Dilantin Paediatric

New Zealand - English - Medsafe (Medicines Safety Authority)

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Active ingredient:
Phenytoin 6 mg/mL
Available from:
Pfizer New Zealand Limited
INN (International Name):
Phenytoin 6 mg/mL
Dosage:
30 mg/5mL
Pharmaceutical form:
Oral suspension
Composition:
Active: Phenytoin 6 mg/mL Excipient: Aluminium magnesium silicate Carmellose sodium Carmoisine Citric acid monohydrate Ethanol Imitation banana flavour 510120E Glycerol Polysorbate 40 Purified water Sodium benzoate Sucrose Sunset yellow FCF Terpeneless orange oil Vanillin
Units in package:
Bottle, 500 mL
Class:
Prescription
Prescription type:
Prescription
Manufactured by:
Pharmacia & Upjohn Company LLC
Product summary:
Package - Contents - Shelf Life: Bottle, - 500 mL - 36 months from date of manufacture stored at or below 25°C
Authorization number:
TT50-1014/4
Authorization date:
1969-12-31

DILANTIN

Dilantin

phenytoin, phenytoin sodium

Consumer Medicine Information

What is in this leaflet

This leaflet answers some common

questions about Dilantin.

It does not contain all the available

information.

It does not take the place of talking to

your doctor or pharmacist.

All medicines have risks and

benefits. Your doctor has weighed

the risks of you taking Dilantin

against the benefits they expect it

will have for you.

If you have any concerns about

taking this medicine, ask your

doctor or pharmacist.

Keep this leaflet with the medicine.

You may need to read it again.

What Dilantin is used

Dilantin is used to control epilepsy.

Epilepsy is a condition where you

have repeated seizures (fits). There

are many different types of seizures,

ranging from mild to severe.

Dilantin belongs to a group of

medicines called anticonvulsants.

These drugs are thought to work by

controlling brain chemicals which

send signals to nerves so that seizures

do not happen.

Dilantin is also used to help prevent

seizures occurring during or after

brain surgery.

Dilantin may be used alone, or in

combination with other medicines, to

treat your condition.

Your doctor may have prescribed

Dilantin for another reason. Ask your

doctor if you have any questions

about why Dilantin has been

prescribed for you.

There is no evidence that Dilantin is

addictive.

This medicine is available only with

a doctor's prescription.

Before you take

Dilantin

When you must not take it

Do not take Dilantin if you have an

allergy to:

phenytoin sodium or phenytoin,

the active ingredients in Dilantin,

or other hydantoin medicines or

any of the ingredients listed at the

end of this leaflet

methylphenobarbitone or any

other barbiturate medicines

other medicines used to treat fits

and convulsions.

Symptoms of an allergic reaction to

Dilantin may include:

shortness of breath, wheezing or

difficulty breathing

swelling of the face, lips, tongue

or other parts of the body

rash, itching or hives on the skin.

Do not take this medicine if you

are taking delavirdine, a medicine

used in the treatment of HIV

infection.

Do not take Dilantin after the

expiry date (EXP) printed on the

pack.

Do not take Dilantin if the

packaging is torn or shows signs of

tampering.

If it has expired or is damaged,

return it to your pharmacist for

disposal.

If you are not sure whether you

should start taking Dilantin, talk to

your doctor or pharmacist.

Before you start to take it

Tell your doctor or pharmacist if

you have allergies to:

any other medicines, especially

barbiturates or any other

anticonvulsant medicines

any other substances, such as

foods, preservatives or dyes.

Tell your doctor if you have or

have had any medical conditions,

especially the following:

liver problems

heart problems

diabetes

high blood sugar levels

lymphadenopathy, a condition of

the lymph glands

Systemic Lupus Erythematosus

porphyria, a rare blood pigment

disorder

hypoalbuminaemia, a decrease in

serum albumin in the blood,

causing water retention

hypersensitivity syndrome, which

results in fever, rash, blood

disorders and hepatitis

a severe skin disorder called

Stevens Johnson syndrome

toxic epidermal necrolysis, a

severe skin reaction with painful

red areas, which blister and peel.

Tell your doctor if you are

pregnant or intend to become

pregnant.

DILANTIN

It is very important to control your

fits while you are pregnant. Your

doctor can help you decide if it is

necessary for you to take Dilantin

during pregnancy. Dilantin has been

known to cause abnormalities and

malignancies in the newborns,

delaying their growth and causing

other harmful side effects.

Tell your doctor if you are

breastfeeding or intend to

breastfeed.

It is not recommended to breastfeed

while taking Dilantin, as it may pass

through breast milk and affect your

baby.

If you do breastfeed, watch your

baby carefully.

If your baby develops a skin rash,

becomes difficult to wake or has

unusual symptoms, don't breastfeed

again until you speak to your doctor.

If you have not told your doctor or

pharmacist about any of the above,

tell them before you start taking

Dilantin.

Taking other medicines

Tell your doctor or pharmacist if

you are taking any other

medicines, including any that you

buy without a prescription from

your pharmacy, supermarket or

health food shop.

