SINERGINA 100 mg TABLETS

2. What you need to know before you take Sinergina

Do not take Sinergina

• if you are allergic (hypersensitive) to phenytoin or any of the other ingredients of this medicine (listed in section 6).
• if you are allergic to medications of the hydantoin type.
• if you are taking a medication for the treatment of HIV infection called delavirdine.

Warnings and precautions

Consult your doctor or pharmacist before starting to take this medicine.

• if you have a liver disease, have other serious diseases or are an elderly patient. If during treatment you notice symptoms suggestive of hepatitis, such as jaundice (yellowing of the skin and whites of the eyes), you should immediately consult your doctor,
• if you have porphyria (a hereditary disease that affects hemoglobin biosynthesis),
• if you are diabetic, as phenytoin may increase glucose levels,
• if you consume large amounts of alcohol or if you do so in small amounts but habitually,
• if you are undergoing cranial radiotherapy or are reducing your treatment with corticosteroids,
• if you are of black race, your immune system is depressed, a family member or you have had a history of drug hypersensitivity syndrome (HSS) or drug rash with eosinophilia and systemic symptoms (DRESS) (a syndrome that usually presents with fever, skin rash, lymph node involvement and other organs, such as the liver, kidneys, heart, lungs, and blood abnormalities), as you are at higher risk of presenting this syndrome. If during treatment you present with fever, skin rash with lymph node swelling, which can be signs of hypersensitivity to the medication, you should immediately consult your doctor,
• skin rashes that can be life-threatening (Stevens-Johnson syndrome and toxic epidermal necrolysis) have been described with the use of this medication. Serious skin effects occur rarely during treatment with phenytoin. Initially, they appear as red spots or 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 risk may be associated with a variant of a gene in some subjects of Thai or Chinese origin. If you are of this ancestry and have been previously analyzed and know that you have the genetic variant (HLA-B*1502), talk to your doctor before taking phenytoin. If you develop rashes or these skin symptoms, go immediately to a doctor and inform them that you are taking this medication,
• if during treatment you suffer from a state of confusion (such as delirium, psychosis, etc.), which can be a sign of an excessive amount of phenytoin in the blood, you should immediately consult your doctor,
• a small number of people treated with antiepileptics, such as Sinergina, have had thoughts of self-harm or suicide. If at any time you have these thoughts, contact your doctor immediately,
• there is a risk of harm to the fetus if Sinergina is used during pregnancy. Women of childbearing age must use effective contraceptive methods during treatment with Sinergina (see "Pregnancy and lactation"),
• if you are of Taiwanese, Japanese, Malay, or Thai origin and tests have shown that you are a carrier of the CYP2C9*3 mutation.

During treatment with this medication, it is essential to maintain good oral hygiene. This way, you can prevent the appearance of adverse effects in the oral area, such as gum thickening.

It is very important that your doctor monitors your treatment in periodic visits and performs regular analyses to rule out the appearance of blood alterations, monitor liver function, and sometimes to control the most suitable dose of Sinergina.

Interaction with laboratory tests

Sinergina may interfere with certain laboratory tests that are performed on you.

Phenytoin may reduce serum levels of protein-bound iodine. It may also produce lower-than-normal results in dexamethasone or metyrapone tests. Phenytoin may produce increases in blood glucose or serum concentrations of alkaline phosphatase and gamma-glutamyl transpeptidase (GGT), as well as affect calcium and glucose metabolism tests in blood.

Other medicines and Sinergina

Before using a new medicine with Sinergina, you must consult your doctor.

Inform your doctor or pharmacist if you are using, have recently used, or may need to use any other medicine, including those obtained without a prescription.

Sinergina and certain medications can influence each other (interactions), causing an imbalance in the levels of both medications in the blood.

