Raltitrexed (Systemic)
VA CLASSIFICATION
Primary: AN300
Commonly used brand name(s): Tomudex.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).
*Not commercially available in the U.S.
Category:
Antineoplastic—
Indications
Accepted
Carcinoma, colorectal (treatment)—Raltitrexed is indicated in the treatment of advanced colorectal cancer. {01}
Pharmacology/Pharmacokinetics
Physicochemical characteristics:
Molecular weight—
458.49{01}
pKa—
The estimated pKa values of the two carboxylic acid groups are 4.5 and 5.7 at 25 °C{01}
Solubility
Solubility is susceptible to pH.{01}
Mechanism of action/Effect:
Raltitrexed is a quinazoline folate analogue that selectively inhibits thymidylate synthase (TS). Inhibition of TS leads to DNA fragmentation and cell death. Once transported into cells via a reduced folate carrier, raltitrexed is extensively polyglutamated, which enhances TS inhibitory potency and duration, which may increase the antitumor activity.{01}
Distribution:
Volume of distribution (Vol D)— Steady state: 548 L.{01}
Protein binding:
Very high (93%).{01}
Biotransformation:
Raltitrexed is transported into cells via a reduced folate carrier and is then extensively polyglutamated by the enzyme folyl polyglutamate synthetase to polyglutamate forms.{01}
Half-life:
Half-life is triphasic.{01}
Second phase—1.79 hours.{01}
Terminal— 198 hours.{01}
Peak plasma concentration
Following intravenous administration at 3 mg/m 2— 656 ng/mL.{01}
The maximum concentrations of raltitrexed increased linearly with dose over the clinical dose range tested.{01}
Elimination:
Primarily excreted unchanged in the urine (approximately 50%).{01}
Fecal excretion also occurs with approximately 15% of the dose being eliminated over a 10 day period.{01}
In one study, approximately half of the radiolabeled raltitrexed was not recovered during the study period suggesting that a proportion (50%) of the dose is retained within tissues, perhaps as polyglutamates. Trace levels of radiolabeled raltitrexed were detected in red blood cells on Day 29. {01}
Following intravenous administration at 3 mg/m 2: • Renal clearance— 25.1 mL/min.{01}
• Total clearance— 51.6 mL/min.{01}
In patients with normal renal function, there was no clinically significant plasma accumulation of raltitrexed during repeat administration at three week intervals. In patients with mild to moderate renal impairment (creatinine clearance of 25 to 65 mL/min), plasma clearance was significantly reduced (approximately 50%).{01}
In patients with mild (WHO grade 2) to moderate (WHO grade 3) hepatic impairment, plasma clearance was reduced by less than 25%.{01}
Additional pharmacokinetic information
Pharmacokinetics are independent of age and gender.{01}
Pharmacokinetics have not been evaluated in children.{01}
Precautions to Consider
Carcinogenicity
The carcinogenic potential of raltitrexed has not been evaluated.{01}
Mutagenicity
Raltitrexed was not mutagenic in the Ames test or in supplementary tests using E. coli or chinese hamster ovary cells. Raltitrexed caused increased levels of chromosome damage in an in vitro assay of human lymphocytes. An in vivo micronucleus study in the rat indicated that at cytotoxic dose levels, raltitrexed is capable of causing chromosome damage in the bone marrow. {01}
Pregnancy/Reproduction
Fertility—
In rats, raltitrexed can cause impairment of male fertility. Fertility returned to normal three months after dosing ceased.{01}
Pregnancy—
Raltitrexed is not recommended during pregnancy. Pregnancy should be excluded before treatment with raltitrexed is begun and should be avoided during treatment and for at least 6 months after discontinuation of treatment if either partner is receiving raltitrexed.{01}
In pregnant rats, raltitrexed caused embryolethality and fetal abnormalities. {01}
Breast-feeding
It is not known whether raltitrexed is distributed into breast milk. However, raltitrexed is not recommended in women who are breast-feeding.{01}
Pediatrics
Raltitrexed is not recommended for use in children. Safety and efficacy have not been established. {01}
Geriatrics
Elderly patients are more vulnerable to the toxic effects of raltitrexed, particularly gastrointestinal toxicity{01}. Elderly patients are more likely to have age-related renal function impairment, which may require reduction of dosage in patients receiving raltitrexed.
