FENITOIN RUBIO 50 mg/mL INJECTABLE SOLUTION

2. What you need to know before starting to use Phenytoin Rubió

Do not usePhenytoin Rubió

• If you are allergic to phenytoin or any of the other components of this medication (listed in section 6).
• If you have any heart disease, such as decreased heart rate, impulse transmission blockage, and neurological convulsions due to rhythm disorders (Adam-Stokes syndrome).

Warnings and precautions

Consult your doctor before starting to use Phenytoin Rubió.

• If you have severe liver or heart problems or low blood pressure (hypotension). Your doctor will perform periodic checks. If you are receiving treatment with vitamin D or derivatives, as their simultaneous use with phenytoin may cause progressive softening of the bones with possible fractures.
• If you have diabetes, as phenytoin may cause a situation of hyperglycemia by increasing blood glucose levels.
• If you are pregnant or breastfeeding.
• Life-threatening skin rashes have been described with the use of Phenytoin Rubió, initially appearing as red spots or circular patches, often with a central blister.
• Other additional signs that may appear are sores in the mouth, throat, nose, genitals, and conjunctivitis (swollen and red eyes).
• These life-threatening skin rashes are often accompanied by flu-like symptoms. The rash can progress to generalized blistering or skin peeling.
• The period of highest risk of severe skin reactions is during the first few weeks of treatment.
• If you have developed Stevens-Johnson syndrome or toxic epidermal necrolysis with the use of Phenytoin Rubió, you should not use Phenytoin Rubió again at any time.
• If you develop rashes or these skin symptoms, stop taking Phenytoin Rubió, go to a doctor immediately, and inform them that you are taking this medication. Abrupt cessation of treatment may precipitate an epileptic crisis.
• If you are of Taiwanese, Japanese, Malay, or Thai origin and tests have shown that you are a carrier of the CYP2C9*3 mutation.

Do not consume alcoholic beverages while being treated with Phenytoin Rubió (see use with food and beverages).

It is not recommended to administer Phenytoin Rubió to children as it contains alcohol as an excipient.

Cases of irritation and inflammation at the injection site, with and without leakage of the phenytoin solution from the vein, have been described. This irritation can range from mild sensitivity to tissue destruction, so inadequate administration of this medication should be avoided to prevent these effects.

Administration of Phenytoin Rubió via the intramuscular route is not recommended, as its effect takes too long to manifest.

Serum levels of phenytoin above therapeutic doses can produce confusion states referred to as delirium, psychosis, or nervous system alterations. Therefore, it is recommended to determine serum levels of phenytoin at the first sign of acute toxicity.

A common complication is gum inflammation, with a higher incidence in patients under 23 years of age. Similarly, there may be an increased incidence of microbial infections and gum bleeding due to the decrease in white blood cells caused by hydantoin medications. In these cases, dental interventions should be postponed until blood counts return to normal.

Consult your doctor, even if any of the above circumstances have occurred to you.

This medication contains less than 23 mg of sodium (1 mmol) per 100 mg or 250 mg dose unit; that is, it is essentially "sodium-free".

There is a risk of fetal harm if Phenytoin Rubió is used during pregnancy. Women of childbearing age should use effective contraceptive methods during treatment with Phenytoin Rubió (see "Pregnancy, breastfeeding, and fertility").

Use of Phenytoin Rubió withother medications

Inform your doctor or pharmacist if you are using, have recently used, or may need to take any other medication.

While being treated with Phenytoin Rubió, you should take the following medications with special caution:

• Chloramphenicol and sulfonamide: antibiotics that may cause an increase in phenytoin levels in the blood, making its effect too strong. The effect of antibiotics may be decreased by the presence of phenytoin.
• Rifampicin and doxycycline: antibiotics whose effect may be decreased by the presence of phenytoin.
• Dicumarol (cumarin anticoagulants): vitamin K antagonist that may cause an increase in phenytoin levels in the blood, making its effect too strong.
• Disulfiram: medication used to treat alcoholism that may cause an increase in phenytoin levels in the blood, making its effect too strong.
• Tolbutamide: medication from the group of sulfonylureas used in the treatment of diabetes that may cause an increase in phenytoin levels in the blood, making its effect too strong.

