Consumer medicine information

Dilantin [9252]

Phenytoin

BRAND INFORMATION

Brand name

Dilantin

Active ingredient

Phenytoin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Dilantin [9252].

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 for

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. 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. 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 Australia - 13 11 26), 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.

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.

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 (PI: 1749) (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 (PI: 1749) (sucrose with 3% maize starch), magnesium stearate, purified talc, titanium dioxide, carbon black and gelatin.
  • Each Dilantin Infatab contains the active ingredient phenytoin 50 mg.
    Inactive ingredients are sunset yellow FCF, Confectioner's sugar (PI: 1749) (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 Australia by:

Pfizer Australia Pty Ltd
Sydney NSW
Toll Free Number: 1800 675 229
www.pfizer.com.au

Australian Registration Numbers:

Dilantin 100 mg AUST R 295265

Dilantin 30 mg AUST R 295264

Dilantin Infatabs AUST R 14308

Dilantin Infatabs AUST R 297268 (new formulation)

Dilantin Paediatric AUST R 14309

This leaflet was revised in April 2019.

© Pfizer Australia Pty Ltd 2019.

Published by MIMS July 2019

BRAND INFORMATION

Brand name

Dilantin

Active ingredient

Phenytoin

Schedule

S4

 

1 Name of Medicine

Phenytoin sodium.
Phenytoin.

6.7 Physicochemical Properties

Chemical name: 5,5-diphenylimidazolidine-2,4-dione. Molecular formula: C15H12N2O2. Molecular weight: 252.272.

Chemical structure.

The molecular structure of phenytoin is shown:

CAS number.

CAS registry number: 57-41-0.

2 Qualitative and Quantitative Composition

Dilantin 30 mg capsules: each 30 mg capsule contains 30 mg phenytoin sodium.
Dilantin 100 mg capsules: each 100 mg capsule contains 100 mg phenytoin sodium.
Dilantin Infatabs 50 mg chewable tablets: each 50 mg chewable infatab contains 50 mg phenytoin.
Dilantin 30 mg/5 mL paediatric oral suspension: each 5 mL of paediatric suspension contains 30 mg phenytoin.
Phenytoin is a white, or almost white, odourless or almost odourless, crystalline powder. It is practically insoluble in water and soluble 1 in 70 alcohol.
Phenytoin sodium is the sodium salt of phenytoin. It is a white, odourless, slightly hygroscopic crystalline powder. It is soluble in water and alcohol.

Excipients with known effect.

All formulations contain sucrose.
The 30 mg capsule new formulation (AUST R 295264) contains lactose monohydrate.
The 100 mg capsule (both old and new formulations AUST R 14305 and AUST R 295265) contains lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Capsules 30 mg.

Opaque hard gelatin capsule with white body/white lid, marked 'PARKE DAVIS' on one end and 'P-D 30' on the other.

Capsules 100 mg.

Opaque hard gelatin capsule with white body/orange lid, marked 'PARKE DAVIS' on one end and 'P-D 100' on the other.

Infatabs 50 mg.

Yellow, triangular, spearmint-flavoured chewable tablets with flat sides, bevelled edge, breaking line on one side and 'P-D 007' imprinted on the other.

Paediatric suspension.

Reddish-pink suspension.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Dilantin is an anticonvulsant drug, which can be useful in the treatment of epilepsy. The primary site of action appears to be the motor cortex, where the spreading of seizure activity is inhibited. It is likely that by promoting sodium efflux from neurones, Dilantin tends to stabilise the threshold against hyperexcitability caused by excessive stimulation or those environmental changes capable of reducing the gradient of sodium ions through membranes. This also applies to the reduction of post-tetanic potentiation at synapse level. Losing post-tetanic potential prevents the cortical seizure foci from deteriorating neighbouring cortical areas. In this sense, Dilantin reduces the maximal activity of brain centres associated with the tonic phase of generalised tonic-clonic (grand mal) seizures.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

In general the reported plasma half-life of phenytoin averages 22 hours, with a range of 7 to 42 hours. Steady-state therapeutic levels are achieved at least 7 to 10 days (5 to 7 half-lives) after initiation of therapy with recommended doses of 300 mg/day.

Distribution.