Some medicines and Dilantin may

interfere with each other. These

include:

disulfiram, a medicine used to

treat alcoholism

other medicines used to treat fits

and convulsions

warfarin, a medicine used to

prevent blood clots

some pain relievers, such as

salicylates and tramadol

benzodiazepines, medicines used

as sleeping tablets, sedatives,

tranquillisers, or to treat anxiety

and panic attacks

medicines used to treat mental

illness such as clozapine,

phenothiazines

medicines used to treat

depression

medicines used to lower

cholesterol

corticosteroids such as cortisone

and prednisolone

ciclosporin, a medicine used to

prevent organ transplant rejection

and to treat severe rheumatoid

arthritis and some severe skin

conditions

some medicines used to treat

cancer

some medicines used to treat

heart problems

some antibiotics and antifungal

medicines used to treat infections

isoniazid, a medicine used to

prevent and treat tuberculosis

(TB)

antiretrovirals, used in the

treatment of HIV infection

medicines used to treat parasitic

worm infections

furosemide, a diuretic (fluid

tablet), which is used to reduce

water retention and high blood

pressure

some medicines used to treat

stomach or duodenal ulcers, such

as omeprazole, sucralfate and

cimetidine

general anaesthetics and muscle

relaxants, medicines used during

an operation

methadone, a medicine used to

control severe pain and to treat

heroin addiction

methylphenidate, a medicine used

to treat Attention Deficit Disorder

St John's wort (Hypericum

perforatum), an ingredient used in

herbal medicines to treat anxiety

and depression

some medicines used to control

diabetes, such as tolbutamide,

glibenclamide, chlorpropamide

and diazoxide

some vitamins such as folic acid

and Vitamin D

theophylline, a medicine used to

treat asthma

estrogens, a hormone used in oral

contraceptives(birth control pills)

and in hormone replacement

therapy.

Your doctor may advise you to

use an additional method of

contraception while taking

Dilantin.

These medicines may be affected by

Dilantin, or may affect how well it

works. Your doctor will tell you if

you need different amounts of your

medicine, or if you need to take

different medicines.

Your doctor and pharmacist may

have more information on medicines

to be careful with or to avoid while

taking Dilantin.

How to take Dilantin

How much to take

Your doctor will tell you how much

medicine to take each day. This may

depend on your age, your condition

and whether or not you are taking

any other medicines.

Your doctor may recommend that

you start with a low dose of Dilantin

and slowly increase the dose to the

lowest amount needed to control

your epilepsy/convulsions.

Follow all directions given to you

by your doctor carefully.

They may differ from the

information contained in this leaflet.

If you do not understand the

instructions on the label, ask your

doctor or pharmacist for help.

How to take it

Capsules: swallow whole with at

least half a glass of water.

Infatabs: chew before swallowing.

Suspension: shake the bottle well

and accurately measure the dose

with a medicine measure before

taking it.

DILANTIN

Shaking the bottle and using a

medicine measure will make sure

that you get the correct dose. You

can get a medicine measure from

your pharmacist.

When to take it

Take Dilantin at about the same

time each day.

Taking Dilantin at the same time

each day will have the best effect. It

will also help you remember when to

take your medicine.

Take Dilantin during or

immediately after a meal.

This will help prevent stomach upset.

If you forget to take it

If it is almost time for your next

dose (within 4 hours), skip the dose

you missed and take your next dose

when you are meant to.

Otherwise, take it as soon as you

remember, and then go back to

taking your medicine as you would

normally.

Do not take a double dose to make

up for the dose that you missed.

This may increase the chance of you

getting an unwanted side effect.

If you are not sure what to do, ask

your doctor or pharmacist.

If you have trouble remembering

to take your medicine, ask your

pharmacist for some hints.

How long to take it

Continue taking Dilantin for as

long as your doctor tells you to.

Dilantin helps control your condition,

but does not cure it. Therefore you

must take your medicine every day,

even if you feel well.

Do not stop taking Dilantin, or

lower the dosage, without checking

with your doctor. Do not let

yourself run out of medicine over

the weekend or on holidays.

Stopping Dilantin suddenly may

cause unwanted effects or make your

condition worse. Your doctor will

slowly reduce your dose before you

can stop taking it completely.

If you take too much

(overdose)

Immediately telephone your doctor

or the Poisons Information Centre

(telephone in New Zealand - 0800

POISON or 0800 764 766), or go to

Accident and Emergency at your

nearest hospital, if you think that

you or anyone else may have taken

too much Dilantin. Do this even if

there are no signs of discomfort or

poisoning.

You may need urgent medical

attention.

While you are taking

Dilantin

Things you must do

Tell your doctor immediately if

you notice any of the following:

increase in seizures (fits)

yellowing of the skin and/or eyes

swelling of the face

strong stomach pains

generally feeling unwell with

tiredness, weakness and vomiting.

These symptoms may mean that you

have a serious condition affecting

your liver. You may need urgent

medical attention.

Tell your doctor immediately if

you have any thoughts about

suicide or self-harm, any unusual

changes in mood or behaviour, or

you show signs of depression.

Some people being treated with anti-

epileptics such as Dilantin have

thoughts of harming or killing

themselves.

Patients and caregivers should be

alert and monitor for these effects.

Signs and symptoms of suicide

include:

thoughts or talk of death or

suicide.

thoughts or talk of self-harm or

harm to others

any recent attempts of self-harm

new or increase in aggressive

behaviour, irritability or agitation

feelings of depression.