• Isoniazid: antitubercular medication that may cause an increase in phenytoin levels in the blood, making its effect too strong.
• Phenylbutazone and salicylates: non-steroidal anti-inflammatory medications that may cause an increase in phenytoin levels in the blood, making its effect too strong.
• Chlordiazepoxide, diazepam, and phenothiazines: medications from the group of benzodiazepines that may cause an increase in phenytoin levels in the blood, making its effect too strong.
• Carbamazepine: medication from the group of benzodiazepines that may decrease the effect of phenytoin.
• Estrogens: female sex hormones that may cause an increase in phenytoin levels in the blood, making its effect too strong. The effect of estrogens may be decreased by the presence of phenytoin.
• Ethosuximide, succinimide: anticonvulsant medications that may cause an increase in phenytoin levels in the blood, making its effect too strong.

• Halothane: medication used in anesthesia that may cause an increase in phenytoin levels in the blood, making its effect too strong.

• Methylphenidate: psychostimulant medication used in the treatment of attention deficit hyperactivity disorder (ADHD) that may cause an increase in phenytoin levels in the blood, making its effect too strong.
• H2 antagonists: antihistamine medications that may cause an increase in phenytoin levels in the blood, making its effect too strong.

• Trazodone: antidepressant medication that acts by inhibiting serotonin reuptake and may cause an increase in phenytoin levels in the blood, making its effect too strong.

• Amiodarone: medication used in the treatment of cardiac arrhythmias that may cause an increase in phenytoin levels in the blood, making its effect too strong.
• Fluoxetine: selective serotonin reuptake inhibitor medication that may cause an increase in phenytoin levels in the blood, making its effect too strong.
• Reserpine: medication used as an antipsychotic and antihypertensive that may reduce the effect of phenytoin.
• Diazoxide: antihypertensive medication that may reduce the effect of phenytoin.
• Folic acid: vitamin that may reduce the effect of phenytoin.
• Sucralfate: medication used in the treatment of gastrointestinal ulcers that may reduce the effect of phenytoin.
• Valproic acid and sodium valproate: antiepileptic medications that may decrease phenytoin levels.
• Phenobarbital: antiepileptic medication that may alter phenytoin levels in the blood.
• Tricyclic antidepressants at high doses: in case of simultaneous administration with phenytoin, the dose of the latter should be adjusted, as otherwise, convulsions may be triggered.
• Lidocaine: its simultaneous administration with phenytoin by intravenous route may lead to excessive cardiac depression.

• Corticosteroids: hormones from the group of steroids whose effect may be decreased by the presence of phenytoin.

• Oral contraceptives: their effect may be decreased by the presence of phenytoin.
• Quinidine and digoxin: antiarrhythmic medications whose effect may be decreased by the presence of phenytoin.
• Vitamin D: its effect may be decreased by the presence of phenytoin.
• Furosemide, theophylline: diuretics whose effect may be decreased by the presence of phenytoin.
• Anticoagulants, such as rivaroxaban, dabigatran, apixaban, and edoxaban.
• Lacosamide.
• Ticagrelor.

Phenytoin Rubió may interfere with the following laboratory tests: metyrapone, dexamethasone, protein-bound iodine, glucose, alkaline phosphatase, and GGT.

Use of Phenytoin Rubió with food, beverages, and alcohol

During treatment with this medication, you should avoid consuming alcohol. High alcohol consumption may increase phenytoin levels in the blood, while chronic alcohol consumption may decrease them.

Pregnancy, breastfeeding, and fertility

Pregnancy

Consult your doctor or pharmacist before using any medication.

