PEMETREXED
Clinical safety rating
cautionComprehensive 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. |
| Molecular Weight | 427.4 Da |
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 | Pemetrexed is contraindicated in the first trimester due to potential teratogenicity based on animal studies showing fetal harm. Use only if benefit outweighs risk. |
| 2nd trimester | Contraindicated in second trimester; fetal risk cannot be excluded. Avoid use unless absolutely necessary. |
| 3rd trimester | Contraindicated in third trimester; may cause fetal harm. Pemetrexed is not recommended during pregnancy. |
Clinical note
Comprehensive clinical and safety monograph for PEMETREXED (PEMETREXED).
| Placental transfer | Pemetrexed is expected to cross the placenta based on its molecular weight and animal studies demonstrating embryotoxicity. In rats, fetal levels were measurable. |
| Breastfeeding | It is not known whether pemetrexed is excreted in human milk. Due to potential serious adverse reactions in breastfed infants, breastfeeding should be discontinued during treatment and for at least one week after the last dose. |
| Lactation Rating | L5 (Contraindicated) |
| 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. |
| 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. |
■ 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 |
Concurrent yellow fever vaccinePregnancyBreastfeedingPre-existing severe renal impairment (CrCl <45 mL/min)
| 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. |
| Food/Dietary | No specific food interactions are documented. However, patients should maintain adequate folic acid intake through diet and supplements as prescribed. Avoid grapefruit or grapefruit juice? There is no known interaction with grapefruit. Patients should maintain a balanced diet and avoid alcohol to prevent liver stress. |
| Clinical Pearls | Pemetrexed requires vitamin B12 and folate supplementation to reduce hematologic and gastrointestinal toxicity. Administer folic acid daily (350-1000 mcg) starting 7 days before first dose and continue for 21 days after last dose. Vitamin B12 (1000 mcg IM) should be given 1 week before first dose and repeated every 3 cycles. Contraindicated in patients with creatinine clearance <45 mL/min; dose reduction required for moderate renal impairment. Monitor for severe cutaneous reactions (Stevens-Johnson syndrome) and interstitial pneumonitis. Premedicate with dexamethasone (4 mg PO BID) on the day before, day of, and day after pemetrexed to reduce skin rash incidence. |
| Patient Advice | Take folic acid daily as prescribed, starting 7 days before your first treatment and continuing for 21 days after the last dose. · You will receive a vitamin B12 injection once every three treatment cycles, beginning 1 week before the first dose. · Report any new or worsening shortness of breath, cough, or fever immediately, as this may indicate lung inflammation. · Avoid nonsteroidal anti-inflammatory drugs (NSAIDs) like ibuprofen or aspirin unless approved by your doctor, especially if you have kidney problems. · Use effective contraception during treatment and for 6 months after the last dose; male patients should avoid fathering a child. · Do not breastfeed while taking this medication. · Stay hydrated and inform your doctor if you experience severe diarrhea, vomiting, or signs of dehydration. · Limit sun exposure and use sunscreen, as pemetrexed may cause photosensitivity. |
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