Pharmacogenetics
Raltitrexed pharmacokinetics are independent of age and gender. {01}
Dental
The bone marrow depressant effects of raltitrexed may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding. Dental work, whenever possible, should be completed prior to initiation of therapy or deferred until blood counts have returned to normal. Patients should be instructed in proper oral hygiene during treatment, including caution in use of regular toothbrushes, dental floss, and toothpicks.
Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
Blood dyscrasia–causing medications (see Appendix II) (leukopenic and/or thrombocytopenic effects of raltitrexed may be increased with concurrent or recent therapy if these medications cause the same effects; dosage adjustment of raltitrexed, if necessary, should be based on blood counts )
» Bone marrow depressants, other (see Appendix II) or
Radiation therapy (additive bone marrow depression may occur; dosage reduction may be required when two or more bone marrow depressants, including radiation, are used concurrently or consecutively)
» Folic acid or
» Leucovorin (folinic acid) or
» Vitamin preparations containing folic or folinic acid (should not be given immediately prior to or during raltitrexed administration due to possible interference with the therapeutic effects of raltitrexed{01})
Immunosuppressants, other (concurrent use with raltitrexed may increase the risk of infection and development of neoplasms)
Vaccines, killed virus (because normal defense mechanisms may be suppressed by raltitrexed therapy, the patient's antibody response to the vaccine may be decreased. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year)
» Vaccines, live virus (because normal defense mechanisms may be suppressed by raltitrexed therapy, concurrent use with a live virus vaccine may potentiate the replication of the vaccine virus, may increase the side/adverse effects of the vaccine virus, and/or may decrease the patient's antibody response to the vaccine; immunization of these patients should be undertaken only with extreme caution after careful review of the patient's hematologic status and only with the knowledge and consent of the physician managing the raltitrexed therapy. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year. Immunization with oral poliovirus vaccine should also be postponed in persons in close contact with the patient, especially family members)
Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
With physiology/laboratory test values
Alanine aminotransferase (ALT [SGPT]), serum and
Alkaline phosphatase, serum and
Aspartate aminotransferase (AST [SGOT], serum (values may be increased transiently{01})
Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).
Except under special circumstances, this medication should not be used when the following medical problem exists:
» Hepatic function impairment, severe {01}
» Renal function impairment, severe{01}
» Sensitivity to raltitrexed{01}
Risk-benefit should be considered when the following medical problems exist
» Bone marrow depression
» Chickenpox, existing or recent (including recent exposure) or
» Herpes zoster (risk of severe generalized disease)
Hepatic function impairment, mild to moderate{01} (elimination may be reduced)
» Infection
Renal function impairment, mild to moderate{01} (reduced elimination; lower dosage is recommended)
» Caution should be used also in patients who have had previous cytotoxic drug or radiation therapy
Patient monitoring
Alanine aminotransferase (ALT [SGPT]) values and
Alkaline phosphatase values and
Aspartate aminotransferase (AST [SGOT]) values and
Bilirubin concentrations, serum (recommended prior to initiation of treatment and before each subsequent treatment{01})
» Blood counts, complete and
» Hematocrit or hemoglobin and
» Leukocyte count, total and, if appropriate, differential and
» Neutrophil count, absolute (ANC) and
» Platelet count (recommended prior to initiation of treatment and before each subsequent treatment{01})
» Creatinine clearance and
» Creatinine, serum (recommended prior to initiation of treatment and before each subsequent treatment{01})
Side/Adverse Effects
Note: Many “side effects” of antineoplastic therapy are unavoidable and represent the medication's pharmacologic action. Some of these (for example, leukopenia and thrombocytopenia) are actually used as parameters to aid in individual dosage titration.
Adverse effects associated with raltitrexed mainly include reversible effects on the gastrointestinal tract, hematopoietic system, and liver enzymes.
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Those indicating need for medical attention
Incidence more frequent
Anemia {01}(pale skin; troubled breathing, exertional; unusual bleeding or bruising; unusual tiredness or weakness), leukopenia {01}( black, tarry stools; chest pain; chills ; cough; fever; painful or difficult urination; shortness of breath; sore throat; sores, ulcers, or white spots on lips or in mouth; swollen glands; unusual bleeding or bruising; unusual tiredness or weakness)
diarrhea {01}(increase in bowel movements ; loose stools; soft stools)—can be severe
Note: Anemia and leukopenia are usually mild to moderate, reaching a nadir in the first or second week after treatment and recovering by the third week. Severe leukopenia of WHO grade 4 can occur and may be life-threatening or fatal, especially if associated with gastrointestinal toxicity{01}.
