Indications and Dosage

Intramuscular
Epilepsy associated with neurosurgery

Adult: 100-200 mg 4 hourly during surgery and continued post-operatively for 48-72 hours, reduced to a maintenance dose of 300 mg daily thereafter, adjusted according to plasma concentrations. Use an alternative route (e.g. intubation) if >1 week of IM therapy is required.

Intravenous
Tonic-clonic status epilepticus

Adult: As an adjunct with a benzodiazepine (e.g. diazepam, lorazepam): Initially, 10-15 mg/kg via slow inj or intermittent infusion at a rate of not more than 50 mg/min. Maintenance: 100 mg (PO or IV) given 6-8 hourly.
Child: 15-20 mg/kg, at a rate not exceeding 1-3 mg/kg/min.

Oral
Epilepsy associated with neurosurgery, Partial seizures, Tonic-clonic epilepsy

Adult: Initially, 3-4 mg/kg daily or 150-300 mg daily given as a single dose or in divided doses, adjust subsequent doses if necessary. Maintenance: 200-500 mg daily.
Child: Initially, 5 mg/kg daily in 2 divided doses. Max: 300 mg daily. Maintenance: 4-8 mg/kg daily in divided doses.

Special Patient Group

Pharmacogenomics:

Individuals who are carriers of human leukocyte antigen (HLA)-B*15:02 may be at risk of phenytoin induced cutaneous adverse reactions such as Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN).

HLA-B*15:02 allele is found almost exclusively across broad areas of Asia. Patients with ancestry from North China, Taiwan, Hong Kong, Thailand, Malaysia, India and parts of the Philippines have a higher likelihood of being a carrier of this allele. Consider HLA-B*15:02 genotype test as a screening tool in these patients. Results are interpreted as “positive” if one or two copies of HLA-B*15:02 are present or as “negative” if no copies of HLA-B*15:02 are present. Avoid use of phenytoin in patients who are HLA-B*15:02-positive.

Not all phenytoin-induced SJS/TEN can be attributed to HLA-B*15:02. All patients taking phenytoin should be appropriately monitored for severe cutaneous adverse reactions as these reactions can still occur infrequently in HLA-B*15:02-negative patients of any ethnicity.

Administration

Should be taken with food. When administering to patients on nasogastric or other enteral feeds, do not administer feeds 2 hr before or after a dose. Be consistent throughout therapy in relation to feed times. Do not switch dosage forms/brands w/o prior consideration.

Reconstitution

IV Infusion: Dilute in 50-100 mL NaCl 0.9% to a provide a final concentration not exceeding 10 mg/mL.

Incompatibility

Dextrose-containing solutions.

Contraindications

History of acute hepatotoxicity attributable to phenytoin. Concomitant use with delavirdine. Inj: Sinus bradycardia, sino-atrial block, 2nd and 3rd degree AV block, Adams-Stokes syndrome.

Special Precautions

Patient with history of adverse haematologic reaction to any drug; diabetes mellitus, hypotension, cardiac disease; conditions associated with low serum albumin levels; hypothyroidism, porphyria. Critically ill, and debilitated patients. Patients who are positive for HLA-B*15:02 allele. Not indicated for the treatment of absence (petit mal) seizures, seizures due to hypoglycaemia or other metabolic causes. Avoid abrupt withdrawal. Hepatic and renal impairment. Pregnancy and lactation.

Adverse Reactions

Significant: Bone effects (e.g. osteopenia, osteoporosis, osteomalacia, bone fractures), vitamin D deficiency, hypocalcaemia, hypophosphataemia, acute hepatotoxicity, acute hepatic failure, hypersensitivity, suicidal ideation and behaviour. IV: extravasation; hypotension, severe cardiac arrhythmia (rapid administration).
Eye disorders: Nystagmus.
Gastrointestinal disorders: Nausea, vomiting, constipation, gingival hyperplasia.
Injury, poisoning and procedural complications: Injection site reactions.
Immune system disorders: Anaphylactoid reactions, anaphylaxis.
Musculoskeletal and connective tissue disorders: Purple glove syndrome.
Nervous system disorders: Ataxia, slurred speech, decreased coordination, mental confusion (dose related); cerebellar atrophy (elevated phenytoin levels/long-term use); headache, dizziness, somnolence, motor twitching, paraesthesia, dysgeusia.
Psychiatric disorders: Insomnia, transient nervousness.
Skin and subcutaneous tissue disorders: Scarlatiniform or morbilliform rashes.
Potentially Life-threatening: Blood dyscrasias (e.g. agranulocytosis, leucopenia, granulocytopenia, thrombocytopenia, pancytopenia with or without bone marrow suppression); dermatologic reactions (e.g. acute generalised exanthematous pustulosis, toxic epidermal necrolysis, Stevens-Johnson syndrome); multiorgan hypersensitivity reactions, drug reaction with eosinophilia and systemic symptoms (DRESS); hepatotoxicity.

