Package leaflet: Information for the user

Phenytoin Hikma, 50 mg/ml, solution for injection
Active substance: sodium phenytoin
Please read the entire leaflet carefully before using this medicine, as it contains important information for the patient.

Keep this leaflet, as you may need to read it again.
Consult your doctor or pharmacist if you have any further questions.
This medicine has been prescribed for a specific individual. Do not pass it on to others. This medicine may harm others, even if their symptoms are the same.
If any of the side effects worsen, or if you notice any side effects not listed in this leaflet, inform your doctor or pharmacist.

Leaflet contents:

What Phenytoin Hikma is and what it is used for
Important information before using Phenytoin Hikma
How to use Phenytoin Hikma
Possible side effects
How to store Phenytoin Hikma
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 sodium phenytoin. Sodium phenytoin belongs to a group of medicines called antiepileptic drugs. Antiepileptic drugs are used to prevent and treat epileptic seizures. This medicine is administered by a doctor as an intravenous injection.

Phenytoin Hikma is used for:

treating the following types of epileptic seizures:
status epilepticus (prolonged epileptic seizure). Status epilepticus is defined as:
an epileptic seizure that does not stop
or multiple epileptic seizures between which the patient does not regain consciousness;
prevention of epileptic seizures occurring during or after neurosurgical procedures (brain surgery).

Phenytoin Hikma does not work when status epilepticus (a specific type of epileptic seizure) is not present, nor is it effective when used to prevent or treat febrile convulsions.

2. Important information before using Phenytoin Hikma

When not to use Phenytoin Hikma

if the patient is allergic to phenytoin or any of the other ingredients of this medicine (listed in section 6),
if the patient has an allergy (hypersensitivity) to other medicines with a chemical structure similar to phenytoin (e.g. hydantoin derivatives),
if the patient's blood cells and bone marrow are severely damaged,
if the patient has second- or third-degree atrioventricular block (heart conduction disorders),
if the patient suffers from heart disorders (Stokes-Adams syndrome) causing fainting and sometimes seizures;
if the patient suffers from sinus bradycardia (slow heart rate – below 50 beats per minute), sick sinus syndrome, or sinoatrial block (heart conduction disorders),
if the patient has had a myocardial infarction within the last three months,
if the patient has low cardiac output (please consult your doctor),
Phenytoin Hikma must not be administered subcutaneously, extravascularly during intravenous administration, or intra-arterially due to its high pH.

Warnings and precautions
A small number of patients treated with antiepileptic medicines such as phenytoin have had thoughts about harming or killing themselves. If such thoughts occur at any time, the patient should contact their doctor immediately.
Phenytoin Hikma should not be administered in cases of:

heart failure (inability of the heart to pump blood properly),
impaired respiration,
severe hypotension (systolic blood pressure below 90 mmHg),
the following cardiac arrhythmias:
first-degree atrioventricular block,
atrial fibrillation,
atrial flutter.

Phenytoin Hikma should be administered with special caution if the patient suffers from:

impaired kidney function,
impaired liver function. The doctor may order blood and urine tests to monitor liver and kidney function. In diabetic patients, hyperglycaemia (high blood sugar levels) is more likely.

Potentially life-threatening skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis) have been reported during treatment with Phenytoin Hikma. In the initial stages, these appear on the trunk as reddish, ring-shaped rashes or circular spots, often with centrally located blisters.
Additional symptoms to watch for include ulceration of the mouth, throat, nose, genital organs, and inflammation of the conjunctiva (red, swollen eyes).
These potentially life-threatening skin reactions are often accompanied by flu-like symptoms.
The rash may progress to generalized blistering or skin peeling.
The highest risk of serious skin reactions occurs during the first weeks of treatment.
If the patient has experienced Stevens-Johnson syndrome or toxic epidermal necrolysis while taking Phenytoin Hikma, they must never restart treatment with Phenytoin Hikma.
Serious skin-related adverse effects occur rarely during treatment with Phenytoin Hikma. This risk may be associated with a specific gene mutation in patients of Chinese or Thai origin. Patients of such origin who have previously been found to carry this gene variant (HLA-B*1502) should discuss this with their doctor before taking Phenytoin Hikma.
If a rash or these skin symptoms occur, the use of Phenytoin Hikma must be discontinued immediately, and the patient should urgently consult a doctor and inform them about taking this medicine.