Mention of suicide or violence must

be taken seriously.

If you or someone you know is

demonstrating these warning signs

of suicide while taking Dilantin,

contact your doctor or a mental

health professional right away.

Tell any other doctors, dentists,

and pharmacists who are treating

you that you are taking Dilantin.

If you are about to be started on

any new medicine, tell your doctor,

dentist or pharmacist that you are

taking Dilantin.

Before you have any surgery or

emergency treatment, tell your

doctor or dentist that you are

taking Dilantin.

Tell your doctor if you feel Dilantin

is not helping your condition.

Your doctor may need to change

your medicine.

Tell your doctor if, for any reason,

you have not taken Dilantin exactly

as prescribed.

Otherwise, your doctor may change

your treatment unnecessarily.

If you become pregnant while

taking Dilantin, tell your doctor.

Tell your doctor if you want to

take oral contraceptives while

taking Dilantin.

You may need a higher dose of oral

contraceptives than usual to prevent

pregnancy, or you may need to

consider other forms of

contraception.

If you need to have any medical

tests while you are taking Dilantin,

tell your doctor.

Dilantin may affect the results of

some tests including test for thyroid

function.

DILANTIN

Be sure to keep all of your doctor's

appointments so that your progress

can be checked.

Your doctor will check your progress

and may want to take some tests

from time to time. This helps to

prevent unwanted side effects.

Things you must not do

Do not give Dilantin to anyone else,

even if their symptoms seem

similar to yours or they have the

same condition as you.

Do not take Dilantin to treat any

other complaints unless your

doctor tells you to.

Do not stop taking it unless your

doctor tells you to.

Things to be careful of

Be careful driving or operating

machinery until you know how

Dilantin affects you.

As with other anticonvulsant

medicines, Dilantin may cause

dizziness, light-headedness,

weakness, tiredness, and decreased

coordination in some people.

Children should not ride a bike,

climb trees or do anything else that

could be dangerous if they are

feeling drowsy or sleepy.

Dilantin may cause drowsiness,

dizziness or sleepiness in some

people and affect alertness.

Be careful when drinking alcohol

while taking Dilantin.

Combining Dilantin and alcohol can

make you more sleepy, dizzy or

lightheaded. Your doctor may

suggest you avoid alcohol while you

are being treated with Dilantin.

Side effects

Tell your doctor or pharmacist as

soon as possible if you do not feel

well while you are taking Dilantin.

Dilantin helps most people with

epilepsy, but it may have unwanted

side effects in a few people. All

medicines can have side effects.

Sometimes they are serious, most of

the time they are not. You may need

medical treatment if you get some of

the side effects. If you are over 65

years of age you may have an

increased chance of getting side

effects.

Ask your doctor or pharmacist to

answer any questions you may

have.

If you get any side effects, do not

stop taking Dilantin without first

talking to your doctor or

pharmacist.

Tell your doctor if...

Tell your doctor or pharmacist if

you notice any of the following and

they worry you:

dizziness or light-headedness

headache

weakness, unsteadiness when

walking, reduced co-ordination or

slowed reactions

forgetfulness, loss of

concentration or confusion

difficulty speaking or slurred

speech

sleeplessness or sleepiness

nausea (feeling sick) or vomiting

constipation

bleeding, tender or enlarged gums

enlargement of facial features

including thickening of lips

aching joints

raised red skin rash or itchy skin

rash

excessive hairiness, especially in

women

sexual disturbances, such as

painful erection

tingling or numbness of the hands

or feet

changes in taste.

These are the more common side

effects of Dilantin. Mostly these are

mild and short-lived.

Tell your doctor as soon as

possible if...

Tell your doctor as soon as possible

if you notice any of the following:

unusual changes in mood or

behaviour

signs of new or increased

irritability or agitation.

Go to hospital if...

Tell your doctor immediately or go

to Accident and Emergency at

your nearest hospital if you notice

any of the following:

thoughts about suicide or self-

harm

more frequent or more severe

seizures (fits)

sudden onset of uncontrollable

muscle spasms affecting the eyes,

head, neck and body

fever, sore throat, swollen glands,

mouth ulcers, unusual bleeding or

bruising under the skin

tiredness, headache, shortness of

breath when exercising, dizziness

or pale skin

persistent nausea or vomiting,

loss of appetite, generally feeling

unwell, fever, itching, yellowing

of the skin and/or eyes, dark

coloured urine, light coloured

bowel motions, pain in the

abdomen

sudden signs of allergy such as

rash, itching or hives, swelling of

the face, lips, tongue, throat or

other parts of the body, shortness

of breath, wheezing or difficulty

in swallowing or breathing

(anaphylactic reactions)

severe skin rash, itching, hives,

blisters or peeling skin, which

may be accompanied by fever,

chills, headache, swollen glands,

stomach pain or aching joints and

muscles.

slow heartbeat. You may

experience severe fatigue,

weakness, sweating or fainting.

DILANTIN

These are very serious side effects.

You may need urgent medical

attention or hospitalisation.

All of these side effects are very rare.

If you are of African or Chinese

descent or are immune-deficient you

may be at a higher risk of developing

some of the above mentioned serious

side effects. If you belong to this

portion of the population, your doctor

will discuss the risks versus the

benefits with you.

