Document: leaflet MAH GENERIC_PL 15413-0019 change

• leaflet CONSILIENT HEALTH (UK)_PL 15413-0019
• leaflet MAH GENERIC_PL 15413-0019

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Product + Component:	Phenytoin Hikma
Identifier:	PIN218-HIK/3
Country:	United Kingdom
Dimensions:	210 x 594 mm
Scale:	1:1
Circular for Corrections:	04
Date:	09.04.2014
Colours:	Black
Front/Reverse:	Front
Fonts:	Frutiger

79 mm

52,5 mm

1 mm9 mm 1 mm

.........H-^—H

Laetus    Laetus

Barcode    Barcode

PACKAGE LEAFLET: INFORMATION FOR THE USER

Phenytoin Hikma 50 mg/ml solution for injection

Active substance: phenytoin sodium

What is in this leaflet:

1.    What Phenytoin Hikma is and what it is used for

2.    What you need to know before you use Phenytoin Hikma

3.    How to use Phenytoin Hikma

4.    Possible side effects

5.    How to store Phenytoin Hikma

6.    Contents of the pack and other information

1.    WHAT PHENYTOIN HIKMA IS AND WHAT IT IS USED FOR

Phenytoin Hikma 50 mg/ml solution for injection contains phenytoin sodium. Phenytoin sodium belongs to a group of medicines called antiepileptics. Antiepileptic medicines are used for the prevention and treatment of seizures (fits). The medicine will be given to you by a doctor and will be injected into a vein (intravenously).

Phenytoin Hikma is used to:

-    Treat the following types of seizure:

-    status epilepticus (a state of persistent seizure). A persistent seizure is when:

-    you have a seizure that does not stop or

-    you have a number of seizures and remain unconscious throughout

-    Prevent seizures happening during or after neurosurgery (surgery on the brain). Phenytoin Hikma is not effective in absence status epilepticus (a special form of seizures) or in the prevention or treatment of febrile convulsions.

2.    WHAT YOU NEED TO KNOW BEFORE YOU USE PHENYTOIN HIKMA

A small number of people being treated with anti-epileptics such phenytoin have had thoughts of harming or killing themselves. If at any

Do not use Phenytoin Hikma

-    if you are allergic to phenytoin or any of the other ingredients of this medicine (listed in section 6).

-    if you are allergic (hypersensitive) to other medicines with a similar chemical structure to phenytoin (e.g. hydantoins)

-    if you have severe damage to the blood cells and bone marrow

-    if you have grade II and grade III AV block (disorder of heart beat regulation)

-    if you have a type of heart disorder that causes fainting and sometimes fits called Stokes-Adams syndrome.

-    if you suffer from sinus bradycardia (slow heart rate of less than 50 beats per minutes), sick sinus syndrome or sino-atrial block (disorders of heart beat regulation)

-    if you have had a heart attack within the last three months

-    if the output of your heart is poor (ask your doctor)

-    subcutaneously or venous perivascular or intra-arterial due to the high pH of the preparation.

Warnings and precautions

A small number of people being treated with anti-epileptics such as phenytoin have had thoughts of harming or killing themselves. If at any time you have these thoughts, immediately contact your doctor."

Phenytoin Hikma should not be given in

-    heart failure (inability of heart to pump properly)

-    impaired breathing function

-    severe hypotension (systolic blood pressure less than 90 mm Hg)

-    the following heart rhythm disturbances:

-    grade I AV block

-    atrial fibrillation

-    atrial flutter

Phenytoin Hikma should be given with special precaution if you suffer from:

-    impaired kidney function

-    impaired liver function

your doctor will take blood and urine samples to monitor your liver and kidney function.

If you are diabetic you are more likely to get hyperglycaemia (high blood sugar).

Potentially life-threatening skin rashes (Stevens-Johnson syndrome, toxic epidermal necrolysis) have been reported with the use of Phenytoin Hikma, appearing initially as reddish target-like spots or circular patches often with central blisters on the trunk. Additional signs to look for include ulcers in the mouth, throat, nose, genitals and conjunctivitis (red and swollen eyes).

