Topiramate Canon, 100 mg 28 pcs

The drug belongs to the class of sulfate-substituted monosaccharides.

Topiramate reduces the frequency of action potentials that are characteristic of the neuron in the state of persistent depolarization, indicating that the drug’s blocking effect on sodium channels depends on the state of the neuron. This active substance potentiates the GABA activity against some GABA receptor subtypes (including GABAA-receptors), modulates the activity of GABAA-receptors themselves, and also prevents kainat activation of kainate/AMPK receptor sensitivity to glutamate and does not affect N-methyl-D-aspartate activity against NMDA-receptors. These effects of topiramate are dose-dependent at plasma concentrations of topiramate between 1 μM and 200 μM, with minimal activity between 1 μM and 10 μM.

In addition, topiramate inhibits the activity of some carboanhydrase isoenzymes, but this effect in topiramate is weaker than in acetazolamide and apparently is not central to the antiepileptic activity of topiramate.

Pharmacokinetics

After oral administration topiramate is absorbed quickly and effectively. Bioavailability is 81%. Food intake has no clinically significant effect on the bioavailability of topiramate. Binding to plasma proteins is 13-17%. After a single dose of up to 1.2 g the average Vd is 0.55-0.8 l/kg.

Vd value depends on sex: in women it is about 50% of values observed in men that is associated with a higher content of adipose tissue in women. Pharmacokinetics of topiramate is linear. Plasma clearance remains constant, while AUC in the dose range from 100 to 400 mg increases in proportion to the dose.

The plasma Css is reached in 4-8 days. After multiple oral doses of 100 mg 2 times/day, Cmax averages 6.76 mcg/ml. After oral administration, about 20% of the administered dose is metabolized. Six virtually inactive metabolites are identified in plasma, urine and feces.

It is mainly excreted by the kidneys unchanged (70%) and as metabolites. Plasma clearance is 20-30 ml/min. After multiple doses of 50 mg and 100 mg 2 times per day the T1/2 of topiramate from plasma averages 21 hours.

Indications

Epilepsy: as monotherapy for initial treatment in patients over 2 years old – partial or primary generalized tonic-clonic seizures; in complex therapy in patients over 2 years old – partial or generalized tonic-clonic seizures, as well as seizures against Lennox-Gastaud syndrome.

Migraine: prevention of migraine attacks in adults.

Active ingredient

Composition

1 tablet topiramate 100 mg

Associated substances:

Lactose monohydrate,

Microcrystalline cellulose,

Pregelatinized starch,

sorbitol,

colloidal silicon dioxide,

magnesium stearate.

Composition of the film coating:

Opadray II (Series 85) – partially hydrolyzed polyvinyl alcohol, macrogol-3350, titanium dioxide E 171, talc, iron oxide yellow dye E 172.Excipients: lactose monohydrate, microcrystalline cellulose, pregelatinized starch, sorbitol, colloidal silicon dioxide, magnesium stearate.

How to take, the dosage

Individual, depending on the indication, age of the patient, kidney function, and effectiveness of current therapy.

Interaction

The effect of topiramate on concentrations of other antiepileptic drugs (PEDs)
Simultaneous use of topiramate with phenytoin and carbamazepine decreases its plasma concentrations. This is due to induction under the influence of phenytoin and carbamazepine of enzymes that participate in metabolism of topiramate. In some cases when using topiramate an increase in plasma concentrations of phenytoin was observed.

Concomitant use of a single dose of topiramate and digoxin may decrease AUC of digoxin.

Concomitant use of an oral contraceptive containing norethindrone and ethinylestradiol had no significant effect on norethindrone clearance, but the plasma clearance of ethinylestradiol was significantly increased. Thus, when topiramate is taken concomitantly with oral contraceptives, their efficacy may be reduced.

