Epymax (Tablets) Instructions for Use

Marketing Authorization Holder

Novosibkhimpharm, JSC (Russia)

Manufactured By

Valenta Pharm, JSC (Russia)

ATC Code

N03AX11 (Topiramate)

Active Substance

Topiramate (Rec.INN registered by WHO)

Dosage Forms

	Epymax	Film-coated tablets, 25 mg: 28 pcs.
		Film-coated tablets, 100 mg: 28 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets of a yellowish-beige color, round, biconvex; white or almost white in fracture.

Excipients: lactose monohydrate, microcrystalline cellulose, pregelatinized starch, sorbitol, colloidal silicon dioxide (aerosil), magnesium stearate.

Shell composition: Opadry II (series 85): partially hydrolyzed polyvinyl alcohol, macrogol 3350, titanium dioxide (E171), talc, iron oxide yellow dye (E172).

28 pcs. – polymer jars (1) – cardboard packs.

Film-coated tablets of a light brown color, round, biconvex; white or almost white in fracture.

Excipients: lactose monohydrate, microcrystalline cellulose, pregelatinized starch, sorbitol, colloidal silicon dioxide (aerosil), magnesium stearate.

Shell composition: Opadry II (series 85): partially hydrolyzed polyvinyl alcohol, macrogol 3350, titanium dioxide (E171), talc, iron oxide yellow dye (E172).

28 pcs. – polymer jars (1) – cardboard packs.

Clinical-Pharmacological Group

Anticonvulsant drug

Pharmacotherapeutic Group

Antiepileptic agent

Pharmacological Action

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 sustained depolarization, which indicates the dependence of the drug’s blocking effect on sodium channels on the state of the neuron.

Topiramate potentiates the activity of GABA towards 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 concentrations of topiramate from 1 µM to 200 µM, with minimal activity in the range from 1 µM to 10 µM.

Furthermore, 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 rapidly and effectively.

The 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 are 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 twice daily, C_max averages 6.76 µg/ml.

After oral administration, about 20% of the administered dose is metabolized.

Six 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 twice daily, 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 associated with Lennox-Gastaut syndrome.

Migraine: prevention of migraine attacks in adults.

ICD codes

Dosage Regimen

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

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

For adjunctive epilepsy therapy, initiate with 25-50 mg nightly for one week. Increase by 25-50 mg weekly in two divided doses. The effective total daily dose is typically 200 mg to 400 mg.

For migraine prevention in adults, initiate with 25 mg once nightly. Increase weekly by 25 mg in two divided doses. The recommended total daily dose is 50 mg to 100 mg.

For patients with moderate to severe renal impairment (CrCl less than 70 mL/min), reduce the total daily dose by 50%. Administer the usual dose before and after a hemodialysis session.

For pediatric patients (2-16 years) with epilepsy, base the initial dose on weight: 25 mg (or 1-3 mg/kg) nightly. Titrate weekly by 1-3 mg/kg/day in two divided doses. The target maintenance dose is 5-9 mg/kg/day.

Swallow tablets whole; do not chew. Administer with a sufficient amount of fluid.

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

Adverse Reactions

Nervous system disorders: paresthesia, drowsiness, dizziness, attention impairment, memory impairment, amnesia, psychomotor disorders, convulsions, incoordination, tremor, lethargy, hypesthesia, nystagmus, dysgeusia, balance disorder, articulation disorder, intention tremor (dynamic), sedative effect, depressed level 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 quality sleep, 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, unresponsiveness to stimuli, learning difficulties.

Psychiatric disorders: depression, slowed thinking, cognitive disorders, insomnia, marked speech impairment, anxiety, confusion, disorientation, aggression, mood lability, agitated anxiety, 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 impairment, emotional flattening, sleep initiation disorder, pathological thinking, loss of libido, listlessness, intrasomnic disorder, pathologically increased distractibility, early morning awakening, 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 eye, 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 deafness, ear discomfort, hearing impairment.

Cardiac disorders: bradycardia, sinus bradycardia, palpitations, orthostatic hypotension, flushing, 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, maculous rash, skin discoloration, allergic dermatitis, facial edema, Stevens-Johnson syndrome, erythema multiforme, skin odor abnormal, 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, urinary urgency, 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, influenza-like illness, inertia, cold extremities, feeling drunk, 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

Adequate and strictly controlled clinical studies on the safety of topiramate use during pregnancy have not been conducted.

The use of topiramate during pregnancy can cause fetal harm.

Pregnancy registry data show that intrauterine exposure to topiramate increases the risk of congenital malformations (e.g., 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 to 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 potential, 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 use during lactation is necessary, the issue of discontinuing 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 withdrawn gradually to minimize the possibility of an increase in the frequency of seizures.

In clinical studies in adults for epilepsy treatment, 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 intake should be increased.

During the use of topiramate, 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 the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Patients (and caregivers, if applicable) should be advised to seek medical advice 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 treating physician deems it possible.

If necessary, measures should be taken to lower intraocular pressure.

To avoid the occurrence of metabolic acidosis, necessary examinations, including determination of serum bicarbonate concentration, are recommended during treatment with topiramate.

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 concomitant use of other drugs that have a depressant effect on the CNS is not recommended.

During treatment, the patient should avoid alcohol consumption.

Effect on ability to drive vehicles and operate machinery

Use with caution in patients engaged in potentially hazardous activities requiring increased attention and speed of psychomotor reactions, as Topiramate may cause drowsiness, dizziness, and visual disturbances.

Drug Interactions

With simultaneous use, phenytoin and carbamazepine reduce the plasma concentration of topiramate.

This is due to the induction by phenytoin and carbamazepine of enzymes involved in the metabolism of topiramate.

In some cases, an increase in the plasma concentration of phenytoin was observed with the use of topiramate.

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 topiramate is taken concomitantly 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 8°C (46°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.