Phenytoin


Generic Medicine Info
Indications and Dosage
Intramuscular
Seizures associated with neurosurgery
Adult: Doses for solution for inj are expressed in terms of phenytoin Na salt. Prophylaxis and treatment in patients who have not previously received phenytoin Na: 100-200 mg 4 hourly during surgery and continued postoperatively for 48-72 hours, then reduce to a maintenance dose of 300 mg daily and adjust based on individual plasma phenytoin concentrations. Use an alternative route (e.g. gastric intubation) if >1 week of IM therapy is required.
Elderly: Lower dosage or less frequent dosing may be necessary.

Intravenous
Tonic-clonic status epilepticus
Adult: Doses for solution for inj or infusion are expressed in terms of phenytoin Na salt. As part of initial therapy with or immediately after the administration of benzodiazepine (e.g. IV diazepam or lorazepam): Loading dose: 10-15 mg/kg via slow inj or intermittent infusion at a rate of not more than 50 mg/min. Maintenance: 100 mg 6-8 hourly given intravenously or orally. Dosage must be individualised and adjusted according to clinical response and plasma phenytoin concentrations.
Child: Doses for solution for inj or infusion are expressed in terms of phenytoin Na salt. As part of initial therapy with or immediately after the administration of benzodiazepine (e.g. IV diazepam or lorazepam): Loading dose: 15-20 mg/kg via slow inj at a rate not exceeding 1-3 mg/kg/min or 50 mg/min (whichever is slower). Dosage must be individualised and adjusted according to clinical response and plasma phenytoin concentrations.
Elderly: Lower dosage or less frequent dosing may be necessary.

Oral
Generalised tonic-clonic seizures, Partial seizures, Seizures associated with head trauma, Seizures associated with neurosurgery
Adult: Doses for conventional tab and conventional or extended-release cap are expressed in terms of phenytoin Na salt; doses for oral susp and chewable tab are expressed in terms of phenytoin base. As phenytoin or phenytoin Na: Initially, 3-4 mg/kg daily or 150-300 mg daily given as a single dose or in divided doses, may gradually increase up to 600 mg daily at a minimum interval of 7-10 days if necessary. Maintenance: 200-500 mg daily as a single dose or in divided doses. Dosage must be individualised and adjusted according to clinical response and plasma phenytoin concentrations.
Child: Doses for conventional tab and conventional or extended-release cap are expressed in terms of phenytoin Na salt; doses for oral susp and chewable tab are expressed in terms of phenytoin base. As phenytoin or phenytoin Na: Initially, 5 mg/kg daily in 2-3 divided doses. Maintenance: 4-8 mg/kg daily in divided doses. Max: 300 mg daily. Dosage must be individualised and adjusted according to clinical response and plasma phenytoin concentrations.
Elderly: Lower dosage or less frequent dosing may be necessary.
Special Patient Group
Pharmacogenomics:

Phenytoin is extensively metabolised in the liver mainly by CYP2C9 isoenzyme and to a lesser extent by CYP2C19 isoenzyme. It has a large interpatient pharmacokinetic variability partly due to CYP2C9 genetic polymorphism, which may influence the metabolism and safety of phenytoin. Moreover, the presence of human leucocyte antigen B (HLA-B) gene, particularly the HLA-B*15:02 variant allele, may be associated with an increased risk of serious cutaneous adverse reactions in response to phenytoin therapy.

HLA-B*15:02
Patients with 1 or 2 copies of HLA-B*15:02 variant allele have an increased risk of developing phenytoin-induced Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). HLA-B*15:02 is most prevalent in East Asian and Central/South Asian populations with allele frequency that ranges from 1% to >20%. Its prevalence varies widely across Asian ancestries with the highest in those from North China, Taiwan, Hong Kong, Thailand, Malaysia and parts of the Philippines and India. Conversely, HLA-B*15:02 is less frequent in the Japanese and European populations (0-1%) and was not detected in several sub-Saharan African populations.

Genetic testing may be considered to screen for the presence of HLA-B*15:02 variant allele prior to treatment initiation in genetically at-risk populations. However, genotyping must not substitute for clinical vigilance and patient management. Avoid the use of phenytoin in patients who are HLA-B*15:02-positive, particularly when alternative therapies are available; although, patients who have previously used phenytoin continuously for >3 months without the development of cutaneous reactions may consider using phenytoin with caution. Avoid carbamazepine or oxcarbazepine as alternatives to phenytoin, as these agents may also be associated with an increased risk of SJS and TEN in the presence of HLA-B*15:02 variant allele.

