Drug Phenytoin

UNIVERSITY COLLEGE OF PHARMACY DRUG PROFILE Drug Name (Generic) PHENYTOIN

1. Sr. No. 1

PRODUCT DESCRIPTION Manufacturer’s Proprietary Name Dilantin®

Dosage Form Capsules, USP

Amount of active Ingredients 30 mg or 100 mg

(extended phenytoin

phenytoin

sodium)

sodium, USP.

Pfizer

Di-hydan 2

3

Storage Conditions Store at controlled room temperature. Preserve in tight, light-resistant containers. Protect from moisture.

Tablets

100mg

Store at controlled room temperature. Preserve in tight, light-resistant containers. Protect from moisture.

Epilantin

Suspension

300mg/5ml

Store in the

Pharmedic

Tablets

30mg

original package

French

in order to protect from light. Do not store above 4

Epitoin

Capsules

100mg

Adamjee

25°C. Store in the original package in order to protect from light. Do not store above

5

Epanutin™

parenteral

250mg/5ml

25°C. Do not store

Pfizer

above 25°C Once opened, use immediately and discard any unused contents.

2.

CHEMISTRY OF PRODUCT Chemical Class

Structure

Nature

Physical Properties

Hydantoin salt

White crystalline powder or granule. Non taste. non smell

Hydantoin Derivative

•

sodium 5,5-diphenyl-2, 4imidazolidinedione

3.

BIO-PHARMACEUTICS

i.

ABSORPTION

Dosage Form Tablets

Route of Administration Oral

ii.

Solubility o Acetone, Ethanol : slightly soluble o Chloroform, Ether : hardly soluble o Water : almost insoluble

Site of Absorption Completely absorbed from GIT

DISTRIBUTION

Bio -availability

%Protein

70-100% oral, 90%

Placenta l Barrier Crosses

Blood Volume of Therapeutic Time for Brain Distribution peak blood Barrier levels Crosses 0.52 and 1.19 1.5-3hrs for

10-20

24.4% for protein rectal and binding in intravenous adults administration

iii.

prompt release & 4 to 12 hrs for extended release administration.

mcg/mL

ELIMINATION

Elimination Half Life 22hours

4.

litres/kg

Site of Metabolism Oxidized in liver

Metabolite(s) Parahydroxyphenyl derivative; Inactive metabolites

Route of Excretion Primarily through the bile, urinary

CLINICAL PHARMACOLOGY Therapeutic Class

Anticonvulsants

Pharmacological Class Anti-epileptics

Mechanism of Action 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 neurotransmitter.

Activity of Metabolite(s) (if any) No

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 •

• •

•

•

• •

•

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

Contraindications / Precautions

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

5 DOSAGE: S Indication r s . N o .

Dosage Form & Route of Administration

1 Loading Dose (IV):

2 Maintenance Oral

3 Loading Dose (IV):

IV injection

Recommended Dosage ranges

Neonates/Infant s mg/kg/day Frequency

Child mg/kg/day Frequency

Adult mg/kg/day Frequency

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

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

recommended daily maintenance dosage is usually 48mg/kg

recommended daily maintenance dosage is usually 4-8mg/kg

one gram of phenytoin capsules is divided into three doses (400 mg, 300 mg, 300 mg) and administered at two-hour intervals 200 to 500mg maintainence dose daily in single or divided doses d by 10 - 20 mg/kg

* O t h e r s

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

6.

ADMINISTRATION GUIDELINES

FOR ORAL ROUTE Type

Could be crushed Y/N

Tablet extended-release capsule Suspension

Interaction

Phenytoin↔

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

Yes No Shake well before use. Take the exact measured dose of suspension with Measuring spoon.

Significance Level / onset

Effects

Phenytoin decreases serum CBZ levels.

4 Delayed Moderate

Serum phenytoin conc. May be elevated increasing risk of toxicity

3 Delayed Major

Phenytoin may decrease the diuretic effect of furosemide

Reduced oral absorption of furosemide

Increased furosemide doses may be needed

1 Delayed Major

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

Possibly decreased cyclosporine absorption or metabolism

Tailor cyclosporin e dose to maintain therapeutic range

Gabapentin Phenytoin↔ furosemide

Phenytoin↔ Cyclosporin

Increased metabolism of CBZ resulting from enzyme induction.CBZ may reduce bioavailability of phenytoin Unknown

Recomme ndations / Managem ent Monitor serum levels of both drugs & adjust the dose to avoid toxicity Monitor serum phenytoin conc.Adjust the dose

2 Delayed Moderate

Carbamazepine

Phenytoin↔

Mechanism

FOR I/V ROUTE Dilution

Compatible

Compatibl

Incompatibilitie

Storage time

Stability

for Dose

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

I/V Fluids

e Drugs

5% glucose or 0.9% sodium chloride solution

s

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

& after temperature dilution after reconstitution The diluted Do not store form is above 25˚C suitable for use as long as it remains clear and free of precipitate

DIRECTIONS FOR USE Route

Directions

Oral 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 Injection

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 Phenytoin may interfere with Metyrapone & 1mg Dexamethasone tests

Nature of Interference Phenytoin produce lower than normal values for dexamethasone or metapyrone tests

Phenytoin may cause raised serum levels of glucose, Blood sugar metabolism tests.

9.

DRUG-FOOD INTERACTION

Type of food Folic acid, calcium & Vitamin D Enteral nutrition Supplements

10.

Mechanism Management Their absorption decreased serum folate concentrations be by phenytoin measured at least once every 6 months, and folic acid supplements given if necessary They decrease phenytoin phenytoin should not be absorption 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

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 nonspecific 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