Epitope (Tablets) Instructions for Use

Marketing Authorization Holder

Gerot Pharmazeutika, GmbH (Austria)

Manufactured By

G.L. Pharma, GmbH (Austria)

Or

Pharmathen, S.A. (Greece)

Quality Control Release

GEROT PHARMAZEUTIKA, GmbH (Austria)

ATC Code

N03AX11 (Topiramate)

Active Substance

Topiramate (Rec.INN registered by WHO)

Dosage Forms

	Epitope	Film-coated tablets, 25 mg: 30 pcs.
		Film-coated tablets, 100 mg: 30 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white, round, biconvex.

10 pcs. – blisters (3) made of PVC/PVDC/PE/Al – cardboard packs.

Film-coated tablets orange, oval, biconvex.

10 pcs. – blisters (3) – cardboard packs.

Clinical-Pharmacological Group

Anticonvulsant drug

Pharmacotherapeutic Group

Anticonvulsant agent

Pharmacological Action

Topiramate is an antiepileptic drug belonging to the class of sulfamate-substituted monosaccharides.

Topiramate reduces the frequency of action potentials characteristic of a neuron in a state of persistent depolarization, which indicates the dependence of the drug’s blocking action on sodium channels on the state of the neuron. Topiramate potentiates the activity of GABA on some subtypes of GABA receptors (including GABA_A receptors), and also modulates the activity of the GABA_A receptors themselves, prevents the activation of kainate-sensitive kainate/AMPA receptors by glutamate, and does not affect the activity of N-methyl-D-aspartate on NMDA receptors. These effects of topiramate are dose-dependent at plasma topiramate concentrations from 1 µM to 200 µM, with minimal activity in the range from 1 µM to 10 µM.

In addition, Topiramate inhibits the activity of some carbonic anhydrase isoenzymes; however, this effect is weaker in topiramate than in acetazolamide and is apparently not the main one in the antiepileptic activity of topiramate.

Pharmacokinetics

After oral administration, Topiramate is absorbed quickly and effectively. Bioavailability is 81%. Food intake does not have a clinically significant effect on the bioavailability of topiramate. Plasma protein binding is 13-17%. After a single dose of up to 1.2 g, the average V_d is 0.55-0.8 L/kg. The V_d value depends on gender: in women it is approximately 50% of the values observed in men, which is associated with a higher fat content in the body of women. The pharmacokinetics of topiramate is linear. Plasma clearance remains constant, while the AUC in the dose range from 100 to 400 mg increases proportionally to the dose. C_ss in plasma is reached in 4-8 days. After multiple oral administration at a dose of 100 mg 2 times/day, C_max averages 6.76 µg/ml. After oral administration, about 20% of the administered dose is metabolized. 6 almost inactive metabolites have been identified in human plasma, urine, and feces. It is excreted mainly by the kidneys unchanged (70%) and in the form of metabolites. Plasma clearance is 20-30 ml/min. After multiple administration at doses of 50 mg and 100 mg 2 times/day, the T_1/2 of topiramate from plasma averages 21 hours.

Indications

Epilepsy: as monotherapy for initial treatment in patients over 2 years of age – partial or primary generalized tonic-clonic seizures; as part of complex therapy in patients over 2 years of age – partial or generalized tonic-clonic seizures, as well as seizures against the background of Lennox-Gastaut syndrome.

Migraine: prevention of migraine attacks in adults.

ICD codes

Dosage Regimen

Determine the dosage individually based on indication, patient age, renal function, and therapeutic response.

For epilepsy monotherapy in adults and children over 2 years, initiate with 25 mg once daily in the evening. Increase the dose weekly by 25-50 mg in two divided doses. Titrate to the effective dose, typically 100 mg to 200 mg twice daily.

For epilepsy adjunctive therapy in adults and children over 2 years, initiate with 25-50 mg daily. Increase by 25-50 mg at weekly intervals. The recommended total daily dose is 200-400 mg in two divided doses.

For migraine prevention in adults, initiate with 25 mg once daily in the evening. Increase the dose weekly by 25 mg to the recommended daily dose of 100 mg in two divided doses.

In patients with moderate to severe renal impairment (creatinine clearance less than 70 mL/min), reduce the total daily dose by 50%. For patients undergoing hemodialysis, administer a supplemental dose equivalent to one-half the daily dose, given in divided doses during dialysis.

When discontinuing, reduce the dose gradually. In adults with epilepsy, decrease by 50-100 mg at weekly intervals. For migraine prevention, decrease by 25-50 mg weekly. In children, withdraw over 2 to 8 weeks.

Swallow tablets whole with water. Do not crush or chew.