CYP2C9
Individuals with genetic variants such as CYP2C9*2 and CYP2C9*3 may have decreased CYP2C9 activity and reduced phenytoin clearance. The prevalence of CYP2C9 intermediate phenotype is approx 35% in White population, 24% in the African-American population, and 15-36% in Asians, while CYP2C9 poor metabolisers are approx 2-3% in the White population, 0.5-4% in Asians, and <1% in the African-American population. CYP2C9 genotyping may be considered before initiating therapy; however, it must not substitute for clinical vigilance and patient management. Product labelling for phenytoin states that CYP2C9 intermediate and poor metabolisers may need lower maintenance doses but no specific dosing recommendations were provided. Published clinical guidelines for CYP2C9 genotype and phenytoin are available for reference.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline as of August 2020:
Phenotype and Genotype Implications Recommendations
CYP2C9 intermediate metaboliser (activity score of 1.5)

Patients carrying 1 normal functional allele and 1 decreased function allele e.g. *1/*2
Slightly reduced phenytoin metabolism; however, side effects do not appear to be increased. No dosage adjustments are needed.
CYP2C9 intermediate metaboliser (activity score of 1)

Patients carrying 1 normal functional allele and 1 non-functional allele, or 2 decreased function alleles e.g. *1/*3, *2/*2
Reduced phenytoin metabolism and higher plasma levels will increase the probability of toxicities. Use the usual initial or loading dose, followed by a maintenance dose that is approx 25% lower than the recommended maintenance dose. Subsequent dose adjustments must be based on therapeutic drug monitoring, clinical response, and side effects.
CYP2C9 poor metaboliser (activity score of 0.5 or 0)

Patients carrying 1 non-functional allele and 1 decreased function allele e.g. *2/*3, or 2 non-functional alleles e.g. *3/*3
Reduced phenytoin metabolism and higher plasma levels will increase the probability of toxicities. Use the usual initial or loading dose, followed by a maintenance dose that is approx 50% lower than the recommended maintenance dose. Subsequent dose adjustments must be based on therapeutic drug monitoring, clinical response, and side effects.

Royal Dutch Pharmacists Association - Pharmacogenetics Working Group (DPWG) Guideline as of May 2021:
DPWG recommends a reduction in the maintenance dose for patients with presence of CYP2C9*1/*2, *1/*3, *2/*2, *2/*3, *3/*3 diplotypes and other CYP2C9 genotypes that may lead to an intermediate metaboliser or poor metaboliser phenotype. Monitor patient response, serum concentrations, and potential adverse events.