For Dilantin Capsules, peak serum levels occur 4 to 12 hours after administration.
Conventionally, with drugs following linear kinetics, the half-life is used to determine the dose rate, drug accumulation and the time to reach steady state. Phenytoin, however, demonstrates non-linear kinetics and therefore the half-life is affected by the degree of absorption, saturation of metabolic pathways, dose and the degree of metabolic enzyme induction. This results in considerable inter- and intra-patient variability in phenytoin pharmacokinetics. As a consequence the clinical relevance of reported phenytoin half-life values are limited and cannot be used in the conventional manner to estimate the dosage regimen. When administering phenytoin to a patient it is necessary to measure serum levels as this provides the most accurate means of deriving a suitable dosage regimen.
Serum level determinations should originally be obtained at least 7 to 10 days after treatment initiation, dosage change, or addition or subtraction of another drug to the regimen so that equilibrium or steady-state will have been achieved. Further serum level determinations may be required to further refine the dosage regimen. Trough levels provide information about clinically effective serum level range and confirm patient compliance and are obtained just prior to the patient's next scheduled dose. Peak levels indicate an individual's threshold for emergence of dose-related side effects and are obtained at the time of expected peak concentration.
Optimum control without clinical signs of toxicity occurs more often with serum levels between 10 microgram/mL and 20 microgram/mL. Therapeutic concentrations of free (unbound) phenytoin, which are frequently monitored in patients with altered protein binding, usually fall in the range of 0.8 microgram/mL to 2 microgram/mL.
In most patients maintained at steady dosage, stable phenytoin serum levels are achieved. There may be wide interpatient variability in phenytoin serum levels with equivalent dosages. Patients with unusually low levels may be noncompliant or hypermetabolisers of phenytoin.
Unusually high levels of phenytoin result from liver disease, congenital enzyme deficiency or drug interactions, which result in metabolic interference. Patients with large variations in phenytoin plasma levels, despite standard doses, present a difficult clinical problem. Serum level determinations in such patients may be particularly helpful. Phenytoin is about 90% protein bound. As phenytoin is highly protein bound, free phenytoin levels may be altered in patients whose protein binding characteristics differ from normal. Protein binding may be lower in neonates and hyperbilirubinaemic infants; also altered in patients with hypoalbuminaemia, uraemia or acute trauma and in pregnancy.

Metabolism.

Phenytoin is metabolised in the liver primarily by CYP2C9 (major) and CYP2C19 (minor) (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). The major inactive metabolite is 5-(p-hydroxyphenyl)-5-phenylhydantoin (HPPH). The rate of metabolism is increased in younger children, pregnant women, in women during menses and in patients with acute trauma. The rate decreased with advancing age. Phenytoin may be metabolised slowly in a small number of individuals due to genetic polymorphism, which may cause isoenzyme mutations (e.g. CYP2C9/19), limited enzyme availability and lack of induction (e.g. CYP3A4). 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.

Excretion.

Most of the drug is excreted in the bile as inactive metabolites which are then reabsorbed from the intestinal tract and excreted in the urine. Urinary excretion of phenytoin and its metabolites occurs partly with glomerular filtration but more importantly with tubular secretion.
The steady-state level may be disproportionately increased, with resultant intoxication, from an increase in dosage of 10% or more.

Food effect of bioavailability of Dilantin capsules.

The Cmax and AUC data from a food-effect study involving administration of Dilantin 100 mg to healthy volunteers under fasting conditions and with a high-fat meal indicated that exposure to the drug is not affected by food.

5.3 Preclinical Safety Data

Genotoxicity.

Phenytoin was negative in the Ames test and in the in vitro clastogenicity assay in Chinese hamster ovary (CHO) cells. In studies reported in the literature, phenytoin was negative in the in vitro mouse lymphoma assay and the in vivo micronucleus assay in mouse. Phenytoin was clastogenic in the in vitro sister chromatid exchange assay in CHO cells.

Carcinogenicity.

In carcinogenicity studies, phenytoin was administered in the diet to mice (10, 25, or 45 mg/kg/day) and rats (25, 50, or 100 mg/kg/day) for 2 years. The incidences of hepatocellular tumors were increased in male and female mice at the highest dose. No increases in tumor incidence were observed in rats. The highest doses tested in these studies were associated with peak serum phenytoin levels below human therapeutic concentrations.
In carcinogenicity studies reported in literature, phenytoin was administered in the diet for 2 years at doses up to 300 ppm (approximately 60 mg/kg/day) and 600 ppm (approximately 160 mg/kg/day) to male and female mice respectively, and up to 2400 ppm (approximately 120 mg/kg/day) to rats. The incidence of hepatocellular tumors were increased in female mice at all but the lowest dose tested. No increases in tumor incidence were observed in rats. Phenytoin-induced hepatic tumors in mice may be secondary to hepatic enzyme induction in those species and are of uncertain clinical relevance.

