Usage
Pemetrexed is an antineoplastic agent, specifically an antifolate antimetabolite, prescribed for the treatment of:
- Malignant pleural mesothelioma: A cancer affecting the lining of the lungs and chest wall. Pemetrexed is used in combination with cisplatin for patients who have not received prior chemotherapy.
- Non-small cell lung cancer (NSCLC): Pemetrexed is used:
- In combination with cisplatin for initial treatment of locally advanced or metastatic non-squamous NSCLC.
- As a single agent for the maintenance treatment of locally advanced or metastatic non-squamous NSCLC in patients whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.
- As a single agent for the treatment of recurrent non-squamous NSCLC in patients who have received prior chemotherapy.
Alternate Names
- Generic Name: Pemetrexed disodium
- Brand Names: Alimta, Axtle, Pemfexy, Pemrydi RTU
How It Works
Pharmacodynamics: Pemetrexed disrupts crucial cellular processes required for DNA and RNA synthesis, ultimately inhibiting tumor growth.
Pharmacokinetics:
- Absorption: Administered intravenously, achieving peak plasma concentrations at the end of the infusion.
- Distribution: Widely distributed throughout the body, including in pleural fluid (fluid surrounding the lungs).
- Metabolism: Minimal hepatic metabolism. Primarily excreted unchanged renally.
- Elimination: Predominantly via renal excretion. Patients with impaired renal function require dose adjustment or may not be candidates for pemetrexed.
Mode of Action: Pemetrexed is a multi-targeted antifolate that inhibits several folate-dependent enzymes essential for purine and pyrimidine synthesis:
- Thymidylate synthase (TS): Inhibits the formation of thymidine, a crucial DNA building block.
- Dihydrofolate reductase (DHFR): Inhibition of DHFR further disrupts folate metabolism, contributing to the suppression of DNA synthesis.
- Glycinamide ribonucleotide formyltransferase (GARFT): Inhibition of GARFT interferes with purine synthesis.
Elimination Pathways: Primarily eliminated unchanged through renal excretion.
Dosage
Standard Dosage
Adults:
- NSCLC (Initial treatment with cisplatin): 500 mg/m² as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle for up to six cycles.
- NSCLC (Maintenance treatment): 500 mg/m² as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle.
- NSCLC (Recurrent disease): 500 mg/m² as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle.
- Malignant pleural mesothelioma: 500 mg/m² as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle, administered with cisplatin.
Children:
The safety and efficacy of pemetrexed in children have not been established. No pediatric dosing recommendations are available.
Special Cases:
- Elderly Patients: No dose adjustments are necessary based solely on age, but close monitoring for adverse effects is recommended.
- Patients with Renal Impairment: Pemetrexed is contraindicated in patients with creatinine clearance less than 45 mL/min. Dose adjustment may be needed for patients with mild to moderate renal impairment.
- Patients with Hepatic Dysfunction: Use with caution in patients with hepatic impairment. No specific dose adjustments have been established.
- Patients with Comorbid Conditions: Patients with pre-existing medical conditions should be monitored closely.
Clinical Use Cases
Pemetrexed is not indicated for use in intubation, surgical procedures, mechanical ventilation, the intensive care unit (ICU), or emergency situations.
Dosage Adjustments
Dosage adjustments are based on hematologic toxicity, renal function, and other adverse effects. Consult the full prescribing information for detailed dosage modification tables.
Side Effects
Common Side Effects:
- Nausea, vomiting, diarrhea, constipation, loss of appetite
- Fatigue, weakness
- Hair loss
- Rash, itching
- Mucositis (inflammation of mucous membranes)
Rare but Serious Side Effects:
- Severe myelosuppression (neutropenia, thrombocytopenia, anemia)
- Stevens-Johnson syndrome
- Toxic epidermal necrolysis
- Interstitial pneumonitis
- Renal failure
Long-Term Effects:
- Potential for irreversible infertility in males
Adverse Drug Reactions (ADR):
- Hypersensitivity reactions
- Severe myelosuppression
- Hepatic dysfunction
Contraindications
- Hypersensitivity to pemetrexed
- Severe myelosuppression
- Breastfeeding
- Concomitant yellow fever vaccination
- Creatinine clearance <45 mL/min
Drug Interactions
- NSAIDs (e.g., ibuprofen): Can increase pemetrexed exposure, particularly in patients with renal impairment. Concurrent use should be avoided or carefully monitored.