Refer to the latest DPWG guideline for detailed recommendations on the specific CYP2C9 diplotypes.
Phenotype Implications Recommendations
Other CYP2C9 intermediate metabolisers (1 allele with reduced activity is neither *2 nor *3) Genetic variation decreases the conversion of phenytoin to inactive metabolites, which increases the risk of side effects. No dosage adjustments are needed for the loading dose. For other doses, use 75% of the standard dose and assess based on the effect and serum concentration after 7-10 days. Monitor for the occurrence of side effects (e.g. ataxia, slurred speech, nystagmus, sedation, rash).
Other CYP2C9 poor metabolisers (at least 1 allele is not *2 or *3) Genetic variation decreases the conversion of phenytoin to inactive metabolites, which increases the risk of side effects. No dosage adjustments are needed for the loading dose. For other doses, use 40-50% of the standard dose and assess based on the effect and serum concentration after 7-10 days. Monitor for the occurrence of side effects (e.g. ataxia, slurred speech, nystagmus, sedation, rash).
Hepatic Impairment
Dosage adjustment may be required.
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 0.9% NaCl solution to provide a final concentration not exceeding 10 mg/mL.
Incompatibility
Solution for inj/infusion: May result in precipitation when mixed with other drugs and dextrose or dextrose-containing solutions.
Contraindications
History of acute hepatotoxicity attributable to phenytoin. IV/IM: Sinus bradycardia, sinoatrial block, 2nd- and 3rd-degree atrioventricular (AV) block, and Adams-Stokes syndrome. Concomitant use with delavirdine.
Special Precautions
Patient with hypotension, cardiac disease, diabetes mellitus, hypothyroidism, hypoalbuminaemia, hyperbilirubinaemia, porphyria, myasthenia gravis; history of adverse haematologic reaction to any drug. Critically ill and debilitated patients. CYP2C9 intermediate and poor metabolisers, and patients who are positive for HLA-B*15:02 allele. Black patients. Avoid extravasation (IV). IM inj is not recommended for the treatment of status epilepticus. Not indicated for the treatment of myoclonic seizures, seizures due to hypoglycaemia or other metabolic causes, and absence (petit mal) seizures. Avoid abrupt withdrawal. Preparations containing phenytoin Na are not necessarily bioequivalent to those containing phenytoin base; dosage adjustments and monitoring of serum level may be necessary when switching dosage forms. Renal and hepatic impairment. Children and elderly. Pregnancy and lactation.
Adverse Reactions
Significant: Angioedema, transient increased serum transaminases, hyperglycaemia; precipitation or aggravation of absence or myoclonic seizures, dose-related CNS effects (e.g. somnolence, nystagmus, ataxia, incoordination, slurred speech), suicidal ideation and behaviour, exacerbation of porphyria; vitamin D deficiency, osteoporosis, osteomalacia, osteopenia, bone fractures, hypocalcaemia, hypophosphataemia (chronic use); lymphadenopathy; confusional states (delirium, psychosis, encephalopathy) or rarely, irreversible cerebellar dysfunction and/or atrophy (for plasma phenytoin levels sustained above the optimal range). IV: Soft tissue irritation and inflammation (e.g. tenderness, skin necrosis and sloughing) at the inj site, purple glove syndrome (oedema, discolouration, and pain distal to the inj site); hypotension (rapid IV administration). IM: Pain, necrosis, and abscess formation at the inj site.
Ear and labyrinth disorders: Vertigo.
Gastrointestinal disorders: Nausea, vomiting, constipation, taste perversion; gingival hyperplasia (mainly in children and patients with poor oral hygiene).
Immune system disorders: Anaphylactoid reactions, anaphylaxis.
Investigations: Abnormal thyroid function test.
Musculoskeletal and connective tissue disorders: SLE, arthropathy. Rarely, Dupuytren's contracture.
Nervous system disorders: Headache, dizziness, motor twitching, paraesthesia. Rarely, dyskinesia, dystonia, tremor, chorea, asterixis.
Psychiatric disorders: Insomnia, transient nervousness.
Renal and urinary disorders: Tubulointerstitial nephritis.
Reproductive system and breast disorders: Rarely, Peyronie's disease.
Respiratory, thoracic and mediastinal disorders: Pneumonitis.
Skin and subcutaneous tissue disorders: Scarlatiniform or morbilliform rash, urticaria, hypertrichosis, hirsutism.
Potentially Fatal: Severe cardiac arrhythmias (including bradycardia, atrial and ventricular conduction depression, ventricular tachycardia or fibrillation progressing to asystole or cardiac arrest) associated with rapid IV administration; severe cutaneous adverse reactions (SCARs), including acute generalised exanthematous pustulosis, toxic epidermal necrolysis, Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS), and exfoliative dermatitis; haematologic effects (e.g. agranulocytosis, leucopenia, granulocytopenia, megaloblastic anaemia, pure red cell aplasia, thrombocytopenia, pancytopenia with or without bone marrow depression); hepatotoxicity (e.g. toxic hepatitis, acute hepatic failure).
IM/IV/Parenteral/PO: Z (Congenital malformations, foetal hydantoin syndrome and haemorrhage have been reported. Use only when benefits outweigh risks. If used, monitor drug levels and adjust dose accordingly.)
Patient Counseling Information
This drug may cause dizziness and drowsiness, if affected, do not drive or operate machinery. Women of childbearing potential must use proven birth control methods during therapy and for 1 month (for oral doses) after stopping the treatment. Consider using other reliable contraceptive methods recommended by the doctor as hormonal contraceptives may be ineffective.