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 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 Dose and Method of Administration).

4.3 Contraindications

Patients with a history of hypersensitivity to phenytoin, or other hydantoin products, or other inactive 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 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.
Phenytoin should not be abruptly discontinued because of the possibility of increased seizure frequency, including 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.
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.
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 and behaviour. Should suicidal thoughts and behaviour emerge during treatment, the 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 Overdose), 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 not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other organ system involvement, such as hepatitis, nephritis, haematological abnormalities, myocarditis, myositis or 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 can cause rare, severe cutaneous adverse reactions (SCARs) such as acute generalized exanthematous pustulosis (AGEP) (see Section 4.8 Adverse Effects (Undesirable Effects), Dermatological system), exfoliative dermatitis, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), 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 and symptoms of HSS/DRESS (see Section 4.4 Special Warnings and Precautions for Use, 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 and other hypersensitivity reactions to 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 B (HLA-B) gene, in 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 and other hydantoins are contraindicated in patients who have experienced phenytoin hypersensitivity. Additionally caution should be exercised if using structurally similar compounds (e.g. barbiturates, succinimides, oxazolidinediones and 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 Adverse Effects (Undesirable Effects), Immunologic).

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 Special Warnings and Precautions for Use, 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.
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 administration of phenytoin. These have included thrombocytopenia, leucopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression.
There have been a number of reports suggesting a relationship between phenytoin and the development of lymphadenopathy (local or 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 Special Warnings and Precautions for Use, 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 Adverse Effects (Undesirable Effects)).

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.

Women of childbearing potential.

Phenytoin may cause fetal harm when administered to a pregnant woman. Prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse development outcomes (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).

Central nervous system effect.

Serum levels of phenytoin sustained above the optimal range may produce confusional states referred to as delirium, psychosis or encephalopathy, or 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.

Use in the elderly.

Phenytoin clearance tends to decrease with increasing age. Phenytoin dosing requirements are highly variable and must be individualised.

Paediatric use.

No data available.

Effects on laboratory tests.

Phenytoin may cause decreased serum levels of protein bound iodine (PBI). It may also produce lower than normal values for dexamethasone or metyrapone tests. Phenytoin may cause raised serum levels of glucose, alkaline phosphatase, and gamma glutamyl transpeptidase (GGT). Raised glucose levels appear to be due to inhibition of insulin secretion.

4.5 Interactions with Other Medicines and Other Forms of Interactions

There are many drugs that may increase or decrease phenytoin levels or that phenytoin may affect. Mechanisms of drug interaction with phenytoin may be complex. In assessing drug-interactions, serum phenytoin concentrations and the clinical status of the patient will be helpful.
In general, phenytoin is a potent inducer of the hepatic cytochrome P450 microsomal isoenzymes CYP3A4, CYP2D6, CYP1A2, CYP2C9 and CYP2C19. However, a patient's susceptibility to enzyme-inducing interactions may be influenced by factors such as age, cigarette smoking or the presence of liver disease. Phenytoin is metabolised primarily by CYP2C9 (major) and CYP2C19 (minor), thus several drugs may inhibit or induce the metabolism of phenytoin.
Oral phenytoin absorption may be reduced by a number of drugs. Phenytoin is highly plasma-protein bound and may be displaced by other drugs, increasing unbound ('free') phenytoin levels. Phenytoin 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.

Effects of other drugs on phenytoin.

See Tables 2 and 3.
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. See Table 4.

Effect of phenytoin on other drugs.

See Table 5.

Seizure threshold lowering drugs.

Although not a pharmacokinetic drug interaction, antidepressants, antipsychotics, tramadol and other seizure threshold lowering drugs may precipitate seizures in susceptible patients by lowering convulsive threshold. Phenytoin dosage may need to be adjusted.

Drug-enteral feeding/nutritional preparations interaction.