The following medications can increase phenytoin levels:

• Analgesics/anti-inflammatory medications such as azapropazone, phenylbutazone, and salicylates.
• Anesthetics such as halothane.
• Antibiotics such as chloramphenicol, erythromycin, isoniazid, sulfadiazine, sulfamethizole, sulfamethoxazole-trimethoprim, sulfaphenazole, sulfisoxazole, and sulfonamides.
• Anticonvulsants such as felbamate, oxcarbazepine, sodium valproate, succinimides, and topiramate.
• Antifungals such as amphotericin B, fluconazole, itraconazole, ketoconazole, miconazole, and voriconazole.
• Antineoplastics such as capecitabine and fluorouracil.
• Benzodiazepines/psychotropics such as chlordiazepoxide, diazepam, disulfiram, methylphenidate, trazodone, and viloxazine.
• Calcium channel blockers/cardiovascular agents such as amiodarone, dicumarol, diltiazem, nifedipine, ticlopidine.
• H2 antagonists such as cimetidine.
• HMG-CoA reductase inhibitors such as fluvastatin.
• Hormones such as estrogens.
• Immunosuppressants such as tacrolimus.
• Oral antidiabetics such as tolbutamide.
• Proton pump inhibitors such as omeprazole.
• Selective serotonin reuptake inhibitors such as fluoxetine, fluvoxamine, sertraline.
• Acute alcohol consumption.

The following medications can decrease phenytoin levels:

• Antibiotics such as ciprofloxacin, rifampicin.
• Anticonvulsants such as vigabatrin.
• Antineoplastics such as bleomycin, carboplatin, cisplatin, doxorubicin, and methotrexate.
• Antiulcer agents such as sucralfate.
• Antiretrovirals such as fosamprenavir, nelfinavir, and ritonavir.
• Bronchodilators such as theophylline.
• Cardiovascular agents such as reserpine.
• Folic acid.
• Hyperglycemic agents such as diazoxide.
• St. John's Wort.
• Chronic alcohol consumption.
• Calcium preparations, including some antacids.

The following medications can increase or decrease phenytoin levels:

• Antibiotics such as ciprofloxacin.
• Anticonvulsants such as carbamazepine, phenobarbital, sodium valproate, and valproic acid.
• Antineoplastics.
• Psychotropics such as chlordiazepoxide, diazepam, and phenothiazines.

The following medications can have their blood levels and/or effects altered by the administration of phenytoin:

• Antibiotics such as doxycycline, rifampicin, and tetracycline.
• Anticoagulants, such as rivaroxaban, dabigatran, apixaban, and edoxaban.
• Anticonvulsants such as carbamazepine, lamotrigine, phenobarbital, sodium valproate, valproic acid.
• Antifungals of the azole family, such as posaconazole and voriconazole.
• Anthelmintics such as albendazole, praziquantel.
• Antineoplastics such as teniposide.
• Antiretrovirals such as delavirdine, efavirenz, fosamprenavir, indinavir, lopinavir/ritonavir, nelfinavir, ritonavir, and saquinavir.
• Bronchodilators such as theophylline.
• Calcium channel blockers/cardiovascular agents such as digitoxin, digoxin, mexiletine, nicardipine, nimodipine, nisoldipine, quinidine, and verapamil.
• Corticosteroids.
• Coumarin anticoagulants.
• Cyclosporin.
• Diuretics such as furosemide.
• HMG-CoA reductase inhibitors such as atorvastatin, fluvastatin, and simvastatin.
• Hormones such as estrogens and oral contraceptives.
• Hyperglycemic agents such as diazoxide.
• Immunosuppressants.
• Neuromuscular blockers such as alcuronium, cisatracurium, pancuronium, rocuronium, and vecuronium.
• Opioid analgesics such as methadone.
• Oral antidiabetics such as chlorpropamide, gliburide, and tolbutamide.
• Psychotropics/antidepressants such as clozapine, paroxetine, quetiapine, and sertraline.
• Vitamin D.
• Lacosamide (antiepileptic)
• Ticagrelor (platelet aggregation inhibitor)

Some medications used to treat depression (tricyclic antidepressants) may precipitate the appearance of seizures in certain patients, so your doctor may decide to change the dose of phenytoin.

Taking Sinergina with food, drinks, and alcohol

Acute alcohol consumption may increase phenytoin levels, while chronic alcohol consumption may decrease them, so you should not drink alcohol during treatment with this medication.

If you have received enteral nutrition preparations and/or nutritional supplements, you may have lower-than-expected plasma levels of phenytoin. Therefore, it is recommended that phenytoin not be administered with enteral nutrition preparations and/or vitamin supplements. Your doctor may monitor the levels of the medication in your blood.