Monitoring Parameters
Consider screening for HLA-B*15:02 allele in patients at increased risk of developing SCARs before therapy initiation. Pregnancy test may be considered in women of childbearing potential to rule out pregnancy before initiating treatment. Obtain CBC, comprehensive metabolic profile, plasma phenytoin concentration, and LFTs; 25-hydroxyvitamin D levels for chronic use. Monitor for signs and symptoms of suicidality, haematologic changes, and hypersensitivity or serious skin reactions. IV: Perform continuous cardiac (heart rate and rhythm, blood pressure) and respiratory monitoring during and after administration. Closely monitor for infusion site reactions.
Overdosage
Symptoms: Nystagmus, blurred vision, ataxia, dysarthria, slurred speech, tremor, lethargy, hyperreflexia, nausea, vomiting, hypotension, coma, bradycardia, asystole/cardiac arrest, apnoea, respiratory and circulatory depression. Management: Symptomatic and supportive treatment. Stomach emptying may be done within 4 hours of ingestion. Support airway if gag reflex is absent. Give oxygen and assisted ventilation for CNS, respiratory, and CV depression. May consider haemodialysis.
Drug Interactions
Serum phenytoin levels may be increased with halothane, cimetidine, fluvastatin, tacrolimus, tolbutamide, omeprazole, salicylates, antibiotics (e.g. chloramphenicol, erythromycin, isoniazid, sulfamethoxazole-trimethoprim), other anticonvulsants (e.g. oxcarbazepine, felbamate, topiramate, ethosuximide), antifungal agents (e.g. amphotericin B, itraconazole, ketoconazole), certain antineoplastic agents (e.g. capecitabine, fluorouracil), benzodiazepines or psychotropic drugs (e.g. disulfiram, methylphenidate, trazodone), CV agents (e.g. amiodarone, diltiazem, nifedipine), and SSRIs (e.g. fluoxetine, fluvoxamine). Serum phenytoin levels may be decreased with rifampicin, vigabatrin, theophylline, reserpine, folic acid, diazoxide, antiretrovirals (e.g. nelfinavir, ritonavir, fosamprenavir), and certain antineoplastic agents (e.g. bleomycin, cisplatin, doxorubicin). Concomitant use with ciprofloxacin, psychotropic agents (e.g. chlordiazepoxide, diazepam, phenothiazines), and certain anticonvulsants (e.g. carbamazepine, phenobarbital, valproic acid) may either increase or decrease serum phenytoin levels. May alter serum levels and/or effects of estrogens and oral contraceptives, vitamin D, doxycycline, rifampicin, ticagrelor, teniposide, furosemide, methadone, tolbutamide, anticoagulants (e.g. apixaban, warfarin), anticonvulsants (e.g. carbamazepine, lamotrigine, phenobarbital, valproic acid, lacosamide), antifungal agents (e.g. posaconazole, voriconazole), antiretrovirals (e.g. efavirenz, fosamprenavir, indinavir, ritonavir, saquinavir), CV agents (e.g. digoxin, disopyramide, mexiletine, verapamil), hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (e.g. atorvastatin, fluvastatin, simvastatin), neuromuscular blocking agents (e.g. pancuronium, rocuronium), and psychotropic agents/antidepressants (e.g. clozapine, paroxetine, quetiapine). Increased risk of hyperammonaemia with valproate.
Potentially Fatal: May cause loss of virologic response and possible resistance to delavirdine or the class of non-nucleoside reverse transcriptase inhibitors.
Food Interaction
Oral absorption may be decreased by concomitant administration of enteral nutrition and/or related nutritional supplements; hold enteral feedings for 2 hours before and after phenytoin administration. Acute alcohol intake may increase phenytoin serum concentrations which may enhance its CNS depressant effects. Chronic alcohol consumption may decrease serum phenytoin levels. Decreased plasma concentrations and clinical effects with St. John's wort.
Lab Interference
May increase the serum concentrations of TSH (usually in the absence of clinical hypothyroidism). May cause falsely low results for serum levels of T4 and T3 and dexamethasone or metyrapone tests. May result in falsely high plasma phenytoin concentrations when measured by immunoanalytical techniques. May affect blood sugar metabolism tests.
Action
Description: Phenytoin is a hydantoin antiepileptic agent. Its exact mechanism of action has not been established but it is expected to stabilise neuronal membranes and reduce seizure activity by increasing efflux or decreasing influx of Na ions across cell membranes in the motor cortex during generation of nerve impulses.
Onset: IV: Approx 0.5-1 hour.
Pharmacokinetics:
Absorption: Slowly but almost completely absorbed from the gastrointestinal tract; absorption following IM inj is slower than after oral administration. Time to peak plasma concentration: 1.5-3 hours (conventional cap, chewable tab, oral susp); 4-12 hours (extended-release cap).
Distribution: Widely distributed throughout the body and into body fluids, including CSF. Crosses the placenta; enters breast milk (small amounts). Volume of distribution: 0.52-1.19 L/kg. Plasma protein binding: Approx 90%, mainly to albumin.
Metabolism: Extensively metabolised in the liver via hydroxylation primarily by CYP2C9 and to a lesser extent by CYP2C19 isoenzyme into inactive metabolites, mainly 5-(4-hydroxyphenyl)-5-phenylhydantoin; undergoes enterohepatic recycling.
Excretion: Via urine (as glucuronides; <5% as unchanged drug). Elimination half-life: Conventional/extended-release cap, conventional tab, oral susp: 22 hours (range: 7-42 hours). Chewable tab: 14 hours (range: 7-29 hours). IV: 10-15 hours.
Chemical Structure

