PEMFEXY
Clinical safety rating: caution
Comprehensive clinical and safety monograph for PEMFEXY (PEMFEXY).
Pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), which are folate-dependent enzymes involved in nucleotide synthesis, leading to disruption of DNA and RNA synthesis.
| Metabolism | Pemetrexed is primarily excreted unchanged in the urine; limited hepatic metabolism occurs via unspecified pathways. It is not significantly metabolized by CYP450 enzymes. |
| Excretion | Renal excretion (70-90% unchanged drug), biliary/fecal (<5%) |
| Half-life | Terminal elimination half-life ~17 hours (range 13-26 hours) in patients with normal renal function; prolonged to >24 hours in renal impairment. Supports every-21-day dosing. |
| Protein binding | ~95% bound to plasma proteins (primarily albumin) |
| Volume of Distribution | Vd ~16 L/m² (approximately 0.4 L/kg); distributes into total body water with extensive tissue binding. |
| Bioavailability | IV only; no oral bioavailability due to poor absorption and extensive first-pass metabolism. |
| Onset of Action | IV: Clinical effect (cytotoxicity) within hours, but measurable antitumor activity requires days; onset depends on cell cycle targeting. |
| Duration of Action | Systemic exposure persists for ~7-10 days post-IV dose; clinical duration of effect spans the entire dosing interval (21 days) due to prolonged intracellular polyglutamation. |
500 mg/m2 intravenously over 10 minutes on day 1 of a 21-day cycle, in combination with cisplatin.
| Dosage form | SOLUTION |
| Renal impairment | CrCl 45-59 mL/min: reduce dose to 400 mg/m2; CrCl 30-44 mL/min: reduce dose to 250 mg/m2; CrCl <30 mL/min: do not administer. |
| Liver impairment | No dosage adjustment required for Child-Pugh class A or B. For Child-Pugh class C, reduce dose by 50%. |
| Pediatric use | Safety and efficacy not established in pediatric patients; not recommended. |
| Geriatric use | No dose adjustment based on age alone; monitor renal function and adjust according to CrCl. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for PEMFEXY (PEMFEXY).
| Breastfeeding | Excreted in human milk. M/P ratio unknown. Potential for serious adverse reactions in nursing infants, including myelosuppression. Advise discontinue breastfeeding or the drug, considering importance to mother. |
| Teratogenic Risk | Category D: Positive evidence of human fetal risk. Avoid in pregnancy unless no safer alternative. First trimester: high risk of neural tube defects, craniofacial and limb malformations, growth restriction. Second/third trimester: increased risk of preterm delivery, low birth weight, fetal myelosuppression. |
■ FDA Black Box Warning
PEMFEXY can cause fetal harm when administered to a pregnant woman. Pemetrexed is contraindicated in patients who are pregnant or may become pregnant. Women of childbearing potential should be advised to avoid becoming pregnant during treatment with PEMFEXY.
| Serious Effects |
["Pregnancy: Pemetrexed can cause fetal harm; contraindicated in pregnant women.","Severe hypersensitivity: History of severe hypersensitivity reaction to pemetrexed or any excipient.","Concomitant yellow fever vaccine: Increased risk of systemic vaccine reaction.","Breastfeeding: Discontinue nursing during treatment due to potential harm to the infant."]
| Precautions | ["Myelosuppression: Pemetrexed can cause severe bone marrow suppression, including neutropenia, thrombocytopenia, and anemia. Monitor blood counts and adjust doses accordingly.","Renal toxicity: Pemetrexed is primarily eliminated renally; reduce dose in patients with creatinine clearance <45 mL/min. Not recommended for patients with CrCl <30 mL/min.","Cutaneous reactions: Severe dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported; discontinue if severe.","Gastrointestinal toxicity: Diarrhea, nausea, and vomiting are common; administer premedication with corticosteroids and folic acid/vitamin B12 to reduce toxicity.","Pneumonitis: Interstitial pneumonitis has been reported; monitor for respiratory symptoms and discontinue if confirmed.","Radiation recall: Increased risk of radiation recall reactions in patients who have received prior radiotherapy."] |
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| Fetal Monitoring |
| Maternal: CBC with differential, platelet count; hepatic and renal function tests; pregnancy test before initiation. Fetal: serial ultrasound for growth, amniotic fluid index, and anatomy if exposed; monitoring for fetal distress. |
| Fertility Effects | May impair fertility in both males and females. In men, oligospermia, azoospermia. In women, ovarian failure, premature menopause, amenorrhea. May be irreversible. |