The oral absorption of phenytoin suspension can be reduced substantially by up to 80% by concurrent administration of enteral feeding preparations and/or related nutritional supplements. Conversely, when enteral feedings are halted, phenytoin levels may rise substantially. If the patient can receive intermittent feedings, it is crucial that phenytoin doses be administered at least two hours following a feeding and that the next feeding be delayed until at least two hours after the phenytoin dose is administered. Patients who must receive continuous enteral feedings should probably receive phenytoin intravenously. Any patients receiving phenytoin orally through a feeding tube should have the suspension diluted prior to administration and the tubing flushed following administration. Serum phenytoin levels should be monitored and the dosage should be adjusted to achieve therapeutic concentrations.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Phenytoin has not been adequately assessed for effects on male or female fertility.
(Category D)
Phenytoin crosses the placenta in humans.
The risk of having an abnormal child as a result of antiepileptic medication is far outweighed by the dangers to the mother and fetus of uncontrolled epilepsy.
It is recommended that:
women on antiepileptic drugs (AEDs) receive pre-pregnancy counselling with regard to the risk of fetal abnormalities;
AEDs should be continued during pregnancy and monotherapy should be used if possible at the lowest effective dose as risk of abnormality is greater in women taking combined medication;
folic acid supplementation (5 mg) should be commenced four weeks prior to and continue for twelve weeks after conception;
specialist prenatal diagnosis including detailed mid-trimester ultrasound should be offered.
Phenytoin should only be used in women of childbearing potential and pregnant women if the potential benefit outweighs the risk. When appropriate, counsel pregnant women and women of childbearing potential about alternative therapeutic options.
This drug taken during pregnancy has been associated with craniofacial defects, fingernail hypoplasia, developmental disability, growth retardation and less frequently, oral clefts and cardiac anomalies. This clinical pattern is sometimes called the 'fetal hydantoin syndrome'.
A number of reports suggest an association between the use of anticonvulsant drugs by women with epilepsy and a higher incidence of birth defects in children born to these women. The risk of a mother with epilepsy giving birth to a baby with an abnormality is about three times that of the normal population. Some of this risk is due to the anticonvulsant drugs taken.
It is important to note that antiepileptic drugs should not be discontinued in patients in whom the drug is administered to prevent major seizures, because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In individual cases where the severity and frequency of the seizure disorder are such that the removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior to and during pregnancy, although it cannot be said with any confidence that even minor seizures do not pose some hazard to the developing embryo or fetus. The prescribing physician will wish to weigh these considerations in treating and counselling epileptic women of childbearing potential.
In addition to the reports of increased incidence of congenital malformations such as cleft lip/palate and heart malformations in children of women receiving phenytoin and other anticonvulsant drugs, there have been reports of a fetal hydantoin syndrome. This consists of prenatal dysmorphic facial features, fingernail and digit hypoplasia, developmental disability, growth retardation (including microcephaly) and mental deficiency in children born to mothers who have received phenytoin.
There have been isolated reports of malignancies including neuroblastoma, in children whose mothers received phenytoin during pregnancy.
An increase in seizure frequency during pregnancy occurs in a high proportion of patients, because of altered phenytoin absorption or metabolism. Periodic measurement of serum phenytoin levels is particularly valuable in the management of a pregnant epileptic patient as a guide to an appropriate adjustment of dosage. However, postpartum restoration of the original dosage will probably be indicated.
Phenytoin also can cause coagulation defects with consequent risk of haemorrhage in the fetus and the newborn infant which may be preventable by the prophylactic administration of vitamin K to the mother prior to delivery.
Women of childbearing potential who are not planning a pregnancy should be advised on the use of effective contraception during treatment. Phenytoin may result in a failure of the therapeutic effect of hormonal contraceptives (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Breastfeeding is not recommended for women taking this drug because phenytoin appears to be secreted in low concentration in human milk. Phenytoin concentration in breast milk is approximately one-third of the corresponding maternal plasma concentration.

4.8 Adverse Effects (Undesirable Effects)

Body as a whole.

Anaphylactoid reaction and anaphylaxis.

Gastrointestinal system.

Nausea, vomiting and constipation. To prevent gastric irritation due to alkalinity, Dilantin should be taken with at least half a glass of water. Gastric irritation may often be minimised by administering Dilantin during or following meals or by using Dilantin Suspension.

Haematopoietic system.

Some fatal haematopoietic complications have occasionally been reported in association with the administration of phenytoin. Included in these are thrombocytopenia, leucopenia, granulocytopenia, agranulocytosis and pancytopenia with or without bone marrow suppression. Macrocytosis and megaloblastic anaemia have also occurred, these conditions usually respond to folic acid therapy.
Lymphadenopathy including benign lymph node hyperplasia, pseudolymphoma, lymphoma and Hodgkin's disease have been reported (see Section 4.4 Special Warnings and Precautions for Use, Haematopoietic effect).

Central nervous system.