Chemical Structure Image
Phenytoin

Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 1775, Phenytoin. https://pubchem.ncbi.nlm.nih.gov/compound/Phenytoin. Accessed Sept. 27, 2022.

Storage
Conventional/extended-release cap, conventional/chewable tab: Store between 20-25°C. Protect from light (cap) and moisture (cap and tab). Oral susp: Store between 20-25°C. Protect from light. Do not freeze. Solution for inj or infusion: Store between 15-30°C. Diluted IV infusion mixture must not be refrigerated.
MIMS Class
Anticonvulsants
ATC Classification
N03AB02 - phenytoin ; Belongs to the class of hydantoin derivatives antiepileptics.
References
Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2C9 and HLA-B Genotypes and Phenytoin Dosing: 2020 Update. Clinical Pharmacology and Therapeutics. 2021 Feb;109(2):302-309. doi: 10.1002/cpt.2008. Accessed 08/08/2022

Annotation of DPWG Guideline for Phenytoin and CYP2C9. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org. Accessed 08/08/2022.

Annotation of DPWG Guideline for Phenytoin and HLA-B. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org. Accessed 08/08/2022.

Annotation of FDA Label for Phenytoin and CYP2C19, CYP2C9, HLA-B. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org. Accessed 08/08/2022.

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Anon. Phenytoin. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 08/08/2022.

Buckingham R (ed). Phenytoin. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 08/08/2022.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2C9 and HLA-B Genotypes and Phenytoin Dosing: 2020 Update. Clinical Pharmacogenetics Implementation Consortium (CPIC). https://cpicpgx.org. Accessed 08/08/2022.

Dilantin Capsule (Viatris Sdn. Bhd.). National Pharmaceutical Regulatory Agency - Ministry of Health Malaysia. https://www.npra.gov.my. Accessed 08/08/2022.

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Dilantin Infatabs Tablet, Chewable (Parke-Davis Div of Pfizer Inc). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 08/08/2022.

Dilantin Steri-vials 250 mg/5 mL (Viatris Sdn. Bhd.). National Pharmaceutical Regulatory Agency - Ministry of Health Malaysia. https://www.npra.gov.my. Accessed 08/08/2022.

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Epanutin 30 mg/5 mL Oral Suspension (Upjohn UK Limited). MHRA. https://products.mhra.gov.uk. Accessed 08/08/2022.

Epanutin Infatabs 50 mg Chewable Tablets (Upjohn UK Limited). MHRA. https://products.mhra.gov.uk. Accessed 08/08/2022.

Epanutin Ready-mixed Parenteral 250 mg/5 mL Solution for Injection or Infusion (Upjohn UK Limited). MHRA. https://products.mhra.gov.uk. Accessed 08/08/2022.

Joint Formulary Committee. Phenytoin. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 08/08/2022.

Phenytoin Sodium Flynn 300 mg Hard Capsules (Flynn Pharma Ltd). MHRA. https://products.mhra.gov.uk. Accessed 08/08/2022.

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Disclaimer: This information is independently developed by MIMS based on Phenytoin from various references and is provided for your reference only. Therapeutic uses, prescribing information and product availability may vary between countries. Please refer to MIMS Product Monographs for specific and locally approved prescribing information. Although great effort has been made to ensure content accuracy, MIMS shall not be held responsible or liable for any claims or damages arising from the use or misuse of the information contained herein, its contents or omissions, or otherwise. Copyright © 2022 MIMS. All rights reserved. Powered by MIMS.com
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