Tell your doctor if you notice

anything else that is making you

feel unwell.

Other side effects not listed above

may happen in some people. Some of

these side effects (for example,

changes in thyroid function, structure

of bones, high cholesterol or blood

pressure) can only be found when

your doctor does blood tests from

time to time to check your progress.

Do not be alarmed by this list of

possible side effects.

You may not experience any of them.

After taking Dilantin

Storage

Keep your tablets and capsules in

the bottle until it is time to take

them.

If you take the tablets or capsules out

of the bottle they will not keep well.

Keep your tablets/capsules/syrup

in a cool dry place where the

temperature stays below 25°C.

Do not store Dilantin or any other

medicine in the bathroom or near a

sink.

Do not leave it on a window sill or

in the car on hot days.

Heat and dampness can destroy some

medicines.

Keep it where children cannot

reach it.

A locked cupboard at least one-and-

a-half metres above the ground is a

good place to store medicines.

Disposal

If your doctor or pharmacist tells

you to stop taking Dilantin or the

medicine has passed its expiry

date, ask your pharmacist what to

do with any that are left over.

Product description

What it looks like

Dilantin capsules 100 mg - white

and orange capsules that are

marked PARKE DAVIS on one

side and P-D 100 on the other

side. They are available in bottles

of 200 capsules.

Dilantin Capsules 30 mg - white

capsules marked PARKE DAVIS

on one side and P-D 30 on the

other side. They are available in

bottles of 200 capsules.

Dilantin Infatabs 50 mg - yellow,

chewable, spearmint-flavoured

triangular tablets. They are

marked P-D 007 on one side and

a break bar on the other side.

They are available in bottles of

200 tablets.

Dilantin Paediatric Suspension - a

reddish-pink suspension which is

available in a 500 mL bottle.

Ingredients

Each white and orange Dilantin

Capsule contains 100 mg of the

active ingredient phenytoin

sodium.

Inactive ingredients are lactose

monohydrate, Confectioner's

sugar (sucrose with 3% maize

starch), purified talc, magnesium

stearate, titanium dioxide, sunset

yellow FCF, erythrosine, carbon

black and gelatin.

Each white Dilantin Capsule

contains 30 mg of the active

ingredient phenytoin sodium.

Inactive ingredients are lactose

monohydrate, Confectioner's

sugar (sucrose with 3% maize

starch), magnesium stearate,

purified talc, titanium dioxide,

carbon black and gelatin.

Each Dilantin Infatab contains the

active ingredient phenytoin 50

Inactive ingredients are sunset

yellow FCF, Confectioner's sugar

(sucrose with 3% maize starch),

quinoline yellow, saccharin

sodium, magnesium stearate,

purified talc and spearmint

flavour.

Dilantin Paediatric Suspension

contains the active ingredient

phenytoin 30 mg/5 mL.

Inactive ingredients are sodium

benzoate, sucrose, glycerol,

aluminium magnesium silicate,

carmellose sodium, polysorbate

40, vanillin, orange oil

terpeneless, ethanol, carmoisine,

sunset yellow FCF, citric acid

monohydrate, hydrochloric acid,

banana flavour and purified

water.

Supplier

Dilantin is supplied in New Zealand

Pfizer New Zealand Limited

PO Box 3998

Auckland, New Zealand

Toll Free Number: 0800 736 363

2This leaflet was revised in April

2019.

© Pfizer Australia Pty Ltd 2019.

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NEW ZEALAND DATA SHEET

1. PRODUCT NAME

Dilantin

30 mg and 100 mg phenytoin sodium capsules

Dilantin

Infatabs 50 mg phenytoin chewable tablets

Dilantin

30 mg/5 mL phenytoin paediatric oral suspension

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 30 mg capsule contains 30 mg phenytoin sodium.

Each 100 mg capsule contains 100 mg phenytoin sodium.

Each 50 mg chewable infatab contains 50 mg phenytoin.

Each 5 mL of paediatric suspension contains 30 mg phenytoin.

Excipients with known effect:

All formulations contain sucrose.

The 30 mg capsule new formulation contains lactose monohydrate.

The 100 mg capsule (both new and old formulations) contains lactose monohydrate.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Capsules 30 mg: white, marked Parke Davis, P-D 30.

Capsules 100 mg: white / orange, marked Parke Davis and P-D 100.

Infatabs 50 mg: chewable tablets, spearmint-flavoured, for children, triangular, yellow, scored,

marked P-D 007. The scoreline is not intended to divide the tablets into equal halves.

Paediatric suspension: reddish-pink suspension.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Dilantin is indicated for the control of generalised tonic-clonic (grand mal) and psychomotor

seizures. Dilantin will prevent or effectively decrease the incidence and severity of convulsive

seizures in a high percentage of cases, with patients exhibiting little tendency to become

resistant to its action. Besides its effectiveness in controlling seizures, Dilantin frequently

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improves the mental condition and outlook of epileptic patients and there is also increasing

evidence that Dilantin is valuable in the prevention of seizures occurring during or after

neurosurgery. Phenytoin serum level determinations may be necessary for optimal dosage

adjustments (see

section 4.2

4.2 Dose and method of administration

Serum concentrations should be monitored and care should be taken when switching a patient

from the sodium salt to the free acid form.