As with other antiepileptics, there is a relationship between the administration of phenytoin and the appearance of congenital malformations. Therefore, Phenytoin Rubió should not be used as a medication of choice during pregnancy, especially during the first trimester, and the benefit-risk ratio should be evaluated in each case.

If Phenytoin Rubió is being administered to prevent grand mal seizures, the antiepileptic medication should not be discontinued, as it may precipitate a status epilepticus, which carries the risk of causing oxygen deficiency in the mother and fetus.

During pregnancy, the frequency of convulsions may increase due to an alteration in the absorption or metabolism of phenytoin. Therefore, it is very important to determine serum levels to establish the adequate dose in each patient. After delivery, the dose prior to pregnancy will probably be necessary again.

Phenytoin administered before delivery produces a lack of vitamin K and, therefore, of the coagulation factors related to this vitamin. This increases the risk of bleeding during delivery for the mother or in the newborn. To avoid this, vitamin K can be administered to the mother in the last month of pregnancy and to the newborn immediately after birth.

Phenytoin Rubió contains alcohol and propylene glycol, and this should be taken into account in the case of pregnant or breastfeeding women, children, and high-risk groups, such as patients with liver or epilepsy.

Phenytoin Rubió may cause serious congenital anomalies. If you take Phenytoin Rubió during pregnancy, your baby has up to 3 times more risk of having a congenital anomaly than women who do not take an antiepileptic medication. Serious congenital anomalies have been reported, such as growth, skull, face, nail, finger, and heart anomalies. Some of these may occur simultaneously as part of a fetal hydantoin syndrome.

Neurological development problems (brain development) have been reported in babies born to mothers who used phenytoin during pregnancy. Some studies have shown that phenytoin negatively affects the neurological development of children exposed to phenytoin in the uterus, although other studies have not found such an effect. The possibility of an effect on neurological development cannot be ruled out.

Breastfeeding

Consult your doctor or pharmacist before using a medication.

The use of Phenytoin Rubió in breastfeeding women is not recommended, as phenytoin is eliminated in breast milk in low concentrations.

Phenytoin Rubió contains alcohol and propylene glycol, and this should be taken into account in the case of breastfeeding women (see section 2 – "Phenytoin Rubió contains ethanol and propylene glycol").

Driving and using machines

Phenytoin Rubió may cause symptoms such as drowsiness, dizziness, or vision changes, and may decrease reaction capacity. These effects, as well as the underlying disease, may impair your ability to drive vehicles or operate machines. Therefore, do not drive, operate machines, or engage in other activities that require special attention until your doctor assesses your response to this medication.

Phenytoin Rubió contains ethanol and propylene glycol

This medication contains 10% ethanol (alcohol), which corresponds to 160 mg of alcohol per 2 ml ampoule, equivalent to 4 ml of beer or 1.7 ml of wine, and 400 mg of alcohol per 5 ml ampoule, equivalent to 10 ml of beer and 4.2 ml of wine. This medication is harmful to people with alcoholism.

The alcohol content should be taken into account in the case of pregnant or breastfeeding women, children, and high-risk groups, such as patients with liver disease or epilepsy.

This medication contains 830.4 mg of propylene glycol in each 2 ml ampoule and 2076 mg in each 5 ml ampoule.

If you are pregnant or breastfeeding, do not take this medication unless it is recommended by your doctor. Your doctor may perform additional checks while you are taking this medication.

If you have liver or kidney failure, do not take this medication unless it is recommended by your doctor. Your doctor may perform additional checks while you are taking this medication.

3. How to use Fenitoína Rubió

Follow exactly the administration instructions of Fenitoína Rubió indicated by your doctor. In case of doubt, consult your doctor again.

To establish a correct dosage regimen, your doctor will need to perform periodic blood tests.

• Status epilepticus and tonic-clonic seizures(epileptic seizures)

Adults: A loading dose of approximately 18 mg/kg/24 h should be administered intravenously at a rate not exceeding 50 mg/min (it will take about 20 minutes in a 70 kg patient). The loading dose should be continued 24 hours later with maintenance doses of 5-7 mg/kg/day intravenously divided into 3 or 4 administrations.

