Topiramate-ALSI, 25 mg 30 pcs

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

Topiramate blocks sodium channels and suppresses the occurrence of repetitive action potentials against the background of prolonged depolarization of the neuronal membrane. Topiramate increases the activity of gamma-aminobutyric acid (GABA) against several subtypes of GABA receptors (including GABA_A-receptors), and also models the activity of GABA_A-receptors, prevents kainat activation of kainat/AMPK (α-amino-3-hydroxy-5-methylisoxalol-4-propionic acid)-receptor subtype sensitivity to glutamate, and does not affect N-methyl-D-aspartate (NMDA) activity with respect to the NMDA-receptor subtype. These effects of topiramate are dose-dependent at plasma concentrations of 1 μmol to

200 μmol, with minimal activity ranging from 1 μmol to 10 μmol.

In addition, topiramate inhibits the activity of some carboanhydrase isoenzymes. Topiramate is significantly inferior to acetazolamide, a known carbo anhydrase inhibitor, in terms of the severity of this pharmacological effect; therefore, this activity of topiramate is not considered to be the main component of its antiepileptic activity.

Pharmacokinetics

Eabsorption

Topiramate is absorbed quickly and efficiently. Its bioavailability is 81%. Food intake has no clinically significant effect on the bioavailability of topiramate.

Distribution

13-17% of topiramate is bound to plasma proteins. After a single dose of up to 1200 mg the average volume of distribution is 0.55-0.8 l/kg. Distribution volume depends on sex: in women it is about 50% of that in men, which is associated with a higher content of adipose tissue in women.

Metabolism

After oral administration about 20% of the administered dose is metabolized. However, in patients receiving concomitant therapy with antiepileptic drugs that induce enzymes responsible for drug metabolism, the metabolism of topiramate is increased up to 50%.

Six virtually inactive metabolites have been isolated and identified from human plasma, urine, and feces. The main route of excretion of unchanged topiramate (70%) and its metabolites is the kidneys. After oral administration the plasma clearance of topiramate is 20-30 ml/min.

Linearity/non-linearity

The pharmacokinetics of topiramate are linear, plasma clearance remains constant, and the area under the concentration-time curve (AUC) in the dose range from

100 to 400 mg increases in proportion to the dose. In patients with normal renal function, it may take 4 to 8 days to reach stable plasma concentrations. The value of maximum concentration (C_max) after multiple oral doses of 100 mg twice daily averaged 6.76 mcg/ml. After multiple doses of 50 and 100 mg twice daily, the plasma half-life of topiramate averaged 21 hours.

Renal disorders

In patients with moderate to severe renal impairment, plasma and renal clearance of topiramate is decreased (creatinine clearance (K_k) ≤ 70 ml/min), as a consequence, the equilibrium plasma concentrations of topiramate may be higher compared to patients with normal renal function. In addition, patients with impaired renal function take longer to reach equilibrium blood concentrations of topiramate. For patients with moderate to severe renal impairment, half the recommended initial and maintenance doses are recommended.

Hemodialysis

Topiramate is effectively eliminated from plasma by hemodialysis. Prolonged hemodialysis may cause blood concentrations of topiramate to fall below the amount required to maintain anticonvulsant activity. An additional dose of topiramate may need to be administered to avoid a rapid drop in plasma concentrations during hemodialysis.

• The duration of hemodialysis;
• the clearance rate of the hemodialysis system used;
• the effective renal clearance of topiramate in a patient on dialysis should be taken into account when adjusting the dose.

Hepatic disorders

The plasma clearance of topiramate is reduced by an average of 26% in patients with moderate to severe hepatic impairment. Therefore, patients with hepatic impairment should use topiramate with caution.

Elderly patients

The plasma clearance of topiramate is not altered in elderly patients without renal disease.

Pharmacokinetics in children (children under 12 years of age)

The pharmacokinetic parameters of topiramate in children, as well as in adults receiving this drug as adjuvant therapy, are linear, with its clearance independent of dose, and equilibrium plasma concentrations increase in proportion to increasing dose. However, the fact that in children, topiramate clearance is higher and the elimination half-life is shorter should be taken into account. Therefore, at the same dose per 1 kg body weight, plasma concentrations of topiramate in children may be lower than in adults. In children, as in adults, antiepileptic drugs that induce microsomal liver enzymes cause lower plasma concentrations of topiramate.

Indications

Epilepsy

As monotherapy:

In adults and children over 3 years of age with epilepsy (including patients with newly diagnosed epilepsy).