Dilantin capsules (30 mg, 100 mg) are formulated with the sodium salt of phenytoin.

The free acid form of phenytoin is used in Dilantin Infatabs (50 mg) and Dilantin Paediatric

Suspension (30 mg/5 mL).

Because there is approximately an 8% increase in drug content with the free form over that of

the sodium salt, dosage adjustments and serum level monitoring may be necessary when

switching from a product formulated with the free acid to a product formulated with the

sodium salt and vice versa.

General

Dosage should be individualised to obtain maximum benefit. In some cases, serum blood

level determinations may be necessary for optimal dosage adjustments. Serum levels between

10 µg/mL and 20 µg/mL are considered to be clinically effective. With the recommended

dosage, a period of at least 7 to 10 days may be required to achieve therapeutic blood levels of

Dilantin, unless therapy is initiated with a loading dose. After the initial dose has been

prescribed, plasma levels should be determined and the dosage adjusted if necessary to obtain

level

therapeutic

range;

10 µg/mL

to 20 µg/mL

(40 µmoles/L

to 80 µmoles/L).

Because phenytoin is hydroxylated in the liver by an enzyme system which is saturable, at

high plasma levels small incremental doses may increase the half-life and produce very

substantial increases in serum levels, when these are in the upper range.

Oral Administration

Although phenytoin has a relatively long plasma half-life, thrice daily dosing may reduce the

incidence of gastric irritation since lower doses can be administered with thrice daily dosing

as compared with twice daily dosing. Recent studies suggest that a better correlation is

achieved between plasma levels and dose by expressing the latter on a body-weight basis.

Adult

Initiate therapy with 4 mg/kg/day to 5 mg/kg/day in 2 to 3 divided doses and assess plasma

levels. A further upward dosage adjustment may be required to a maximum of 600 mg/day;

dosage increments should be made at about 2 week intervals. Plasma phenytoin levels should

be monitored should higher doses be required.

An initial dose of 6 mg/kg/day to 7 mg/kg/day would be more likely to ensure therapeutic

levels, however, there is a risk that such a dose may achieve levels exceeding 20 µg/mL and

increase the risk of toxicity.

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Paediatric

Initiate therapy with 5 mg/kg/day in 2 to 3 equally divided doses not to exceed 300 mg daily.

A recommended daily maintenance dosage is usually 4 mg/kg to 8 mg/kg. Children over

6 years may require the minimum adult dose (300 mg/day).

Paediatric dosage forms available include Dilantin Chewable Infatabs and Dilantin Paediatric

Suspension.

Dilantin Paediatric Suspension is not for parenteral use.

Dosing in special populations

Patients with Renal or Hepatic Disease:

(see

section 4.4, General

Elderly Patients:

Phenytoin clearance is decreased slightly in elderly patients and lower or

less frequent dosing may be required (see

section 4.4, Use in the Elderly

4.3 Contraindications

Patients with a history of hypersensitivity to phenytoin, or other hydantoin products, or the

other ingredients in this product.

Co-administration of phenytoin with delavirdine is contraindicated due to the potential for

loss of virologic response and possible resistance to delavirdine or to the class of non-

nucleoside reverse transcriptase inhibitors.

4.4 Special warnings and precautions for use

General

Phenytoin is not effective for absence (petit-mal) seizures. If generalised tonic-clonic (grand-

mal) and absence (petit-mal) seizures are present, combined drug therapy is needed.

Phenytoin is not indicated for seizures due to hypoglycaemic or other metabolic causes.

Appropriate diagnostic procedures should be performed as indicated.

Abrupt withdrawal of phenytoin in epileptic patients may precipitate status epilepticus, hence

any need for dosage reduction, discontinuation, or substitution of alternative antiepileptic

medication should be implemented gradually. However, in the event of an allergic or

hypersensitivity reaction, rapid substitution of an alternative therapy may be necessary. In this

case, alternative therapy should be an antiepileptic drug not belonging to the hydantoin

chemical class.

In some individuals, the rate of phenytoin metabolism has been shown to be slower than

normal. This slow rate of degradation may be due to enzymatic unavailability or to defective

induction mechanisms, effects that appear to be genetically determined.

Acute alcoholic intake may increase phenytoin serum levels while chronic alcoholic use may

decrease serum levels.

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Due to an increased fraction of unbound phenytoin in patients with renal or hepatic disease, or

in those with hypoalbuminaemia, the interpretation of total phenytoin plasma concentrations

should be made with caution. Unbound concentration of phenytoin may be elevated in

patients with hyperbilirubinaemia. Unbound phenytoin concentrations may be more useful in

these patient populations.

Suicidal Behaviour and Ideation

Antiepileptic drugs (AEDs), including phenytoin, increase the risk of suicidal thoughts or

behaviour in patients taking these drugs for any indication. Patients treated with any AED for

any indication should be monitored for the emergence or worsening of depression, suicidal

thoughts or behaviour, and/or any unusual changes in mood or behaviour.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11

different AEDs showed that patients randomised to one of the AEDs had approximately twice

the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behaviour

compared to patients randomised to placebo. In these trials, which had a median treatment

duration of 12 weeks, the estimated incidence rate of suicidal behaviour or ideation among

27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated

patients, representing an increase of approximately one case of suicidal thinking or behaviour

for every 530 patients treated. There were four suicides in drug-treated patients in the trials

and none in placebo-treated patients, but the number is too small to allow any conclusion

about drug effect on suicide.

