinetics of raltitrexed (Tomudex ZD1694). Br J Cancer 1998; 78(9):1188-93.

Cunningham D, Zalcberg JR, Rath U, et al. Final results of a randomised trial comparing 'Tomudex' (raltitrexed) with 5-fluorouracil plus leucovorin in advanced colorectal cancer. "Tomudex" Colorectal Cancer Study Group [published erratum appears in Ann Oncol 1997 Apr; 8(4):407]. Ann Oncol 1996; 7(9):961-5.

Cocconi G, Cunningham D, Van Cutsem E, et al. Open, randomized, multicenter trial of raltitrexed versus fluorouracil plus high- dose leucovorin in patients with advanced colorectal cancer. Tomudex Colorectal Cancer Study Group. J Clin Oncol 1998; 16(9):2943- 52.

Pazdur R, Vincent M. Raltitrexed (Tomudex) versus 5-fluorouracil and leucovorin (5-FU + LV) in patients with advanced colorectal cancer (ACC): Results of a randomized, multicenter, North American trial. Proc Am Soc Clin Oncol 1997; 16:228a.

Smith I, Jones A, Spielmann M, et al. A phase II study in advanced breast cancer: ZD1694 ('Tomudex') a novel direct and specific thymidylate synthase inhibitor. Br J Cancer 1996; 74(3):479-81.

Eatock MM, Anthony DA, El-Abassi M, et al. A dose-finding study of raltitrexed (tomudex) with cisplatin and epirubicin in advanced gastro-oesophageal adenocarcinoma. Br J Cancer 2000; 82(12):1925-31.

Fizazi K, Doubre H, Viala J, et al. The combination of raltitrexed ('Tomudex') and oxaliplatin is an active regimen in malignant mesothelioma: Results of a phase II study. Proc Am Soc Clin Oncol 2000; 19:578a.

BCCA Gastrointestinal Tumour Group. BCCA protocol summary for palliative chemotherapy for metastatic colorectal cancer using raltitrexed in patients with previous fluorouracil toxicity (GIRALT). :; 01 December 2000.

Raderer M, Fiebiger W, Wrba F, et al. Fatal liver failure after the administration of raltitrexed for cancer chemotherapy: a report of two cases. Cancer 2000; 89(4):890-2.

Anonymous. Drug-company decision to end cancer trial [editorial]. Lancet 1999; 354(9184):1045.

Clarke S, Hanwell J, de Boer M, et al. Phase I trial of ZD1694, a new folate-based thymidylate synthase inhibitor, in patients with solid tumors. J Clin Oncol 1996; 14(5):1495-503.

Kohne CH, Thuss-Patience P, Friedrich M, et al. Raltitrexed (Tomudex): an alternative drug for patients with colorectal cancer and 5-fluorouracil associated cardiotoxicity. Br J Cancer 1998; 77(6):973-7.

Mel JR, Feliu J, Camps C, et al. Tomudex (Raltitrexed) in elderly patients with advanced colorectal cancer (ACC): An effective palliative treatment. Proc Am Soc Clin Oncol 2000; 19:257a.

Facchini T, Genet D, Berdah JF, et al. Raltitrexed ('Tomudex') has a manageable toxicity profile in elderly patients with metastatic colorectal cancer: Final analysis of a multicentre study. Proc Am Soc Clin Oncol 2000; 19:298a.

Ford HE, Cunningham D, Ross PJ, et al. Phase I study of irinotecan and raltitrexed in patients with advanced gastrointestinal tract adenocarcinoma. Br J Cancer 2000; 83(2):146-52.

Interpatient variability	considerable interpatient variability 4
Distribution	actively transported into cells 4 ; long half life probably due to a slow return of raltitrexed to the plasma from a deep tissue compartment or binding site
	cross blood brain barrier?	no information found
	volume of distribution	548 L
	plasma protein binding	93%
Metabolism	transported into cells via a reduced folate carrier and then extensively metabolized to polyglutamate forms 3 without metabolic degradation 4
	active metabolite(s)	polyglutamate forms
	inactive metabolite(s)	none
Excretion	active tubular secretion may contribute to the renal excretion
	urine	50% excreted unchanged
	feces	15% excreted over 10 days
	terminal half life	198 h
	clearance	52 mL/min; 1 mL/min/kg; mild to moderate hepatic impairment leads to < 25% reduction in clearance 3 ; mild to moderate renal impairment leads to 50% reduction in clearance 3,8
Gender	no clinically significant difference
Elderly	no clinically significant difference
Children	no information found
Race	no information found

Primary uses:	Other uses:
* Colorectal cancer 9-11	Breast cancer 12
Gastroesophageal cancer 13
Mesothelioma 14

AGENT	EFFECT	MECHANISM	MANAGEMENT
folic acid	may reduce efficacy of raltitrexed	may interfere with action of raltitrexed	avoid immediately before or during raltitrexed administration
irinotecan 22	no pharmacokinetic interactions observed
leucovorin	may reduce efficacy of raltitrexed	may interfere with action of raltitrexed	avoid immediately before or during raltitrexed administration
nonsteroidal antiinflammatory drugs	no clinically significant interaction	interferes with active renal tubular secretion of raltitrexed
vitamin preparations containing folic acid or leucovorin	may reduce efficacy of raltitrexed	may interfere with action of raltitrexed	avoid immediately before or during raltitrexed administration
warfarin	no clinically significant interaction	no displacement between raltitrexed and warfarin in vitro

BCCA administration guideline noted in bold , italics
Subcutaneous	no information found
Intramuscular	no information found
Direct intravenous	no information found
Intermittent infusion	in 50 mL NS over 15 min
Continuous infusion	no information found
Intraperitoneal	no information found
Intrapleural	no information found
Intrathecal	no information found
Intra-arterial	no information found
Intravesical	no information found

Toxicity	Dose
grade 2 diarrhea: increase of 4-6 stools per day, or nocturnal stools	75%
grade 2 stomatitis: painful erythema, edema, or ulcers, but can eat or swallow	75%
grade 3 diarrhea: increase of greater than 6 stools per day or incontinence; or need for parenteral support for dehydration	50%
grade 3 stomatitis: painful erythema, edema, or ulcers requiring IV hydration	50%
grade 3 diarrhea or stomatitis with grade 4 hematologic toxicity (neutrophils < 0.5 x 10 9 /L or platelets < 10 x 10 9 /L)	discontinue
grade 4 diarrhea (hemodynamic collapse or requires intensive care) or stomatitis (severe ulceration or requires parenteral or enteral nutrition or prophylactic intubation)	discontinue

SYNONYM(S):