VALMID
Clinical safety rating: caution
Comprehensive clinical and safety monograph for VALMID (VALMID).
Valproate increases gamma-aminobutyric acid (GABA) concentrations in the brain either by inhibiting GABA transaminase or by increasing glutamic acid decarboxylase activity, thereby enhancing inhibitory neurotransmission.
| Metabolism | Extensively metabolized in the liver primarily via glucuronidation (approx. 50%) and beta-oxidation (approx. 40%), with minor contributions from CYP2C9, CYP2A6, and CYP2B6 isoenzymes. |
| Excretion | Renal excretion accounts for >90% of elimination, primarily as unchanged drug via glomerular filtration and tubular secretion. Biliary/fecal excretion is minimal (<5%). |
| Half-life | Terminal elimination half-life is 2-4 hours in adults with normal renal function; prolonged to 10-20 hours in severe renal impairment (CrCl <30 mL/min), necessitating dose adjustment. |
| Protein binding | Approximately 92% bound to albumin; minimal binding to alpha-1-acid glycoprotein. |
| Volume of Distribution | Vd = 0.5-0.8 L/kg, indicating distribution primarily into extracellular fluid; higher Vd in obesity. |
| Bioavailability | Oral bioavailability is 85-95% due to extensive absorption; food decreases rate but not extent of absorption. Intravenous bioavailability is 100%. |
| Onset of Action | Oral: 30-60 minutes; Intravenous: 5-15 minutes. |
| Duration of Action | 4-6 hours for oral; 3-5 hours for intravenous. Duration is dose-dependent; at higher doses, effects may persist up to 8 hours. |
| Molecular Weight | 252.27 |
250 mg orally three times daily.
| Dosage form | CAPSULE |
| Renal impairment | CrCl 50–80 mL/min: no adjustment; CrCl 30–49 mL/min: 250 mg twice daily; CrCl 15–29 mL/min: 250 mg once daily; CrCl <15 mL/min or hemodialysis: 250 mg every other day. |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: reduce dose by 50%; Child-Pugh C: contraindicated. |
| Pediatric use | 20 mg/kg/day orally divided every 8 hours; maximum 750 mg/day. |
| Geriatric use | Initiate at 125 mg twice daily; titrate cautiously based on renal function. |
| 1st trimester | Avoid; associated with fetal hydantoin syndrome (cleft lip/palate, congenital heart defects, microcephaly, developmental delay). |
| 2nd trimester | Avoid; continued risk of fetal abnormalities and growth restriction. |
| 3rd trimester | Avoid; risk of neonatal hemorrhage due to vitamin K depletion, neonatal sedation, and withdrawal symptoms. |
Clinical note
Comprehensive clinical and safety monograph for VALMID (VALMID).
| Placental transfer | Phenytoin crosses the placenta readily; fetal serum levels approximate maternal levels. Evidence of fetal accumulation and teratogenicity, particularly with first-trimester exposure. |
| Breastfeeding | Phenytoin (VALMID) is excreted into breast milk in low concentrations (approximately 10% of maternal serum level). Generally considered compatible with breastfeeding, but monitor infant for drowsiness, poor feeding, and allergic reactions. Caution in premature infants or those with hepatic impairment. |
■ FDA Black Box Warning
Hepatotoxicity, including fatal hepatic failure, especially in children under 2 years of age and those with congenital metabolic disorders, severe seizure disorders, or organic brain disease. Fatal pancreatitis has occurred in children and adults. Valproate is contraindicated in patients with known mitochondrial disorders caused by POLG mutations.
| Common Effects | Application site reactions burning irritation itching and redness |
| Serious Effects |
Hypersensitivity to phenytoin or any excipientSinus bradycardiaSinoatrial blockSecond- or third-degree AV blockAdams-Stokes syndromeCo-administration with delavirdine
| Precautions | Hepatotoxicity risk is highest in children under 2; pancreatitis can occur at any time; teratogenicity including neural tube defects; thrombocytopenia; hyperammonemia; hypothermia; multi-organ hypersensitivity reactions; monitoring of liver function, platelet counts, and ammonia levels recommended. |
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| Lactation Rating | L2 (Probably Compatible) |
| Teratogenic Risk | Valmid (ethinamate) is a sedative-hypnotic with limited data in pregnancy. First trimester: potential for teratogenicity based on animal studies; avoid. Second/third trimester: may cause neonatal withdrawal or sedation; use only if clearly needed. |
| Fetal Monitoring | Monitor maternal sedation, respiratory depression, and neonatal withdrawal signs (irritability, tremors) if used near term. |
| Fertility Effects | Animal studies suggest possible impairment of fertility at high doses; human data insufficient. |
| Food/Dietary |
| Avoid alcohol completely. No specific food restrictions, but high-fat meals may delay absorption; take on an empty stomach for consistent effect. |
| Clinical Pearls | VALMID is a brand name for ethchlorvynol, a sedative-hypnotic rarely used due to high abuse potential and narrow therapeutic index. Monitor for respiratory depression, especially in elderly or those with pulmonary disease. Rapid onset requires caution with IV use; avoid extravasation due to tissue necrosis risk. Withdrawal can be severe, resembling barbiturate withdrawal. Not recommended for long-term use due to tolerance and dependence. |
| Patient Advice | Take exactly as prescribed; do not increase dose or frequency without consulting your doctor. · Avoid alcohol and other CNS depressants (e.g., opioids, benzodiazepines) as they can cause dangerous drowsiness or respiratory depression. · Do not drive or operate heavy machinery until you know how this medication affects you. · Do not stop taking abruptly; a gradual dose reduction is needed to avoid withdrawal symptoms (anxiety, tremors, seizures). · Store in a cool, dry place away from light; keep out of reach of children. |