These potentially life-threatening skin rashes are often accompanied by flu-like symptoms. The rash may progress to widespread blistering or peeling of the skin.

The highest risk for occurrence of serious skin reactions is within the first weeks of treatment.

If you have developed Stevens-Johnson syndrome or toxic epidermal necrolysis with the use of Phenytoin Hikma, you must not be re-started on Phenytoin Hikma at any time. Serious skin side effects can rarely occur during treatment with Phenytoin Hikma. This risk may be associated with a variant in genes in a subject with Chinese or Thai origin.

If you are of such origin and have been tested previously carrying this genetic variant (HLA-B*1 502), discuss this with your doctor before taking Phenytoin Hikma.

If you develop a rash or these skin symptoms, stop taking Phenytoin Hikma, seek urgent advice from a doctor and tell him that you are taking this medicine.

Important information regarding treatment

If you suffer from slow hvdroxvlation

Slow hydroxylation is an inherited disorder. It affects the way your body uses and reacts to medicine.

If you suffer from slow hydroxylation you should therefore take care. You may develop signs of overdose even at moderate doses (see "What you must do if you are given too much Phenytoin Hikma"). In this case your dose should be reduced. Your doctor will take a blood sample to check that the levels of phenytoin are not too high.

If you switch to another form of medicine that contains phenytoin Other medicines that contain phenytoin may not provide you with the same levels of phenytoin as Phenytoin Hikma. If you change your phenytoin medicine, your doctor will monitor you until your phenytoin levels even out. This may take up to 2 weeks.

If you suddenly stop taking Phenytoin Hikma

-    you may suffer seizures more often

-    you may develop status epilepticus (a state of persistent seizure).

To avoid these problems your doctor may:

-    reduce your dose of Phenytoin Hikma slowly

-    start the new antiepileptic medication at a low dose and gradually increase it

If you switch treatment to an oral form of phenytoin (e.g. tablets or syrup):

Your doctor will monitor your progress and take blood samples regularly.

If you are a child, your doctor will also monitor the function of your thyroid gland.

Your doctor will decide if any of the test results mean that you should change or stop treatment.

If you have low plasma protein levels (hypoproteinaemia) you are more likely to develop undesirable effects on your nervous system.

Other medicines and Phenytoin Hikma

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

A number of medicines can increase or decrease the levels of phenytoin in the blood. Phenytoin can alter the levels of other medicines in the blood. These effects are called interactions. If your doctor thinks that you are having a drug interaction he will check your phenytoin levels.

The following substances can increase your phenytoin levels:

-    Alcohol (rapid consumption)

-    Oral anticoagulants (blood-thinning medicines e.g. dicumarol)

-    Benzodiazepines (tranquillisers e.g. chlorodiazepoxide, diazepam, trazodone)

-    Anaesthetics (e.g. halothane)

-    Other antiepileptic drugs (e.g. sulthiame, valproate, ethosuximide, mesuximide, felbamate)

-    Non-steroidal antirheumatics (NSAIDs)(e.g. salicylate, azapropazone, phenylbutazone)

-    Antibiotics (e.g. chloramphenicol, erythromycin, isoniazide, sulfonamide)

-    Antimycotics (antifungal medicines e.g. amphotericin B, fluconazole, ketoconazole, miconazole, itraconazole)

-    Calcium channel inhibitors (heart medicines e.g. amiodarone, diltiazem, nifedipine)

-    Hormones (e.g. oestrogen)

-    Disulfiram (used to treat addiction to alcohol)

-    Methylphenidate (used to treat attention deficit hyperactive disorder [ADHD])

-    Cimetidine, omeprazole, ranitidine (used to treat stomach ulcers)

-    Ticlopidine (used to prevent thrombosis)

-    Viloxazine, fluoxetine (an antidepressant medicine)

-    Para-amino salicylic acid (PAS), cycloserine (used to treat tuberculosis)

-    Tricyclic antidepressant drugs (e.g. amitriptyline, clomipramine)

-    Tolbutamide (used to treat diabetes)

