DIPHENYLAN SODIUM
Clinical safety rating
cautionComprehensive clinical and safety monograph for DIPHENYLAN SODIUM (DIPHENYLAN SODIUM).
Phenytoin, the active component, stabilizes neuronal membranes by promoting sodium efflux and inhibiting sodium influx, thereby limiting the spread of seizure activity. It also reduces voltage-gated sodium channel activity.
| Metabolism | Primarily hepatic metabolism via CYP2C9 and CYP2C19 isoenzymes, with saturation kinetics at therapeutic concentrations. Major metabolite: 5-(p-hydroxyphenyl)-5-phenylhydantoin (HPPH). |
| Excretion | Primarily hepatic metabolism via CYP450; <5% excreted unchanged in urine. Biliary/fecal excretion accounts for approximately 20-30% of metabolites. |
| Half-life | 22 hours (range 10-34 hours); prolonged in hepatic impairment or with CYP inhibitors; correlates with time to steady state (~5 days). |
| Protein binding | 90-95% mainly to albumin; displaces and is displaced by other highly protein-bound drugs. |
| Volume of Distribution | 0.6-0.8 L/kg; larger in neonates (up to 1.2 L/kg); indicates extensive tissue binding, particularly in brain and adipose. |
| Bioavailability | Oral: 85-95% (capsules and tablets); intramuscular: 70-80% due to precipitation at injection site. |
| Onset of Action | Oral: 20-60 minutes; intravenous: 3-5 minutes; intramuscular: 30-120 minutes (slow and erratic absorption). |
| Duration of Action | Oral: 6-24 hours (dose-dependent); IV: 1-3 hours for antiarrhythmic effect; prolonged with loading dose due to tissue redistribution. |
| Molecular Weight | 252.27 |
100 mg orally every 8 hours
| Dosage form | CAPSULE |
| Renal impairment | No adjustment required for GFR >30 mL/min; for GFR 10-30 mL/min, administer every 12-24 hours; for GFR <10 mL/min, administer every 24 hours with monitoring of serum levels |
| Liver impairment | Child-Pugh Class A: no adjustment; Child-Pugh Class B: reduce dose by 25-50%; Child-Pugh Class C: avoid use or reduce dose by 50-75% with close monitoring |
| Pediatric use | 5-7 mg/kg/day orally divided every 8-12 hours, not to exceed 300 mg/day |
| Geriatric use | Initial dose of 50 mg orally every 8 hours, titrate slowly based on response and tolerability; monitor renal function and serum levels |
| 1st trimester | Associated with congenital malformations including neural tube defects, cleft palate, and cardiac defects. Avoid unless seizure control outweighs risks. |
| 2nd trimester | Increased risk of fetal hydantoin syndrome and other anomalies. Use lowest effective dose and monitor fetal growth. |
| 3rd trimester | Risk of neonatal hemorrhage (vitamin K-dependent) and withdrawal symptoms. Administer vitamin K to mother before delivery. |
Clinical note
Comprehensive clinical and safety monograph for DIPHENYLAN SODIUM (DIPHENYLAN SODIUM).
| Placental transfer | Extensive placental transfer; fetal plasma concentrations approximate maternal levels. Fetal hydantoin syndrome linked to in utero exposure. |
| Breastfeeding | Phenytoin is excreted into breast milk at low concentrations (milk:plasma ratio ~0.18). Case reports of drowsiness, decreased sucking, and allergic reactions in infants. Benefits of breastfeeding generally outweigh risks for most infants; monitor for adverse effects. |
| Lactation Rating | L3 (Moderately Safe) |
| Teratogenic Risk | First trimester: Increased risk of major congenital malformations including neural tube defects, cleft palate, and congenital heart defects. Second and third trimesters: Risks of bleeding disorders in the newborn due to vitamin K deficiency, and potential for neonatal withdrawal and growth restriction. |
| Fetal Monitoring | Maternal: Serum drug levels (if toxicity suspected), liver function tests, complete blood count, and neurological status. Fetal: Ultrasound for anomalies (first trimester), fetal growth monitoring, and nonstress testing/comprehensive fetal assessment in third trimester. |
| Fertility Effects | Limited data; animal studies suggest no significant impairment of fertility. In humans, no conclusive evidence of adverse effects on fertility. |
■ FDA Black Box Warning
Intravenous administration: Risk of serious cardiovascular reactions including hypotension and cardiac arrest, especially in elderly patients and those with underlying cardiac disease. Rate of infusion should not exceed 50 mg/min in adults.
| Serious Effects |
Hypersensitivity to phenytoin or hydantoinsSinus bradycardiaAV blockSick sinus syndromeHistory of hepatotoxicity due to phenytoin
| Precautions | 1. Cardiovascular risk with IV administration. 2. Suicide risk and behavioral changes. 3. Hepatotoxicity (monitor LFTs). 4. Hematologic effects (agranulocytosis, thrombocytopenia). 5. Lymphadenopathy. 6. Teratogenicity (fetal hydantoin syndrome). 7. Hyperglycemia. 8. Withdrawal seizures. 9. Dermatologic reactions (Stevens-Johnson syndrome). 10. Osteoporosis with chronic use. |
| Food/Dietary | Avoid grapefruit and grapefruit juice as it inhibits CYP metabolism and can increase phenytoin levels. Enteral feeding formulas may reduce absorption; administer phenytoin 1-2 hours before or after enteral feeds. High doses of folic acid may decrease phenytoin levels. Chronic use can lead to vitamin D and folate deficiency; consider supplementation if indicated. Alcohol consumption should be minimized—acute intake can increase levels while chronic use decreases them. |
| Clinical Pearls | Diphenylan Sodium (phenytoin sodium) is a hydantoin anticonvulsant used for generalized tonic-clonic and complex partial seizures. It exhibits zero-order kinetics at therapeutic levels; small dose increases can cause disproportionate toxicity. Monitor for nystagmus, ataxia, and mental status changes as early signs of toxicity. Due to high protein binding (90%), hypoalbuminemia or uremia increases free fraction—adjust doses based on free phenytoin levels. Can cause folate deficiency, megaloblastic anemia, and bone density loss. Gingival hyperplasia occurs in 40% of patients; meticulous oral hygiene can reduce severity. Dosing must be individualized with therapeutic range 10-20 mg/L total (1-2 mg/L free). Intravenous loading requires cardiac monitoring due to risk of bradycardia and hypotension; avoid IM use due to crystallization and erratic absorption. |
| Patient Advice | Take exactly as prescribed; do not stop abruptly as withdrawal can trigger seizures. · Avoid alcohol and grapefruit juice; they can affect drug levels and increase side effects. · Practice good oral hygiene with regular brushing and flossing to prevent gum overgrowth. · Report any rash, fever, sore throat, or easy bruising immediately—these may signal serious blood disorders. · Use non-hormonal contraception if on birth control; phenytoin reduces efficacy of oral contraceptives. · May cause dizziness or drowsiness; avoid driving until you know how you react. · Wear a medical alert bracelet if you have epilepsy. · Do not take antacids within 2 hours of phenytoin. · Regular blood tests are needed to monitor drug levels and liver function. · If you become pregnant, discuss with your doctor immediately. |
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