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raltitrexed
Raltitrexed is a quinazoline folate analogue that selectively inhibits thymidylate synthase (TS). TS is a key enzyme in the de novo synthesis of thymidine triphosphate (TTP), a nucleotide required exclusively for DNA synthesis. Inhibition of TS leads to DNA fragmentation and cell death. Raltitrexed is transported into cells and is then extensively polyglutamated. These polyglutamate forms are retained in cells and are even more potent inhibitors of TS, which may both increase antitumour activity as well as toxicity.
Following intravenous administration, peak concentrations are reached at the end of the infusion, followed by a rapid initial decline in concentration and then a slow elimination phase. Pharmacokinetics are linear.
| Cross blood brain barrier? | no information found |
| PPB | 93 % |
Apart from intracellular polyglutamination, raltitrexed is not extensively metabolized.
| Active metabolites |
Yes |
| Inactive metabolites |
None |
Excreted unchanged in the urine (approximately 50%) and in the feces (approximately 15%). About 50% of dose retained in tissues.
| Half-life |
198 hours (terminal) |
- Colorectal cancer
Refer to the product monograph for a full list of approved indications.
Other Uses:
- Pleural mesothelioma
- Gastric cancer
- Esophageal cancer
Emetogenic Potential:
Extravasation Potential: None
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Arrhythmia (3%) | E | |||
| Dermatological | Alopecia (6%) | E | |||
| Rash (14%) | I E | ||||
| Gastrointestinal | Abdominal pain (18%) | E | |||
| Anorexia, weight loss (26%) | E | ||||
| Constipation (15%) | E | ||||
| Diarrhea (37%) (11% severe) | E | ||||
| Dyspepsia (6%) | E | ||||
| Mucositis (11%) | E | ||||
| Nausea, vomiting (57%) | I E | ||||
| General | Edema (10%) | E | |||
| Fatigue (46%) | E | ||||
| Hematological | Myelosuppression ± infection, bleeding (20%) (12% severe) | E | |||
| Hepatobiliary | ↑ LFTs (18%) (may be severe) | E | |||
| Metabolic / Endocrine | ↓ K (2%) | E | |||
| Musculoskeletal | Musculoskeletal pain (3%) | E | |||
| Nervous System | Depression (3%) | E | |||
| Dizziness (5%) | E | ||||
| Dysgeusia (6%) | E | ||||
| Headache (6%) | E | ||||
| Insomnia (4%) | E | ||||
| Paresthesia (3%) | E | ||||
| Ophthalmic | Conjunctivitis (3%) | E | |||
| Renal | Creatinine increased (3%) | E | |||
| Respiratory | Cough, dyspnea (5%) | E | |||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
The most common side effects for raltitrexed include nausea, vomiting, fatigue, diarrhea, anorexia, weight loss, myelosuppression ± infection, bleeding, ↑ LFTs, abdominal pain, rash and mucositis.
Diarrhea, nausea and vomiting are usually mild to moderate; however, severe diarrhea can occur, and may be associated with concurrent hematological suppression.
Refer to protocol by which patient is being treated.
Screen for hepatitis B virus in all cancer patients starting systemic treatment. Refer to the hepatitis B virus screening and management guideline.
Dose: 3 mg/m2 IV every 3 weeks
Patients should not receive subsequent courses of raltitrexed until they have recovered from prior toxicity including GI, neutropenia, thrombocytopenia, and transaminase elevations (if present) show reversibility.
Dosage in Myelosuppression ± Gastrointestinal Toxicity:
The dose of raltitrexed should be reduced based upon the worst hematologic and GI toxicity experienced in the previous cycle. Doses should not be re-escalated if reduced for toxicity.
|
Worst Toxicity in previous cycle |
Action1
|
Dose |
||
|
grade 3 neutropenia / thrombocytopenia
|
OR
|
grade 2 GI toxicity
|
Hold until complete recovery
|
75%
|
|
grade 4 neutropenia / thrombocytopenia
|
OR
|
grade 3 GI toxicity
|
50%
|
|
|
grade 3 or 4 ↑ LFTs
|
Hold until ≤ grade 2
|
100%; if recurs consider ↓ to 75%.
|
||
|
grade 4 GI toxicity
|
Discontinue treatment
|
N/A
|
||
|
grade 4 neutropenia / thrombocytopenia
|
AND
|
grade 3 GI toxicity
|
||
|
1 Retreat only when GI toxicity resolved, platelets are ≥ 100 x 109/L, ANC ≥ 2 x 109/L, and WBC ≥ 4 x 109/L. |
||||
| Hepatic Impairment | Starting Dose |
| Mild to moderate | No dose adjustment recommended. Use with caution. |
| Severe | Contraindicated. |
Raltitrexed is contraindicated in severe renal impairment.