As part of complex therapy:

In adults and children over 3 years of age with partial or generalized tonic-clonic seizures, and for the treatment of seizures against the background of Lennox-Gastaud syndrome.

Migraine

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

Active ingredient

Composition

One film-coated tablet contains:

the active substance: topiramate – 25.0 mg;

excipients: microcrystalline cellulose – 31.4 mg, pregelatinized starch – 23.0 mg, magnesium stearate – 0.4 mg, colloidal silicon dioxide (aerosil) – 0.2 mg,

tablet shell: Opadray II Yellow (85F32830) – 3.2 mg (polyvinyl alcohol – 1.28 mg, macrogol (polyethylene glycol) – 0.65 mg, talc – 0.47 mg, titanium dioxide – 0.23 mg, quinoline yellow aluminum dye – 0.53 mg and sunset yellow aluminum dye – 0.04 mg).

How to take, the dosage

The tablets are taken orally, regardless of meals. To achieve optimal control of epileptic seizures in children and adult patients, it is recommended to start treatment with low doses of the drug with subsequent gradual titration to an effective dose.

Partial or generalized tonic-clonic seizures, as well as seizures against the background of Lennox-Gastaud syndrome.

Performance in combination with other anticonvulsants in adult patients

The minimum effective dose is 200 mg daily. Usually the total daily dose is 200 mg to 400 mg and is taken in two doses. Some patients may need to increase the daily dose to a maximum of 1600 mg. It is recommended to start treatment with a low dose followed by a gradual adjustment to an effective dose. The dose is started at 25-50 mg, taken at night for 1 week. Thereafter, at weekly or bi-weekly intervals, the dose may be increased by 25-50 mg and taken in two doses. Dose selection should be guided by clinical effect. In some patients, the effect can be achieved by taking the drug once a day. It is not necessary to monitor the plasma concentrations of Topiramate-ALSI to achieve optimal treatment effect.

These dose recommendations apply to all adult patients, including the elderly, as long as they do not have renal disease (see section “Special Precautions”).

Combined anticonvulsant therapy in children over 3 years of age

The recommended total daily dose of Topiramate-ALSI as adjunctive therapy is 5 to 9 mg/kg and is taken in two doses. Dose selection should begin with 25 mg (or less, based on an initial dose of 1 to

3 mg/kg per day), taken at night for 1 week. Thereafter, at weekly or bi-weekly intervals, the dose may be increased by 1 to 3 mg/kg and taken in two doses. Dose selection should be guided by the clinical effect. The dose selection is started with Topiramate-ALSI in a dosage of 25 mg. The daily dose of up to 30 mg/kg is usually well tolerated.

Epilepsy (including newly diagnosed)

Monotherapy: general considerations

When withdrawing concomitant anticonvulsants for topiramate monotherapy, the possible effect of this step on seizure frequency must be considered. Where it is not necessary to abruptly withdraw concomitant anticonvulsants for safety reasons, it is recommended to reduce their doses gradually, reducing the dose of concomitant antiepileptic drugs by one-third every 2 weeks.

When drugs that are inducers of microsomal liver enzymes are withdrawn, blood concentrations of topiramate will increase. In these situations, the dose of Topiramate-ALSI may be reduced if clinically indicated.

Monotherapy: adults

At the beginning of treatment, the patient should take Topiramate-ALSI at a dosage of

25 mg before bedtime for 1 week. Then the dose is increased at 1-2 week intervals by 25 or 50 mg (the daily dose is divided into two doses). If a patient cannot tolerate this mode of dose increase, the intervals between dose increases may be increased, or the dose may be increased more gently. Dose selection should be guided by clinical effect. The starting dose for monotherapy with topiramate in adults is 100 mg per day, and the maximum daily dose should not exceed 500 mg. Some patients with refractory forms of epilepsy tolerate topiramate monotherapy in doses up to 1000 mg per day. These dosing recommendations apply to all adults, including elderly patients, without renal disease.

Monotherapy: children

In children over 3 years of age, topiramate should be given at a dose of 0.5-1 mg/kg body weight before bedtime in the first week of treatment. Then the dose is increased at 1-2 week intervals by 0.5-1 mg/kg/day (the daily dose is divided into two doses). If the child cannot tolerate this mode of dose increase, you may increase the dose more gently, or increase the intervals between dose increases. The magnitude of the dose and the rate of dose escalation should be determined by clinical outcome.