Pregnancy, breastfeeding, and fertility

If you are pregnant or breastfeeding, think you may be pregnant, or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

If you are pregnant or think you may be pregnant, inform your doctor immediately. Do not stop taking your medication until you have discussed it with your doctor. Stopping your medication without consulting your doctor could lead to seizures that could be dangerous for you and the fetus. Your doctor may decide to change your treatment.

Pregnancy

If you think you may be pregnant or plan to become pregnant, inform your doctor before taking Sinergina; he will indicate the potential risks to which you and your baby are exposed. This medication should only be administered to pregnant women if, in the doctor's judgment, the expected benefit to the mother is greater than any possible risk to the fetus.

Sinergina may cause serious congenital anomalies. If you take Sinergina during pregnancy, your baby is up to 3 times more likely to have a congenital anomaly than women who do not take an antiepileptic medication. Serious congenital anomalies have been reported, such as growth anomalies, skull, face, nail, finger, and heart anomalies. Some of these can occur at the same time 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 womb, although other studies have not found such an effect. The possibility of an effect on neurological development cannot be ruled out.

Fertility

If you are a woman of childbearing age and are not planning to become pregnant, you must use an effective contraceptive method during treatment with Sinergina. This medication may affect how hormonal contraceptives, such as birth control pills, work and make them less effective in preventing pregnancy. Consult your doctor, who will consider with you the most suitable contraceptive method to use while taking Sinergina.

If you are a woman of childbearing age and are planning to become pregnant, consult your doctor before stopping contraception and before becoming pregnant about changing to other suitable treatments to avoid exposing the fetus to phenytoin.

Breastfeeding

It is not recommended to take Sinergina during breastfeeding.

Driving and using machines

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

3. How to take Sinergina

Follow exactly the administration instructions of this medication indicated by your doctor or pharmacist. It is very important that you comply with them strictly. Inform your doctor of any reason that may prevent you from taking this medication, such as an operation.

In case of doubt, consult your doctor or pharmacist again.

This medication should be taken with at least half a glass of water. If you tend to have nausea or stomach heaviness, you can take the medication during or after meals.

Adults

The initial dose of treatment is 300 mg of Sinergina per day, divided into three equal doses (1 tablet every 8 hours before meals). Your doctor will indicate the maintenance dose you need, which should not exceed the maximum dose of 600 mg per day.

For patients who need to rapidly achieve high serum levels of phenytoin at steady state, the recommended loading dose is 1000 mg of phenytoin orally, divided into three doses [400 mg (4 tablets), 300 mg (3 tablets), and 300 mg (3 tablets)], at 2-hour intervals. This should be done in hospitalized patients, as monitoring of serum levels of the medication is necessary. After 24 hours of oral loading dose administration, your doctor will establish the maintenance dose.

Use in elderly patients

The dose of Sinergina in elderly patients who may be taking other medications needs to be adjusted by their doctor.

Use in children and adolescents

The initial dose is 5 mg/kg/day, divided into 2-3 equal doses. From there, the maintenance dose should be established by your doctor on an individual basis, not exceeding the maximum dose of 300 mg/day.

The recommended daily maintenance dose is 4 mg/kg/day to 8 mg/kg/day. If the daily dose cannot be divided equally, the larger dose should be given at night.

This presentation is not suitable for use in newborns, infants, children, and adolescents or for patients for whom the dose adjustment is not possible with this presentation due to their weight. For example, patients weighing less than 40 kilograms, due to the impossibility of dividing the dose into at least two separate doses.

The score lines are only for breaking the tablet if you find it difficult to swallow it whole.

If you take more Sinergina than you should

It is dangerous to take Sinergina at doses higher than those due. The initial symptoms are: involuntary eye movements, lack of muscular coordination, difficulty speaking, tremors, exaggerated reflexes, drowsiness, numbness, prolonged sleep, slurred speech, blurred vision, nausea, and vomiting. The patient may reach a state of coma and hypotension.

In case of overdose or accidental ingestion, consult your doctor or pharmacist immediately or call the Toxicology Information Service, phone: 91 562 04 20, indicating the medication and the amount ingested.