Important information regarding treatment
Patients with slow hydroxylation
Slow hydroxylation is a hereditary condition. It affects how the medicine is processed and how the body reacts to it.
Therefore, patients with slow hydroxylation should exercise caution. Symptoms of overdose may occur even at moderate doses (see "Use of a dose higher than recommended of Phenytoin Hikma"). In such cases, the dose of the medicine should be reduced. The doctor will order blood tests to check whether phenytoin concentrations are too high.
Switching from another phenytoin-containing medicine
After using other phenytoin-containing medicines, phenytoin concentrations may differ from those achieved with Phenytoin Hikma. When changing to another phenytoin-containing medicine, the doctor will monitor the patient's condition until phenytoin concentrations stabilize. This may take up to two weeks.
Sudden discontinuation of Phenytoin Hikma

more frequent epileptic seizures may occur,
status epilepticus (prolonged epileptic seizure) may occur.

To avoid these problems, the doctor may:

gradually reduce the dose of Phenytoin Hikma,
start a new antiepileptic medicine at a low dose and gradually increase it.

Switching to oral phenytoin formulation (e.g. tablets or syrup):
The doctor will monitor the patient's condition and regularly order blood tests.
In children, the doctor will also monitor thyroid function.
The doctor will decide whether any test results indicate the need to change or discontinue treatment.
In patients with low plasma protein levels (hypoproteinaemia), adverse effects on the nervous system are more likely.

Other medicines and Phenytoin Hikma
Tell your doctor or pharmacist about all medicines you are currently taking or have recently taken, as well as any medicines you plan to take.
Many medicines can increase or decrease blood phenytoin concentrations. Phenytoin can alter blood concentrations of other medicines. These effects are known as interactions. If drug interactions are suspected, the doctor will check the patient's blood phenytoin concentrations.
The following substances may increase phenytoin concentrations:

alcohol (rapid consumption),
oral anticoagulants (blood-thinning medicines, e.g. dicoumarol),
benzodiazepines (sedatives, e.g. chlordiazepoxide, diazepam, trazodone),
anaesthetics (e.g. halothane),
other antiepileptic medicines (e.g. sultiame, valproic acid, ethosuximide, methsuximide, felbamate),
non-steroidal anti-inflammatory drugs (NSAIDs, e.g. salicylic acid, azapropazone, phenylbutazone),
antibiotics (e.g. chloramphenicol, erythromycin, isoniazid, sulfonamides),
antifungal medicines (e.g. amphotericin B, fluconazole, ketoconazole, miconazole, itraconazole),
calcium channel blockers (heart medicines, e.g. amiodarone, diltiazem, nifedipine),
hormones (e.g. oestrogen),
disulfiram (used in the treatment of alcohol dependence),
methylphenidate (used in the treatment of attention deficit hyperactivity disorder [ADHD]),
cimetidine, omeprazole, ranitidine (used in the treatment of stomach ulcers),
ticlopidine (used to prevent thrombosis),
viloxazine, fluoxetine (antidepressants),
para-aminosalicylic acid (PAS), cycloserine (used in the treatment of tuberculosis),
tricyclic antidepressants (e.g. amitriptyline, clomipramine),
tolbutamide (used in the treatment of diabetes),
other antiepileptic medicines (e.g. oxcarbazepine, eslicarbazepine acetate and – in some patients – topiramate).

Substances that may decrease phenytoin concentrations:

antibiotics (e.g. ciprofloxacin, rifampicin),
other antiepileptic medicines (e.g. carbamazepine, vigabatrin, phenobarbital, primidone),
reserpine (used in the treatment of high blood pressure),
sucralfate (used in the treatment of duodenal ulcers),
diazoxide (used in the treatment of high blood pressure),
theophylline (used in the treatment of breathing difficulties),
long-term alcohol abuse (chronic, long-term alcohol abuse),
nelfinavir (used in the treatment of viral infections caused by HIV [AIDS]).

Substances that may increase or decrease phenytoin concentrations:

antiepileptic medicines (e.g. carbamazepine, sodium valproate, valproic acid, phenobarbital),
chlordiazepoxide (a sedative),
diazepam (a sedative).

