PROSPECTO : INFORMATION FOR THE USER

Fenitoína Rubió 50 mg/ml injectable solution

Read this prospect carefully before starting to use the medicine, because it contains important information for you.

• Keepthis prospect, as you may need to read it again.
• If you have any doubts, consult your doctor or pharmacist.
• This medicine has been prescribed only for you, and you must not give it to other people even if they have the same symptoms as you, as it may harm them.
• If you experience any adverse effects, consult your doctor or pharmacist even if they are not listed in this prospect. See section 4.

1. What is Fenitoína Rubió and for what it is used

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

3. How to use Fenitoína Rubió

4. Possible adverse effects

5. Storage of Fenitoína Rubió

6. Contents of the package and additional information

Phenitoin Rubió contains the active ingredient phenitoin. It belongs to a group of medicines called antiepileptics.

Phenitoin Rubió is indicated for:

• Treatment of different types of epilepsy.
• Treatment of seizures that affect the entire body, or some of its parts with muscle rigidity, and that may lead to loss of consciousness. Treatment and prevention of seizures in neurosurgery.
• Treatment of irregular heartbeats (atrial and ventricular arrhythmias), especially when caused by medication overdose used to treat heart problems (digoxin).

No useFenitoína 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, blockage in the transmission of impulses, and neurological convulsions due to rhythm disturbances (Adam-Stokes syndrome).

Warning and Precautions

Consult your doctor before starting to use Fenitoína Rubió.

• If you have severe liver or heart problems or low blood pressure (hypotension). Your doctor will perform regular checks.If you are receiving treatment with vitamin D or derivatives, as simultaneous use with phenytoin may cause progressive softening of the bones with possible fractures.
• If you have diabetes, as phenytoin may cause hyperglycemia by increasing blood glucose levels.
• If you are pregnant or breastfeeding.
• Severe skin eruptions that can be life-threatening (Stevens-Johnson syndrome and toxic epidermal necrolysis) have been described with the use of Fenitoína Rubió, initially appearing as red circular spots with a central blister.
• Additional signs that may appear include mouth, throat, nose, genital, and conjunctivitis (swollen and red eyes).
• These life-threatening skin eruptions often occur with flu-like symptoms. The rash may progress to generalized blistering or skin peeling.
• The highest risk period for severe skin reactions is during the first weeks of treatment.
• If you have developed Stevens-Johnson syndrome or toxic epidermal necrolysis with the use of Fenitoína Rubió, do not use Fenitoína Rubió again at any time.
• If you develop rashes or these skin symptoms, stop taking Fenitoína Rubió, immediately see a doctor, and inform them that you are taking this medication.The abrupt discontinuation of treatment may precipitate a seizure.
• If you are of Taiwanese, Japanese, Malay, or Thai origin and have been shown to be a carrier of the CYP2C9*3 mutation.

Do not ingest alcoholic beverages while taking Fenitoína Rubió (see use with food and beverages).

Do not administer Fenitoína Rubió to children as it contains alcohol as an excipient.

There have been cases of irritation and inflammation at the injection site, with and without the solution of phenytoin leaking from the vein. This irritation may range from mild sensitivity to tissue destruction, so avoid improper administration of this medication to prevent these effects.

Administration of Fenitoína Rubió by intramuscular route is not recommended, as its effect takes too long to manifest.

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

A common complication is gingival inflammation, with a higher incidence in patients under 23 years old. Additionally, an increase in the incidence of microbial infections and gingival hemorrhage may occur due to the decrease in white blood cells caused by medications in the hydantoin group. In these cases, dental interventions should be postponed until blood counts return to normal.

Consult your doctor, even if any of the circumstances mentioned above have occurred at any time.

