PEMETREXED FOR INJECTION
Clinical safety rating
cautionComprehensive 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). |
| Molecular Weight | 427.4 Da (anhydrous free acid); 597.5 Da (disodium salt heptahydrate) |
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 | Pemetrexed is contraindicated in the first trimester due to teratogenicity. It is an antifolate that causes fetal harm, including malformations and miscarriage. |
| 2nd trimester | Avoid use in the second trimester; animal studies show embryotoxicity and fetotoxicity. There are no adequate human data. |
| 3rd trimester | Avoid use in the third trimester; risk of fetal harm and neonatal toxicity (e.g., myelosuppression). Use only if potential benefit justifies risk. |
Clinical note
Comprehensive clinical and safety monograph for PEMETREXED FOR INJECTION (PEMETREXED FOR INJECTION).
| Placental transfer | Pemetrexed is an antifolate that crosses the placenta in animal studies. It is expected to cross the human placenta, potentially causing fetal harm. |
| Breastfeeding | It is not known whether pemetrexed is excreted in human milk. Due to potential serious adverse reactions in nursing infants, advise women to discontinue breastfeeding during treatment and for at least 1 week after the last dose. |
| Lactation Rating | L5 (Contraindicated) |
| 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. |
| 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. |
■ 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 pemetrexedConcomitant yellow fever vaccine
| 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. |
| Food/Dietary | No specific dietary restrictions. However, vitamin B12 (from animal products) and folic acid (from leafy greens) are essential supplements. Avoid high-folate foods only if advised by physician (unlikely, as supplementation is required). |
| Clinical Pearls | Pemetrexed requires folic acid and vitamin B12 supplementation to reduce hematologic and gastrointestinal toxicity. Administer dexamethasone prophylaxis to prevent skin rash. Contraindicated in patients with creatinine clearance <45 mL/min. Avoid concurrent NSAIDs in patients with mild to moderate renal impairment (CrCl 45-79 mL/min) as they may increase pemetrexed toxicity. |
| Patient Advice | Take folic acid daily and vitamin B12 injections as prescribed to reduce side effects. · Report any skin rash, diarrhea, or mouth sores immediately. · Avoid aspirin and NSAIDs unless approved by your doctor, especially if you have kidney problems. · Stay hydrated and monitor for signs of infection (fever, chills). · Do not skip or stop your vitamin supplements even if you feel well. |
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