-    Other antiepileptic drugs (e.g. oxcarbazepine, eslicarbazepine acetate and in individual patients topirmate

Substances that can decrease your phenytoin levels:

-    Antibiotics (e.g. ciprofloxacin, rifampicin)

-    Other antiepileptic drugs (e.g. carbamazepine, vigabatrine, phenobarbital, primidone)

-    Reserpine (used to treat high blood pressure)

-    Sucralfate (used to treat duodenal ulcers)

-    Diazoxide (used to treat high blood pressure)

-    Theophylline (used to treat breathing difficulties)

-    Chronic alcohol abuse (persistent long-term alcohol abuse)

-    Nelfinavir (used to treat viral infections caused by HIV (AIDS))

Substances that can increase or decrease your phenytoin levels:

-    Antiepileptics (e.g. carbamazepine, sodium valproate, valproic acid, phenobarbital)

-    Chlordiazepoxide (a sedative)

-    Diazepam (a tranquilliser)

Valproic acid (an antiepileptic medicine): If you are given valproic acid in addition to phenytoin or the dose of valproic acid is increased you may experience more side effects. In particular, you are more likely to suffer brain damage (see section 4 "Possible side effects").

Phenytoin can alter the concentration of the following medicines in your blood and the effect of the medicine:

-    Clozapine (used to treat schizophrenia)

-    Corticosteroids (e.g. dexamethasone, prednisone, fludrocortisone)

-    Oral anticoagulants (blood thinning medicines e.g. dicumarol)

-    Doxycycline, tetracycline (antibiotics)

-    Praziquantel (used to treat infestation with worms)

-    Rifampicin (used to treat tuberculosis)

-    Itraconazole (an antifungal medicine)

-    Antiepileptics (e.g. lamotrigine, carbamazepine, valproate, felbamate, topiramate, zonisamide or tiagabine and the active metabolite of oxcarbazepine (i.e. MHD) and eslicarbazepine acetate (i.e. eslicarbazepine))

-    Oestrogen (used in hormone replacement therapy [HRT])

-    Alcuronium, pancuronium, vecuronium (muscle relaxants)

-    Cyclosporine (used to prevent organ transplant rejection)

-    Diazoxide (used to treat high blood pressure)

-    Furosemide (a diuretic [water tablet] used to treat heart failure)

-    Paroxetine, sertraline (antidepressants)

-    Theophylline (used to treat breathing difficulties)

-    Digitoxin (a heart medicine)

-    Nicardipine, verapamil (used to treat high blood pressure)

-    Nimodipine (used to prevent spasm of the blood vessels in the brain)

-    Quinidine (a heart medicine)

-    Tricyclic antidepressant drugs (e.g. amitriptyline, clomipramine)

-    Methadone (used to treat heroin addiction)

-    Chlorpropamide, glibenclamide (used to treat diabetes)

-    Tolbutamide (used to treat diabetes)

-    Vitamin D

-    Teniposide (an anticancer medicine)

-    Oral contraceptives: If you take the contraceptive pill its effect may be unreliable.

-    Blood thinning medicines (anticoagulants): If you are taking such medicines you should regularly check your blood clotting time (INR value).

-    Methotrexate (an anticancer medicine): You may experience:

-    a greater number of unwanted side effects of methotrexate treatment or

-    worsening of side effects of methotrexate treatment

-    Folic acid: Your phenytoin may not be so effective if you take folic acid at the same time.

Phenytoin Hikma, when administered concomitantly with paracetamol products may increase the metabolism of paracetamol which can result in liver damage.

Pregnancy and Breast-feeding

Pregnancy

You should note that the contraceptive pill may not work when you are taking Phenytoin Hikma.

If you are planning to become pregnant or are already pregnant, you should only use Phenytoin Hikma if your doctor tells you to, after a careful risk-benefit assessment.