Valproic acid (an antiepileptic medicine): in patients receiving valproic acid and phenytoin, or when increasing the dose of valproic acid, more adverse effects may occur. In particular, there is an increased risk of brain damage (see section 4 "Possible adverse effects").
Phenytoin may alter blood concentrations and effects of the following medicines in the patient:

clozapine (used in the treatment of schizophrenia);
corticosteroids (e.g. dexamethasone, prednisone, fludrocortisone);
oral anticoagulants (blood-thinning medicines, e.g. dicoumarol);
doxycycline, tetracycline (antibiotics);
praziquantel (used in the treatment of worm infections);
rifampicin (used in the treatment of tuberculosis);
itraconazole (an antifungal medicine);
antiepileptic medicines (e.g. lamotrigine, carbamazepine, valproic acid, felbamate, topiramate, zonisamide or tiagabine, as well as 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 rejection of transplanted organs);
diazoxide (used in the treatment of high blood pressure);
furosemide (a diuretic used in the treatment of heart failure);
paroxetine, sertraline (antidepressants);
theophylline (used in the treatment of breathing difficulties);
digitoxin (a heart medicine);
nicardipine, verapamil (used in the treatment of high blood pressure);
nimodipine (used to prevent cerebral blood vessel spasm);
quinidine (a heart medicine);
tricyclic antidepressants (e.g. amitriptyline, clomipramine);
methadone (used in the treatment of heroin addiction);
chlorpropamide, glibenclamide (used in the treatment of diabetes);
tolbutamide (used in the treatment of diabetes);
vitamin D;
teniposide (an anticancer medicine);
oral contraceptives: when taking contraceptive pills, their effectiveness may be unreliable;
blood-thinning (anticoagulant) medicines: in patients taking such medicines, blood clotting time (INR value) should be regularly checked;
methotrexate (an anticancer medicine): the patient may experience:
a higher number of adverse effects from methotrexate treatment or
worsening of adverse effects from methotrexate treatment.
folic acid: phenytoin may be less effective when taken concomitantly with folic acid.

Phenytoin may, when administered concomitantly with products containing paracetamol, enhance the metabolism of paracetamol, which may lead to liver damage.

Pregnancy and breastfeeding
Pregnancy
It should be noted that contraceptive pills may not work effectively when taken concomitantly with Phenytoin Hikma.
If the patient plans to become pregnant or is already pregnant, she should take Phenytoin Hikma only if prescribed by a doctor, after careful assessment of risks and benefits.
In women who are pregnant and treated with any antiepileptic medicine, the likelihood of fetal malformations is higher (data suggest this likelihood is 2–3 times greater). Possible malformations include:

cleft lip,
heart defects,
underdevelopment of fingernails or toenails, fingers or toes, face,
neural tube defects (the neural tube is the part of the body from which the nervous system develops),
growth retardation.

Women planning pregnancy or who are already pregnant should discuss this immediately with their doctor. The doctor will check whether treatment with Phenytoin Hikma is necessary.
If urgent treatment with Phenytoin Hikma is required during pregnancy:

The patient should, if possible, avoid taking other antiepileptic medicines. Taking multiple antiepileptic medicines increases the risk of fetal malformations.
During the first three months of pregnancy, the patient should receive the lowest effective dose. This is the lowest possible dose at which seizures are well controlled. The doctor will decide on the appropriate dose.
The patient's and fetus's condition will be monitored:
Blood serum phenytoin concentrations change during pregnancy and after its completion. The doctor may monitor serum phenytoin concentrations to ensure the patient receives the correct dose.
An ultrasound scan (USG) should be performed. This examination provides a detailed image of the fetus. The patient should be informed of any problems concerning her child's condition.

During pregnancy, Phenytoin Hikma should not be discontinued abruptly. Sudden discontinuation of treatment may cause epileptic seizures, which may be harmful to both mother and fetus.
Care of the newborn
Bleeding may occur in the newborn during the first 24 hours after delivery. To prevent this:

During the last week of pregnancy, the doctor should administer a dose of vitamin K1 to the patient;
The doctor should administer a dose of vitamin K1 to the newborn.

Prevention of folic acid deficiency
To prevent possible folic acid deficiency, the patient should take folic acid during pregnancy. It can be taken in tablet form or as dietary supplements. The doctor will inform the patient about the appropriate dose. When taking folic acid, the effect of phenytoin may be weaker (see also "Other medicines and Phenytoin Hikma").
Breastfeeding
Small amounts of the active substance (phenytoin sodium) pass into human milk. It is recommended that the patient not breastfeed while taking Phenytoin Hikma. However, if the patient wishes to breastfeed, the infant should be monitored to ensure that:

it gains weight normally,
its sleep requirement is not increased.