The increased risk of suicidal thoughts or behaviour with AEDs was observed as early as one

week after starting drug treatment with AEDs and persisted for the duration of treatment

assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the

risk of suicidal thoughts or behaviour beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behaviour was generally consistent among drugs in the data

analysed. The finding of increased risk with AEDs of varying mechanisms of action and

across a range of indications suggests that the risk applies to all AEDs used for any indication.

The risk did not vary substantially by age (5-100 years) in the clinical trials analysed. Table 1

shows absolute and relative risk by indication for all evaluated AEDs.

Table 1. Risk by indication for antiepileptic drugs in the pooled analysis

Indication

Placebo

Patients with

Events Per 1000

Patients

Drug Patients

with Events Per

1000 Patients

Relative Risk:

Incidence of

Events in Drug

Patients/Incidence

in Placebo Patients

Risk Difference:

Additional Drug

Patients with

Events Per 1000

Patients

Epilepsy

Psychiatric

Other

Total

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The relative risk for suicidal thoughts or behaviour was higher in clinical trials for epilepsy

than in clinical trials for psychiatric or other conditions, but the absolute risk differences were

similar for the epilepsy and psychiatric indications.

Anyone considering prescribing phenytoin or any other AED must balance this risk with the

risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are

themselves associated with morbidity and mortality and an increased risk of suicidal thoughts

behaviour.

Should

suicidal

thoughts

behaviour

emerge

during

treatment,

prescriber needs to consider whether the emergence of these symptoms in any given patient

may be related to the illness being treated.

Patients, their caregivers, and families should be informed that AEDs increase the risk of

suicidal thoughts and behaviour and should be advised of the need to be alert for the

emergence or worsening of the signs and symptoms of depression, any unusual changes in

mood or behaviour, or the emergence of suicidal thoughts, behaviour, or thoughts about self-

harm. Behaviours of concern should be reported immediately to the treating doctor.

Cardiac Effects

Cases of bradycardia and asystole/cardiac arrest have been reported, most commonly in

association with phenytoin toxicity (see

section 4.9

), but also at recommended phenytoin

doses and levels.

Hypersensitivity Syndrome/Drug Reaction with Eosinophilia and Systemic Symptoms

Hypersensitivity syndrome (HSS) or drug reaction with eosinophilia and systemic symptoms

(DRESS) has been reported in patients taking anticonvulsant drugs, including phenytoin.

Some of these events have been fatal or life threatening.

HSS/DRESS

typically,

although

exclusively,

presents

with

fever,

rash,

and/or

lymphadenopathy, in association with other organ system involvement, such as hepatitis,

nephritis,

haematological

abnormalities,

myocarditis,

myositis

pneumonitis.

Initial

symptoms may resemble an acute viral infection. Other common manifestations include

arthralgias, jaundice, hepatomegaly, leucocytosis, and eosinophilia. The interval between the

first drug exposure and symptoms is usually 2 to 4 weeks but has been reported in individuals

receiving anticonvulsants for 3 or more months. If such signs and symptoms occur, the

patient should be evaluated immediately. Phenytoin should be discontinued if an alternative

aetiology for the signs and symptoms cannot be established and appropriate supportive

measures provided.

Patients at higher risk for developing HSS/DRESS include black patients, patients who have

experienced this syndrome in the past (with phenytoin or other anticonvulsant drugs), patients

who have a family history of this syndrome and immunosuppressed patients. The syndrome is

more severe in previously sensitised individuals.

Serious Dermatologic Reactions

Phenytoin

cause

rare,

severe

cutaneous

adverse

reactions

(SCARs)

such

acute

generalized exanthematous pustulosis (AGEP) (see

section

4.8,

Dermatologic

System

exfoliative dermatitis, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN),

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and DRESS, which can be fatal. Although serious skin reactions may occur without warning,

patients should be alert for the signs and symptoms of skin rash and blisters, fever, itching and

other

signs

symptoms

HSS/DRESS

(see

section

4.4,

Hypersensitivity

Syndrome/Drug Reaction with Eosinophilia and Systemic Symptoms

), and should seek

medical advice from their physician immediately when observing any indicative signs or

symptoms. The physician should advise the patient to discontinue treatment if the rash

appears. If the rash is of a milder type (measles-like or scarlatiniform), therapy may be

resumed after the rash has completely disappeared. If the rash recurs upon reinstitution of

therapy, further phenytoin medication is contraindicated. The risk of serious skin reactions

other

hypersensitivity

reactions

phenytoin,

including

skin

rash,

SJS,

TEN,

hepatotoxicity and HSS may be higher in black patients.

Studies in patients of Chinese ancestry have found a strong association between the risk of

developing SJS/TEN and the presence of HLA-B*1502, an inherited allelic variant of the

human

leucocyte

antigen

(HLA-B)

gene,

patients

using

carbamazepine.

Limited

evidence suggests that HLA-B*1502 may be a risk factor for the development of SJS/TEN in

patients of Asian ancestry taking drugs associated with SJS/TEN, including phenytoin.