If you are pregnant and treated with any antiepileptic drug it is more likely that your unborn child will have an abnormality. Evidence suggests that it is 2 to 3 times more likely. Possible abnormalities include:

-    hare lip

-    heart abnormalities

-    underdeveloped nails or fingers, toes, face

-    neural tube defects (the neural tube is the part of the body which develops into the nervous system)

-    retarded growth

Therefore you should speak to your doctor immediately if you are planning to become pregnant or are already pregnant. Your doctor will check whether treatment with Phenytoin Hikma is necessary.

If it is urgent that you receive treatment with Phenytoin Hikma during pregnancy:

-    You should not be given other antiepileptic medications if possible. Taking more epilepsy medicines will increase the risk of abnormalities in your unborn child.

-    During the first 3 months of pregnancy in particular, you should be given the lowest effective dose. This is the lowest possible dose at which your seizures are well controlled. Your doctor will decide this dose.

-    Your condition and that of your unborn child will be monitored:

The following information is intended for medical or healthcare professionals only:

Method of administration

The solution for injection is for intravenous use only as absorption is delayed and unreliable after intramuscular administration. Phenytoin Hikma should be injected slowly directly into a large vein through a large-gauge needle or intravenous catheter. Subcutaneous or venous injection should be avoided, as the alkaline phenytoin solution for injection can cause tissue necrosis.

Handling and Preparation

The solution for injection must not be mixed with other solutions, as phenytoin can crystallise out.

Before use, the ampoules should be checked for precipitation and discolouration.

The product should not be used if a precipitate or haziness develops in the solution in the ampoule.

Phenytoin is suitable for use as long as it remains free of haziness and precipitate.

A precipitate might form if the product has been kept in a refrigerator or freezer. This precipitate will dissolve if allowed to stand at room temperature. The product will then be suitable for use.

Only a clear solution should be administered. A slight yellow discolouration has no effect on the efficacy of this solution.

For single use only. Any unused product should be discarded.

Duration of administration is dependent on the underlying disease and the course of the illness. If the medicine is well-tolerated, it can be used indefinitely.

Dosage

The therapeutic range for plasma concentration is generally between 10 and 20 micrograms/ml phenytoin; concentrations over 25 micrograms/ml phenytoin may be in the toxic range.

Status epilepticus and series of seizures

Continuous monitoring of ECG, blood pressure and neurological status and regular determination of plasma phenytoin concentrations is essential. In addition, resuscitation facilities should be readily available.

Adults and adolescents over 12 years of age

The initial dose is 1 ampoule of Phenytoin Hikma (equivalent to 230 mg phenytoin), administered at a maximum rate of 0.5 ml/min (equivalent to 23 mg phenytoin per minute). If the seizures do not stop after 20 to 30 minutes, the dose can be repeated.

If the seizures stop, a dose of 1 ampoule Phenytoin Hikma (equivalent to 230 mg phenytoin) can be given every 1.5 to 6 hours up to a maximum daily dose of 17 mg/kg bodyweight (or 6 ampoules - equivalent to 1380 mg phenytoin), to achieve rapid saturation.

At a maximum daily dose of 17 mg/kg bodyweight, this is equivalent to Bodyweight    Ampoules    Phenytoin

41 kg    3    690 mg

920 mg 1150 mg 1380 mg

Children up to 12 years of age

On day 1 the maximum daily dose is 30 mg/kg bodyweight, on day 2 20 mg/kg bodyweight, on day 3 10 mg/kg bodyweight. The maximum injection rate is 1 mg/kg bodyweight per minute.

Day 1

At a maximum daily dose of 30 mg/kg bodyweight, this is equivalent to Bodyweight    Ampoules    Phenytoin

8 kg    1    230 mg

15 kg    2    460 mg

23 kg    3    690 mg

31 kg    4    920 mg

38 kg    5    1150 mg

46 kg    6    1380 mg

Day 2

At a maximum daily dose of 20 mg/kg bodyweight, this is equivalent to

Bodyweight    Ampoules    Phenytoin

12 kg    1    230 mg

23 kg    2    460 mg

35 kg    3    690 mg

46 kg    4    920 mg

Day 3

At a maximum daily dose of 10 mg/kg bodyweight, this is equivalent to Bodyweight    Ampoules    Phenytoin

23 kg    1    230 mg

46 kg    2    460 mg

-    Your serum levels of phenytoin will change during and after pregnancy. Your doctor may monitor your serum levels of phenytoin to help make sure that you get the right dose.

