PEMETREXED DISODIUM
Clinical safety rating: caution
Comprehensive clinical and safety monograph for PEMETREXED DISODIUM (PEMETREXED DISODIUM).
Pemetrexed is a folate analog metabolic inhibitor that disrupts folate-dependent metabolic processes essential for cell replication. It inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), thereby inhibiting de novo synthesis of thymidine and purine nucleotides.
| Metabolism | Pemetrexed is primarily eliminated unchanged in urine. It undergoes minimal hepatic metabolism. The drug is a substrate for multidrug resistance-associated proteins (MRPs) and possibly other transporters. |
| Excretion | Primarily renal excretion (70-90% as unchanged drug within 24 hours). Biliary/fecal excretion accounts for <5%. |
| Half-life | Terminal half-life is 3.5 hours in patients with normal renal function. Increases in renal impairment (up to 20 hours if CrCl <45 mL/min). |
| Protein binding | ~81% bound primarily to albumin. |
| Volume of Distribution | Vd = 0.2 L/kg (approximately 16 L in adults). Indicates limited distribution to extravascular spaces. |
| Bioavailability | Intravenous: 100% (only route of administration). |
| Onset of Action | Intravenous: Onset within 1-2 hours (inhibition of thymidylate synthase). |
| Duration of Action | Duration of pharmacodynamic effect (enzyme inhibition) persists for several days; clinical effects depend on dosing schedule (typically 21-day cycles). |
500 mg/m2 intravenously over 10 minutes on Day 1 of each 21-day cycle, with vitamin B12 and folic acid supplementation.
| Dosage form | POWDER |
| Renal impairment | CrCl ≥45 mL/min: No adjustment. CrCl <45 mL/min: Not recommended. For CrCl 40-59 mL/min, no adjustment; CrCl <40 mL/min, not recommended based on clinical trial criteria. |
| Liver impairment | No specific dose adjustment guidelines for hepatic impairment. Use caution with bilirubin >1.5 times ULN and/or AST/ALT >3 times ULN. Child-Pugh classification not formally studied. |
| Pediatric use | Safety and efficacy not established in pediatric patients. No recommended dosing. |
| Geriatric use | No specific dose adjustment recommended based on age alone. Monitor renal function closely as elderly patients may have reduced CrCl. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for PEMETREXED DISODIUM (PEMETREXED DISODIUM).
| Breastfeeding | No data available on the presence of pemetrexed in human milk, its effects on the breastfed infant, or on milk production. Due to the potential for serious adverse reactions in the breastfed infant (including myelosuppression, gastrointestinal toxicity, and carcinogenesis), breastfeeding is not recommended during therapy and for at least 1 week after the last dose. The M/P ratio is unknown. |
| Teratogenic Risk | Pemetrexed is contraindicated in pregnancy. It is an antifolate antimetabolite that inhibits thymidylate synthase and other folate-dependent enzymes, essential for DNA synthesis and cell division. Based on its mechanism of action and animal studies, it is expected to cause fetal harm when administered to a pregnant woman. First trimester: High risk of teratogenicity (neural tube defects, craniofacial, cardiovascular malformations) due to folate antagonism. Second and third trimesters: Risk of fetal growth restriction, oligohydramnios, and fetal death. Embryofetal toxicity and teratogenicity have been demonstrated in mice and rats at doses lower than the human therapeutic dose. |
■ FDA Black Box Warning
Pemetrexed can cause severe myelosuppression, which may lead to infection and bleeding. Patients must be monitored for bone marrow suppression. Adequate folic acid and vitamin B12 supplementation is required to reduce toxicity.
| Serious Effects |
["History of severe hypersensitivity reaction to pemetrexed or any excipient.","Patients with creatinine clearance <45 mL/min (contraindicated for use in combination with cisplatin due to increased toxicity)."]
| Precautions | ["Bone marrow suppression: Monitor blood counts regularly; dose adjust or hold for severe neutropenia, thrombocytopenia, or anemia.","Renal toxicity: Avoid in creatinine clearance <45 mL/min; monitor renal function.","Gastrointestinal toxicity: Severe diarrhea, mucositis may occur; manage with supportive care.","Dermatologic toxicity: Severe rash may occur; premedicate with corticosteroids.","Radiation recall: Risk of severe radiation recall in patients who have received prior radiotherapy.","Folic acid and vitamin B12 supplementation: Required to reduce hematologic and gastrointestinal toxicity.","Pregnancy: Can cause fetal harm; advise women of reproductive potential to use effective contraception."] |
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| Fetal Monitoring | Pemetrexed is not recommended for use in pregnant women; however, if exposure occurs, monitoring should include: Complete blood counts (CBC) with differential and platelets at baseline and before each dose (to assess myelosuppression); renal function tests (serum creatinine, blood urea nitrogen); hepatic function tests; assessment of fluid retention (pemetrexed requires corticosteroid premedication for rash prophylaxis); fetal monitoring by ultrasound for growth and amniotic fluid volume if inadvertent use in pregnancy; consider fetal echocardiography due to potential cardiac effects. Patients of childbearing potential must use effective contraception during treatment and for at least 6 months after the last dose. |
| Fertility Effects | Pemetrexed may impair fertility in humans. In animal studies, testicular degeneration and reduced spermatogenesis were observed in male mice, and ovarian atrophy and menstrual cycle disruption occurred in female mice. Based on its mechanism, it may cause azoospermia or amenorrhea. The reversibility is uncertain. |