Diarrhea is usually mild or moderate in intensity. However, severe diarrhea can occur, and may be associated with concurrent hematological suppression, especially leukopenia. Subsequent treatment may need to be discontinued or the dose reduced depending on the grade of toxicity {01}.
Incidence less frequent
Arrhythmias {01}(dizziness; fainting ; fast, slow, or irregular heartbeat), congestive heart failure {01}(chest pain; decreased urine output; dilated neck veins; extreme fatigue ; irregular breathing; irregular heartbeat ; shortness of breath; swelling of face, fingers, feet, or lower legs; tightness in chest; troubled breathing; weight gain; wheezing)
thrombocytopenia {01}(black, tarry stools; chest pain; chills; cough; fever ; painful or difficult urination; shortness of breath; sore throat; sores, ulcers, or white spots on lips or in mouth; swollen glands; unusual bleeding or bruising; unusual tiredness or weakness)
Note: Thrombocytopenia is usually mild to moderate, reaching a nadir in the first or second week after treatment and recovering by the third week. Severe thrombocytopenia of WHO grade 4 can occur and may be life-threatening or fatal, especially if associated with gastrointestinal toxicity{01}
Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
Abdominal pain {01}(stomach or abdomen pain), anorexia {01}(loss of appetite; weight loss), constipation {01}
nausea {01}
stomatitis {01}(swelling or inflammation of the mouth), vomiting {01}
asthenia {01}( lack or loss of strength)
fever {01}
flu syndrome {01}(chills; cough; diarrhea; fever; general feeling of discomfort or illness; headache; joint pain; loss of appetite; muscle aches and pains; nausea; runny nose ; shivering; sore throat; sweating; trouble sleeping; unusual tiredness or weakness; vomiting)
rash {01}
Note: Asthenia and fever are usually mild to moderate and reversible. However, severe asthenia can occur and may be associated with malaise and a flu-like syndrome {01}.
Nausea and vomiting are usually mild or moderate and responsive to antiemetics {01}.
Incidence less frequent
Headache {01}
peripheral edema {01}(bloating or swelling of face, arms, hands, lower legs, or feet; rapid weight gain; tingling of hands or feet)
Those not indicating need for medical attention
Incidence more frequent
Alopecia {01}(hair loss; thinning of hair )
Incidence less frequent
Taste disturbance {01}(change in taste; bad unusual or unpleasant (after)taste)
weight loss {01}
Those indicating need for medical attention only if they occur after medication is discontinued
Bone marrow depression (black, tarry stools; blood in urine or stools; cough or hoarseness; fever or chills; lower back or side pain; painful or difficult urination; pinpoint red spots on skin ; unusual bleeding or bruising)
Overdose
For specific information on the agents used in the management of raltitrexed overdose, see: Leucovorin (Systemic) .
For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).
Clinical effects of overdose
Expected manifestations of overdose are likely to be an exaggerated form of the adverse drug reactions anticipated with the administration of raltitrexed, particularly gastrointestinal and hematological toxicity {01}.
Treatment of overdose
There is no clinically proven antidote to raltitrexed; however, 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 intravenously every 6 hours. Leucovorin should be administered as soon as possible following accidental raltitrexed overdosage. The efficacy of leucovorin in reducing raltitrexed toxicity may decrease as the time between raltitrexed administration and the initiation of leucovorin therapy increases{01}.
Supportive care—Patients should be managed with appropriate supportive therapy, including intravenous hydration and bone marrow support.{01}Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.
Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Raltitrexed (Systemic).
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):
Before using this medication
» Conditions affecting use, especially:
Sensitivity to raltitrexed
Mutagenicity—
Caused chromosome damage in an in vitro assay of human lymphocytes; caused chromosome damage in the bone marrow of rats, at cytotoxic dose levels
Pregnancy—Not recommended for use during pregnancy (while taking this medication and avoid pregnancy for at least 6 months after last dose)
Breast-feeding—Not recommended because of risk of serious side effects.
Use in children——Not recommended for use in children.