-    You should be offered an ultrasound scan. Such a scan can show a detailed picture of your unborn child. You should be told of any problems with the condition of your unborn child.

Do not suddenly stop treatment with Phenytoin Hikma during pregnancy. Suddenly stopping treatment can cause seizures. This can be harmful for you and your unborn child.

Care of your new-born child

Your newborn child may develop bleeding disorders in the first 24 hours after birth. To prevent this:

-    Your doctor should give you a dose of vitamin K1 in the last week of pregnancy

-    Your doctor should give your new-born child a dose of vitamin K1

Prevention of folic acid deficiency

To prevent possible folic acid deficiency you should take folic acid during pregnancy. This can be taken as tablets or as a food supplement. Your doctor will tell you how much to take. When you take folic acid your phenytoin may not be so effective (see also "Using other medicines").

Breast-feeding

Small amounts of the active substance (phenytoin sodium) pass into human breast milk.

It is recommended that you do not breast-feed while receiving treatment with Phenytoin Hikma. However, should you still wish to breast-feed, your baby should be monitored to make sure:

-    it is gaining weight properly

-    it does not have an increased need to sleep

Driving and using machines

Do not drive or use machines if your ability to drive and use machines is reduced.

Before driving or using machines seek your doctor's advice.

Your ability to drive or operate machinery may be impaired:

-    at the start of treatment with Phenytoin Hikma

-    at high doses

-    when this medicine is combined with drugs that affect your central nervous system (especially alcohol)

Important information about some of the ingredients of Phenytoin Hikma

Phenytoin Hikma contains less than 23 mg sodium in each glass vial (ampoule). It is almost "sodium-free".

Phenytoin Hikma contains propylene glycol which may cause alcohol-like symptoms.

This medicinal product contains 10 vol % ethanol (alcohol), i.e. up to 394 mg per dose, equivalent to 10 ml beer, 4.17 ml wine per dose.

Harmful for those suffering from alcoholism.

To be taken into account in pregnant or breast-feeding women, children and high-risk groups such as patients with liver disease, or epilepsy.

3.    HOW TO USE PHENYTOIN HIKMA

More detailed information on dosage, handling and preparation of Phenytoin Hikma is given at the end of this package leaflet under the subheading 'The following information is intended for medical or healthcare professionals only'.

Phenytoin Hikma will be given to you by your doctor by slow injection into a vein. Your doctor will decide on how much you need and when it is to be given. This will depend on your age and weight and the condition for which you need to take Phenytoin Hikma.

When you are given Phenytoin Hikma your doctor will:

-    continuously monitor your heart, blood pressure and nervous system

-    regularly measure your phenytoin levels

Duration of therapy

Phenytoin Hikma can be used long-term.

Duration of therapy depends on:

-    which illness you are being treated for

-    how well you respond to treatment

-    how well you tolerate the side-effects (see Section 4 "Possible side effects").

During long-term treatment with Phenytoin Hikma your plasma levels will be monitored so that you can be given the lowest effective dose. This will help to minimise side-effects. Please speak to your doctor or pharmacist if you feel that the effect of Phenytoin Hikma is too strong or too weak.

If you use more Phenytoin Hikma than you should:

If you are given too much Phenytoin Hikma you may experience the following: symptoms: Early symptoms

-    involuntary rapid eye movement (nystagmus)

-    cerebellar ataxia (a disorder of movement coordination)

-    dysarthria (impaired speech)

Other symptoms

-    tremor (shaking)

-    hyperreflexia (increased reflexes)

-    somnolence (drowsiness)

-    exhaustion

-    lethargy (sluggishness)

-    slurred speech

-    diplopia (double vision)

-    dizziness

-    nausea (feeling sick)

-    vomiting

-    coma (loss of consciousness)

-    your pupillary reflex (when the pupil of your eye gets smaller in response to light) may disappear

-    fall in blood pressure

-    effects on breathing. These can be fatal.

