PENETREX
Clinical safety rating: caution
Comprehensive clinical and safety monograph for PENETREX (PENETREX).
Penetrex (pemetrexed) inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), disrupting folate-dependent purine and pyrimidine synthesis, leading to inhibition of DNA replication and cell death.
| Metabolism | Pemetrexed is primarily excreted unchanged in the urine (70-90%). Minimal hepatic metabolism occurs through undefined pathways; less than 5% is metabolized. Active tubular secretion contributes to renal clearance. |
| Excretion | Renal excretion of unchanged drug accounts for approximately 65% of elimination; biliary/fecal elimination accounts for 25% as metabolites; the remaining 10% is via other routes. |
| Half-life | Terminal elimination half-life is 8 hours (range 6–10 hours); clinically, steady-state is achieved after 2–3 days of twice-daily dosing. |
| Protein binding | Approximately 85% bound to albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Volume of distribution is 1.8 L/kg (range 1.5–2.1 L/kg), indicating extensive tissue penetration. |
| Bioavailability | Oral: 75% (range 70–80%); intramuscular: 90% (range 85–95%). |
| Onset of Action | Oral: 1–2 hours; intravenous: 5–10 minutes; intramuscular: 15–30 minutes. |
| Duration of Action | Oral: 8–12 hours; intravenous: 6–8 hours; intramuscular: 8–12 hours. Duration is dose-dependent and prolonged in renal impairment. |
1 g intravenously every 12 hours.
| Dosage form | TABLET |
| Renal impairment | For GFR 15-30 mL/min: 1 g intravenously every 24 hours; for GFR <15 mL/min: 0.5 g intravenously every 24 hours. |
| Liver impairment | For Child-Pugh A: no adjustment; Child-Pugh B: 1 g intravenously every 12 hours; Child-Pugh C: 0.5 g intravenously every 12 hours. |
| Pediatric use | For children ≥2 years: 30 mg/kg/dose intravenously every 12 hours, maximum 1 g per dose. |
| Geriatric use | No specific dose adjustment beyond renal function; initiate at lower end of dosing range due to potential age-related renal impairment. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for PENETREX (PENETREX).
| Breastfeeding | Meropenem and vaborbactam are excreted into human breast milk in low amounts. The milk-to-plasma (M/P) ratio for meropenem is approximately 0.01-0.1. Vaborbactam M/P ratio is not established. While levels are low, potential for infant gut flora alteration exists. Consider alternatives if breastfed infant has gastrointestinal illness or allergy to beta-lactams. Use with caution. |
| Teratogenic Risk | PENETREX (meropenem and vaborbactam) is classified as FDA Pregnancy Category B. Animal studies have not demonstrated fetal harm, but adequate human studies are lacking. In the first trimester, risk is considered low; however, use only if clearly needed. During second and third trimesters, no specific teratogenic effects have been reported. Potential for altered gut flora leading to neonatal diarrhea or candidiasis if administered near delivery. |
■ FDA Black Box Warning
Pemetrexed can cause severe myelosuppression, which may be fatal. Patients must be monitored for nadir counts; dose reductions or delays may be required. No boxed warning is explicitly required by FDA for pemetrexed as of current labeling.
| Serious Effects |
["Hypersensitivity to pemetrexed or any excipient","Concurrent yellow fever vaccine","Severe renal impairment (creatinine clearance <45 mL/min, not recommended)"]
| Precautions | ["Myelosuppression (neutropenia, thrombocytopenia, anemia) - monitor complete blood counts prior to each dose","Renal toxicity - avoid in creatinine clearance <45 mL/min","Gastrointestinal toxicity (nausea, vomiting, diarrhea) - premedicate with corticosteroids and antiemetics","Fatigue, febrile neutropenia, infection","Severe cutaneous reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis) - discontinue if rash progresses","Interstitial pneumonitis - monitor for pulmonary symptoms","Folic acid and vitamin B12 supplementation required to reduce toxicity"] |
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| Fetal Monitoring | Monitor maternal renal function (serum creatinine, BUN) as dosing is based on creatinine clearance. Monitor for signs of hypersensitivity or infusion reactions. In neonates exposed in utero, monitor for sepsis evaluation if maternal infection present. No specific fetal monitoring required except standard prenatal care. |
| Fertility Effects | No known impact on human fertility. Animal studies with meropenem and vaborbactam at doses up to 1.6 times the human dose showed no effects on fertility or reproductive performance. |