Consideration should be given to avoiding use of drugs associated with SJS/TEN, including

phenytoin, in HLA-B*1502 positive patients when alternative therapies are otherwise equally

available.

Literature reports suggest that the combination of phenytoin, cranial irradiation and the

gradual reduction of corticosteroids may be associated with the development of erythema

multiforme, and/or SJS, and/or TEN.

Phenytoin

other

hydantoins

contraindicated

patients

have

experienced

phenytoin hypersensitivity. Additionally caution should be exercised if using structurally

similar

compounds

e.g.

barbiturates,

succinimides,

oxazolidinediones

other

related

compounds) in these same patients.

Angioedema

Angioedema has been reported in patients treated with phenytoin. Phenytoin should be

discontinued immediately if symptoms of angioedema, such as facial, perioral, or upper

airway swelling occur (see

section

4.8, Immune System Disorders

Hepatic Injury

The main site of biotransformation of phenytoin is the liver.

Toxic hepatitis and liver damage have been reported and may, in rare cases, be fatal.

Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been

reported with phenytoin. These incidents usually occur within the first 2 months of treatment

and may be associated with HSS/DRESS (see

section 4.4, Hypersensitivity Syndrome/Drug

Reaction

with

Eosinophilia

and

Systemic

Symptoms

Patients

with

impaired

liver

function, elderly patients or those gravely ill, may show early signs of toxicity on standard

dosage. Care should be exercised with dose adjustment in these patients.

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The clinical course of acute phenytoin hepatotoxicity ranges from prompt recovery to fatal

outcomes. In these patients with acute hepatotoxicity, phenytoin should be immediately

discontinued and not re-administered.

The risk of hepatotoxicity and other hypersensitivity reactions to phenytoin may be higher in

black patients.

Haematopoietic Effect

Haematopoietic complications, some fatal, have occasionally been reported in association

with the administration of phenytoin. These have included thrombocytopenia, leucopenia,

granulocytopenia,

agranulocytosis

pancytopenia

with

without

bone

marrow

suppression.

There have been a number of reports suggesting a relationship between phenytoin and the

development

lymphadenopathy

(local

generalised)

including

benign

lymph

node

hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's disease. Although a cause-and-

effect relationship has not been established, the occurrence of lymphadenopathy indicates the

need to differentiate such a condition from other types of lymph node pathology. Lymph node

involvement may occur with or without signs and symptoms resembling HSS/DRESS (see

section 4.4, Hypersensitivity Syndrome/Drug Reaction with Eosinophilia and Systemic

Symptoms

). In all cases of lymphadenopathy, follow-up observation for an extended period

is indicated, and every effort should be made to achieve seizure control using alternative

antiepileptic drugs.

While macrocytosis and megaloblastic anaemia have occurred, these conditions usually

respond to folic acid therapy. If folic acid is added to phenytoin therapy, a decrease in seizure

control may occur.

It is recommended that patients receiving long-term Dilantin therapy should undergo regular

blood counts as serious haematological abnormalities have been reported (see

section 4.8

Metabolic Effect

In view of isolated reports associating phenytoin with exacerbation of porphyria, caution

should be exercised in using this medication in patients suffering from this disease.

Hyperglycaemia, resulting from the drug's inhibitory effects on insulin release, has been

reported. Phenytoin may also raise the serum glucose level in diabetic patients.

Hypoalbuminaemia, from any cause, may be potentially toxic through its effect on increasing

unbound phenytoin levels.

Musculoskeletal Effect

Phenytoin and other anticonvulsants that have been shown to induce the CYP450 enzyme are

thought to affect bone mineral metabolism indirectly by increasing the metabolism of vitamin

D3. This may lead to vitamin D deficiency and heightened risk of osteomalacia, bone

fractures, osteoporosis, hypocalcaemia and hypophosphataemia in chronically treated epileptic

patients.

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Women of Childbearing Potential

Phenytoin may cause fetal harm when administered to a pregnant woman. Prenatal exposure

phenytoin

increase

risks

congenital

malformations

other

adverse

development outcomes (see

section 4.6

Central Nervous System Effect

Serum levels of phenytoin sustained above the optimal range may produce confusional states

referred

delirium,

psychosis

encephalopathy,

rarely

irreversible

cerebellar

dysfunction and/or cerebellar atrophy. Accordingly, at the first sign of acute toxicity,

determination of plasma drug levels is recommended. Dose reduction of phenytoin therapy is

indicated if plasma drug levels are excessive; if symptoms persist, termination of phenytoin

therapy is recommended.

St John’s Wort

Herbal preparations containing St John’s wort (

Hypericum perforatum

) should not be used

while taking phenytoin due to the risk of decreased plasma concentrations and reduced clinical

effects of phenytoin.

Use in the Elderly

Phenytoin clearance tends to decrease with increasing age. Phenytoin dosing requirements are

highly variable and must be individualised.

4.5 Interaction with other medicines and other forms of interaction

Phenytoin

extensively

bound

serum

plasma

proteins

and is prone to competitive

displacement.

Phenytoin

metabolised

hepatic

cytochrome

(CYP)

P450

enzymes

CYP2C9 and CYP2C19 and is particularly susceptible to inhibitory drug interactions because

it is subject to saturable metabolism. Inhibition of metabolism may produce significant

increases in circulating phenytoin concentrations and enhance the risk of drug toxicity.

