About Pharmacology

• Absorption: Leucovorin is rapidly absorbed after oral administration.
• Apparent bioavailability: – 97% for 25 mg – 75% for 50 mg – 37% for 100 mg
  Peak plasma time: Oral (PO): 2 hours, Intravenous (IV) as folate: 10 minutes, as
  tetrahydrofolate: 1 hour
• Distribution: Distributed to all body tissues, predominantly in the liver.

Metabolism: 

• Primarily metabolized in the liver and intestinal mucosa.
• Rapidly converted to tetrahydrofolate (THF) derivatives, with the major metabolite
  being 5-methyltetrahydrofolate (5-methyl-THF).
• Leucovorin is also converted to 5,10-methylenetetrahydrofolate, which stabilize
  luorodeoxyridylic acid binding to thymidylate synthase, enhancing enzyme inhibition.
• Excretion: Primarily excreted in urine (80-90%), a smaller portion is excreted in feces (5-8%).
  Elimination & Half-life : Half-life elimination: 4-8 hours. 
• Terminal half-life of total reduced folates: 6.2 hours.

Toxicity –

• LD50: >8000 mg/kg (oral in rats). 
• Excessive leucovorin may counteract the effects of folic acid antagonists used in chemotherapy due to enhanced toxicity.

Drug interactions :

• Folic acid in large amounts may counteract the antiepileptic effect of phenobarbital, phenytoin
  and primidone, and increase the frequency of seizures in susceptible pediatric patients.
• High doses of leucovorin may reduce the efficacy of intrathecally administered methotrexate to treat cancer. Leucovorin may enhance the toxicity of 5-fluorouracil. Dermatologic,
• gastrointestinal and central nervous system toxicity is most commonly reported.
  Healthcare professionals should be intimidated if the patient being considered leucovorin
  treatment is under any medication from the list below. The dosage of one or both of the
  medicines will be adjusted by the doctor, based on the net effect and balance between negative
  and positive effects of such a combined therapy:
• Capecitabine
• Doxifluridine
• Fluorouracil
• Antibiotics (sulfa drugs) like
• Sulfamethoxazole and Trimethoprim
• Tegafur
  Some drug drug interactions cause increased risk of side effects, but the benefit outweighs this
  drawback and hence the doctor may still prescribe the combination and adjust the dosage.
• Glucarpidase
•  Phenobarbital and Primidone are used as antiepileptic drugs to prevent six=zures. Leucovoorin
  may have counteracting effects, increasing the frequency of seizures.
  This may not be a complete list of medicines that can interact with leucovorin. Always check with your
  healthcare provider.
• Other interactions include possible reactions with food, alcohol, tobacco and supplements.
  The healthcare provider should be informed about any prescription or over the counter
  medicines, vitamin or mineral supplements, herbal products or other supplements the patient
  may be using.

Important:

• Prior to initiating treatment, it is essential to engage in a comprehensive discussion with your healthcare provider regarding any current medications, medical conditions, pregnancy status, or intentions for breastfeeding. This dialogue allows your doctor to evaluate potential drug interactions and customize a treatment regimen that aligns with your specific requirements, emphasizing your safety and health. For personalized information and guidance, it is recommended to seek further
  clarification and advice from your doctor. The medicine is to be administered by a healthcare professional in a proper hospital setting, in the form of an injection (strictly intravenous administration). Intrathecal administration is strongly prohibited.
  The dose, route of administration, and frequency will be decided by the physician based on your
  diagnosis.

Use in Specific Population

General Considerations

• The risks and benefits of leucovorin should be carefully weighed before use.
  Patients should inform their healthcare provider of any allergies to medications, foods, dyes, preservatives, or animals.

Pediatric Use:

• In children with seizure disorders, leucovorin may increase seizure frequency. (See DRUG
  INTERACTIONS). Hence, use in pediatric patients should be closely monitored.

Geriatric Use:

• No significant differences in safety or efficacy have been established so far between elderly and
  younger adults in clinical studies with over 65 and younger patients. Renal function should be
  monitored, as leucovorin is excreted by the kidneys and elderly patients are more likely to have
  impaired renal function due to toxic reactions.
  Other clinical experience has not identified differences in responses between the elderly and
  younger patients, but greater sensitivity of some older patients cannot be ruled out.

Pregnancy (Category C)

• Teratogenic effects unknown as adequate animal reproduction studies have not been conducted.
  There is no confirmed risk to fetal development, but leucovorin should only be used during
  pregnancy if clearly necessary.

Breastfeeding

• There is a lack of sufficient evidence establishing the secretion of leucovorin in human milk.
  Since many drugs pass into breast milk, caution is advised, and potential benefits should be
  weighed against potential risks.

Patients with Renal Impairment

• As leucovorin is primarily excreted by the kidneys, patients with renal dysfunction may be at
  higher risk of toxicity.
  Dose adjustments and renal function monitoring may be necessary.

Contraindications

• Leucosad is not the correct therapy for patients with underlying issues like pernicious anemia and other megaloblastic anemias caused due to Vitamin B12 deficiency. A hematologic remission may occur while neurologic manifestations continue to progress.