Phenytoin Rubio 50 mg/ml solution for injection

Package leaflet: Information for the user

Introduction

PACKAGE LEAFLET: INFORMATION FOR THE USER

Phenytoin Rubió 50 mg/ml injection solution

Read the entire package leaflet carefully before you start using this medicine, as it contains important information for you.

• Keep this leaflet, as you may need to read it again.
• If you have any questions, consult your doctor or pharmacist.
• This medicine has been prescribed for you only, and you should not give it to others, even if they have the same symptoms as you, since it could harm them.
• If you experience any adverse effects, consult your doctor or pharmacist, even if such effects are not listed in this leaflet. See section 4.

Contents of the package leaflet:

1. What Phenytoin Rubió is and what it is used for
2. What you need to know before using Phenytoin Rubió
3. How to use Phenytoin Rubió
4. Possible adverse effects
5. Storage of Phenytoin Rubió
6. Contents of the pack and other information

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

Fenitoína Rubió contains the active substance phenytoin. It belongs to a group of medicines called antiepileptics.

Fenitoína Rubió is indicated for:

• Treatment of various types of epilepsy.
• Treatment of seizures affecting the entire body or certain parts with muscle rigidity, which 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 poisoning due to medications used to treat heart problems (digoxin).

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

Do not use Phenytoin Rubió

• If you are allergic to phenytoin or to any of the other components of this medicine (listed in section 6).
• If you have heart disease such as: reduced heart rate, conduction block, or neurological seizures due to rhythm disturbances (Adam-Stokes syndrome).

Warnings and precautions

Talk to 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 being treated with vitamin D or its 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 hyperglycemia by increasing blood glucose levels.
• If you are pregnant or breastfeeding.
• Life-threatening skin rashes (Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported with the use of Phenytoin Rubió. These initially appear as red spots or circular lesions, often with a central blister.
• Other additional signs that may occur include 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 may progress to widespread blistering or skin peeling.
• The period of highest risk for severe skin reactions is during the first weeks of treatment.
• If you have previously developed Stevens-Johnson syndrome or toxic epidermal necrolysis with Phenytoin Rubió, you must never use Phenytoin Rubió again.
• If you develop skin rashes or these symptoms, stop taking Phenytoin Rubió immediately, seek medical attention right away, and inform your doctor that you are taking this medicine. Abrupt discontinuation of treatment may trigger an epileptic seizure.
• If you are of Taiwanese, Japanese, Malaysian, or Thai origin and genetic testing has shown that you carry the CYP2C9*3 mutation.

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

Phenytoin Rubió is not recommended for use in children due to the presence of alcohol as an excipient.

Cases of irritation and inflammation at the injection site, with or without leakage of the phenytoin solution from the vein, have been reported. This irritation may range from mild tenderness to tissue destruction; therefore, improper administration of this medicine must be avoided to prevent these effects.

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

Serum levels of phenytoin above therapeutic doses may cause confusion states referred to as delirium, psychosis, or nervous system disturbances. Therefore, it is recommended to measure serum phenytoin levels at the first sign of acute toxicity.

A common complication is gum inflammation, with higher incidence in patients under 23 years of age. An increased incidence of microbial infections and gum bleeding may also occur due to decreased white blood cell counts caused by hydantoin-group drugs. In such cases, dental procedures should be postponed until blood counts return to normal.

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

This medicine contains less than 23 mg of sodium (1 mmol) per 100 mg or 250 mg dose unit; hence, it is essentially “sodium-free.”

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

Use of Phenytoin Rubió with other medicines

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

While being treated with Phenytoin Rubió, you should take special care with the following medicines:

• Chloramphenicol and sulfonamides: antibiotics that may increase blood levels of phenytoin, making its effect too strong. The effect of these antibiotics may be reduced by phenytoin.
• Rifampicin and doxycycline: antibiotics whose effects may be reduced by phenytoin.
• Dicoumarol (coumarin anticoagulants): vitamin K antagonist that may increase blood levels of phenytoin, making its effect too strong.
• Disulfiram: a medicine used to treat alcoholism that may increase blood levels of phenytoin, making its effect too strong.
• Tolbutamide: a sulfonylurea medicine used to treat diabetes that may increase blood levels of phenytoin, making its effect too strong.
• Isoniazid: an antituberculosis medicine that may increase blood levels of phenytoin, making its effect too strong.
• Phenylbutazone and salicylates: non-steroidal anti-inflammatory drugs (NSAIDs) that may increase blood levels of phenytoin, making its effect too strong.
• Chlordiazepoxide, diazepam, and phenothiazines: benzodiazepine-derived medicines that may increase blood levels of phenytoin, making its effect too strong.
• Carbamazepine: a medicine from the benzodiazepine group that may reduce the effect of phenytoin.
• Estrogens: female sex hormones that may increase blood levels of phenytoin, making its effect too strong. The effect of estrogens may be reduced by phenytoin.
• Ethosuximide, succinimides: anticonvulsant medicines that may increase blood levels of phenytoin, making its effect too strong.
• Halothane: an anesthetic medicine that may increase blood levels of phenytoin, making its effect too strong.
• Methylphenidate: a psycho-stimulant medicine used to treat attention deficit hyperactivity disorder (ADHD) that may increase blood levels of phenytoin, making its effect too strong.
• H2 antagonists: antihistamine medicines that may increase blood levels of phenytoin, making its effect too strong.
• Trazodone: an antidepressant medicine that inhibits serotonin reuptake and may increase blood levels of phenytoin, making its effect too strong.
• Amiodarone: a medicine used to treat cardiac arrhythmias that may increase blood levels of phenytoin, making its effect too strong.
• Fluoxetine: a selective serotonin reuptake inhibitor that may increase blood levels of phenytoin, making its effect too strong.
• Reserpine: a medicine used as an antipsychotic and antihypertensive that may reduce the effect of phenytoin.
• Diazoxide: an antihypertensive medicine that may reduce the effect of phenytoin.
• Folic acid: a vitamin that may reduce the effect of phenytoin.
• Sucralfate: a medicine used to treat gastrointestinal ulcers that may reduce the effect of phenytoin.
• Valproic acid and sodium valproate: antiepileptic medicines that may reduce phenytoin levels.
• Phenobarbital: an antiepileptic medicine that may alter blood levels of phenytoin.
• Tricyclic antidepressants at high doses: when administered simultaneously with phenytoin, the dose of phenytoin should be adjusted, otherwise seizures may be triggered.
• Lidocaine: simultaneous intravenous administration with phenytoin may lead to excessive cardiac depression.
• Corticosteroids: steroid hormones whose effect may be reduced by phenytoin.
• Oral contraceptives: their effect may be reduced by phenytoin.
• Quinidine and digitoxin: antiarrhythmic medicines whose effects may be reduced by phenytoin.
• Vitamin D: its effect may be reduced by phenytoin.
• Furosemide, theophylline: diuretics whose effects may be reduced by phenytoin.
• Anticoagulants, for example, 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, drinks, and alcohol

During treatment with this medicine, alcohol consumption should be avoided. High alcohol intake may increase phenytoin blood levels, while chronic alcohol use may decrease them.

Pregnancy, breastfeeding, and fertility

Pregnancy

Consult your doctor or pharmacist before using any medicine.

As with other antiepileptics, there is an association between phenytoin use and the occurrence of congenital malformations. Therefore, Phenytoin Rubió should not be used as a first-choice medicine during pregnancy, especially during the first trimester. The benefit-risk ratio should be evaluated in each individual case.

If Phenytoin Rubió is being administered to prevent grand mal seizures, antiepileptic treatment should not be discontinued, as this may precipitate status epilepticus, which carries the risk of oxygen deprivation in both mother and fetus.

During pregnancy, seizure frequency may increase due to altered absorption or metabolism of phenytoin. Therefore, it is very important to monitor serum levels to establish the appropriate dose for each patient. After delivery, the pre-pregnancy dose will likely be required again.

Phenytoin administered before delivery causes vitamin K deficiency and, consequently, deficiency of vitamin K-dependent clotting factors. This increases the risk of bleeding during delivery for the mother or in the newborn. To prevent this, vitamin K may be administered to the mother during the last month of pregnancy and to the newborn immediately after birth.

Phenytoin Rubió contains alcohol and propylene glycol, which should be taken into account in pregnant women (see section 2 – “Phenytoin Rubió contains ethanol and propylene glycol”).

Phenytoin Rubió may cause serious congenital anomalies. If you take Phenytoin Rubió during pregnancy, your baby has up to 3 times higher risk of congenital malformations compared to babies of women not taking antiepileptic medicines. Serious congenital anomalies have been reported, such as growth abnormalities, skull, face, nails, fingers, and heart defects. Some of these may occur together 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 neurological development in children exposed in utero, although other studies have not found such an effect. A possible effect on neurological development cannot be ruled out.

Breastfeeding

Consult your doctor or pharmacist before using any medicine.

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

Phenytoin Rubió contains alcohol and propylene glycol, which should be taken into account in breastfeeding women (see section 2 – “Phenytoin Rubió contains ethanol and propylene glycol”).

Driving and use of machines

Phenytoin Rubió may cause symptoms such as drowsiness, dizziness, or visual disturbances, and may reduce reaction ability. These effects, as well as the underlying disease itself, may impair your ability to drive or operate machinery. Therefore, do not drive, operate machinery, or engage in other activities requiring special attention until your doctor has assessed your response to this medicine.

Phenytoin Rubió contains ethanol and propylene glycol

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

The alcohol content should be considered in pregnant or breastfeeding women, children, and high-risk groups such as patients with liver disease or epilepsy.

This medicine contains 830.4 mg of propylene glycol in each 2 ml vial and 2076 mg in each 5 ml vial.

If you are pregnant or breastfeeding, do not take this medicine unless recommended by your doctor. Your doctor may perform additional monitoring while you are taking this medicine.

If you have hepatic or renal insufficiency, do not take this medicine unless recommended by your doctor. Your doctor may perform additional monitoring while you are taking this medicine.

3. How to use Fenitoína Rubió

Follow exactly the instructions for administering Fenitoína Rubió as given by your doctor. If in doubt, consult your doctor again.

