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raltitrexed

( rall-tee-TREX-edd )
Funding:
New Drug Funding Program
  • Raltitrexed - Advanced Malignant Pleural Mesothelioma (MPM)
  • Raltitrexed - Metastatic Colorectal Small Bowel or Appendiceal Cancer
Other Name(s): Tomudex® (Pfizer)
Appearance: Colourless solution mixed into larger bags of fluids
A - Drug Name

raltitrexed

SYNONYM(S):   Raltitrexed disodium; ZD 1694

COMMON TRADE NAME(S):   Tomudex® (Pfizer)

 
B - Mechanism of Action and Pharmacokinetics

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. Ralitrexed 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.



Absorption
Oral absorption:  No information found
Distribution

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 %
Metabolism

Not metabolized. Active metabolites include polyglutamates.

Inactive metabolites None
Elimination

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)
 
C - Indications and Status
Health Canada Approvals:

  •  Advanced colorectal cancer


Other Uses:

  •  Pleural mesothelioma (in combination with cisplatin)
 
D - Adverse Effects

Emetogenic Potential:  

Low

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.
Dose-limiting side effects are underlined.

** 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.

Myelosuppression is common and may be severeThe use of leucovorin as a rescue agent should be considered with severe toxicity.
 
E - Dosing

Refer to protocol by which patient is being treated. Numerous dosing schedules exist depending on disease, response and concomitant therapy.

Adults:

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 with Toxicity:

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.

 
 


Dosage with Hepatic Impairment:

Grade

Initial Dose (baseline values)

1

100% 

2

100%, watch carefully

3

Extreme caution (no data)

4

Do not treat (no data)



Dosage with 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.  (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.)



Dosage in the elderly:

Use with extreme caution as the elderly are more susceptible to toxicity.

Children:

Use is not recommended as safety and effectiveness in children have not been established.

 
F - Administration Guidelines

  • 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


 
G - Special Precautions
Contraindications:

  • 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)

 
H - Interactions

AGENT EFFECT MECHANISM MANAGEMENT
Folinic acid, folic acid or vitamin preparation containing these agents May interfere with ralitrexed 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 Ralitrexed may displace protein bound drugs thus increasing plasma concentrations Caution (no evidence)
 
I - Recommended Clinical Monitoring
Recommended Clinical Monitoring

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



 
J - Supplementary Public Funding

New Drug Funding Program (NDFP Website )

  • Raltitrexed - Advanced Malignant Pleural Mesothelioma (MPM)
  • Raltitrexed - Metastatic Colorectal Small Bowel or Appendiceal Cancer

 
K - References

Product Monograph: Tomudex® (raltitrexed). Hospira Healthcare Corp., April 23, 2008.


November 2017 updated public funding form title

 
L - Disclaimer

Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.

The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.

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