PEMETREXED FOR INJECTION
Clinical safety rating: caution
Comprehensive clinical and safety monograph for PEMETREXED FOR INJECTION (PEMETREXED FOR INJECTION).
Pemetrexed is a folate analog metabolic inhibitor that inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), enzymes involved in folate-dependent de novo synthesis of thymidine and purine nucleotides, thereby disrupting DNA and RNA synthesis.
| Metabolism | Pemetrexed is minimally metabolized; it is primarily excreted unchanged in urine via active tubular secretion and glomerular filtration. No significant hepatic metabolism. Enzymes: not extensively metabolized by CYP450. |
| Excretion | Approximately 70-90% of the administered dose is excreted unchanged in the urine within 24 hours. Renal elimination is the primary route, with negligible biliary or fecal excretion (<5%). |
| Half-life | The terminal elimination half-life is approximately 3-4 hours in patients with normal renal function (creatinine clearance ≥90 mL/min). In patients with impaired renal function (creatinine clearance 45-79 mL/min), the half-life may be prolonged to 4-5 hours. |
| Protein binding | Approximately 81-88% bound to plasma proteins, primarily albumin. |
| Volume of Distribution | The volume of distribution at steady state is approximately 16.1 L/m² (or roughly 0.4 L/kg based on average body surface area). This low value suggests limited extravascular distribution, consistent with a hydrophilic drug. |
| Bioavailability | Pemetrexed is administered only intravenously; oral bioavailability is not applicable (0% due to lack of oral formulation). |
| Onset of Action | Not applicable for conventional administration. Pemetrexed is administered as a 10-minute intravenous infusion; clinical effect (antitumor activity) is typically assessed after multiple cycles of therapy (weeks to months). |
| Duration of Action | The pharmacodynamic effect (inhibition of thymidylate synthase and other folate-dependent enzymes) persists for the duration of drug exposure and for a period after clearance. Typical dosing every 21 days is based on recovery of normal tissue (e.g., bone marrow). |
500 mg/m² IV over 10 minutes on Day 1 of each 21-day cycle, in combination with cisplatin 75 mg/m² IV over 2 hours starting 30 minutes after pemetrexed completion. Administer folic acid 350-1000 µg po daily starting 7 days before first dose and continuing until 21 days after last dose, vitamin B12 1000 µg IM 7 days before first dose and every 3 cycles thereafter, and dexamethasone 4 mg po twice daily on day before, day of, and day after pemetrexed.
| Dosage form | INJECTABLE |
| Renal impairment | CrCl ≥45 mL/min: No dose adjustment. CrCl <45 mL/min: Contraindicated; do not administer. For CrCl between 40-79 mL/min, consider dose reduction to 400 mg/m² if prior grade 3/4 toxicity. Monitor CrCl prior to each cycle. |
| Liver impairment | Child-Pugh Class A or B: No recommended dose adjustment. Class C: No data; use with caution. Bilirubin >5 times ULN: Avoid use. AST/ALT >5 times ULN: Consider dose reduction to 400 mg/m² if severe transaminase elevation with bilirubin >3 times ULN. |
| Pediatric use | Safety and efficacy not established in pediatric patients. No recommended dose. |
| Geriatric use | No dose adjustment based on age alone. Monitor renal function (CrCl) closely; elderly more likely to have decreased CrCl and require dose reduction or discontinuation per renal adjustment criteria. Evaluate for increased risk of myelosuppression and fatigue. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for PEMETREXED FOR INJECTION (PEMETREXED FOR INJECTION).
| Breastfeeding | No data on pemetrexed excretion in human milk. Due to potential for serious adverse reactions in nursing infants (e.g., myelosuppression, gastrointestinal toxicity), breastfeeding is contraindicated during treatment and for at least 1 week after last dose. M/P ratio not established. |
| Teratogenic Risk | Pemetrexed is teratogenic and embryotoxic in animal studies. In humans, it is contraindicated in pregnancy (FDA Pregnancy Category D). First trimester exposure carries high risk of major congenital malformations, spontaneous abortion, and fetal death. Second and third trimester exposure increases risk of intrauterine growth restriction, oligohydramnios, and fetal myelosuppression. |
■ FDA Black Box Warning
Pemetrexed can cause severe myelosuppression, including severe neutropenia, anemia, and thrombocytopenia. Fatalities have been reported. Patients must have absolute neutrophil count (ANC) ≥1500 cells/mm³ and platelet count ≥100,000 cells/mm³ prior to initiation. Dose reduction or delay is required based on nadir counts.
| Serious Effects |
History of severe hypersensitivity reaction to pemetrexed; CrCl <45 mL/min for patients with mesothelioma receiving cisplatin; concurrent yellow fever vaccine (live attenuated).
| Precautions | Bone marrow suppression (dose-dependent); renal toxicity (requires adequate renal function, CrCl ≥45 mL/min); gastrointestinal toxicity (nausea, vomiting, mucositis); dermatologic reactions (rash, desquamation); radiation recall; requires folic acid and vitamin B12 supplementation to reduce toxicity; pregnancy category D; fetal harm; hypersensitivity reactions. |
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| Fetal Monitoring | Monitor complete blood counts (CBC) with differential and platelets at baseline and before each dose; monitor renal function (serum creatinine), hepatic function (AST, ALT, bilirubin), and uric acid. Perform pregnancy test before initiation. Fetal monitoring with ultrasound for growth restriction, amniotic fluid volume, and fetal well-being if inadvertent exposure occurs. |
| Fertility Effects | Pemetrexed may impair fertility in both males and females. In males, it can cause oligospermia, azoospermia, and testicular atrophy. In females, it may cause amenorrhea, ovarian failure, and premature menopause. Effects may be irreversible. |