To establish the correct dosing 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 (approximately 20 minutes for a 70 kg patient). The loading dose should be followed 24 hours later by maintenance doses of 5–7 mg/kg/day administered intravenously in 3 or 4 divided doses.

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 initial dose, 1/4 dose at 8 h, and 1/4 dose at 16 h), followed by maintenance doses of 5–7 mg/kg/24 h given in 3 divided doses (every 8 hours), i.e., at 24, 32, 40 h, and thereafter.

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

• Arrhythmias

Administer 50 to 100 mg every 10 to 15 minutes until the arrhythmia resolves or until the maximum dose of 1000 mg is reached. The injection must be administered with extreme caution, with continuous ECG and blood pressure monitoring recommended. The injection rate must not exceed 25–50 mg/min.

• Elderly patients and/or with hepatic impairment

In elderly, critically ill, debilitated patients, or those with severe liver disease, the total dose and the rate of administration should be reduced to 25 mg per minute or even as low as 5–10 mg per minute to reduce the risk of adverse effects.

If you use more Fenitoína Rubió than you should

If you have used more Fenitoína Rubió than you should, contact your doctor or pharmacist as soon as possible, indicating the medicine and the amount taken. You may also call the Toxicology Information Service at telephone number 91 562 04 20, stating the medicine and the amount ingested.

Initial symptoms include: involuntary eye movements, muscle spasms, and difficulty speaking. Other symptoms include: tremor, excessive flexion, numbness, slurred speech, nausea, and vomiting. In such cases, the dose should be reduced or treatment discontinued. Treatment consists of maintaining respiration and blood circulation and providing appropriate supportive measures.

If you forget to use Fenitoína Rubió

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

If you stop treatment with Fenitoína Rubió

Consult your doctor for advice on how to restart treatment.

If you have any further questions 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 everyone may experience them.

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

Skin rashes may occur that could be life-threatening (Stevens-Johnson syndrome, toxic epidermal necrolysis) (see section 2).

Bone abnormalities have been reported, including osteopenia and osteoporosis (bone demineralization) and fractures. Consult your doctor or pharmacist if you are on long-term treatment with antiepileptics, have a history of osteoporosis, or are taking steroids.

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

Very Common (affects more than 1 in 10 people)

Cardiovascular disorders: hypotension (avoid rapid administration).

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

Common (affects 1 to 10 in 100 people)

Gastrointestinal disorders: nausea, vomiting, constipation.

Skin and subcutaneous tissue disorders: skin rash sometimes accompanied by fever.

Rare (affects 1 to 10 in 10,000 people)

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 of these complications have been fatal. Abnormalities in blood test results and lymph node disease may occur.

Hepatobiliary disorders: liver damage.

Nervous system disorders: involuntary movements, including jerky movements, rigidity, tremor, and jerking tremors in the wrists.

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

Skin and subcutaneous tissue disorders: widespread peeling of the skin.

Very rare (affects fewer than 1 in 10,000 people) or frequency not known (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 may affect many organs of the body (systemic lupus erythematosus), inflammation of the tissues surrounding arteries with nodule formation (nodular periarteritis), and immunoglobulin abnormalities (immunizing proteins).

Hepatobiliary disorders: toxic liver inflammation.

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

Musculoskeletal and connective tissue disorders: coarsening of facial features, lip enlargement, and abnormalities in penile erection (Peyronie's disease).

If you consider any of the adverse effects you experience to be severe, or if you notice any adverse effect not mentioned in this leaflet, 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 not listed in this leaflet. You can also report them directly via the Spanish Pharmacovigilance System for Human Medicinal Products: www.notificaram.es. By reporting adverse reactions, you can help provide more information on the safety of this medicine.

5. Storage of Fenitoína Rubió

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

This medicine does not require special storage conditions.

Do not use Fenitoína Rubió after the expiry date stated on the packaging after EXP. The expiry date is the last day of the month indicated.

Do not use Fenitoína Rubió if the solution appears cloudy or if precipitates are present.

6. Contents of the container and other information

Composition of Fenitoína Rubió

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

Appearance of the product and contents of the pack

Fenitoína Rubió is presented as an injectable solution for intravenous administration.

Each ampoule contains 50 mg/ml of phenytoin.

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

Not all pack sizes 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 most recent revision of this leaflet: June 2021

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

This information is intended for healthcare professionals only:

Phenytoin solution is compatible only with physiological saline, at a final concentration of 1–10 mg/ml. No other intravenous infusion solutions are recommended due to the low solubility of the drug at pH values below 10.

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

The solution may be administered directly via intravenous route. It may also be given by intravenous infusion after dilution exclusively in physiological saline to a final concentration of 1–10 mg/ml. It is advisable to administer sterile saline solution before and after the infusion through the same catheter or needle to prevent local venous irritation caused by the alkalinity of the solution.

Plasma phenytoin level monitoring is recommended to ensure efficacy and to adjust maintenance doses accordingly. Therapeutic serum levels range between 10 and 20 µg/ml.

During infusion, monitoring of vital signs and ECG is recommended.