PEMETREXED
Clinical safety rating: caution
Comprehensive clinical and safety monograph for PEMETREXED (PEMETREXED).
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), leading to inhibition of de novo purine and pyrimidine synthesis.
| Metabolism | Pemetrexed is primarily eliminated unchanged in the urine. It undergoes minimal hepatic metabolism. Renal excretion accounts for approximately 70-90% of elimination. |
| Excretion | Primarily eliminated unchanged in urine (70-90% of dose via renal excretion over 24 hours); minimal biliary/fecal excretion (<5%). |
| Half-life | Terminal half-life is approximately 3.5 hours in patients with normal renal function (creatinine clearance ≥60 mL/min). Clinically, half-life is prolonged in renal impairment (up to 20 hours in severe impairment), requiring dose adjustment. |
| Protein binding | Approximately 81% bound to plasma proteins, primarily albumin (given its structure as a folate analog). |
| Volume of Distribution | Volume of distribution is about 16.1 L/m² (total body water); in weight-based terms ~0.3-0.4 L/kg, indicating limited tissue distribution consistent with a polar molecule. |
| Bioavailability | Only administered intravenously; oral bioavailability is negligible (<1%) due to poor intestinal absorption and first-pass metabolism, thus no oral formulation available. |
| Onset of Action | Peak plasma concentrations achieved at end of 10-minute intravenous infusion; clinical antitumor effect typically observed after 2–3 cycles (weeks) of treatment. |
| Duration of Action | Pharmacodynamic effects (cytotoxicity) persist for days; dosing interval is every 21 days due to schedule-dependent toxicity and need for folate/B12 supplementation. |
500 mg/m2 IV over 10 minutes on Day 1 of each 21-day cycle, with folic acid and vitamin B12 supplementation.
| Dosage form | INJECTABLE |
| Renal impairment | CrCl ≥45 mL/min: no adjustment. CrCl <45 mL/min: not recommended; consider dose reduction to 500 mg/m2 if CrCl 40–45 mL/min with close monitoring; do not use if CrCl <40 mL/min. |
| Liver impairment | Child-Pugh A and B: no adjustment. Child-Pugh C: insufficient data; use with caution. |
| Pediatric use | Not FDA approved; limited data: 500 mg/m2 IV over 10 minutes Day 1 every 21 days, with folic acid and B12 supplementation, based on adult protocol. Weight-based for patients <1.5 m²: calculate BSA and dose accordingly. |
| Geriatric use | No specific dose adjustment; monitor renal function (CrCl) due to age-related decline; ensure folic acid and vitamin B12 supplementation. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for PEMETREXED (PEMETREXED).
| Breastfeeding | No human data on excretion into breast milk. Pemetrexed is a small molecule (molecular weight 427.46 g/mol) with low protein binding (~81%) and a terminal half-life of 3.5 hours; it is likely excreted into milk. M/P ratio unknown. Due to potential for serious adverse reactions (myelosuppression, gastrointestinal toxicity), breastfeeding is contraindicated during therapy and for at least 1 week after last dose. |
| Teratogenic Risk | Pemetrexed is a folate analog antimetabolite that inhibits thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. It is teratogenic in animal studies at doses below the recommended human dose. In humans, there are no adequate studies in pregnant women; however, based on its mechanism of action, there is potential for fetal harm. First trimester exposure carries the highest risk for major congenital malformations (neural tube, cardiac, skeletal defects). Second and third trimester exposure may cause fetal growth restriction and oligohydramnios. Late pregnancy administration may cause neonatal myelosuppression and toxicity. |
■ FDA Black Box Warning
Pemetrexed can cause severe and sometimes fatal myelosuppression, renal failure, and severe gastrointestinal toxicity. Patients must be pretreated with corticosteroids and folic acid and vitamin B12 to reduce toxicity.
| Serious Effects |
History of severe hypersensitivity reaction to pemetrexed; concomitant administration of yellow fever vaccine; severe renal impairment (creatinine clearance <45 mL/min) (relative contraindication due to increased toxicity).
| Precautions | Bone marrow suppression (including neutropenia, thrombocytopenia, anemia); renal toxicity (monitor renal function); gastrointestinal toxicity (e.g., diarrhea, mucositis); dermatologic reactions (e.g., rash, exfoliation); radiation recall reactions; increased risk of toxicity in patients with pleural effusion or ascites (consider drainage); embryo-fetal toxicity. |
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| Fetal Monitoring | Baseline and periodic complete blood counts (CBC) with differential and platelets, renal function (serum creatinine), liver function tests (ALT, AST, bilirubin). Fetal ultrasound for growth and amniotic fluid volume if used during pregnancy. Monitor for myelosuppression (neutropenia, thrombocytopenia) in mother and neonate if given near term. |
| Fertility Effects | Pemetrexed can cause ovarian failure and azoospermia based on animal studies. In humans, it may impair fertility in both males and females due to its antimitotic effects. Reversibility is uncertain. |