-    heart failure. This can be fatal.

-    irreversible brain damage

If you experience any of these symptoms, you should tell your doctor immediately. Your doctor will take steps to remove the excess phenytoin from your system. Your heart and breathing will be monitored and your symptoms will be treated.

4.    POSSIBLE SIDE EFFECTS

Like all medicines, Phenytoin Hikma can cause side effects, although not everybody gets them.

Very common side effects (may affect more than 1 in 10 people):

-    nystagmus (rapid eye movement), movement coordination disorders (ataxia), paresthesia ("pins and needles" feeling), mental confusion, dizziness, vertigo, insomnia, headache, increasing irritability, high-frequency tremor at rest, bulbar speech disorders, exhaustion, memorising disturbances and intellectual capacity disorders.

-    double vision (diplopia)

Common side effects (may affect up to 1 in 10 people):

-    apathy and sedation, perception disorders and clouding of consciousness, or even coma, have been reported for long-term treated patients

-    transient symptoms such as dizziness, vomiting and dry mouth can develop if intravenous administration is too fast, which generally subside within 60 minutes unless the patient has received a medication containing phenytoin before. Loss of appetite, nausea, vomiting, weight loss, constipation, have also been reported for long-term treated patients.

-    morbiliform rash (measles-like)

Uncommon side effects (may affect up to 1 in 100 people):

-    polyneuropathy may develop in the context of long-term therapy (with risk of occurrence of irreversible cerebellar atrophy).

-    severe general changes on the ECG have been reported for patients undergoing long-term treatment with phenytoin.

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Prophylaxis of seizures

Adults and adolescents over 12 years of age receive 1 to 2 ampoules of Phenytoin Hikma (equivalent to 230 to 460 mg phenytoin) daily at a maximum rate of injection of 0.5 ml/min (equivalent to 23 mg phenytoin per minute).

Children up to 12 years of age receive 5 to 6 mg/kg bodyweight. Rate of injection is reduced according to the weight/age of the child.

At a daily dose of 5 mg/kg bodyweight, this is equivalent to

Bodyweight	ml	Phenytoin
9 kg	1	46 mg
18 kg	2	92 mg
28 kg	3	138 mg
37 kg	4	184 mg
46 kg	5	230 mg
At a daily dose of 6 mg/kg bodyweight, this is equivalent
Bodyweight	ml	Phenytoin
8 kg	1	46 mg
15 kg	2	92 mg
23 kg	3	138 mg
31 kg	4	184 mg
38 kg	5	230 mg
46 kg	6	276 mg

When Phenytoin Hikma is taken long-term, Phenytoin Hikma plasma levels must be monitored and blood count and liver enzyme activity should be checked at regular intervals (several weeks). A blood count showing moderate, stable leukopenia or an isolated increase in gamma-GT should not normally necessitate withdrawal of treatment. Osteomalacia (soft bones) may develop in susceptible patients or patients with a calcium metabolism disorder (increased alkaline phosphatase). This normally responds well to administration of vitamin D. Alkaline phosphatase should therefore be checked regularly. Additionally in children, thyroid function should be monitored.

Switching preparations

Due to the relatively narrow therapeutic range and the varying bioavailability of the numerous pharmaceutical preparations, when changing from one preparation to another containing phenytoin, the phenytoin-plasma concentrations must be monitored closely. If the dose is kept the same, steady state can be expected after 5 to 14 days.

Therefore the dose (if possible) should be reduced slowly and the new antiepileptic medicine started at a low dose and gradually increased. Abrupt withdrawal of Phenytoin Hikma may increase seizure frequency or lead to status epilepticus.

Rare side effects (may affect up to 1 in 1,000 people):

-    changes in blood count, e.g. leukopenia (decrease number of white blood cells), megaloblastic anaemia (formation of very large red blood cells), porphyria (disorders of certain enzymes that normally participate in the production of porphyrins and heme) may occur, if they do develop, it is recommended that phenytoin is withdrawn. The symptoms may also gradually subside if the dose is reduced.