Adverse Reactions

Nervous system disorders: paresthesia, drowsiness, dizziness, attention impairment, memory impairment, amnesia, psychomotor disorders, convulsions, impaired coordination, tremor, lethargy, hypesthesia, nystagmus, dysgeusia, balance disorder, articulation disorder, intention tremor (dynamic), sedative effect, depression of consciousness, grand mal convulsions, visual field defect, complex partial seizures, speech disorder, psychomotor hyperactivity, syncope, sensory disturbances, drooling, aphasia, speech repetition, hypokinesia, dyskinesia, postural dizziness, poor sleep quality, burning sensation, loss of sensation, parosmia, cerebellar syndrome, dysesthesia, hypogeusia, stupor, clumsiness, aura, ageusia, dysgraphia, dysphasia, peripheral neuropathy, presyncope, dystonia, apraxia, circadian rhythm sleep disorder, hyperesthesia, hyposmia, anosmia, essential tremor, akinesia, lack of response to stimuli, learning difficulties.

Psychiatric disorders: depression, slowed thinking, cognitive disorders, insomnia, severe speech disorders, anxiety, confusion, disorientation, aggression, mood lability, anxious agitation, emotional lability, depressed mood, anger, inappropriate behavior, suicidal ideation or attempts, auditory and visual hallucinations, psychotic disorder, apathy, lack of spontaneous speech, sleep disorders, affective lability, decreased libido, restlessness, tearfulness, dysphemia, euphoria, paranoid states, perseveration of thinking, panic attack, lachrymation, reading skill impairment, emotional flattening, sleep onset disorder, pathological thinking, loss of libido, sluggishness, intrasomnic disorder, pathologically increased distractibility, early morning awakenings, panic reaction, mania, panic disorder, feeling of despair, hypomanic state.

Eye disorders: blurred vision, diplopia, visual impairment, decreased visual acuity, scotoma, myopia, eye discomfort, dry eyes, photophobia, blepharospasm, increased lacrimation, photopsia, mydriasis, presbyopia, unilateral blindness, transient blindness, glaucoma, accommodation disorder, depth perception impairment, flickering scotoma, eyelid edema, night blindness, amblyopia, angle-closure glaucoma, maculopathy, oculomotor disorders.

Blood and lymphatic system disorders: anemia, leukopenia, thrombocytopenia, lymphadenopathy, eosinophilia, neutropenia.

Immune system disorders: hypersensitivity, allergic edema, conjunctival edema.

Metabolism and nutrition disorders: anorexia, decreased appetite, metabolic acidosis, hypokalemia, increased appetite, polydipsia, hyperchloremic acidosis.

Ear and labyrinth disorders: vertigo, tinnitus, ear pain, deafness, unilateral deafness, sensorineural hearing loss, ear discomfort, hearing impairment.

Cardiac disorders: bradycardia, sinus bradycardia, palpitations, orthostatic hypotension, hot flush, hyperemia, Raynaud’s phenomenon.

Respiratory, thoracic and mediastinal disorders: nasopharyngitis, dyspnea, epistaxis, nasal congestion, rhinorrhea, cough, exertional dyspnea, sinus hypersecretion, dysphonia.

Gastrointestinal disorders: nausea, diarrhea, vomiting, constipation, upper abdominal pain, dyspepsia, abdominal pain, dry mouth, stomach discomfort, oral paresthesia, gastritis, abdominal discomfort, pancreatitis, flatulence, gastroesophageal reflux disease, lower abdominal pain, oral hypesthesia, gingival bleeding, abdominal distension, epigastric discomfort, generalized abdominal tenderness, salivary hypersecretion, oral pain, halitosis, glossodynia, hepatitis, hepatic failure.

Skin and subcutaneous tissue disorders: alopecia, pruritus, rash, anhidrosis, facial hypesthesia, urticaria, erythema, generalized pruritus, maculopapular rash, skin discoloration, allergic dermatitis, facial edema, Stevens-Johnson syndrome, erythema multiforme, skin odor unpleasant, periorbital edema, localized urticaria, toxic epidermal necrolysis.

Musculoskeletal and connective tissue disorders: arthralgia, muscle spasms, myalgia, muscle cramps, muscle weakness, chest muscle pain, joint swelling, muscle stiffness, flank pain, muscle fatigue, limb discomfort.

Renal and urinary disorders: nephrolithiasis, pollakiuria, dysuria, urinary calculi, stress urinary incontinence, hematuria, urgent painful urination, renal colic, renal pain, ureteral calculus, renal tubular acidosis.

Reproductive system and breast disorders: erectile dysfunction, sexual dysfunction.

General disorders and administration site conditions: fatigue, pyrexia, asthenia, irritability, gait disturbance, unusual sensations, malaise, hyperthermia, thirst, flu-like condition, inertia, cold extremities, feeling of drunkenness, feeling of anxiety, facial edema, calcification.