Driving and operating machinery
Do not drive or operate machinery, as the ability to drive and operate machinery is reduced.
Before driving or operating machinery, consult your doctor.
The ability to operate machinery or drive may be impaired:

at the beginning of treatment with Phenytoin Hikma,
when high doses of the medicine are used,
when this medicine is used concomitantly with substances affecting the central nervous system (especially alcohol).

Important information about certain ingredients of Phenytoin Hikma
Phenytoin Hikma contains less than 23 mg of sodium per glass vial (ampoule). It is practically "sodium-free".
Phenytoin Hikma contains propylene glycol, which may cause symptoms similar to those after alcohol consumption.
This medicinal product contains 10% vol. ethanol (alcohol), i.e. up to 394 mg per dose, equivalent to 10 ml of beer or 4.17 ml of wine per dose.
This may be harmful for individuals suffering from alcoholism.
This should be taken into account in pregnant or breastfeeding women, children, and high-risk patient groups such as patients with liver disease or epilepsy.

3. How to use Phenytoin Hikma

Detailed information on dosage, handling and preparation of Phenytoin Hikma is provided at the end of this package leaflet under the heading
"Information intended for healthcare professionals only".
Phenytoin Hikma will be administered to the patient by a physician as a slow intravenous injection.
The physician will decide how much medicine the patient needs and when it should be given. This depends on the patient's age and body weight, as well as the condition for which the patient is being treated with Phenytoin Hikma.
During administration of Phenytoin Hikma, the physician will:

continuously monitor the heart, blood pressure and nervous system,
regularly measure plasma concentrations of phenytoin in the patient's blood.

Duration of treatment
Phenytoin may be used for a prolonged period.
The duration of treatment depends on:

the condition for which the patient is being treated,
how well the patient responds to treatment,
how well the patient tolerates adverse effects (see section 4 "Possible side effects").

During long-term treatment with Phenytoin Hikma, plasma levels of the drug will be monitored so that the patient can receive the lowest effective dose. This will help minimize adverse effects.
If the patient feels that Phenytoin Hikma is having too strong or too weak an effect, they should discuss this with their doctor or pharmacist.
Use of a higher than recommended dose of Phenytoin Hikma:
If too high a dose of Phenytoin Hikma is administered, the following symptoms may occur in the patient:
Early symptoms

involuntary rapid eye movements (nystagmus),
cerebellar ataxia (impaired coordination of movement),
dysarthria (speech impairment).

Other symptoms

tremor;
hyperreflexia (exaggerated reflexes);
drowsiness;
fatigue;
lethargy;
slurred speech;
diplopia (double vision);
dizziness;
nausea;
vomiting;
coma (loss of consciousness);
possible loss of pupillary reflex (reduced pupil response to light);
drop in blood pressure;
respiratory disturbances, which may lead to death;
cardiac failure, which may lead to death;
irreversible brain damage.

If any of these symptoms occur, the physician must be informed immediately. The physician will take measures to remove excess phenytoin from the patient's body. The patient's heart and respiration will be monitored, and symptoms will be treated.

4. Possible adverse effects

Like all medicines, this medicine can cause adverse effects, although not everyone experiences them.

Very common adverse effects (affecting more than 1 in 10 patients):

nystagmus (rapid involuntary eye movements), incoordination (ataxia), paraesthesia (tingling and numbness), confusion, central or vestibular dizziness, insomnia, headache, increasing irritability, high-frequency tremor at rest, dysarthria (difficulty in speaking), fatigue, memory disturbances and intellectual impairment;
double vision (diplopia).

Common adverse effects (affecting up to 1 in 10 patients):

in patients treated for a prolonged period, drowsiness and sedation, perceptual disturbances and clouding of consciousness or even coma have been reported;
when the medicine is administered intravenously too rapidly, transient symptoms such as dizziness, vomiting and dry mouth may occur, which usually resolve within 60 minutes, provided the patient has not previously received a medicine containing phenytoin; in patients treated for a prolonged period, loss of appetite, nausea, vomiting, weight loss and constipation have also been reported;
measles-like rash.

Uncommon adverse effects (affecting up to 1 in 100 patients):

in patients undergoing long-term treatment, peripheral neuropathy (with risk of irreversible cerebellar atrophy) may occur;
in patients undergoing long-term treatment with phenytoin, serious changes in ECG recordings have been reported.

