Note: Prior to treatment WBC should be >4,000/mm3, ANC >2,000/mm3, and platelets >100,000/mm3.
Colorectal cancer, advanced: IV: 3 mg/m2 once every 3 weeks in the absence of toxicity.
Malignant pleural mesothelioma, advanced (off-label use): IV: 3 mg/m2 once every 3 weeks (in combination with cisplatin) until disease progression or unacceptable toxicity occurs (van Meerbeeck 2005).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
CrCl >65 mL/minute: No dosage adjustment necessary.
CrCl 55 to 65 mL/minute: Reduce dose to 75% of usual dose once every 4 weeks.
CrCl 25 to 54 mL/minute: Reduce dose to percentage of dose equivalent to CrCl once every 4 weeks (eg, reduce dose to 25% of usual dose for CrCl of 25 mL/minute)
CrCl <25 mL/minute: Do not administer (use is contraindicated in severe renal impairment)
Preexisting impairment: Use is not recommended in clinical jaundice or decompensated liver disease.
Mild to moderate impairment: No dosage adjustment necessary; use with caution.
Severe impairment: Use is contraindicated.
Hepatotoxicity during treatment: Interrupt raltitrexed until hepatic enzymes return to grade 2 or lower.
Refer to adult dosing; use with caution.
American Society of Clinical Oncology guidelines for appropriate systemic therapy dosing in adults with cancer with a BMI ≥30 kg/m2 : Utilize patient's actual body weight for calculation of BSA- or weight-based dosing; manage regimen-related toxicities in the same manner as for patients with a BMI <30 kg/m2; if a dose reduction is utilized due to toxicity, may consider resumption of full, weight-based dosing (or previously tolerated dose level) with subsequent cycles only if dose escalations are allowed in the prescribing information, if contributing underlying factors (eg, hepatic or kidney impairment) are sufficiently resolved, AND if performance status has markedly improved or is considered adequate (ASCO [Griggs 2021]). Note: Once a dose reduction is made for some toxicities, the manufacturer recommends all subsequent dosing be administered at that reduced dosing level; refer to prescribing information for further information.
Delay dose in subsequent cycles until recovery from toxicity. May consider administering leucovorin if appropriate. Once a dose reduction has been made, do not escalate dose in subsequent cycles.
Grade 4 GI toxicity (diarrhea or mucositis) or grade 3 GI toxicity in combination with grade 4 hematologic toxicity: Discontinue raltitrexed and manage with supportive measures (consider administering leucovorin).
Grade 3 hematologic toxicity (neutropenia or thrombocytopenia) or grade 2 GI toxicity (diarrhea or mucositis): Reduce dose by 25%.
Grade 4 hematologic toxicity (neutropenia or thrombocytopenia) or grade 3 GI toxicity (diarrhea or mucositis): Reduce dose by 50%.
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Reconstituted, Intravenous:
Tomudex: 2 mg (1 ea)
Not available in the US
IV: Administer as an infusion over 15 minutes.
When used in combination with cisplatin for malignant pleural mesothelioma (off-label use), administer raltitrexed first, followed by cisplatin (van Meerbeeck 2005).
This medication is not on the NIOSH (2016) list; however, it may meet the criteria for a hazardous drug. Raltitrexed may cause teratogenicity, reproductive toxicity, genotoxicity, and has a structural or toxicity profile similar to existing hazardous agents.
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
Note: Not approved in the US.
Colorectal cancer, advanced: Treatment of advanced colorectal cancer
Malignant pleural mesothelioma, advanced
Raltitrexed may be confused with methotrexate, PEMEtrexed, PRALAtrexate.
Tomudex may be confused with Temodal.
This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes that have a heightened risk of causing significant patient harm when used in error.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults.
>10%:
Dermatologic: Skin rash (14%)
Gastrointestinal: Abdominal pain (17% to 18%), anorexia (26% to 28%), constipation (13% to 15%), diarrhea (37% to 38%; grades 3/4: 11%), mucous membrane abnormality (12%), nausea (57% to 58%; grades 3/4: ≤12%), stomatitis (11%; grades 3/4: 2%), vomiting (37% to 38%; grades 3/4: ≤12%)
Hematologic & oncologic: Anemia (15% to 18%; grades 3/4: 7% to 8%), leukopenia (including neutropenia: 20% to 22%; grades 3/4: 12% to 13%)
Hepatic: Increased serum alanine aminotransferase (14% to 15%), increased serum aspartate aminotransferase (16% to 18%)
Nervous system: Asthenia (46% to 49%)
Miscellaneous: Fever (2% to 23%)
1% to 10%:
Cardiovascular: Cardiac abnormality (2%; including heart failure), cardiac arrhythmia (3%; including atrial fibrillation, sinus tachycardia, supraventricular tachycardia), peripheral edema (10%)
Dermatologic: Alopecia (6%), cellulitis (3%), diaphoresis (3% to 4%), pruritus (3%)
Endocrine & metabolic: Dehydration (6% to 7%), hypokalemia (2%), weight loss (6%)
Gastrointestinal: Dysgeusia (6%), dyspepsia (6%), flatulence (2% to 3%), xerostomia (2% to 3%)
Genitourinary: Urinary tract infection (3%)
Hematologic & oncologic: Thrombocytopenia (5% to 6%; grades 3/4: 4%)
Hepatic: Hyperbilirubinemia (2% to 3%), increased serum alkaline phosphatase (2% to 3%)
Infection: Infection (3%), sepsis (2% to 3%)
Nervous system: Chills (4%), depression (3%), dizziness (4% to 5%), headache (6%), hypertonia (<2%), insomnia (3% to 4%), malaise (4%), pain (4%), paresthesia (2% to 3%)
Neuromuscular & skeletal: Arthralgia (<2%), myalgia (3%)
Ophthalmic: Conjunctivitis (2% to 3%)
Renal: Increased serum creatinine (2% to 3%)
Respiratory: Dyspnea (4% to 5%), flu-like symptoms (6% to 8%), increased cough (5%), pharyngitis (4% to 5%)
Frequency not defined: Dermatologic: Desquamation
Postmarketing:
Gastrointestinal: Gastrointestinal hemorrhage
Hepatic: Acute hepatic failure (Raderer 2000), hepatotoxicity (including increased gamma-glutamyl transferase) (Massacesi 2003)
Respiratory: Interstitial pneumonitis (Schallier 2000)
Hypersensitivity to raltitrexed or any component of the formulation; severe renal and/or hepatic impairment; pregnancy or breastfeeding; use in patients who may become pregnant; use in children (<18 years of age).