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

Concomitant use of topiramate with drugs that predispose to nephrolithiasis may increase the risk of kidney stones.The concomitant use of topiramate with other PEPs (phenytoin, carbamazepine, valproic acid, phenobarbital, primidone) has no effect on their equilibrium plasma concentrations, except in individual patients in whom the addition of topiramate to phenytoin may increase phenytoin plasma concentrations. In every patient who takes phenytoin and develops clinical signs or symptoms of toxicity, plasma phenytoin concentrations should be monitored.
In a study of pharmacokinetics in epilepsy patients, the addition of topiramate to lamotrigine had no effect on the equilibrium concentration of the latter at topiramate doses of 100-400 mg daily. During therapy and after withdrawal of lamotrigine (mean dose 327 mg daily), the equilibrium concentration of topiramate did not change.
Effects of other antiepileptic drugs on topiramate concentrations
Phenytoin and carbamazepine reduce plasma concentrations of topiramate. Addition or withdrawal of phenytoin or carbamazepine during treatment with topiramate may require changing the dose of the latter. The dose should be adjusted with a view to achieving the desired clinical effect. Addition or withdrawal of valproic acid does not cause clinically significant changes in plasma concentrations of Topiramate and therefore does not require a change in Topiramate dose.
Other Drug Interactions
Digoxin: In a study, the AUC of digoxin in plasma was reduced by 12% when Topiramate was taken simultaneously using a single dose of digoxin. Special attention should be paid to routine monitoring of serum digoxin concentrations when using or withdrawing Topiramate in patients taking digoxin.
Topiramate should not be taken with alcohol or other drugs that inhibit CNS function.
Oral contraceptives: Significant dose-dependent reduction in ethinylestradiol effectiveness was observed at Topiramate doses of 200-800 mg daily. The risk of decreased contraceptive efficacy and increased breakthrough bleeding should be considered in patients taking oral contraceptives in combination with Topiramate. Patients taking estrogen-containing contraceptives should be advised of any changes in the timing and pattern of menstruation. The efficacy of contraceptives may be further reduced in the absence of breakthrough bleeding.
Lithium drugs: When topiramate and lithium drugs are used concomitantly, plasma lithium concentrations should be monitored.
Risperidone: Concurrent use of topiramate at doses of 250 or 400 mg daily decreases AUC of risperidone taken at doses of 1-6 mg daily by 16% and 33% respectively. Total pharmacokinetics of active substances (risperidone and 9-hydroxyrisperidone) did not change significantly.
Hydrochlorothiazide: Concomitant administration of topiramate and hydrochlorothiazide increases maximum concentration of topiramate by 27% and AUC of topiramate by 29%. The use of hydrochlorothiazide in patients taking topiramate may require adjustment of the topiramate dose. Pharmacokinetic parameters of hydrochlorothiazide were not significantly altered by concomitant therapy with topiramate.
Metformin: Concomitant administration of topiramate and metformin increased maximum concentration and AUC of metformin by 18% and 25% respectively, while metformin clearance was decreased by 20% when concomitantly used with topiramate. Topiramate had no effect on the time to reach maximum metformin plasma concentration. Clearance of topiramate is decreased when coadministered with metformin. The extent of identified changes in clearance has not been studied. The clinical significance of the effect of metformin on topiramate pharmacokinetics is not clear. If Topiramate is added or withdrawn in patients receiving metformin, special attention should be paid to a careful study of patients with diabetes.
Pioglitazone: In clinical trials, a 15% decrease in the AUC of pioglitazone was found, with no change in the maximum concentration of the drug. These changes were not statistically significant. When patients co-administer Topiramate and pioglitazone, special attention should be paid to the careful study of patients with diabetes.
Glibenclamide: A drug interaction study was conducted to study the pharmacokinetics of glibenclamide (5 mg daily) in equilibrium used alone or simultaneously with topiramate (150 mg daily) in type 2 diabetic patients. When topiramate was used, the AUC of glibenclamide was reduced by 25%. Systemic exposure to active metabolites was also reduced. Glibenclamide had no effect on the pharmacokinetics of topiramate in equilibrium. When topiramate is used in patients receiving glibenclamide (or the use of glibenclamide in patients receiving topiramate), the patient should be carefully monitored to assess the course of diabetes.
Other drugs: concomitant use of topiramate with drugs that predispose to nephrolithiasis may increase the risk of kidney stones.
Valproic acid: Combined use of topiramate and valproic acid in patients who tolerate each drug separately well is accompanied by hyperammonemia with or without encephalopathy. In most cases, symptoms and signs disappear after withdrawal of one of the drugs. This adverse event is not caused by pharmacokinetic interaction. An association between hyperammonemia and the use of topiramate alone or in combination with other drugs has not been established.
Additional drug interaction studies have shown:
Amitriptyline: concomitant use of amitriptyline with topiramate results in a 20% increase in maximum concentration and AUC of the nortriptyline metabolite;
Haloperidol: concomitant use of haloperidol with topiramate increases the AUC of haloperidol by 31%;
Diltiazem: concomitant use of diltiazem with topiramate decreases the AUC of diltiazem by 25% and increases the AUC of topiramate by 20%.