-    anaphylaxis and anaphylaxis-type reactions and have been reported and may in rare cases be fatal (the syndrome may include but is not limited to, symptoms such as arthralgias, eosinophilia, fever, liver dysfunction, lymphadenopathy or rash)

-    Laboratory tests should be performed every six months, especially in children, owing to possible impairment of thyroid function.

-    dyskinesia (diminished voluntary movements and the presence of involuntary movements), chorea (involuntary movement disorder), dystonia (twisting and repetitive movements or abnormal postures), tremor and asterixis (flapping tremor). asystole (flatline), conduction blockade and suppression of the ventricular escape rhythm in patients with total AV block, especially when phenytoin is administered intravenouslly. Proarrhythmic effects in the form of changes or increases in cardiac arrythmias can occur which can lead to severe impairment of cardiac activity or even cardiac arrest. ith intravenous administration in particular, decreased blood pressure, deterioration in existing heart and respiratory failure can occur. In isolated cases ventricular fibrillation has been triggered. Atrial fibrillation and flutter is not cured by phenytoin. However, as AV node refractory time can be shortened, acceleration in ventricular rate is possible.

-    liver function disorders, possibly with involvement of other organs, if developed, it is recommended to discontinue phenytoin treatment. The symptoms may also gradually subside if the dose is reduced. Therefore, when phenytoin is taken long-term, liver enzyme activity should be checked at regular intervals (several weeks).

-    allergic rashes (exanthema); severe allergic reactions e.g. skin inflammation with exfoliative dermatitis.

-    softening of the bones caused by defective bone mineralization (osteomalacia), may develop in susceptible patients or patients with a calcium metabolism disorder (increased alkaline phosphatase). This normally responds well to administration of vitamin D. Alkaline phosphatase should therefore be checked regularly.

-    fever (together with rash). Local irritation, inflammation and tenderness have been reported. Necrosis and sloughing have been reported after subcutaneous or perivascular injection, which are not recommended administration routes. Soft tissue irritation and inflammation have occurred at the site of injection with and without extravasation of phenytoin given intravenously

Very rare side effects (may affect up to 1 in 10,000 people):

-    systemic lupus erythematosus, periarteritis nodosa (vasculitis of medium and small-sized arteries) and immunoglobulin abnormalities may occur.

-    excessive growth of gum tissue (gingival hyperplasia), skin changes e.g. and hair growth (hypertrichosis, hirsutism), have been reported. Dupuytren's contracture, Stevens-Johnson and Lyell's syndrome, have also been reported. Severe cutaneous adverse reactions (SCARs): Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported (see section 4.4).

-    muscle weakness (myasthenic syndrome) which subside after phenytoin is withdrawn.

Side effects which frequency is not known (Frequency cannot be estimated from the available data):

-    Purple Glove Syndrome (skin disease in which the extremities become swollen, discoloured and painful) has been reported. Tell your doctor immediately if you experience skin discolouration, swelling and pain where the injection was given which then starts to spread down your arm to your hands and fingers. This may mean you have of a condition known as "purple glove syndrome". In most cases this will improve on its own but in some cases it can be serious and require urgent medical treatment.

Side effects of long-term therapy

Frequency not known: (cannot be estimated from the available data)

-    sensory peripheral polyneuropathy (disturbed nerve function) and tonic seizures

-    irreversible cerebellar atrophy (permanent wasting away of the brain)

If you take phenytoin long-term (especially when taken by mouth) you may develop signs of brain damage (encephalopathy). This is especially likely when taken together with other antiepileptic medicines, especially valproic acid. Signs of brain damage include:

Frequency not known: (cannot be estimated from the available data)

-    more frequent seizures

-    loss of drive (stupor)

-    weak muscles (muscular hypotension)

-    choreatic dyskinesia (a movement disorder)

-    severe general changes on your brain scan (EEG)

-    There have been reports of bone disorders including osteopenia and osteoporosis (thinning of the bone) and fractures. Check with your doctor or pharmacist if you are on long-term antiepileptic medication, have a history of osteoporosis, or take steroids.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.