Investigations: weight decreased, weight increased, crystalluria, abnormal tandem gait test, leukopenia, increased hepatic enzymes, hypokalemia, decreased blood bicarbonate.

Contraindications

Hypersensitivity to topiramate.

Use in Pregnancy and Lactation

There have been no adequate and strictly controlled clinical studies of the safety of topiramate use during pregnancy.

The use of topiramate during pregnancy can cause fetal damage. Pregnancy registry data show that intrauterine exposure to topiramate increases the risk of developing congenital malformations (for example, craniofacial defects such as cleft lip/palate, hypospadias, and malformations of various body systems). These malformations have been recorded both with topiramate monotherapy and with its use as part of combination therapy. Compared with the group of patients not taking antiepileptic drugs, pregnancy registry data for topiramate monotherapy indicate an increased frequency of low birth weight (less than 2500 g). A causal relationship has not been established.

When treating women of childbearing age, the expected benefit of therapy for the mother and the potential risk to the fetus should be weighed and alternative treatment options should be considered. If Topiramate is used during pregnancy or if pregnancy occurs during treatment, the patient should be warned about the potential risk to the fetus.

A limited number of observations suggest that Topiramate is excreted in breast milk. If it is necessary to use it during lactation, the issue of stopping breastfeeding should be decided.

Use in Hepatic Impairment

Use with caution in patients with impaired liver function due to a possible decrease in topiramate clearance.

Pediatric Use

Do not use in children under 2 years of age.

Special Precautions

The use of topiramate for the treatment of acute migraine attacks has not been studied.

Use with caution in renal and hepatic insufficiency, nephrourolithiasis (including personal and family history), hypercalciuria.

Patients with impaired renal function and patients on hemodialysis require adjustment of the topiramate dosage regimen.

Topiramate should be discontinued gradually to minimize the possibility of an increase in the frequency of seizures. In clinical studies in adults for the treatment of epilepsy, doses were reduced by 50-100 mg at 1-week intervals and by 25-50 mg in adults receiving Topiramate at a dose of 100 mg/day for migraine prevention. In children in clinical studies, Topiramate was gradually withdrawn over 2-8 weeks. If rapid discontinuation of topiramate is medically necessary, patient monitoring is recommended.

To reduce the risk of nephrolithiasis during treatment, the volume of fluid consumed should be increased.

Against the background of topiramate use, decreased sweating and hyperthermia are possible, especially in young children, in conditions of elevated ambient temperature. Adequate fluid replacement before and during activities such as exercise or exposure to high temperatures may reduce the risk of heat-related complications.

During treatment, patients should be monitored for signs of suicidal ideation and appropriate treatment should be prescribed. Patients (and caregivers if necessary) should be advised to seek medical attention immediately if signs of suicidal ideation or suicidal behavior appear.

If visual disturbances occur, including a syndrome consisting of myopia associated with angle-closure glaucoma, Topiramate should be discontinued as soon as the attending physician deems it possible. If necessary, measures should be taken to reduce intraocular pressure.

To avoid the occurrence of metabolic acidosis, during treatment with topiramate, it is recommended to conduct the necessary studies, including determining the concentration of bicarbonates in the serum. If metabolic acidosis occurs and persists, it is recommended to reduce the dose or discontinue topiramate. In children, chronic metabolic acidosis can lead to growth retardation. The effect of topiramate on growth and possible complications associated with the skeletal system has not been systematically studied in children and adults.

If body weight decreases during treatment, the diet should be adjusted.

The simultaneous use of other drugs that have a depressant effect on the central nervous system is not recommended.

During treatment, the patient should avoid drinking alcohol.

Effect on ability to drive vehicles and operate machinery

Use with caution in patients engaged in potentially hazardous activities that require increased attention and speed of psychomotor reactions, because Topiramate can cause drowsiness, dizziness, and visual disturbances.

Drug Interactions

With simultaneous use with topiramate, phenytoin and carbamazepine reduce its plasma concentration. This is due to the induction by phenytoin and carbamazepine of enzymes involved in the metabolism of topiramate. In some cases, with the use of topiramate, an increase in the plasma concentration of phenytoin was observed.

With simultaneous use of a single dose of topiramate and digoxin, a decrease in the AUC of digoxin is possible.

With simultaneous use of an oral contraceptive containing norethindrone and ethinyl estradiol, Topiramate did not have a significant effect on the clearance of norethindrone, but the plasma clearance of ethinyl estradiol increased significantly. Thus, when taking topiramate simultaneously with oral contraceptives, their effectiveness may be reduced.

In patients taking metformin, pioglitazone, glibenclamide, fluctuations in plasma glucose levels are possible with simultaneous use or withdrawal of topiramate. With these combinations, plasma glucose levels should be monitored.

With simultaneous use of topiramate with drugs that predispose to the development of nephrolithiasis, the risk of kidney stone formation may increase.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.