Concerns related to adverse effects:
• Bone marrow suppression: Neutropenia, leukopenia, anemia, and thrombocytopenia may occur; neutropenia and thrombocytopenia may be severe. Bone marrow suppression is typically mild to moderate and generally occurs 7 to 14 days after treatment; recovery usually occurs by day 21. Use with caution in patients with preexisting bone marrow suppression.
• Gastrointestinal toxicity: Diarrhea, mucositis, and stomatitis may occur. Severe diarrhea with concomitant hematologic toxicity (neutropenia) may be life-threatening.
• Hepatotoxicity: Asymptomatic and self-limiting reversible ALT and AST elevations may occur.
• Malaise/weakness: May cause malaise/weakness; caution patients concerning operation of machinery/driving.
Special populations:
• Older adult: Use with caution in older adult patients. Monitor closely, especially for GI toxicity, such as diarrhea or mucositis.
• Radiation therapy recipients: Use with caution in patients who have received prior radiation therapy.
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
5-Aminosalicylic Acid Derivatives: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid combination
Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Risk C: Monitor therapy
Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk X: Avoid combination
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Risk C: Monitor therapy
Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Risk D: Consider therapy modification
Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Risk X: Avoid combination
Fexinidazole: Myelosuppressive Agents may enhance the myelosuppressive effect of Fexinidazole. Risk X: Avoid combination
Folic Acid: May diminish the therapeutic effect of Raltitrexed. Risk X: Avoid combination
Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Management: Avoid the use of lenograstim 24 hours before until 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Risk D: Consider therapy modification
Leucovorin Calcium-Levoleucovorin: May diminish the therapeutic effect of Raltitrexed. Risk X: Avoid combination
Levomefolate: May diminish the therapeutic effect of Raltitrexed. Risk X: Avoid combination
Lipegfilgrastim: Antineoplastic Agents may diminish the therapeutic effect of Lipegfilgrastim. Management: Avoid concomitant use of lipegfilgrastim and myelosuppressive cytotoxic chemotherapy. Lipegfilgrastim should be administered at least 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Risk D: Consider therapy modification
Methylfolate: May diminish the therapeutic effect of Raltitrexed. Risk X: Avoid combination
Multivitamins/Minerals (with ADEK, Folate, Iron): May diminish the therapeutic effect of Raltitrexed. Specifically, the folic acid contained in multivitamins is responsible for this potential interaction. Risk X: Avoid combination
Olaparib: Myelosuppressive Agents may enhance the myelosuppressive effect of Olaparib. Risk C: Monitor therapy
Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. Risk D: Consider therapy modification
Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
Pyrimethamine: May enhance the adverse/toxic effect of Raltitrexed. Risk C: Monitor therapy
Ropeginterferon Alfa-2b: Myelosuppressive Agents may enhance the myelosuppressive effect of Ropeginterferon Alfa-2b. Management: Avoid coadministration of ropeginterferon alfa-2b and other myelosuppressive agents. If this combination cannot be avoided, monitor patients for excessive myelosuppressive effects. Risk D: Consider therapy modification
Use is contraindicated in patients who may become pregnant during treatment. Pregnancy should be excluded prior to treatment. Pregnancy should be avoided during treatment and for 6 months after the last raltitrexed dose if either partner is receiving treatment.
Use is contraindicated in patients who are pregnant.
Pregnant patients should not handle this medication.
Use in breastfeeding patients is contraindicated by the manufacturer.
Avoid folic acid, folinic acid (leucovorin calcium), and multivitamins with folic acid close to and during administration.
CBC with differential (at baseline, prior to each treatment, or weekly if GI toxicity observed); hepatic function tests and serum creatinine (at baseline and prior to each treatment). Monitor for signs of GI toxicity. Evaluate pregnancy status prior to use in patients who may become pregnant.
The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
Raltitrexed is a folate analogue that selectively inhibits thymidylate synthase, blocking purine synthesis. This results in an overall inhibition of DNA synthesis.
Distribution: Vss: 548 L
Protein binding: 93%
Metabolism: Undergoes extensive intracellular metabolism to active polyglutamate forms; appears to be little or no systemic metabolism of the drug
Half-life elimination: Triphasic; Beta: ~2 hours; Terminal: 198 hours
Excretion: Urine (~50% as unchanged drug); feces (~15%)
Altered kidney function: Plasma clearance is reduced approximately 50% in patients with CrCl 25 to 65 mL/minute.
Hepatic function impairment: Mild to moderate impairment results in a reduction in plasma clearance of less than 25%.