Rare adverse effects (affecting up to 1 in 1,000 patients):

changes in blood cell counts may occur, such as leucopenia (reduced white blood cell count), megaloblastic anaemia (formation of abnormally large red blood cells), porphyria (disorders involving certain enzymes normally involved in the production of porphyrins and haem). If these occur, discontinuation of phenytoin is recommended. These symptoms may also gradually resolve if the dose is reduced;
anaphylaxis and anaphylactoid reactions have been reported. In rare cases, these may lead to death (this syndrome may include symptoms such as arthralgia, eosinophilia, fever, liver function disturbances, lymphadenopathy or rash);
laboratory tests should be performed every six months, especially in children, due to the possibility of impaired thyroid function;
dyskinesia (reduced voluntary movements and occurrence of involuntary movements), chorea (a disorder characterised by involuntary movements), dystonia (muscle spasms and repetitive movements or abnormal postures), tremor and asterixis (flapping tremor), asystole (flat ECG line), conduction block and suppression of ventricular escape rhythm in patients with complete atrioventricular block, particularly when phenytoin is administered intravenously. Proarrhythmic effects may occur, manifesting as new or worsened cardiac rhythm disturbances, which may lead to severe impairment of cardiac function or even circulatory arrest; hypotension, worsening of existing heart failure and respiratory failure may also occur, particularly with intravenous administration. Atrial fibrillation has been reported in isolated cases. Atrial fibrillation and flutter do not resolve with phenytoin administration. However, an increase in ventricular rate may occur due to shortening of the refractory period in the atrioventricular node;
if liver function disturbances occur, possibly involving other organs, treatment with phenytoin should be discontinued. These symptoms may also gradually resolve if the dose is reduced. Therefore, liver enzyme activity should be monitored regularly (every few weeks) during long-term phenytoin therapy;
allergic skin rashes (exanthema); severe allergic reactions, e.g. dermatitis or exfoliative dermatitis;
in susceptible patients or patients with disturbances in calcium metabolism (increased alkaline phosphatase activity), softening of bones due to abnormal bone mineralisation (osteomalacia) may occur. Patients with this condition usually respond well to vitamin D supplementation. Therefore, alkaline phosphatase levels should be monitored regularly;
fever (with rash). Local irritation, inflammation and tenderness have been reported. Necrosis and desquamation have been reported after subcutaneous or perivascular injection, which are not recommended routes of administration. Soft tissue irritation and inflammation occurred at the injection site with extravasation of intravenously administered phenytoin as well as without extravasation.

Very rare adverse effects (affecting up to 1 in 10,000 patients):

Purple Glove Syndrome, periarteritis nodosa (inflammation of medium and small arteries) and immunoglobulin abnormalities may occur;
excessive growth of gum tissue (gingival hyperplasia), skin changes such as hyperpigmentation (bronzing) and hirsutism (excessive hair growth) have been reported. Dupuytren's contracture, Stevens-Johnson syndrome and Lyell's syndrome have also been reported. Severe skin adverse reactions have been reported: Stevens-Johnson syndrome and toxic epidermal necrolysis (see section 4.4).
muscle weakness (myasthenic syndrome), which resolves after discontinuation of phenytoin.

Adverse effects for which frequency is unknown (frequency cannot be estimated from available data):

Purple Glove Syndrome (a skin condition in which limbs are swollen, discoloured and painful) has been reported. If skin discolouration, swelling and pain at the injection site occur and begin to spread towards the hand and fingers, inform your doctor immediately. This may indicate a condition known as Purple Glove Syndrome. In most cases, it resolves spontaneously, but in some cases it may be serious and require urgent treatment.

Adverse effects during long-term treatment
Frequency unknown: (frequency cannot be estimated from available data)

peripheral sensory polyneuropathy (nerve function disturbances) and tonic seizures,
irreversible cerebellar atrophy (permanent degeneration of the cerebellum).

With long-term use of phenytoin (especially with oral administration), symptoms of brain damage (encephalopathy) may occur. This is particularly likely when other antiepileptic medicines, especially valproic acid, are used concomitantly. Symptoms of brain damage include: Frequency unknown: (frequency cannot be estimated from available data)

increased frequency of epileptic seizures,
loss of drive (apathy),
muscle weakness (reduced muscle tone),
choreic dyskinesia (movement disorders),
severe generalised changes in brain examination (EEG),
bone disorders have been reported, including osteopenia and osteoporosis (thinning of bones) and fractures. If long-term antiepileptic treatment, history of osteoporosis or steroid use is present, consult your doctor or pharmacist.