Special Instructions

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

With caution should be used in renal and hepatic impairment, nephrourolithiasis (including personal and family history), hypercalciuria.

Patients with impaired renal function and patients on hemodialysis require dosing adjustment of topiramate.

Periramate should be withdrawn gradually to minimize the possibility of increased seizure frequency. In clinical trials in adults treated for 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 to prevent migraine. In children in clinical trials, topiramate was gradually withdrawn over 2-8 weeks. If a rapid withdrawal of topiramate is medically necessary, it is advisable to monitor the patient’s condition.

In order to reduce the risk of nephrolithiasis, fluid intake should be increased during treatment.

The use of topiramate may cause decreased sweating and hyperthermia, especially in young children, in high ambient temperatures. Adequate fluid replacement before and during activities such as exercise or exposure to high temperatures can reduce the risk of overheating-related complications.

Patients should be monitored during treatment 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.

In the event of visual disturbances, including syndrome involving myopia associated with closed-angle glaucoma, topiramate should be discontinued as soon as the treating physician considers it possible. If necessary, measures should be taken to lower intraocular pressure.

In order to avoid the occurrence of metabolic acidosis, necessary tests, including determination of serum bicarbonate concentrations, 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 may lead to growth retardation. The effects of topiramate on growth and possible bone-related complications have not been systematically studied in children and adults.

If body weight decreases with treatment, dietary adjustments should be made.

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

Patients should avoid alcohol during treatment.

Impact on driving and operating machinery

Patients engaged in potentially hazardous activities requiring increased attention and rapid psychomotor reactions should be used with caution, since topiramate may cause drowsiness, dizziness, visual disturbances.

Contraindications

Hypersensitivity to topiramate.

Perhaps with caution in patients with hepatic impairment because of possible decreased clearance of topiramate.

Side effects

Nervous system disorders: paresthesias, somnolence, dizziness, attention deficit, memory impairment, amnesia, psychomotor disorders, seizures, improper coordination, tremor, lethargy, hypoesthesia, nystagmus, dysgeusia, balance disorder, articulation disorder, intensional tremor (dynamic), sedation, depressed consciousness, grand mal seizure type seizures, visual field defect, complex partial seizures, speech disorder, psychomotor hyperactivity, syncope, sensory disturbances, salivation, aphasia, repetitive speech, hypokinesia, dyskinesia, postural vertigo, poor sleep quality, burning sensation, loss of sensation, parosmia, cerebellar syndrome, dysesthesia, hypogeusia, stupor, clumsiness, aura, agueusia dysgraphia, dysphasia, peripheral neuropathy, preconsciousness, dystonia, apraxia, circadian sleep disturbance, hyperaesthesia, hyposmia, anosmia, essential tremor, akinesia, lack of response to stimuli, learning difficulties.

Mental disorders: Depression, slowed thinking, cognitive impairment, insomnia, marked speech disorders, restlessness, confusion, disorientation, aggression, mood lability, anxiety agitation, emotional lability, depressed mood, anger, inadequate behavior, suicidal ideas or attempts, auditory and visual hallucinations, psychotic disorder, apathy, lack of spontaneous speech, sleep disorders, affective lability decreased libido, anxiety, tearfulness, dysphemia, euphoria, paranoid states, perseveration of thought, panic attack, tearfulness, impaired reading skills, flattened emotions, falling asleep disorder, pathological thinking, loss of libido, lethargy, intrasomnic disorder, pathologically increased distractibility, early morning waking, panic response, mania, panic disorder, despair, hypomaniacal state.

Visual side: blurred vision, diplopia, visual disturbances, decreased visual acuity, scotoma, myopia, abnormal eye sensations, dry eyes, photophobia, blepharospasm, increased lacrimation, photopsia, mydriasis, presbyopia, unilateral blindness, transient blindness, glaucoma, accommodation disorder, depth perception disorder, atrial fibrillation scotoma, eyelid edema, night blindness, amblyopia, closed-angle glaucoma, maculopathy, oculomotor disorders.

Hematopoietic system disorders: anemia, leukopenia, thrombocytopenia, lymphadenopathy, eosinophilia, neutropenia.