Newborns and children: A loading dose of 15-20 mg/kg usually produces therapeutic plasma concentrations (10-20 ?g/ml). The injection rate should be less than 1-3 mg/kg/min.

Maintenance doses will be 5 mg/kg/24 h.

• Neurosurgery

Adults: administer a loading dose of 15-18 mg/kg/24 h, divided into 3 doses (1/2 dose initially, 1/4 dose at 8 h and 1/4 dose at 16 h), continue with maintenance doses of 5-7 mg/kg/24 h fractionated into 3 doses (one every 8 h) i.e. at 24, 32, 40 h and subsequent.

Newborns and children: loading dose 15 mg/kg/24 h and maintenance doses 5 mg/kg/24 h.

• Arrhythmias

Administer 50 to 100 mg every 10 to 15 minutes until the arrhythmia reverts or the maximum dose of 1000 mg is reached. The injection should be performed with great caution, advising continuous monitoring of the ECG and blood pressure. The injection rate should not exceed 25-50 mg/min.

• Elderly and/or liver failure patients

In elderly, very ill, debilitated, or patients with severe liver disease, the total dose as well as the administration rate should be reduced to 25 mg per minute or even up to 5-10 mg per minute to decrease the possibility of adverse effects.

If you use more Fenitoína Rubió than you should

If you have used more Fenitoína Rubió than you should, go to your doctor or pharmacist as soon as possible, indicating the medication and the amount taken. You can also call the Toxicology Information Service, phone 91 562 04 20, indicating the medication and the amount taken.

The initial symptoms are: involuntary eye movements, muscle spasms, and difficulty speaking. Other symptoms are: tremors, excessive flexion, numbness, stuttering speech, nausea, and vomiting. In these cases, the doses should be reduced or treatment should be discontinued. The treatment consists of maintaining respiration and blood circulation and taking adequate supportive measures.

If you forget to use Fenitoína Rubió

Do not use a double dose to make up for forgotten doses.

If you interrupt treatment with Fenitoína Rubió

Consult your doctor to indicate how to restart treatment.

If you have any other doubts about the use of this product, ask your doctor or pharmacist.

4. Possible adverse effects

Like all medicines, this medicine can cause adverse effects, although not all people suffer from them.

The main signs of toxicity associated with intravenous administration of phenytoin are alterations in the heart and circulation and/or decrease in the functions of the central nervous system. When administered rapidly, a drop in blood pressure (hypotension) may appear.

Skin rashes may appear that can threaten the patient's life (Stevens-Johnson syndrome, toxic epidermal necrolysis) (see section 2).

Bone alterations, including osteopenia and osteoporosis (decalcification of bones) and fractures, have been reported. Consult your doctor or pharmacist if you are undergoing prolonged treatment with antiepileptics, have a history of osteoporosis, or take steroids.

The following adverse reactions related to phenytoin have also been described:

Very frequent (affect more than 1 patient in 10)

Cardiovascular disorders:hypotension (avoid rapid administration).

Nervous system disorders:involuntary eye movements (nystagmus), inability to coordinate movements (ataxia), stuttering speech, decreased coordination, and mental confusion, dizziness, insomnia, nervousness, and headache.

Frequent (affect 1 to 10 patients in 100)

Gastrointestinal disorders:nausea, vomiting, constipation.

Skin and subcutaneous tissue disorders:skin rash sometimes with fever.

Rare (affect 1 to 10 patients in 10,000)

Cardiovascular disorders:decreased heart function, and ventricular fibrillation. These complications usually occur more frequently in elderly or seriously ill patients.

Blood and lymphatic system disorders:some complications found have been fatal. Alterations in blood test results and lymph node disease may appear.

Hepatobiliary disorders:liver damage.

Nervous system disorders:involuntary movements, including sudden movements, rigidity, tremors, and shock-like tremors in the wrists.

