Raltitrexed (Tomudex) manufactured by AstraZeneca is an antimetabolite (a thymidylate synthase inhibitor) that is used as a chemotherapeutic drug for the treatment of advanced colorectal cancer.

Raltitrexed Uses:

• Advanced Colorectal Cancer:

  • It is indicated for the treatment of advanced colorectal cancer

• Off Label Use of Raltitrexed in Adults:

  • It is also used in the treatment of malignant pleural mesothelioma.

Raltitrexed (Tomudex) Dose in Adults

Note: Treatment initiation is only indicated if the baseline WBC is greater than 4,000/mm³, ANC is greater than 2,000/mm³, and platelet counts is greater than 100,000/mm³

Raltitrexed (Tomudex) Dose in the treatment of advanced colorectal cancer:

• IV: 3 mg/m² once every 3 weeks in the absence of toxicity

Raltitrexed (Tomudex) Dose in the treatment of malignant pleural mesothelioma (off-label):

• IV: 3 mg/m² once every 3 weeks combined with cisplatin until toxicity is observed or the disease progresses despite the treatment.

Use in Children:

It is contraindicated in children.

Pregnancy Risk Category: X

• It is not recommended for women who are pregnant, or might become pregnant.
• Negative pregnancy outcomes were seen in animal reproduction studies.
• It is best to avoid pregnancy prior to treatment initiation. 
• It is also recommended that women with male partners who are on treatment avoid becoming pregnant. Pregnant women should not take the drug.

Breastfeeding:

• It is not recommended for use in lactating mothers.

Dose in Kidney Disease:

• CrCl >65 mL/minute:
  • Dosage adjustment is not necessary.
• CrCl 55 to 65 mL/minute:
  • Reduce the dose to 75% of the usual dose once monthly.
• CrCl 25 to 54 mL/minute:
  • Reduce the dose to the percentage of a dose equivalent to CrCl once monthly (eg, reduce dose to 25% of usual dose for CrCl of 25 mL/minute)
• CrCl <25 mL/minute:
  • Do not administer the drug. It is contraindicated in severe renal impairment.

Dose in Liver disease:

• Adults with preexisting hepatic impairment:
  • It should be avoided in patients with decompensated liver disease or clinical jaundice.
• Mild to moderate impairment:
  • Dosage adjustment is not necessary, however, use it with caution.
• Severe impairment:
  • Use is contraindicated.
• Hepatotoxicity during treatment:
  • The treatment should be interrupted until improvement or toxicity returns to grade 2 or lower.

Common Side Effects of Raltitrexed (Tomudex):

• Dermatologic:

  • Skin Rash

• Gastrointestinal:

  • Nausea
  • Diarrhea
  • Vomiting
  • Anorexia
  • Abdominal Pain
  • Constipation
  • Mucositis
  • Stomatitis

• Hematologic & Oncologic:

  • Leukopenia
  • Anemia

• Hepatic:

  • Increased Serum AST
  • Increased Serum ALT

• Neuromuscular & Skeletal:

  • Weakness

• Miscellaneous:

  • Fever

Less Common Side Effects Of Raltitrexed (Tomudex):

• Cardiovascular:

  • Peripheral Edema
  • Cardiac Arrhythmia
  • Cardiac Abnormality

• Central Nervous System:

  • Headache
  • Dizziness
  • Chills
  • Malaise
  • Pain
  • Insomnia
  • Depression
  • Paresthesia
  • Hypertonia

• Dermatologic:

  • Alopecia
  • Diaphoresis
  • Cellulitis
  • Pruritus

• Endocrine & Metabolic:

  • Dehydration
  • Weight Loss
  • Hypokalemia

• Gastrointestinal:

  • Dysgeusia
  • Dyspepsia
  • Flatulence
  • Xerostomia

• Genitourinary:

  • Urinary Tract Infection

• Hematologic & Oncologic:

  • Thrombocytopenia

• Hepatic:

  • Hyperbilirubinemia
  • Increased Serum Alkaline Phosphatase

• Infection:

  • Infection
  • Sepsis

• Neuromuscular & Skeletal:

  • Myalgia
  • Arthralgia

• Ophthalmic:

  • Conjunctivitis

• Renal:

  • Increased Serum Creatinine

• Respiratory:

  • Flu-Like Symptoms
  • Cough
  • Dyspnea
  • Pharyngitis

Contraindications to Raltitrexed (Tomudex):

• Allergy to raltitrexed, or any component of this formulation
• Grave liver or kidney disease
• Patients who are pregnant or may become pregnant
• Breast-feeding women
• Use with children.

Warnings and precautions

• Suppression of bone marrow

  • Cytopenias can be severe, mainly anemia, neutropenia and leukopenia. 
  • Sometimes, thrombocytopenia and neutropenia can be severe enough to require treatment interruption.
  • Most often, bone marrow suppression occurs between 7 and 14 days after treatment. Most patients recover by the 21st day.
  • Patients who have marrow suppression or preexisting conditions should be cautious about taking the drug.

• Gastrointestinal toxicities:

  • Gastrointestinal toxicities are common and can manifest as nausea, vomiting, or diarrhea. 
  • Mucositis can manifest as oral ulcers, stomatitis, or diarrhea.
  • Diarrhea can be serious, especially if there is concomitant hematologic toxicities like neutropenia.
  • This could be life-threatening. It is possible to interrupt or stop treatment. Following treatment interruption or discontinuation, dose reduction might be recommended.
  • Other gastrointestinal-related toxicities like nausea or vomiting are usually treated with common antiemetics, and may not require treatment interruption.

• Malaise and weakness

  • It can cause weakness and malaise. Patients who drive or perform heavy tasks should be cautious.

• Hepatic impairment

  • Patients with mild to moderate liver impairment should use it with caution. 
  • It should not be used in severe hepatic impairment, patients with clinical jaundice, or those suffering from decompensated liver disease.
  • Treatment-related liver toxicities should be treated immediately. 
  • The treatment can be restarted if the liver enzymes are back to normal, or at the very least, to grade 2 or lower.
  • Transaminitis, which may be self-limiting but reversible, may occur.

• Renal impairment

  • It should be used with caution in patients with mild or moderate renal impairment. It should not be used in the case of severe renal impairment.

Raltitrexed (United States: Not available): Drug Interaction

Monitoring parameters:

• Monitor CBC with differential at baseline, before each treatment, and weekly if gastrointestinal toxicity is observed
• Liver function tests and serum creatinine at baseline and before each treatment
• Signs of GI toxicity.

How to administer Raltitrexed (Tomudex)?

• It is administered as a slow intravenous infusion over 15 minutes.
• When used to treat malignant pleural mesothelioma, in combination with cisplatin, administer raltitrexed first, followed by cisplatin.

Mechanism of action of Raltitrexed (Tomudex):

Raltitrexed, an analog folate, inhibits DNA synthesis by inhibiting selectively thymidylate synthase and blocking purine synthesis.

Protein binding:

• 93%

Metabolism:

• It undergoes extensive intracellular metabolism to active polyglutamate forms; appears to be little or no systemic metabolism of the drug

Half-life elimination:

• Triphasic;
• Beta: about 2 hours;
• Terminal: 198 hours

Excretion:

• Urine (about 50% as unchanged drug);
• feces (~15%)

International Brand Names of Raltitrexed:

• Tomudex

Raltitrexed Brand Names in Pakistan:

No Brands Available in Pakistan.