UNIVERSITY COLLEGE OF PHARMACY

DRUG PROFILE

Drug Name (Generic) PHENYTOIN

1. PRODUCT DESCRIPTION

Sr. No.

Manufacturer’s Proprietary Name

Dosage Form Amount of active

Ingredients

Storage Conditions

1 Dilantin®

(extended phenytoin

sodium)

Pfizer

Capsules, USP 30 mg or 100 mg

phenytoin

sodium, USP.

Store at

controlled room

temperature.

Preserve in tight,

light-resistant

containers.

Protect from

moisture.

2

Di-hydan

French

Tablets 100mg Store at

controlled room

temperature.

Preserve in tight,

light-resistant

containers.

Protect from

moisture.

3

Epilantin

Pharmedic

Suspension

Tablets

300mg/5ml

30mg

Store in the

original package

in order to

protect from

light. Do not

store above 25°C.

4 Epitoin

Adamjee

Capsules 100mg Store in the

original package

in order to

protect from

light. Do not

store above 25°C.

5 Epanutin™

Pfizer

parenteral 250mg/5ml Do not store

above 25°C Once

opened, use

immediately and

discard any

unused contents.

2. CHEMISTRY OF PRODUCT

Chemical Class

Structure Nature Physical Properties

Hydantoin Derivative

sodium 5,5-diphenyl-2, 4-imidazolidinedione

Hydantoin salt White crystalline powder or granule. Non taste. non smell

Solubility o Acetone,

Ethanol : slightly soluble

o Chloroform, Ether : hardly soluble

o Water : almost insoluble

3. BIO-PHARMACEUTICS

i. ABSORPTION

Dosage Form Route of Administration Site of AbsorptionTablets

OralCompletely absorbed from GIT

ii. DISTRIBUTION

Bio -availability

%Protein Placental Barrier

Blood Brain

Barrier

Volume of Distribution

Time for peak blood

levels

Therape

Serum Level

70-100% oral, 24.4% for rectal and intravenous administration

90% protein binding in adults

Crosses Crosses 0.52 and 1.19 litres/kg

1.5-3hrs for prompt release & 4 to 12 hrs for extended release administration.

10-20 mcg/mL

iii. ELIMINATION

Elimination Half Life

Site of Metabolism

Metabolite(s) Route of Excretion

22hours Oxidized in liver Parahydroxyphenyl derivative; Inactive metabolites

Primarily through the bile, urinary

4. CLINICAL PHARMACOLOGY

Therapeutic Class

Pharmacological Class

Mechanism of Action Activity of Metabolite(s) (if

any)Anticonvulsants Anti-epileptics The mechanism by which

phenytoin exerts its anticonvulsant action has not been fully elucidated however, possible contributory effects include: 1. Non-synaptic effects to reduce sodium conductance, enhance active sodium extrusion, block repetitive firing and reduce post-tetanic potentiation 2. Post-synaptic action to enhance gaba-mediated inhibition and reduce excitatory synaptic transmission 3. Pre-synaptic actions to reduce calcium entry and block release of

No

neurotransmitter.

Effects on Organ Systems Therapeutic Uses Spectrum (if antibiotic)

used in generalized epilepsy, partial epilepsy, preventing or treating seizures caused by brain surgery or a head injury and trigeminal neuralgia

Monitoring of Blood levels (if required / for narrow therapeutic index drugs)

Measurement of serum phenytoin levels is recommended when using phenytoin in the management of status epilepticus and in establishing a maintenance dose. The usually accepted therapeutic level is 10-20 mg/litre, although some patients with tonic-clonic seizures can be controlled with lower serum levels

Adverse Effects Contraindications / Precautions

Phenytoin may cause a febrile reaction, hypotension (during intravenous infusion), or bradycardia.

Mouth - Gingival hyperplasia Neurologic : Hyperreflexia or

hyporeflexia, Abnormal gait (bradykinesia, truncal ataxia) , Respiratory distress, Encephalopathy , Meningeal irritation with pleocytosis , Tremor (intention) , Irritability or agitation, Confusion , Hallucinations , Mental status varies from completely normal to the extremes of stupor and coma, particularly if co-ingestants are present , Peripheral neuropathy (chronic use) , Priapism ,Urinary incontinence, Choreoathetoid movements,, Dysarthria , Dysphagia ,Seizures (rare) ,Death (rare)

Eyes : Nystagmus (horizontal, vertical) , Ophthalmoplegia , Diplopia ,Miosis or mydriasis

Hypersensitivity reactions: Fever, rash, and lymphadenopathy, commonly observed together , Systemic lupus erythematosus (SLE), Polyarteritis , Polymyositis , Eosinophilia , Megaloblastic anemia, Pseudolymphoma, Lymphadenopathy

Vascular - Phlebitis Skin :Hirsutism ,Acne ,Rashes, can

be mild, morbilliform, scarlatinoid or as severe as Stevens-Johnson syndrome ,Jaundice ,Facial or periorbital edema ,Erythema multiforme (EM) , Toxic epidermal necrolysis (TEN)

GI/abdomen : Hepatitis

Phenytoin is contraindicated in those patients who are hypersensitive to phenytoin or other hydantoinsPhenytoin should be administered caution in patients with renal, hepatic impairments & diabetics.

5 DOSAGE:

Sr. No.