General disorders and administration site conditions:local irritation, inflammation, allergy, tissue destruction, and eschar.

Skin and subcutaneous tissue disorders:widespread skin peeling.

Very rare (affect less than 1 patient in 10,000) or unknown frequency (cannot be estimated from available data)

Blood and lymphatic system disorders:a decrease in the number of a type of red blood cell (pure red cell aplasia).

Immune system disorders:chronic inflammatory disease that can affect many organs in the body (systemic lupus erythematosus), inflammation of the tissues surrounding the arteries with nodule production (periarteritis nodosa), and abnormalities in immunoglobulins (immunizing proteins).

Hepatobiliary disorders:toxic liver inflammation.

Skin and subcutaneous tissue disorders:gum inflammation, acute skin and mucous membrane inflammation (Stevens-Johnson syndrome, toxic epidermal necrolysis), and blisters and tissue destruction.

Musculoskeletal and connective tissue disorders:coarsening of the features, thickening of the lips, and alterations in penile erection (Peyronie's disease).

If you consider that any of the adverse effects you suffer from is serious or if you notice any adverse effect not mentioned in this prospectus, inform your doctor or pharmacist.

Reporting of adverse effects

If you experience any type of adverse effect, consult your doctor or pharmacist, even if it is a possible adverse effect not listed in this prospectus. You can also report them directly through the Spanish Pharmacovigilance System for Human Use Medicines: www.notificaram.es. By reporting adverse effects, you can contribute to providing more information on the safety of this medicine.

5. Conservation of Fenitoína Rubió

Keep this medicine out of sight and reach of children.

This medicine does not require special storage conditions.

Do not use Fenitoína Rubió after the expiration date shown on the packaging after CAD. The expiration date is the last day of the month indicated.

Do not use Fenitoína Rubió if you notice that the solution is cloudy or precipitates appear.

6. Package contents and additional information

Composition of Fenitoína Rubió

• The active ingredient is Sodium Phenytoin.
• The other components are: ethanol, propylene glycol (E-1520), sodium hydroxide to adjust pH to 12, and water for injection c.s.

Appearance of the product and package contents

Fenitoína Rubió is presented in the form of an injectable solution for intravenous administration.

Each ampoule contains 50 mg/ml of phenytoin.

It is available in packages containing 1, 50, or 100 ampoules with 250 mg of phenytoin / 5 ml (50 mg/ml) and in packages containing 1, 50, or 100 ampoules with 100 mg of phenytoin / 2 ml (50 mg/ml).

Not all formats may be marketed.

Marketing authorization holder and manufacturer

LABORATORIOS RUBIÓ, S.A.

C/ Industria 29, Pol. Ind. Comte de Sert

08755 – Castellbisbal (Barcelona, SPAIN)

Date of the last revision of this prospectus:June 2021

Detailed information about this medicine is available on the website of the Spanish Agency for Medicines and Health Products (AEMPS) http://www.aemps.gob.es

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This information is intended only for doctors or healthcare professionals:

The phenytoin solution is only compatible with physiological serum at a final concentration of 1-10 mg/ml. No other solution for intravenous infusion is recommended due to the low solubility of the medication at pH below 10.

It should be administered slowly: in adults, the rate should not exceed 50 mg/min; in children and the elderly, it should not exceed 25 mg/min, and in neonates, the rate should not exceed 1-3 mg/kg/min.

The solution can be administered directly intravenously. It can also be administered in intravenous infusion by diluting exclusively in physiological serum at a final concentration between 1-10 mg/ml. It is recommended to administer, before and after the infusion, sterile saline solution through the same catheter or needle to avoid local venous irritation due to the alkalinity of the solution.

Determination of phenytoin plasma levels is recommended to ensure efficacy and adjust subsequent maintenance doses as needed. Therapeutic serum levels are between 10 and 20 ?g/ml.

During infusion administration, it is recommended to monitor vital signs and ECG.