Other medications, especially folic acid, leucovorin (folinic acid), other bone marrow depressants, previous cytotoxic drug therapy or radiation therapy, or vitamin preparations containing folic or folinic acid
Other medical problems, especially bone marrow depression, chickenpox, herpes zoster, severe hepatic function impairment, infection, or severe renal function impairment
Proper use of this medication
Caution with combination therapy; taking each medication at the right time
Frequency of nausea and vomiting; importance of continuing medication despite stomach upset
» Proper dosing
Consult physician
Precautions while using this medication
» Importance of close monitoring by physician
» Raltitrexed may cause a general feeling of discomfort or illness and unusual tiredness or weakness following the infusion; this may impair the ability to drive or use machinery
» Avoiding immunizations unless approved by physician; other persons in patient's household should avoid immunizations with oral poliovirus vaccine; avoiding other persons who have taken oral poliovirus vaccine or wearing a protective mask that covers nose and mouth
Caution if bone marrow depression occurs
» Avoiding exposure to persons with infections, especially during periods of low blood counts; checking with physician immediately if fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination occurs
» Checking with physician immediately if unusual bleeding or bruising; black, tarry stools; blood in urine or stools; or pinpoint red spots on skin occur
Caution in use of regular toothbrush, dental floss, or toothpick; physician, dentist, or nurse may suggest alternatives; checking with physician before having dental work done
Not touching eyes or inside of nose unless hands are washed immediately before
Using caution to avoid accidental cuts with use of sharp objects such as safety razor or fingernail or toenail cutters
Avoiding contact sports or other situations where bruising or injury could occur
Side/adverse effects
Signs of potential side effects, especially anemia, leukopenia, diarrhea, arrhythmias, congestive heart failure, and thrombocytopenia
Physician or nurse can help in dealing with side effects
Possibility of hair loss; normal hair growth should resume after treatment has ended
General Dosing Information
Patients receiving raltitrexed should be under supervision of a physician experienced in cancer chemotherapy and in the management of related toxicities.
It is recommended that raltitrexed be administered as a single short, intravenous infusion in 0.9% sodium chloride or 5% dextrose (over a 15 minute period).
Prior to the initiation of treatment and before each subsequent treatment a full blood count (including a differential count and platelets), liver transaminases, serum bilirubin, and serum creatinine measurements should be performed. The total white cell count should be greater than 4000/mm 3, the neutrophil count greater than 2000/mm 3, and the platelet count greater than 100,000/mm 3 prior to treatment.
In the event of toxicity the next scheduled dose should be withheld until signs of toxic effects regress. Gastrointestinal and hematological toxicity should have resolved completely before subsequent treatment is permitted. Patients who develop signs of gastrointestinal toxicity should have their full blood counts monitored at least weekly for signs of hematological toxicity. Treatment in patients with elevated liver enzymes should be deferred until they show signs of reversibility to at least WHO grade 2.
Based on the worst grade of gastrointestinal and hematological toxicity observed on the previous treatment and provided that such toxicity has resolved completely, the following dose reductions are recommended for subsequent treatments: • 25% dose reduction in patients with WHO grade 3 hematological toxicity (neutropenia or thrombocytopenia) or WHO grade 2 gastrointestinal toxicity (diarrhea or mucositis).
• 50% dose reduction in patients with WHO grade 4 hematological toxicity (neutropenia or thrombocytopenia) or WHO grade 3 gastrointestinal toxicity (diarrhea or mucositis).
Once a dose reduction has been made, all subsequent doses should be given at the reduced dose level.
Treatment should be discontinued in the event of any WHO grade 4 gastrointestinal toxicity (diarrhea or mucositis) or in the event of a WHO grade 3 gastrointestinal toxicity associated with WHO grade 4 hematological toxicity. Patients with mild to moderate renal impairment (creatinine clearance of 25 to 65 mL/min) will require a dosage adjustment. For patients with abnormal serum creatinine, before the first or any subsequent treatment, a creatinine clearance should be obtained.
Patients with mild (WHO grade 2) to moderate (WHO grade 3) hepatic impairment do not require a dosage adjustment. However, these patients should be monitored carefully.
Special precautions are recommended in patients who develop thrombocytopenia as a result of administration of raltitrexed. These may include extreme care in performing invasive procedures; regular inspection of intravenous sites, skin (including perirectal area), and mucous membrane surfaces for signs of bleeding or bruising; limiting frequency of venipuncture and avoiding intramuscular injections; testing urine, emesis, stool, and secretions for occult blood; care in use of regular toothbrushes, dental floss, toothpicks, safety razors, and fingernail and toenail cutters; avoiding constipation; and using caution to prevent falls and other injuries. Such patients should avoid alcohol and any aspirin intake because of the risk of gastrointestinal bleeding. Platelet transfusions may be required.