The recommended dose range for topiramate monotherapy in children over

3 years of age is 100-400 mg/day. Children with newly diagnosed partial seizures may be prescribed up to 500 mg daily.

Migraine

The recommended total daily dose of topiramate for the prevention of migraine attacks is 100 mg taken in 2 doses. At the beginning of treatment the patient should take 25 mg of Topiramate-ALSI before sleep for 1 week. The dose is then increased at 1 week intervals by 25 mg per day. If the patient cannot tolerate this dose escalation regimen, the intervals between dose escalations may be increased, or the dose may be increased more gently. Dose selection should be guided by clinical effect.

In some patients, positive results are achieved at a daily dose of 50 mg topiramate. In clinical trials, patients received different daily doses of topiramate, but no more than 200 mg per day.

Patient Special Groups

Patients with moderate to severe renal impairment may need to reduce the dose. Half the recommended initial and maintenance dose is recommended.

Since topiramate is removed from plasma by hemodialysis, an additional dose of Topiramate-ALSI equal to approximately half the daily dose should be given on hemodialysis days. The additional dose should be divided into two doses administered at the beginning and after the completion of hemodialysis. The additional dose may vary depending on the characteristics of the equipment used to perform hemodialysis.

Patients with hepatic impairment should use topiramate with caution.

Interaction

The effect of topiramate on concentrations of other antiepileptic drugs (AEDs)

. Concomitant administration of topiramate with other PEPs (phenytoin, carbamazepine, valproic acid, phenobarbital, primidone) has no effect on the values of their equilibrium plasma concentrations, except for individual patients in whom the addition of topiramate to phenytoin may cause increased phenytoin plasma concentrations. This may be due to inhibition of a specific polymorphic isoform of the cytochrome P450 system enzyme (CYP2C19 isoenzyme). Therefore, every patient who takes phenytoin and develops clinical signs or symptoms of toxicity should have their plasma phenytoin concentrations monitored. In a pharmacokinetics study in epileptic patients, the addition of topiramate to lamotrigine did not affect the equilibrium concentration of the latter at topiramate doses of 100-400 mg per day. During therapy and after withdrawal of lamotrigine (mean dose 327 mg per day), the equilibrium concentration of topiramate did not change.

The effect of other antiepileptic drugs on topiramate concentrations

Phenytoin and carbamazepine decrease plasma concentrations of topiramate. Addition or withdrawal of phenytoin or carbamazepine during treatment with Topiramate-ALSI may require a change in 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 changes in the dose of Topiramate-ALSI.

Other drug interactions

Digoxin: In a single-dose study, the area under the AUC (“concentration-time”) curve of digoxin in plasma was reduced by 12% when topiramate was taken simultaneously. The clinical significance of this observation is unclear. When prescribing or discontinuing Topiramate-ALSI in patients taking digoxin, special attention should be paid to monitoring serum digoxin concentrations.

CNS depressants: The effects of concomitant administration of topiramate with alcohol or other CNS depressants have not been studied in clinical studies. It is recommended that Topiramate-ALSI should not be taken with alcohol or other CNS-depressant drugs.

St. John’s Wort

When topiramate and preparations based on Hypericum perforatum (Hypericum perforatum L.) are taken together, plasma concentrations of topiramate may decrease and, as a consequence, the effectiveness of the drug may also decrease. No clinical studies on the interaction of the drug Topiramate-ALSI and preparations on the basis of Hypericum perforatum L. have been conducted.

The oral contraceptives: In a study of drug interactions with oral contraceptives using a combination drug containing norethisterone (1 mg) and ethinylestradiol (35 mcg), topiramate at doses of 50-800 mg daily had no significant effect on the effectiveness of norethisterone and at doses

50-200 mg daily on the effectiveness of ethinylestradiol. A significant dose-dependent decrease in ethinylestradiol efficacy was observed at doses of topiramate

200-800 mg per day. The clinical significance of the described changes is unclear. The risk of decreased contraceptive efficacy and increased “breakthrough” bleeding should be considered in patients taking oral contraceptives in combination with Topiramate-ALSI. Patients taking estrogen-containing contraceptives should be advised of any changes in the timing and nature of their periods. The effectiveness of contraceptives may be reduced even in the absence of “breakthrough” bleeding.