If any adverse effects occur, including any possible adverse effects not listed in this leaflet, consult your doctor or pharmacist.

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 stated on the carton after EXP.
The expiry date refers to the last day of the specified month.
No special storage conditions are required for this medicinal product.
After first opening the packaging: Phenytoin Hikma must be used immediately.
Do not use the ampoule if the solution inside is cloudy or contains solid particles.
Medicines must not be disposed of via the sewage system or household waste. Ask your pharmacist how to dispose of medicines no longer required. 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 of phenytoin sodium (equivalent to 46 mg of phenytoin).
Each 5 ml ampoule of injection solution contains 250 mg of phenytoin sodium (equivalent to 230 mg of phenytoin).
The other ingredients are:
propylene glycol,
ethyl alcohol,
sodium hydroxide,
water for injections.

What Phenytoin Hikma looks like and contents of the pack
Phenytoin Hikma is supplied in transparent glass containers called ampoules.
Phenytoin Hikma is a clear solution.
Pack sizes:
Phenytoin Hikma is available in packs containing 5 or 50 ampoules.
1 ampoule contains 5 ml of injection solution.

Marketing Authorisation Holder and Manufacturer
Hikma Farmacêutica (Portugal), S.A.
Estrada do Rio da Mó n.º 8, 8A and 8B – Fervença
2705-906 Terrugem SNT
Portugal
Tel.: ++351-21 960 84 10
Fax: ++351-21 961 51 02

This medicinal product is authorised in the European Economic Area countries under the following names:
Germany: Phenytoin Hikma 50 mg/ml Injektionslösung
Italy: Phenytoin Hikma 50 mg/ml Soluzione iniettabile
Poland: Phenytoin Hikma 50 mg/ml Solution for injection
Portugal: Fenitoina Hikma 50 mg/ml Solução injectável
Romania: Phenytoin Hikma 50 mg/ml Soluţie injectabilă
United Kingdom: Phenytoin 50 mg/ml Solution for injection

Information intended exclusively for healthcare professionals or medical personnel:

Route of Administration
The injection solution is intended for intravenous use only. Absorption after intramuscular administration is delayed and variable. Phenytoin Hikma should be administered slowly directly into a large vein through a large-bore needle or intravenous catheter. Subcutaneous or perivascular injections should be avoided, as the phenytoin injection solution is alkaline and may cause tissue necrosis.

Handling and Preparation
The injection solution must not be mixed with other solutions, as this may lead to precipitation of phenytoin.
Before use, ampoules should be inspected for the presence of precipitate or discoloration. The product must not be used if precipitate or cloudiness is observed in the solution within the ampoule. Phenytoin Hikma is suitable for use as long as no cloudiness or precipitate is present. Precipitate may form if the product has been stored in a refrigerator or freezer. This precipitate will dissolve if the product is left at room temperature for some time, after which it may be used.
Only clear solutions should be administered. Slight yellow discoloration does not affect the efficacy of the solution.
For single use only. Any unused portions must be discarded.
The duration of therapy depends on the underlying disease and its course. It is unlimited, provided the drug is well tolerated.

Dosage
The therapeutic plasma concentration range for phenytoin is generally 10 to 20 µg/mL. Toxic symptoms may occur at plasma concentrations above 25 µg/mL.

Status epilepticus or recurrent seizures occurring in rapid succession
Continuous monitoring of ECG, blood pressure, and neurological status is required, along with regular blood level determinations of phenytoin. Immediate access to resuscitation equipment must be ensured.
Adults and adolescents over 12 years of age:
Initial dose: 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 seizures persist after 20–30 minutes, the dose may be repeated.
After cessation of seizures, 1 ampoule of Phenytoin Hikma (equivalent to 230 mg phenytoin) may be administered intravenously every 1.5 to 6 hours. The maximum daily dose is 17 mg/kg body weight (or 6 ampoules – equivalent to 1380 mg phenytoin) to achieve rapid saturation.

Maximum daily dose of 17 mg/kg body weight corresponds to:
Body weight Number of ampoules Phenytoin dose
41 kg 3 690 mg
54 kg 4 920 mg
68 kg 5 1150 mg
81 kg 6 1380 mg

Children up to 12 years of age:
On the first day, the maximum daily dose is 30 mg/kg body weight; on the second day, 20 mg/kg body weight; on the third day, 10 mg/kg body weight. The maximum intravenous infusion rate is 1 mg/kg body weight per minute.

