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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 via the reduced folate carrier and is then extensively polyglutamated by enzyme folyl polyglutamate synthetase to polyglutamate forms. These are retained in cells and are even more potent inhibitors of thymidylate synthase, which may both increase antitumour activity as well as toxicity.
Oral absorption: No information found
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 % |
Not metabolized. Active metabolites include polyglutamates.
| 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 t½) |
- Advanced colorectal cancer
Other Uses:
- Pleural mesothelioma (in combination with cisplatin)
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 (28%) | E | ||||
| Constipation (15%) | E | ||||
| Diarrhea (38%) (may be severe) | E | ||||
| Dyspepsia (6%) | E | ||||
| Mucositis (12%) | E | ||||
| Nausea, vomiting (58%) | I E | ||||
| General | Edema (10%) | E | |||
| Fatigue (49%) | E | ||||
| Hematological | Myelosuppression ± infection, bleeding (13%) (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 adverse events associated with raltitrexed in phase III trials were gastrointestinal and hematological in nature. 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. Numerous dosing schedules exist depending on disease, response and concomitant therapy.
Dose: 3 mg/m2 IV as a 15 minute infusion.
In the absence of toxicity, treatment may be repeated every 3 weeks. Dose escalation is not recommended.
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 (% previous 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. | ||||
Grade | Initial Dose (baseline values) |
1 | 100% |
2 | 100%, watch carefully |
3 | Extreme caution (no data) |
4 | Do not treat (no data) |
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. (Continued on next page)
Creatinine Clearance mL/min | Dose as % of 3mg/m2 | Dosing Interval |
>65 | 100 | q3w |
55-65 | 75 | q4w |
25-54 | % equivalent to mL/min* | q4w |
<25 | Discontinue | not applicable |
*(e.g. if 30mL/min, give 30% of full dose.) | ||
Use with extreme caution as the elderly are more susceptible to toxicity.
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
- 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
Other Warnings/Precautions:
- Caution is necessary in patients with depressed bone marrow function, poor general condition, prior radiotherapy, mild to moderate hepatic impairment and in elderly patients.
- Raltitrexed results in asthenia and malaise; it may impair ability to drive and to operate machinery.
Other Drug Properties:
- Carcinogenicity: Unknown
Pregnancy and Lactation:
- Embryotoxicity: Yes
- Fetotoxicity: Yes
Raltitrexed is not recommended for use in pregnancy. Adequate contraception should be used by both sexes during treatment, and for at least 6 months after the last dose.
- 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 |
| 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) |
| Monitor Type | Monitor Frequency |
|---|---|
Liver function tests | Baseline and at each visit |
Renal function tests | Baseline and at each visit |
CBC | Baseline and at each visit |
| CBC, for patients who develop signs of GI toxicity | weekly |
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
Product Monograph: Tomudex® (raltitrexed). Hospira Healthcare Corp., April 23, 2008.
April 2023 added NDFP forms
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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