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

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

Use of Fenitoína Rubió with other medications

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

While taking Fenitoína 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 reduced by the presence of phenytoin.
• Rifampicin and doxycycline: antibiotics whose effect may be reduced by the presence of phenytoin.
• Dicumarol (cumarin anticoagulants): antagonist of vitamin K that may cause an increase in phenytoin levels in the blood, making its effect too strong.
• Disulfiram: medication used for alcoholism treatment that may cause an increase in phenytoin levels in the blood, making its effect too strong.
• Tolbutamide: medication in the sulfonilurea group used in diabetes treatment that may cause an increase in phenytoin levels in the blood, making its effect too strong.

• Isoniazid: antituberculosis medication that may cause an increase in phenytoin levels in the blood, making its effect too strong.
• Phenylbutazone and salicylates: anti-inflammatory non-steroidal medications that may cause an increase in phenytoin levels in the blood, making its effect too strong.
• Chlordiazepoxide, diazepam, and phenothiazines: medications derived from the benzodiazepine group that may cause an increase in phenytoin levels in the blood, making its effect too strong.
• Carbamazepine: medication derived from the benzodiazepine group that may reduce 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 reduced 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: antihistamines 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: medication that inhibits selective serotonin reuptake and 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 valproate sodium: 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 seizures may be triggered.
• Lidocaine: simultaneous administration with phenytoin by intravenous route may lead to excessive cardiac depression.

• Corticosteroids: hormones in the steroid group whose effect may be reduced by the presence of phenytoin.

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

Fenitoína Rubió may interfere with the following laboratory tests: metirapone, dexamethasone, iodine-bound proteins, glucose, alkaline phosphatase, and GGT.

Use of Fenitoína Rubió with food, beverages, and alcohol

During treatment with this medication, you should avoid taking alcohol. A high dose of alcohol may increase phenytoin levels in the blood, while chronic alcohol consumption may decrease them.

Pregnancy, lactation, and fertility

Pregnancy

Consult your doctor or pharmacist before using any medication.

Like other antiepileptic medications, there is a relationship between the administration of phenytoin and the occurrence of congenital malformations, so Fenitoína Rubió should not be used as a first-line medication during pregnancy, especially during the first trimester, and each case should be evaluated for benefit-risk.

If you are taking Fenitoína Rubió to prevent grand mal seizures, do not discontinue the antiepileptic medication, as this may precipitate status epilepticus, which carries the risk of hypoxia in the mother and fetus.

During pregnancy, the frequency of seizures may increase due to altered absorption or metabolism of phenytoin. Therefore, it is essential to determine serum levels to establish the appropriate dose for each patient. After delivery, the previous dose before pregnancy may be necessary.

Phenytoin administered before delivery produces a lack of vitamin K and related clotting factors. This increases the risk of hemorrhage during delivery for the mother or newborn. To prevent this, vitamin K may be administered to the mother in the last month of pregnancy, and to the newborn immediately after birth.

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

Fenitoína Rubió may cause severe congenital anomalies. If you take Fenitoína Rubió during pregnancy, your baby may have up to three times the risk of having a congenital anomaly compared to women who do not take an antiepileptic medication. Severe congenital anomalies, such as growth, skull, face, nail, finger, and heart abnormalities, have been reported. Some of these may occur together as part of a hydantoin syndrome.

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

Lactation

Consult your doctor or pharmacist before using a medication.

The use of Fenitoína Rubió in lactating women is not recommended, as phenytoin is excreted in breast milk in low concentrations.

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

Driving and operating machinery

Fenitoína Rubió may cause symptoms such as drowsiness, dizziness, or visual disturbances, and may decrease your reaction time. These effects, as well as the underlying disease, may impair your ability to drive vehicles or operate machinery. Therefore, do not drive, operate machinery, or engage in other activities that require special attention until your doctor evaluates your response to this medication.

Fenitoína Rubió contains ethanol and propylene glycol

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

The alcohol content should be taken into account in the case of pregnant women, lactating 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 lactating, do not take this medication unless recommended by your doctor. Your doctor may perform additional checks while you are taking this medication.

