1 Name of Medicine
Phenytoin sodium.
Phenytoin.
2 Qualitative and Quantitative Composition
Dilantin 30 mg capsules: each 30 mg capsule contains 30 mg phenytoin sodium.
Dilantin 100 mg capsules: each 100 mg capsule contains 100 mg phenytoin sodium.
Dilantin Infatabs 50 mg chewable tablets: each 50 mg chewable tablet contains 50 mg phenytoin.
Dilantin paediatric suspension 30 mg/5 mL: each 5 mL of oral suspension contains 30 mg phenytoin.
Excipients with known effect. Lactose and sugars (30 and 100 mg capsules); saccharin and sugars (chewable tablets); sugars and benzoates (oral suspension).
For the full list of excipients, see Section 6.1 List of Excipients.
3 Pharmaceutical Form
Capsules 30 mg. White opaque hard gelatin capsule with 'P-D 30' on one end and 'Parke Davis' on the other.
Capsules 100 mg. Orange and white opaque hard gelatin capsule imprinted with a 'P-D 100' on one end and 'Parke-Davis' on the other.
Chewable tablets 50 mg. Yellow triangular tablet with flat sides, bevelled edge, breaking line on one side and 'VLE007' imprinted on the other.
Oral suspension 30 mg/5 mL. Viscous, cherry-red suspension with a characteristic odour of banana and orange.
4 Clinical Particulars
4.9 Overdose
Signs and symptoms. There are marked variations among individuals with respect to phenytoin plasma levels where toxicity may occur. Nystagmus or lateral gaze usually appears at 20 microgram/mL, ataxia at 30 microgram/mL, dysarthria and lethargy appear when the plasma concentration is over 40 microgram/mL, but as high a concentration as 50 microgram/mL has been reported without evidence of toxicity. As much as 25 times the therapeutic dose has been taken to result in a serum concentration above 100 microgram/mL with complete recovery. The lethal dose in children is not known. The lethal dose in adults is estimated to be 2 g to 5 g.
The cardinal initial symptoms are nystagmus, ataxia, dysarthria and CNS depression. Other signs that may be seen are tremor, hyperreflexia, somnolence, drowsiness, lethargy, hallucinations, confusion, mental status changes, slurred speech, blurred vision, nausea, vomiting, choreoathetosis, dyskinesias, hyperglycaemia and mild hypoglycaemia. Severe poisoning may result in respiratory depression. Cardiotoxicity has not been reported with oral overdoses. Irreversible cerebellar dysfunction and atrophy have been reported as a delayed effect following severe overdoses. The patient may become comatose and hypotensive. Bradycardia and asystole/cardiac arrest have been reported (see Section 4.4 Special Warnings and Precautions for Use, Cardiac effects). Death is due to respiratory and circulatory depression.
Pharmacokinetic information. In overdose settings, saturation of the hepatic hydroxylation system occurs and zero order kinetics predominate. Elimination follows a Michaelis-Menten model with a prolonged half-life. As phenytoin is continually excreted, elimination changes from zero order to first order kinetics and drug levels decrease more.
Serial plasma phenytoin concentrations should be monitored. In acute overdose, peak levels are frequently delayed for 24 to 48 hours, and occasionally as long as 7 days.
The proportion of phenytoin in plasma not bound to protein is an important measure of potential toxicity with free phenytoin levels of < 1.5 microgram/mL indicating no signs of toxicity; 1.5 microgram/mL to 5 microgram/mL seen with mild to moderate intoxication; and levels above 5 microgram/mL associated with severe intoxication.
Treatment of overdosage. Treatment is non-specific since there is no known antidote. Most cases of overdosage may be managed conservatively with symptomatic and supportive care. Signs and symptoms of toxicity may persist up to 7 to 10 days after ingestion.
Phenytoin is poorly absorbed in the stomach, therefore, although routine use of activated charcoal is not recommended, it may be considered in the rare patient with a life threatening ingestion. In patients who are not fully conscious or have impaired gag reflex, consideration should be given to administering activated charcoal via a nasogastric tube, once the airway is protected. Administration of a further dose of activated charcoal may be considered in patients with rising serum phenytoin levels or worsening clinical condition despite initial decontamination.
Peritoneal dialysis, diuresis, haemodialysis, plasmapheresis, haemofiltration and total exchange transfusion may be of little benefit although the latter has been used in the treatment of severe intoxication in children.
In acute overdosage the possibility of other CNS depressants, including alcohol, should be borne in mind.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).
5 Pharmacological Properties
5.3 Preclinical Safety Data
Genotoxicity. Phenytoin was negative in the Ames test and in the in vitro clastogenicity assay in Chinese hamster ovary (CHO) cells. In studies reported in the literature, phenytoin was negative in the in vitro mouse lymphoma assay and the in vivo micronucleus assay in mouse. Phenytoin was clastogenic in the in vitro sister chromatid exchange assay in CHO cells.
Carcinogenicity. In carcinogenicity studies, phenytoin was administered in the diet to mice (10, 25, or 45 mg/kg/day) and rats (25, 50, or 100 mg/kg/day) for 2 years. The incidences of hepatocellular tumors were increased in male and female mice at the highest dose. No increases in tumor incidence were observed in rats. The highest doses tested in these studies were associated with peak serum phenytoin levels below human therapeutic concentrations.
In carcinogenicity studies reported in literature, phenytoin was administered in the diet for 2 years at doses up to 300 ppm (approximately 60 mg/kg/day) and 600 ppm (approximately 160 mg/kg/day) to male and female mice, respectively, and up to 2400 ppm (approximately 120 mg/kg/day) to rats. The incidence of hepatocellular tumors were increased in female mice at all but the lowest dose tested. No increases in tumor incidence were observed in rats. Phenytoin-induced hepatic tumors in mice may be secondary to hepatic enzyme induction in those species and are of uncertain clinical relevance.
6 Pharmaceutical Particulars
6.7 Physicochemical Properties
Chemical structure. The molecular structure of phenytoin is shown below:
https://stagingapi.mims.com/au/public/v2/images/fullchemgif/CSPHENYT.gif Chemical name: 5,5-diphenylimidazolidine-2,4-dione.
Molecular formula: C15H12N2O2.
Molecular weight: 252.272.
Phenytoin is a white, or almost white, odourless or almost odourless, crystalline powder. It is practically insoluble in water and soluble 1 in 70 alcohol.
Phenytoin sodium is the sodium salt of phenytoin. It is a white, odourless, slightly hygroscopic crystalline powder. It is soluble in water and alcohol.
CAS number. CAS registry number: 57-41-0.
7 Medicine Schedule (Poisons Standard)
S4 (Prescription Only Medicine).
Summary Table of Changes
https://stagingapi.mims.com/au/public/v2/images/fulltablegif/DILANTST.gif