The most common manifestations encountered with phenytoin therapy are referable to this system and are usually dose-related. These include nystagmus, ataxia, slurred speech, decreased coordination and mental confusion. Cerebellar atrophy has been reported and appears more likely in settings of elevated phenytoin levels and/or long-term phenytoin use (see Section 4.4 Special Warnings and Precautions for Use, Central nervous system effect). Cases of dizziness, vertigo, insomnia, transient nervousness, motor twitchings, headache, paraesthesia and somnolence have also been reported.
There have also been rare reports of phenytoin induced dyskinesias, including chorea, dystonia, tremor and asterixis, similar to those induced by phenothiazine and other neuroleptic drugs. A predominantly sensory peripheral polyneuropathy has been observed in patients receiving long-term phenytoin therapy.

Immunologic.

HSS/DRESS (which may include, but is not limited to, symptoms such as arthralgias, eosinophilia, fever, liver dysfunction, lymphadenopathy or rash), systemic lupus erythematosus, periarteritis nodosa and immunoglobulin abnormalities (see Section 4.4 Special Warnings and Precautions for Use, Hypersensitivity syndrome/ drug reaction with eosinophilia and systemic symptoms). Angioedema has been reported (see Section 4.4 Special Warnings and Precautions for Use, Angioedema).

Investigations.

Thyroid function test abnormal.

Connective tissue system.

Coarsening of the facial features, enlargement of the lips, gingival hyperplasia, hypertrichosis and Peyronie's Disease.

Musculoskeletal system.

Bone fractures and osteomalacia have been associated with long-term (> 10 years) use of phenytoin by patients with chronic epilepsy. Osteoporosis and other disorders of bone metabolism such as hypocalcaemia, hypophosphataemia and decreased serum levels of vitamin D metabolites have also been reported.

Dermatological system.

Dermatological manifestations sometimes associated with fever have included scarlatiniform or morbilliform rashes. The latter case is the most common with other types of dermatitis being more rare. In general, rashes are more frequent in children and young adults. More serious forms that may be fatal have also been reported and they include bullous, exfoliative or other purpuric dermatitis, lupus erythematosus, AGEP, SJS and TEN (see Section 4.4 Special Warnings and Precautions for Use, Serious dermatologic reactions). Urticaria has been reported.
Hirsutism.

Hepatic system.

Potentially fatal cases of acute hepatic failure, toxic hepatitis and liver damage may occur (see Section 4.4 Special Warnings and Precautions for Use, Hepatic injury). This effect may be the result of a hypersensitivity reaction.

Special senses.

Taste perversion.

Miscellaneous.

Gingival hyperplasia occurs frequently and its incidence may be reduced by good oral hygiene, including gum massage, frequent brushing and appropriate dental care.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

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.

Dosage.

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 microgram/mL and 20 microgram/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 a level in the therapeutic range; 10 microgram/mL to 20 microgram/mL (40 micromoles/L to 80 micromoles/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.

Method of administration.

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 microgram/mL and increase the risk of toxicity.

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.

Dosage adjustment.

Patients with renal or hepatic disease.

(See Section 4.4 Special Warnings and Precautions for Use, General).

Elderly patients.

Phenytoin clearance is decreased slightly in elderly patients and lower or less frequent dosing may be required (see Section 4.4 Special Warnings and Precautions for Use, Use in the elderly).

4.7 Effects on Ability to Drive and Use Machines

Patients should be advised not to drive a car or operate potentially dangerous machinery until it is known that this medication does not affect their ability to engage in these activities.

4.9 Overdose

Signs and symptoms.

There are marked variations among individuals with respect to phenytoin plasma levels where toxicity may occur. Nystagmus or lateral gaze usually appears at 20 microgram/mL, ataxia at 30 microgram/mL, dysarthria and lethargy appear when the plasma concentration is over 40 microgram/mL, but as high a concentration as 50 microgram/mL has been reported without evidence of toxicity. As much as 25 times the therapeutic dose has been taken to result in a serum concentration above 100 microgram/mL with complete recovery. The lethal dose in children is not known. The lethal dose in adults is estimated to be 2 g to 5 g.
The cardinal initial symptoms are nystagmus, ataxia, dysarthria and CNS depression. Other signs that may be seen are tremor, hyperreflexia, somnolence, drowsiness, lethargy, hallucinations, confusion, mental status changes, slurred speech, blurred vision, nausea, vomiting, choreoathetosis, dyskinesias, hyperglycaemia and mild hypoglycaemia. Severe poisoning may result in respiratory depression. Cardiotoxicity has not been reported with oral overdoses. Irreversible cerebellar dysfunction and atrophy have been reported as a delayed effect following severe overdoses. The patient may become comatose and hypotensive. Bradycardia and asystole/cardiac arrest have been reported (see Section 4.4 Special Warnings and Precautions for Use, Cardiac effects). Death is due to respiratory and circulatory depression.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

Pharmacokinetic information.