Mild to moderate renal impairment results in a significant reduction in raltitrexed clearance and doses must be modified for renal impairment. Patients with renal impairment should be monitored carefully.
|
Creatinine Clearance |
Dose as % of 3 mg/m2 |
Dosing Interval |
|
> 65 |
100 |
q3w |
|
55-65 |
75 |
q4w |
|
25-54 |
% equivalent to mL/min* |
q4w |
|
< 25 |
Contraindicated |
Not applicable |
|
*(e.g. if 30mL/min, give 30% of full dose.) |
||
Use with extreme caution as the elderly are more susceptible to toxicity (especially GI).
Use is not recommended as safety and effectiveness in children have not been established.
-
Mix in 50-250 mL (NS, D5W); infuse IV over 15 minutes.
-
Do not admix with other drugs.
- Store unopened vials at 2 to 25°C protected from light.
- Reconstituted and diluted solutions do not need to be protected from light.
- Patients with hypersensitivity to the drug or any of its components
- Patients with severe renal and/or hepatic impairment
- Children < 18 years of age
- Caution is necessary in patients with depressed bone marrow function, poor general condition, prior radiotherapy, mild to moderate hepatic impairment and in elderly patients.
Other Drug Properties:
-
Carcinogenicity:
Unknown
-
Embryotoxicity:
Yes
-
Fetotoxicity:
Yes
Raltitrexed is contraindicated in pregnancy. Adequate contraception should be used by patients and their partners during treatment, and for at least 6 months after the last dose.
-
Breastfeeding:
Breastfeeding is contraindicated.
-
Fertility effects:
Yes
(especially in males)
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| Folinic acid, folic acid or vitamin preparation containing these agents | May interfere with raltitrexed action | Theoretical competition for the enzyme folyl polyglutamate synthetase and also competition for the binding of TS | Avoid immediately before or during raltitrexed administration. |
| Renally secreted drugs (e.g. NSAID’s) | Potential competition interaction with actively secreted drugs | Raltitrexed may compete for active tubular secretory sites | Caution (no evidence) |
| Highly protein bound drugs (e.g. warfarin) | Potential displacement | Raltitrexed may displace protein bound drugs thus increasing plasma concentrations | Caution (no evidence) |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
Refer to the hepatitis B virus screening and management guideline for monitoring during and after treatment.
| Monitor Type | Monitor Frequency |
|---|---|
CBC |
Baseline and at each visit |
CBC, for patients who develop signs of GI toxicity |
Weekly |
Liver function tests |
Baseline and at each visit |
Renal function tests |
Baseline and at each visit |
Clinical assessment of GI toxicity, rash, infection and bleeding |
At each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
New Drug Funding Program (NDFP Website )
- Raltitrexed - Advanced Malignant Pleural Mesothelioma (MPM)
- Raltitrexed - Metastatic Colorectal Small Bowel or Appendiceal Cancer
- Raltitrexed - Metastatic Esophageal, Gastroesophageal Junction, or Gastric Cancer
- Raltitrexed - Adjuvant Colorectal, Small Bowel, or Appendiceal Cancer
- Raltitrexed - Adjuvant Esophageal, Gastroesophageal Junction, or Gastric Cancer
Blair EY, Rivory LP, Clarke SJ, McLachlan AJ. Population pharmacokinetics of raltitrexed in patients with advanced solid tumours. Br J Clin Pharmacol. 2004 Apr;57(4):416-26.
Product Monograph: Tomudex® (raltitrexed). Hospira Healthcare Corp., December 7, 2021.
Summary or Product Characteristics: Tomudex® (raltitrexed). Hospira UK Ltd., March 2024.
June 2024 Modified Dosage in Hepatic Impairment, Adverse effects, Contraindications, Pregnancy/lactation, and Interactions sections
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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