Indications

Dosage Form & Route of Administration

Recommended Dosage ranges

Neonates/Infants

mg/kg/day Frequency

Child mg/kg/day Frequency

Adult mg/kg/day Frequency

* Others

1

Loading Dose

(IV):

5 mg/kg/day in two or three equally divided doses

5 mg/kg/day in two or three

equally divided doses

one gram of phenytoin capsules is divided into three doses

(400 mg, 300 mg, 300 mg)

and administered at two-hour

intervals2 Maintenance

Oralrecommended daily

maintenance dosage is usually 4-

8mg/kg

recommended daily

maintenance dosage is usually

4-8mg/kg

200 to 500mg maintainence dose daily in

single or divided doses

d by 3 Loading Dose

(IV): IV injection

10 - 20 mg/kg

* Others: Pregnancy, Cardiac Patients, Renal / Liver impairment.

6. ADMINISTRATION GUIDELINES

FOR ORAL ROUTE

Type Could be crushedY/N

Directions for reconstitution (in case of granules for susp. or

syp.)Tabletextended-release capsuleSuspension

YesNo

Shake well before use. Take the exact measured dose of suspension with Measuring spoon.

Interaction Significance Level / onset

Effects Mechanism Recommendations / Managem

ent 2Delayed

Phenytoin decreases serum CBZ levels.

Increased metabolism of CBZ

Monitor serum

Phenytoin↔

Carbamazepine

Moderate resulting from enzyme induction.CBZ may reduce bioavailability of phenytoin

levels of both drugs & adjust the dose to avoid toxicity

Phenytoin↔

Gabapentin

4DelayedModerate

Serum phenytoin conc. May be elevated increasing risk of toxicity

Unknown Monitor serum phenytoin conc.Adjust the dose

Phenytoin↔furosemide

3DelayedMajor

Phenytoin may decrease the diuretic effect of furosemide

Reduced oral absorption of furosemide

Increased furosemide doses may be needed

Phenytoin↔

Cyclosporin

1DelayedMajor

Cyclosporin conc. May be decreased by phentoin resulting in decreased immunosuppressive activity

Possibly decreased cyclosporine absorption or metabolism

Tailor cyclosporine dose to maintain therapeutic range

FOR I/V ROUTE

Dilution for Dose

Compatible I/V Fluids

Compatible Drugs

Incompatibilities Storage time &

temperature after

reconstitution

Stability after

dilution

parenteral phenytoin should be Diluted in 50-100 ml of normal saline,final conc. Not exceeding 10mg/ml

5% glucose or 0.9% sodium chloride solution

Phenytoin Parenteral should not be mixed with other drugs because of precipitation of phenytoin acid.

Do not store above 25˚C

The diluted form is suitable for use as long as it remains clear and free of precipitate

DIRECTIONS FOR USE

Route Directions

Oral

Injection

Shake the bottle well before each dose. Take this medication by mouth as directed, with a full glass (8 oz or 240 ml) of water, or as directed by your doctor. Patient may take it with food if stomach upset occurs. Take the medicine at the right time

This drug must be administered slowly, at a rate not exceeding 50 mg/minute in adults. In neonates, the drug should be administered at a rate not exceeding 1-3 mg/kg/min. The response to phenytoin may be significantly altered by the concomitant use of other drugs

7. DRUG – DRUG INTERACTIONS

8. DRUG – LAB INTERACTIONS

Lab Test Nature of InterferencePhenytoin may interfere with Metyrapone & 1mg Dexamethasone tests

Blood sugar metabolism tests.

Phenytoin produce lower than normal values for dexamethasone or metapyrone tests

Phenytoin may cause raised serum levels of glucose,

9. DRUG-FOOD INTERACTION

Type of food Mechanism Management Folic acid, calcium & Vitamin D

Their absorption decreased by phenytoin

serum folate concentrations be measured at least once every 6 months, and folic acid supplements given if necessary

Enteral nutrition Supplements

They decrease phenytoin absorption

phenytoin should not be administered concomitantly with an enteral feeding preparation. Do not take enteral feeds or other nutritional supplements two hours before, or two hours after, taking medicine.If administered then monitor the serum phenytoin level and increase the dose of phenytoin

10. TOXICOLOGY

Toxic Dose Sign & Symptoms

Lethal Dose Management/Treatment (including

antidote)

There are marked variations among individuals with respect to phenytoin serum levels where toxicity may occur. Nystagmus on lateral gaze usually appears at 20mg/l, and ataxia at 30mg/l, dysarthria and lethargy appear when the serum concentration is greater than 40mg/l

The initial symptoms are nystagmus, ataxia, and dysarthria. Other signs are tremor, hyperreflexia, lethargy, slurred speech, nausea, vomiting. The patient may become comatose and hypotensive. Death is due to respiratory and circulatory depression

The lethal dose in children is not known, in adults 2 to 5 grams

Treatment is non-specific since there is no known antidote. If ingested within the previous 4 hours the stomach should be emptied. If the gag reflex is absent, the airway should be supported. Oxygen, and assisted ventilation may be necessary for central nervous system, respiratory and cardiovascular depression. Haemodialysis can be considered since phenytoin is not completely bound to plasma proteins. Total exchange transfusion has been utilised in the treatment of severe intoxication in children

REFERENCES http://emc.medicines.org.uk/emc/assets/c/html/DisplayDoc.asp? DocumentID=13289#CLINICAL_PARTS

http://www.rxlist.com/dilantin-drug.htm#

http://www.drugs.com/phenytoin.html

http://en.wikipedia.org/wiki/Phenytoin

http://chrom.tutms.tut.ac.jp/JINNO/DRUGDATA/21phenytoin.html#Property

http://www.globalrph.com/anticonvulsants.htm

Pakistan Drug Manual

Drug Interaction Facts