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

Metabolic disorders: anorexia, decreased appetite, metabolic acidosis, hypokalemia, increased appetite, polydipsia, hyperchloremic acidosis.

Hearing and balance: vertigo, tinnitus, ear pain, deafness, unilateral deafness, sensorineural deafness, tinnitus discomfort, hearing loss.

Cardiovascular system disorders: bradycardia, sinus bradycardia, palpitations, orthostatic hypotension, hot flashes, hyperemia, Raynaud’s phenomenon.

Respiratory system disorders: nasopharyngitis, dyspnea, nasal bleeding, nasal congestion, rhinorrhea, cough, dyspnea on exercise, hypersecretion in paranasal sinuses, dysphonia.

Digestive system disorders: Nausea, diarrhea, vomiting, constipation, upper abdominal pain, dyspepsia, abdominal pain, dry mouth, stomach discomfort, oral paraesthesia, gastritis, abdominal discomfort, pancreatitis, flatulence, gastroesophageal reflux disease, lower abdominal pain Oral hypoesthesia, bleeding gums, abdominal bloating, epigastric discomfort, pain throughout the abdomen, salivary gland hypersecretion, oral pain, bad breath, glossodynia, hepatitis, liver failure.

Skin and subcutaneous tissue disorders: Alopecia, itching, rash, anhidrosis, facial hypoesthesia, urticaria, erythema, generalized itching, macular rash, skin discoloration, allergic dermatitis, facial edema, Stevens-Johnson syndrome, erythema multiforme, unpleasant smelling skin, periorbital edema, localized urticaria, toxic epidermal necrolysis.

Muscular system disorders: arthralgia, muscle spasms, myalgia, muscle cramps, muscle weakness, muscle chest pain, joint swelling, muscle stiffness, pain in the side, muscle fatigue, discomfort in the extremities.

Urinary system disorders: nephrolithiasis, pollakiuria, dysuria, urinary calculi, urinary incontinence, hematuria, urgent painful urge to urinate, renal colic, renal pain, ureteral calculi, renal tubular acidosis.

Reproductive system: erectile dysfunction, sexual dysfunction.

General reactions: fatigue, pyrexia, asthenia, irritability, gait disturbance, unusual sensations, malaise, hyperthermia, thirst, flu-like state, inertia, coldness of extremities, feeling intoxicated, feeling of anxiety, facial edema, calcinosis.

Laboratory findings: decreased body weight, increased body weight, crystalluria, abnormal tandem walk test, leukopenia, increased liver enzyme activity, hypokalemia, decreased blood hydrocarbonate content.

Overdose

Symptoms: seizures, somnolence, speech and vision disturbances, diplopia, thinking disorders, coordination disorders, dizziness, lethargy, stupor, arterial hypotension, abdominal pain, dizziness, agitation and depression, metabolic acidosis. In most cases, the clinical consequences were not severe, but fatal cases have been reported after overdose with a mixture of several drugs, including topiramate. A case is known of an overdose of up to 110 g of topiramate that resulted in a coma within 20-24 h, followed by a full recovery after 3-4 days.

Treatment: there is no specific antidote to the drug, symptomatic therapy is given if necessary. It is necessary to induce immediate vomiting and gastric lavage, increase water intake. Inin vitro studies it has been shown that activated charcoal adsorbs topiramate. Hemodialysis is the most effective way to remove topiramate from the body. Patients are advised to increase their fluid intake adequately.

Pregnancy use

There are no adequate and strictly controlled clinical safety studies of topiramate in pregnancy.

The use of topiramate in pregnancy may cause fetal damage. Pregnancy registry data show that intrauterine exposure to topiramate increases the risk of fetal birth defects (e.g., craniofacial defects such as cleft lip/wolf’s mouth, hypospadias, and abnormalities of various body systems). These malformations were recorded both with topiramate monotherapy and with its use as part of combination therapy. Compared with the group of patients not taking antiepileptic drugs, the data from the register of pregnant women treated with topiramate monotherapy show an increased frequency of low birth weight babies (less than 2500 g). A causal relationship has not been established.

When treating women of childbearing age, the expected benefit of therapy to 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.

Limited observations suggest that topiramate is excreted with breast milk. If use during lactation is necessary, discontinuation of breastfeeding should be considered.

Pediatric use

Do not use in children under 2 years of age.

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