Phenytoin is a potent inducer of hepatic drug-metabolising enzymes and may reduce the levels

of drugs metabolised by these enzymes.

There are many drugs that may increase or decrease phenytoin levels or that phenytoin may

affect. These may result through an effect on metabolic degradation of phenytoin, interference

with

protein

binding,

alteration

absorption

other

mechanisms.

Serum

level

determinations for phenytoin are especially helpful when possible drug interactions are

suspected.

The most commonly occurring drug interactions are listed below:

Effects of Other Drugs on Phenytoin

Drugs That May Increase Phenytoin Serum Levels

Drug Classes

Drugs in each Class (such as)*

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Drug Classes

Drugs in each Class (such as)*

Alcohol

Alcohol (acute intake).

Analgesic / Anti-inflammatory

agents

Salicylates.

Antibacterial agents

Chloramphenicol, erythromycin, isoniazid, sulfadiazine,

sulfamethoxazole-trimethoprim, sulfonamides.

Anticonvulsants

Oxcarbazepine, sodium valproate, succinimides

(ethosuximide), topiramate.

Antifungal agents

Amphotericin B, fluconazole, itraconazole,

ketoconazole, miconazole, voriconazole.

Antineoplastic agents

Capecitabine**, fluorouracil**.

Antiplatelet agents

Clopidogrel.

Benzodiazepines / Psychotropic

agents

Diazepam, disulfiram, methylphenidate.

Calcium channel blockers /

Cardiovascular agents

Amiodarone, diltiazem, nifedipine, ticlopidine.

H2-antagonists

Cimetidine.

HMG-CoA reductase inhibitors

Fluvastatin.

Hormones

Estrogens.

Immunosuppressant drugs

Tacrolimus.

Oral hypoglycaemic agents

Tolbutamide.

Proton pump inhibitors

Omeprazole.

Serotonin re-uptake inhibitors

Fluoxetine, fluvoxamine, sertraline.

* This list is not intended to be inclusive or comprehensive. Individual drug Data Sheet should be consulted.

** Increased phenytoin plasma concentrations have been reported during concomitant use of phenytoin with

capecitabine or its metabolite fluorouracil (5FU). Formal interaction studies between phenytoin and capecitabine

have not been conducted, but the mechanism of interaction is presumed to be inhibition of the CYP2C9

isoenzyme system by capecitabine. Patients taking phenytoin concomitantly with capecitabine or fluorouracil

should be regularly monitored for increased phenytoin plasma levels.

Drugs That May Decrease Phenytoin Serum Levels

Drug Classes

Drugs in each Class (such as)*

Alcohol

Alcohol (chronic intake).

Antibacterial agents /

fluoroquinones

Ciprofloxacin, rifampicin.

Anticonvulsants

Vigabatrin.

Antineoplastic agent

Bleomycin, carboplatin, cisplatin, doxorubicin,

methotrexate.

Antiulcer agents

Sucralfate.

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Antiretrovirals

Fosamprenavir, nelfinavir**, ritonavir.

Bronchodilators

Theophylline.

Folic acid

Folic acid.

Hyperglycaemic agents

Diazoxide.

St John’s wort

Hypericum perforatum

(St John’s wort).

* This list is not intended to be inclusive or comprehensive. Individual drug Data Sheet should be consulted.

** A pharmacokinetic interaction study between nelfinavir and phenytoin both administered orally showed that

nelfinavir reduced AUC values of phenytoin (total) and free phenytoin by 29% and 28% respectively. Therefore,

phenytoin concentration should be monitored during co-administration with nelfinavir, as nelfinavir may reduce

phenytoin plasma concentration.

Calcium ions may interfere with the absorption of phenytoin. Ingestion times of phenytoin

and antacid preparations containing calcium should be staggered in patients with low serum

phenytoin levels to prevent absorption problems.

Drugs That May Either Increase or Decrease Phenytoin Serum Levels

Drug Classes

Drugs in each Class (such as)*

Antibacterial agents

Ciprofloxacin

Anticonvulsants**

Carbamazepine, phenobarbital, sodium valproate,

valproic acid.

Antineoplastic agents

Antineoplastic agents.

Psychotropic agents

Chlordiazepoxide, diazepam, phenothiazines.

* This list is not intended to be inclusive or comprehensive. Individual drug Data Sheet should be consulted.

** The effect of phenytoin on carbamazepine, phenobarbital, valproic acid and sodium valproate serum levels is

unpredictable.

Effect of Phenytoin on Other Drugs

The most common types of drugs whose serum levels and/or effects may be altered by

phenytoin are listed below:

Drugs Whose Serum Levels and/or Effects May be Altered by Phenytoin

Drug Classes

Drugs in each Class (such as)*

Antibacterial agents

Doxycycline, rifampicin, tetracycline.

Anticonvulsants

Carbamazepine, lamotrigine, phenobarbital, sodium

valproate, valproic acid.

Antifungal agents

Azoles, posaconazole, voriconazole.

Antihelminthics

Albendazole, praziquantel.

Antineoplastic agents

Teniposide.

Antiretrovirals

Delavirdine, efavirenz, indinavir, lopinavir/ritonavir,

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