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

Followexactly theadministration instructionsfor Fenitoína Rubió as indicated byyour 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 crises)

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

Newborns and children: Loading doses of 15-20 mg/kg usually produce 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 initial dose, 1/4 dose at 8 hours, and 1/4 dose at 16 hours), followed by maintenance doses of 5-7 mg/kg/24 h divided into 3 doses (one every 8 hours), i.e., at 24, 32, 40 hours, and subsequent ones.

Newborns and children: Loading doses of 15 mg/kg/24 h and maintenance doses of 5 mg/kg/24 h.

• Arrhythmias

Administer50 to100 mg every10 to15 minutes until the arrhythmia reverses or the maximum dose of 1000 mg is reached. The injection should be performed with maximum precautions, advising continuous monitoring of ECG and blood pressure. The injection rate should not exceed 25-50 mg/min.

• Geriatric patients and/or patients with liver insufficiency

In elderly patients, severely ill, debilitated, or with severe liver disease, the total dose and administration rate should be reduced to 25 mg per minute or even to 5-10 mg per minute to minimize the risk of adverse effects.

If you use more Fenitoína Rubió than you should

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

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 the treatment suspended. Treatment consists of maintaining respiration and blood circulation and taking the necessary supportive measures.

If you forget to use Fenitoína Rubió

Do not use a double dose to compensate for the missed doses.

If you interrupt treatment with Fenitoína Rubió

Consult your doctor to be instructed on how to resume treatment.

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

Like all medicines, this medicine can cause side effects, although not everyone will experience them.

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

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

Bone alterations, including osteopenia and osteoporosis (bone decalcification), 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 Common (affect more than 1 in 10 patients)

Cardiovascular disorders:hypotension (avoid rapid administration).

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

Common (affect from 1 to 10 patients per 100)

Gastrointestinal disorders:nausea, vomiting, constipation.

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

Rare (affect from 1 to 10 patients per 10,000)

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

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

Hepatobiliary disorders:liver damage.

Central nervous system disorders:involuntary movements, including sudden movements, rigidity, tremors, and tremors in the wrists.

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

Skin and subcutaneous tissue disorders:widespread skin peeling.

Very rare (affect less than 1 in 10,000 patients) or unknown (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 the production of nodules (periarteritis nodosa), and abnormalities in immunoglobulins (antibody proteins).

Hepatobiliary disorders:toxic liver inflammation.

Skin and subcutaneous tissue disorders:inflammation of the gums, acute inflammation of the skin and mucous membranes (Stevens-Johnson syndrome, toxic epidermal necrolysis), and blisters and tissue destruction.

Musculoskeletal and connective tissue disorders:rough facial skin, lip swelling, and alterations in penile erection (Peyronie's disease).

If you consider that any of the side effects you are experiencing are severe or if you notice any side effect not mentioned in this prospectus, inform your doctor or pharmacist.

Reporting of adverse reactions

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

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

This medicationdoes not require special conditions for conservation.

Do not use Phenobarbital Rubió after the expiration date that appears on the packaging after CAD. Theexpiration date is the last day of the month indicated.

Do not use Phenobarbital Rubió if you observe that thesolutionis cloudy or precipitates appear.

Fenitoína Rubió Composition

• The active principle 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 contents of the package

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

Not all formats may be commercially available.

Holder of the marketing authorization and responsible for manufacturing

Laboratorios Rubió, S.A.

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

08755 – Castellbisbal (Barcelona, SPAIN)

Date of the last review of this leaflet:June 2021

The detailed information of this medicine is available on the website of the Spanish Agency for Medicines and Medical Devices (AEMPS) http://www.aemps.gob.es

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This information is intended solely for doctors or healthcare professionals:

The phenytoin solution is only compatible with physiological saline 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 via intravenous injection. It can also be administered in intravenous infusion by diluting exclusively in physiological saline at a final concentration of 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.

It is recommended to determine the plasma levels of phenytoin to ensure efficacy and adjust the maintenance doses as necessary. Therapeutic serum levels range from 10 to 20?mcg/ml.

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