Day 1
Maximum daily dose of 30 mg/kg body weight corresponds to:
Body weight Number of ampoules Phenytoin dose
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
Maximum daily dose of 20 mg/kg body weight corresponds to:
Body weight Number of ampoules Phenytoin dose
12 kg 1 230 mg
23 kg 2 460 mg
35 kg 3 690 mg
46 kg 4 920 mg

Day 3
Maximum daily dose of 10 mg/kg body weight corresponds to:
Body weight Number of ampoules Phenytoin dose
23 kg 1 230 mg
46 kg 2 460 mg

Prevention of epileptic seizures
Adults and adolescents over 12 years of age receive 1 to 2 ampoules of Phenytoin Hikma (equivalent to 230 to 460 mg phenytoin) per day, administered at a maximum rate 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 body weight. The infusion rate should be adjusted according to the child's body weight and age.

Daily dose of 5 mg/kg body weight corresponds to:
Body weight mL Phenytoin dose
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

Daily dose of 6 mg/kg body weight corresponds to:
Body weight mL Phenytoin dose
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

With long-term use of Phenytoin Hikma, regular monitoring (every few weeks) of serum phenytoin concentrations, blood morphology, and liver enzyme activity is required. Mild, stable leukopenia or isolated elevation of GGT in blood morphology usually does not necessitate discontinuation of treatment.
In susceptible patients or those with calcium metabolism disorders (elevated alkaline phosphatase activity), osteomalacia (softening of bones) may occur. This condition usually responds well to vitamin D supplementation. Therefore, alkaline phosphatase levels should be monitored regularly.
Additionally, thyroid function should be monitored in children.

Switching between products
Due to the relatively narrow therapeutic range of phenytoin in plasma and differing bioavailability among various formulations, serum phenytoin concentrations must be closely monitored when switching from one phenytoin-containing product to another. Steady-state (stable plasma concentration) can be expected after 5 to 14 days of consistent dosing.
Therefore, the dose should be tapered gradually (if possible), and new antiepileptic drugs should be introduced starting at a low dose and gradually increased. Abrupt discontinuation of Phenytoin Hikma may lead to increased seizure frequency or status epilepticus.

Additional information for specific patient groups
Patients with renal or hepatic impairment:
There are no specific dosage adjustment recommendations for this patient group; however, caution is advised in patients with kidney or liver disease (see section 4.4). Renal and hepatic impairment require careful monitoring.
Elderly patients (over 65 years of age):
Same as for adults. However, adverse effects may occur more frequently in elderly patients.
Neonates:
Oral absorption of phenytoin has been shown to be unreliable. Phenytoin Hikma should be administered slowly intravenously at a rate of 1–3 mg/kg/min, at a dose of 15–20 mg/kg. This usually achieves serum phenytoin concentrations within the generally accepted therapeutic range of 10–20 mg/L.
Infants and children:
Same as for adults. However, phenytoin metabolism in children is often faster than in adults. This should be considered when determining the dosing regimen. In such cases, serum concentration monitoring is particularly beneficial.

Management of Overdose

Symptoms of overdose
Symptoms of overdose may occur at various serum phenytoin concentrations. Early signs include involuntary, rapid eye movements (nystagmus), cerebellar ataxia, and dysarthria. Additional symptoms may include tremor, hyperreflexia, drowsiness, fatigue, lethargy, slurred speech, diplopia, dizziness, nausea, and vomiting. The patient may progress to coma, pupillary reflexes may be lost, and arterial blood pressure may drop. Death may result from central respiratory depression or circulatory failure. The estimated average lethal dose (single administration) is 2–5 g of phenytoin in adults. The lethal dose in children and adolescents is unknown. Overdose may lead to irreversible degenerative changes in the cerebellum.

Treatment of poisoning
Initial management should include gastric lavage, administration of activated charcoal, and monitoring in an intensive care unit. Hemodialysis, forced diuresis, and peritoneal dialysis are less effective. There is insufficient experience regarding the efficacy of activated charcoal hemoperfusion, plasma exchange, or blood transfusion. Therefore, intensive internal medical treatment should be provided without specific detoxification procedures, but serum phenytoin concentrations should be monitored.

Phenytoin hikma