If you forget to take Sinergina

Do not take a double dose to make up for forgotten doses. If you forget to take a dose, take it as soon as you realize, unless it is close to the next dose, in which case, do not take the forgotten dose and wait for the next dose, continuing with your established dosing regimen. In case of doubt, consult your doctor or pharmacist.

If you interrupt treatment with Sinergina

Do not interrupt treatment with Sinergina unless your doctor indicates it. If you stop taking the medication abruptly, you may increase the frequency of seizures. If your doctor considers it necessary to interrupt treatment with this medication, they will decide on the most suitable alternative treatment for you.

If you have any other questions about the use of this medication, 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.

Tell your doctor immediately,if you experience any of the following symptoms after taking this medicine, as they may be serious:

Other adverse effects that may appear are:

• General disorders and administration site conditions: allergic reaction.
• Nervous system disorders: nystagmus (abnormal eye movements), ataxia (instability), slurred speech, decreased coordination, dizziness, vertigo, insomnia, transient nervousness, motor tremors (uncontrolled movements of different parts of the body), headache, paresthesias (tingling or decreased sensitivity, usually in a foot or hand), somnolence. Rarely, cases of different types of dyskinesias (uncontrolled movements or postures of different parts of the body) have been reported. In very prolonged treatments: peripheral polyneuropathy predominantly sensory (alteration of pain and touch sensation). Alteration of taste.
• Skin and subcutaneous tissue disorders: facial feature hardening, lip thickening, gum thickening, hirsutism (excessive localized or generalized hair growth).
• Reproductive system and breast disorders: Peyronie's disease (fibrous hardening of the penis that causes deviation or curvature of the penis during erection).
• Gastrointestinal disorders: vomiting, nausea, constipation.
• Immune system disorders: systemic lupus erythematosus (immune disease with involvement of different organs), polyarteritis nodosa (a type of inflammation of the arteries), alterations in immunoglobulins (proteins produced in the immune response).
• Musculoskeletal and connective tissue disorders: osteoporosis (decalcification of bones) and other alterations, including decreased levels of calcium, phosphorus, vitamin D, 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.
• Blood and lymphatic system disorders: decrease in the number of a type of red blood cell (pure red cell aplasia).
• Vascular disorders: vasculitis (inflammation of blood vessel walls).

Other adverse effects in children and adolescents

Adverse events reported are generally similar in children and adults. Gingival hyperplasia occurs more frequently in pediatric patients and in those with poor oral hygiene.

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 that does not appear in this prospectus. You can also report them directly through the Spanish Pharmacovigilance System for Human Use Medicines: https://www.notificaRAM.es/. By reporting adverse effects, you can contribute to providing more information on the safety of this medicine.

5. Storage of Sinergina

It does not require special storage conditions.

Keep this medicine out of sight and reach of children.

Do not use this medicine after the expiration date that appears on the packaging after CAD. The expiration date is the last day of the month indicated.

Medicines should not be thrown away through wastewater or household waste. Deposit the packaging and medicines you no longer need at the SIGRE Point in the pharmacy. In case of doubt, ask your pharmacist how to dispose of the packaging and medicines you no longer need. This way, you will help protect the environment.

6. Package Contents and Additional Information

Composition of Sinergina 100 mg tablets

• The active ingredient is phenytoin. Each tablet contains 100 mg of phenytoin.
• The other components are: microcrystalline cellulose, magnesium stearate, and povidone K 29/32.

Appearance of the product and package contents

Sinergina 100 mg are round, birranurated, slightly convex tablets, 8 mm in diameter, and white in color. They are presented in a package containing 100 tablets in PVC/AL blisters.

Marketing Authorization Holder

Faes Farma, S.A.

Autonomia Etorbidea, 10

48940 Leioa (Bizkaia)

Spain

Manufacturer

Faes Farma, S.A.

Maximo Agirre Kalea, 14

48940 Leioa (Bizkaia)

Spain

O

Faes Farma, S.A.

Parque Científico y Tecnológico de Bizkaia

Ibaizabal Bidea, Edificio 901

48160 Derio (Bizkaia)

Spain

Date of the last revision of this prospectus: November 2022

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