- Other nephrotoxic drugs: Combined use can increase the risk of renal toxicity.
- Drugs that affect bone marrow function: Can worsen myelosuppression.
- Folic acid and vitamin B12: Administering these reduces pemetrexed-related toxicity.
Pregnancy and Breastfeeding
- Pregnancy: Pemetrexed can cause fetal harm. Women of childbearing potential should use effective contraception during treatment and for 6 months after the last dose. Men should use contraception during treatment and for 3 months after the last dose.
- Breastfeeding: Pemetrexed is contraindicated during breastfeeding.
Drug Profile Summary
- Mechanism of Action: Multi-targeted antifolate antimetabolite inhibiting TS, DHFR, and GARFT.
- Side Effects: Myelosuppression, gastrointestinal toxicity, fatigue, rash, mucositis.
- Contraindications: Hypersensitivity, severe myelosuppression, breastfeeding, concomitant yellow fever vaccine.
- Drug Interactions: NSAIDs, nephrotoxic drugs.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: 500 mg/m² IV infusion over 10 minutes on Day 1 of each 21-day cycle.
- Monitoring Parameters: Complete blood counts, renal function tests, hepatic function tests.
Popular Combinations
- Cisplatin is a common combination used in the initial treatment of malignant pleural mesothelioma and NSCLC.
Precautions
- Monitor blood counts, renal function, and liver function regularly.
- Premedication with folic acid and vitamin B12 is mandatory to reduce toxicity.
- Administer corticosteroids to reduce skin reactions.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Pemetrexed?
A: 500 mg/m² IV infusion over 10 minutes on Day 1 of each 21-day cycle. Adjustments may be needed for renal impairment.
Q2: How does Pemetrexed work?
A: It’s an antifolate antimetabolite, disrupting DNA and RNA synthesis by inhibiting key enzymes like thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase.
Q3: What are the common side effects of Pemetrexed?
A: Common side effects include myelosuppression (low blood cell counts), nausea, vomiting, diarrhea, fatigue, hair loss, and skin rash.
Q4: What are the serious side effects of Pemetrexed?
A: Serious side effects can include severe myelosuppression, Stevens-Johnson syndrome, toxic epidermal necrolysis, interstitial pneumonitis, and renal failure.
Q5: Can Pemetrexed be used during pregnancy?
A: No, Pemetrexed is contraindicated during pregnancy due to its potential to cause fetal harm. Effective contraception is necessary during treatment and for a period after the last dose.
Q6: What are the important drug interactions with Pemetrexed?
A: NSAIDs like ibuprofen can increase pemetrexed levels. Other drug interactions can occur with nephrotoxic medications and drugs affecting bone marrow function.
Q7: What precautions should be taken with Pemetrexed administration?
A: Monitor blood counts, renal and liver function regularly. Corticosteroids are administered to reduce skin reactions. Folic acid and vitamin B12 supplementation is mandatory.
Q8: How is Pemetrexed eliminated from the body?
A: Pemetrexed is primarily eliminated unchanged through the kidneys.
Q9: Is there a risk of infertility with Pemetrexed?
A: Yes, Pemetrexed can cause potentially irreversible infertility in males. Counseling regarding sperm banking should be offered.
Q10: What is the role of folic acid and Vitamin B12 in Pemetrexed therapy?
A: Supplementation with folic acid and vitamin B12 is essential to reduce the severity of hematologic and gastrointestinal side effects.