Pregnancy Category (US FDA)

IM/IV/Parenteral/PO: D

Patient Counseling Information

This drug may cause dizziness and drowsiness, if affected, do not drive or operate machinery.

Monitoring Parameters

Monitor CBC, LFT, vitamin D status, plasma phenytoin concentrations? signs of suicidal ideation.

Overdosage

Symptoms: Nystagmus, ataxia, dysarthria, apnoea, tremor, lethargy, nausea, vomiting, coma, hypotension, respiratory and circulatory depression. Management: Symptomatic and supportive treatment. Stomach emptying may be done within 4 hours of ingestion. Employ supportive measures (e.g. oxygen, vasopressors, assisted ventilation) for CNS, respiratory and CV depression. May consider haemodialysis.

Drug Interactions

Increased serum levels with salicylates; antibacterial agents (e.g. chloramphenicol, clarithromycin, isoniazid, sulfadiazine, sulfamethoxazole-trimethoprim, sulfonamides); anticonvulsants (e.g. oxcarbazepine, succinimides, topiramate); antifungal agents (e.g. amphotericin B, fluconazole, itraconazole, ketoconazole, miconazole); antineoplastic agents (e.g. capecitabine, fluorouracil); benzodiazepines/psychotropic drugs (e.g. disulfiram, methylphenidate, trazodone); CV agents (e.g. amiodarone, diltiazem, nifedipine); cimetidine, fluvastatin, tacrolimus, tolbutamide, omeprazole; serotonin re-uptake inhibitors (e.g. fluoxetine, fluvoxamine). Decreased serum levels with vigabatrin; antineoplastic agents (e.g. bleomycin, carboplatin, cisplatin, doxorubicin); sucralfate, reserpine, folic acid, rifampicin; antiretroviral (e.g. fosamprenavir, nelfinavir, ritonavir); theophylline, diazoxide. May increase or decrease serum levels with ciprofloxacin; psychotropic agents (e.g. chlordiazepoxide, diazepam, phenothiazines). May alter serum levels and/or effects of doxycycline; anticonvulsants (e.g. carbamazepine, lamotrigine, phenobarbital, Na valproate, valproic acid); antifungal agents (e.g. posaconazole, voriconazole); methotrexate; antiretrovirals (e.g. efavirenz, fosamprenavir, indinavir, lopinavir/ritonavir, ritonavir, saquinavir); theophylline; CV agents (e.g. digoxin, disopyramide, mexiletine, nicardipine, nimodipine, verapamil), warfarin, furosemide; HMG-CoA reductase inhibitors (e.g. atorvastatin, fluvastatin, simvastatin); oestrogens, oral contraceptives; neuromuscular blocking agents (e.g. pancuronium, rocuronium, vecuronium); methadone, tolbutamide; psychotropic agents/antidepressants (e.g. clozapine, paroxetine, quetiapine, sertraline); vitamin D.
Potentially Fatal: May cause loss of virologic response and possible resistance to delavirdine or to the class of non-nucleoside reverse transcriptase inhibitors.

Food Interaction

Decreased plasma concentrations with St John’s wort. Acute alcohol intake may increase phenytoin serum levels, while chronic use may decrease serum levels.

Lab Interference

Falsely high plasma phenytoin concentrations when measured by immunoanalytical techniques. Falsely low results for dexamethasone and metyrapone tests. Increased serum levels of thyroid stimulating hormone (TSH, usually in the absence of clinical hypothyroidism).

Action

Description: Phenytoin, a hydantoin antiepileptic, stabilizes neuronal membranes and decreases seizure activity by increasing efflux or decreasing influx of Na ions across cell membranes in the motor cortex during generation of nerve impulses.
Synonym: Diphenylhydantoin
Onset: IV: Approx 0.5-1 hour.
Pharmacokinetics:
Absorption: Slowly but almost completely absorbed from the gastrointestinal tract. Bioavailability: 70-95% (oral); 83-100% (IM).
Distribution: Widely distributed throughout the body. Crosses placenta; enters breast milk (small amounts). Volume of distribution: 0.52-0.78 L/kg. Plasma protein binding: Approx 90%.
Metabolism: Extensively metabolised in the liver to inactive metabolites, chiefly 5-(4-hydroxyphenyl)-5-phenylhydantoin; undergoes enterohepatic recycling.
Excretion: Via urine (<5% as unchanged drug; as glucuronides). Mean plasma half-life: Approx 22 hours (steady state).

Chemical Structure

Phenytoin

Source: National Center for Biotechnology Information. PubChem Database. Phenytoin, CID=1775, https://pubchem.ncbi.nlm.nih.gov/compound/Phenytoin (accessed on Jan. 22, 2020)

Storage

Tab/cap/susp: Store between 20-25°C. Protect from light and moisture. Soln for inj: Store between 15-30°C.

MIMS Class

Anticonvulsants

ATC Classification

N03AB02 – phenytoin ; Belongs to the class of hydantoin derivatives antiepileptics.