In overdose settings, saturation of the hepatic hydroxylation system occurs and zero order kinetics predominate. Elimination follows a Michaelis-Menten model with a prolonged half-life. As phenytoin is continually excreted, elimination changes from zero order to first order kinetics and drug levels decrease more.
Serial plasma phenytoin concentrations should be monitored. In acute overdose, peak levels are frequently delayed for 24 to 48 hours, and occasionally as long as 7 days.
The proportion of phenytoin in plasma not bound to protein is an important measure of potential toxicity with free phenytoin levels of < 1.5 microgram/mL indicating no signs of toxicity; 1.5 microgram/mL to 5 microgram/mL seen with mild to moderate intoxication; and levels above 5 microgram/mL associated with severe intoxication.

Treatment of overdosage.

Treatment is non-specific since there is no known antidote. Most cases of overdosage may be managed conservatively with symptomatic and supportive care. Signs and symptoms of toxicity may persist up to 7 to 10 days after ingestion.
Phenytoin is poorly absorbed in the stomach, therefore, although routine use of activated charcoal is not recommended, it may be considered in the rare patient with a life threatening ingestion. In patients who are not fully conscious or have impaired gag reflex, consideration should be given to administering activated charcoal via a nasogastric tube, once the airway is protected. Administration of a further dose of activated charcoal may be considered in patients with rising serum phenytoin levels or worsening clinical condition despite initial decontamination.
Peritoneal dialysis, diuresis, haemodialysis, plasmapheresis, haemofiltration and total exchange transfusion may be of little benefit although the latter has been used in the treatment of severe intoxication in children.
In acute overdosage the possibility of other CNS depressants, including alcohol, should be borne in mind.
Contact the Poisons Information Centre on 13 11 26 for advice on the management of an overdose.

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Dilantin 30 mg capsules contain lactose monohydrate, Confectioner's sugar (PI: 1749) (sucrose with 3% maize starch), magnesium stearate, purified talc, titanium dioxide, carbon black and gelatin.

Note.

Dilantin 30 mg old formulation (AUST R 14306) does not contain lactose monohydrate.
Dilantin 100 mg capsules contain lactose monohydrate, Confectioner's sugar (PI: 1749) (sucrose with 3% maize starch), purified talc, magnesium stearate, titanium dioxide, sunset yellow FCF, erythrosine, carbon black and gelatin.
Dilantin Capsules in vivo performance is characterised by a slow and extended rate of absorption with peak blood concentrations expected in 4 to 12 hours.
Dilantin Infatabs contain sunset yellow FCF, maize starch, quinoline yellow, saccharin sodium, magnesium stearate, purified talc, Confectioner's sugar (PI: 1749) (sucrose with 3% maize starch) and spearmint flavour natural 11584 (PI: 1228).
Dilantin Paediatric Suspension contains phenytoin 30 mg/5 mL. Dilantin Paediatric Suspension also contains sodium benzoate, sucrose, glycerol, aluminium magnesium silicate, carmellose sodium, polysorbate 40, vanillin, orange flavour, ethanol, carmoisine, sunset yellow FCF, citric acid monohydrate, hydrochloric acid, banana flavour and purified water.

6.2 Incompatibilities

See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Capsules.

Store below 30°C.

Infatabs.

Store below 30°C.

Paediatric suspension.

Store below 25°C.

6.5 Nature and Contents of Container

Capsules.

Capsules 30 mg and 100 mg are packaged in HDPE bottles with a child-resistant polypropylene cap. One bottle contains 200 capsules.

Infatabs.

Infatabs 50 mg are packaged in HDPE bottles with a child-resistant polypropylene cap. One bottle contains 200 tablets.

Paediatric suspension.

Paediatric Suspension (30 mg/5 mL) is packaged in an amber glass bottle (Type III) fitted with either an aluminium roll-on cap or a white, child-resistant, tamper-evident polypropylene cap lined with Triseal (polyethylene) or Melinex (polyester) wad. One bottle contains 500 mL.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

Summary Table of Changes