5.    HOW TO STORE PHENYTOIN HIKMA

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton after EXP..

The expiry date refers to the last day of that month.

This medicinal product does not require any special storage conditions.

After first opening: Phenytoin Hikma should be used immediately.

If the solution in the ampoule is cloudy or contains solids, the ampoule should not be used. Do not throw away any medicines via wastewater. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6.    CONTENTS OF THE PACK AND OTHER INFORMATION

What Phenytoin Hikma contains

The active substance is phenytoin sodium.

Each ml of solution contains 50 mg phenytoin sodium (equivalent to 46 mg phenytoin). Each 5 ml-ampoule of solution for injection contains 250 mg phenytoin sodium (equivalent to 230 mg phenytoin).

The other ingredients are:

-    propylene glycol

-    ethanol

-    sodium hydroxide

-    water for injection

What Phenytoin Hikma looks like and contents of the pack

Phenytoin Hikma is supplied in clear glass vials called ampoules.

Phenytoin Hikma is a clear solution.

Pack size:

Phenytoin Hikma is available in packs of 5 or 50 ampoules.

1 ampoule contains 5 ml solution for injection.

Marketing Authorisation Holder and Manufacturer

Hikma Farmaceutica (Portugal), S.A.

Estrada do Rio da Mo n.° 8, 8A e 8B - Fervenga

2705-906 Terrugem SNT

Portugal

Tel.: ++351-21 960 84 10 Fax: ++351-21 961 51 02

This medicinal product is authorized in the Member States of the EEA under the following names:

Germany:    Phenytoin    Hikma    50    mg/ml    Injektionslosung

Italy:    Phenytoin    Hikma    50    mg/ml    Soluzione iniettabile

Poland:    Phenytoin    Hikma    50    mg/ml    Roztwor do wstrzykiwan

Portugal:    Fenitoina Hikma 50 mg/ml Solugao injectavel

Romania:    Phenytoin    Hikma    50    mg/ml    Solufie injectabila

United Kingdom:    Phenytoin    Hikma    50    mg/ml    Solution for injection

This leaflet was last approved in 04/2014

PIN218-HIK/3

Additional information on special populations

Patients with renal/hepatic impairment:

There is no reference for dosage adjustment for this special group; however, caution should be taken in patients with renal and hepatic disease (see section 4.4). Impaired renal and hepatic functions require careful monitoring.

Elderly (over 65 years):

As for adults; however, complications may occur more readily in elderly patients.

Neonates:

In neonates it has been shown that absorption of phenytoin is unreliable after oral administration. Phenytoin should be injected slowly intravenously at a rate of 1-3 mg/kg/min at dose of 15-20 mg/kg. This will usually produce serum concentrations of phenytoin within the generally accepted therapeutic range of 10-20 mg/l.

Infants and children:

As for adults. Children tend to metabolise phenytoin more rapidly than adults. This should be considered when determining dosage regimens; monitoring serum levels is therefore particularly beneficial in such cases.

Therapy of overdosage

Symptoms of an overdose

Signs of overdose can develop in individuals who have different phenytoin plasma levels. Early symptoms include involuntary, rapid eye movement, cerebellar ataxia and dysarthria. Additional symptoms may include: tremor, hyperreflexia , somnolence , exhaustion, lethargy, slurred speech, diplopia , dizziness, nausea, vomiting. The patient may fall into a coma, the pupillary reflex may disappear, and blood pressure fall. Death can result e.g. from central respiratory depression or circulatory failure. The mean lethal (acute) dose is estimated to be 2-5 g phenytoin in adults. The lethal dose for paediatric patients is unknown. Overdose can lead to irreversible degenerative cerebellar changes.

Treatment of intoxication

Initial treatment must include gastric lavage, administration of activated charcoal and monitoring on intensive care. Haemodialysis, forced diuresis and peritoneal dialysis are less effective. Experience on the efficacy of haematogenic charcoal perfusion, total plasma substitution and transfusion is inadequate. For this reason, intensive internal treatment without special detoxification procedures should be performed, but phenytoin plasma levels should be checked.