Patients who develop leukopenia should be observed carefully for signs of infection. Antibiotic support may be required. In neutropenic patients who develop fever, broad-spectrum antibiotic coverage should be initiated empirically, pending bacterial cultures and appropriate diagnostic tests.
Safety considerations for handling this medication
There is limited but increasing evidence and concern that personnel involved in preparation and administration of parenteral antineoplastics may be at some risk because of the potential mutagenicity, teratogenicity, and/or carcinogenicity of these agents, although the actual risk is unknown. USP advisory panels recommend cautious handling both in preparation and disposal of antineoplastic agents. Precautions that have been suggested include: • Use of a biological containment cabinet during reconstitution and dilution of parenteral medications and wearing of disposable surgical gloves and masks.
• Use of proper technique to prevent contamination of the medication, work area, and operator during transfer between containers (including proper training of personnel in this technique).
• Cautious and proper disposal of needles, syringes, vials, ampuls, and unused medication.
A number of medical centers have developed detailed guidelines for handling of antineoplastic agents.
For treatment of adverse effects
WHO grade 4 gastrointestinal toxicity or WHO grade 3 gastrointestinal toxicity associated with WHO grade 4 hematological toxicity should be managed promptly with standard supportive care measures including intravenous hydration and bone marrow support.
To improve intestinal damage and recovery of neutrophil and platelet numbers, leucovorin (folinic acid) may be given at a dose of 25 mg/m 2 intravenously every 6 hours until the resolution of symptoms.{01}
Parenteral Dosage Forms
RALTITREXED DISODIUM INJECTION
Usual adult and adolescent Dose
Carcinoma, colorectal
Intravenous, 3 mg per square meter of body surface area every 3 weeks.{01}
Note: RENAL IMPAIRMENT: Adults with impaired renal function (creatinine clearance £ 65 mL/min) may require a change in dosing as follows:
| Creatinine clearance | Dose as % of 3 mg/m2 | Dosing interval |
| > 65 mL/min | Full dose | 3–weekly |
| 55 to 65 mL/min | 75% | 4–weekly |
| 25 to 54 mL/min | % equivalent to mL/min* | 4–weekly |
| < 25 mL/min | No therapy | Not applicable |
{01}
Note: HEPATIC IMPAIRMENT: Adults with mild (WHO grade 2) to moderate (WHO grade 3) hepatic impairment do not require a dosage adjustment. However, these patients should be monitored carefully.{01}
Usual adult and adolescent prescribing limits
Dose escalation above 3 mg per square meter of body surface area is not recommended, since higher doses have been associated with an increased incidence of life-threatening or fatal toxicity. {01}
Usual Pediatric Dose
Not recommended for use in children. Safety and efficacy have not been established.{01}
Usual Geriatric Dose
See Usual adult and adolescent dose. See Precautions section.
Strength(s) usually available
U.S.—
Not commercially available.
Canada—
2 mg of raltitrexed disodium per single dose vial. (Rx) [Tomudex (sterile lyophilized powder) (mannitol, dibasic sodium phosphate, sodium hydroxide)]
Packaging and storage:
Store at 2 to 25 °C. Protect from light.{01}
Preparation of dosage form:
Each vial, containing 2 mg of raltitrexed, should be reconstituted with 4 mL of sterile water for injection to produce a 0.5 mg/mL solution. The appropriate dose of solution is diluted in 50 to 250 mL of either 0.9% sodium chloride or 5% dextrose solution.{01}
Stability:
The reconstituted solution is stable for 24 hours at 25 °C exposed to ambient light. The solution may be refrigerated (2 to 8 °C) for up to 24 hours. Reconstituted and diluted solutions do not need to be protected from light. {01}
Incompatibilities:
Raltitrexed should not be mixed with any other drug.
Caution:
Raltitrexed should not be handled by pregnant women.
Developed: 08/08/2000
References
- Product Information: Tomudex(R), raltitrexed disodium. AstraZeneca, Mississauga, Ontario, (PI revised 7/1998) reviewed 7/2000.