Lithium: In healthy volunteers, there was an 18% reduction in the AUC of lithium with concomitant administration of topiramate at a dose of 200 mg daily. In patients with manic depressive psychosis, the use of topiramate at doses up to 200 mg daily had no effect on the pharmacokinetics of lithium, but at higher doses (up to 600 mg daily) the AUC of lithium was increased by 26 %. When topiramate and lithium are used concomitantly, plasma concentrations of the latter should be monitored.

Risperidone: Drug interaction studies conducted with single and repeated administration of topiramate in healthy volunteers and patients with bipolar disorder gave similar results. Simultaneous administration of topiramate at doses of 250 or 400 mg daily decreased AUC of risperidone taken at doses of 1-6 mg daily by 16 % and 33 %, respectively. At the same time, the pharmacokinetics of

9-hydroxyrisperidone did not change, and the total pharmacokinetics of the active substances (risperidone and 9-hydroxyrisperidone) did not change significantly. The change in systemic exposure to risperidone/9-hydroxyrisperidone and topiramate was not clinically significant, and this interaction is unlikely to be of clinical significance.

Hydrochlorothiazide: Drug interactions were evaluated in healthy volunteers when hydrochlorothiazide (25 mg) and topiramate (96 mg) were used separately and together. Results showed that concomitant administration of topiramate and hydrochlorothiazide resulted in a 27% increase in the maximum concentration of topiramate and a 29% increase in the area under the topiramate AUC curve.

The clinical significance of these studies has not been identified. Administration of hydrochlorothiazide to patients taking topiramate may require adjustment of the topiramate dose. The pharmacokinetic parameters of hydrochlorothiazide were not significantly altered by concomitant therapy with topiramate.

Metformin: drug interactions were evaluated in healthy volunteers receiving metformin or a combination of metformin and topiramate. The results showed that concomitant administration of topiramate and metformin increased maximum concentration and AUC curve area of metformin by 18% and 25%, respectively, whereas metformin clearance was decreased by 20% when concomitantly used with topiramate.

Topiramate had no effect on the time to reach maximum metformin plasma concentration. Topiramate clearance is decreased when used concomitantly 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-ALSI is added or withdrawn in patients receiving metformin, the patient should be closely monitored to assess the course of diabetes.

Pioglitazone: Drug interactions have been evaluated in healthy volunteers with separate and concomitant use of pioglitazone and topiramate. A 15% decrease in the area under the AUC curve of pioglitazone was found, with no change in the maximum concentration of the drug. These changes were not statistically significant. For the active hydroxymetabolite pioglitazone also showed a decrease in maximum concentration and area under the AUC curve by 13 % and 16 %, respectively, and for the active ketometabolite a decrease in maximum concentration and area under the AUC curve by 60 % was detected. The clinical significance of these data has not been clarified. When patients concomitantly use Topiramate-ALSI and pioglitazone, the patient’s condition should be carefully monitored to assess the course of diabetes mellitus.

Glibenclamide: A drug interaction study has been conducted to examine the pharmacokinetics of glibenclamide (5 mg daily) in equilibrium used alone or concomitantly with topiramate (150 mg daily) in patients with type 2 diabetes. The AUC of glibenclamide was reduced by 25% when topiramate was used. Systemic exposure of 4-trans-hydroxy-glibenclamide and 3-cis-hydroxy-glibenclamide was also reduced (by 13 % and 15 %, respectively). Glibenclamide had no effect on the pharmacokinetics of topiramate in equilibrium. A statistically non-significant decrease in AUC of pioglitazone by 15% was found with no change in Cmax. When prescribing topiramate to patients receiving glibenclamide (or prescribing glibenclamide to patients receiving topiramate), the patient should be closely monitored to assess the course of diabetes mellitus.

Other drugs: concomitant use of Topiramate-ALSI with drugs that predispose to nephrolithiasis may increase the risk of kidney stone formation. During treatment with Topiramate-ALSI, the use of drugs predisposing to nephrolithiasis should be avoided because they may cause physiological changes that contribute to nephrolithiasis.

Valproic acid: The 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 reaction is not caused by a pharmacokinetic interaction.

When topiramate and valproic acid are taken together, hypothermia (an unintentional drop in body temperature below 35°C) may occur in conjunction with hyperammonemia or independently. This phenomenon can occur either after starting valproic acid and topiramate together or when the daily dose of topiramate is increased.

Additional drug interaction studies: A number of clinical studies have been conducted to evaluate potential drug interactions between topiramate and other medications.

Special Instructions

Antiepileptic drugs, including Topiramate-ALSI, should be withdrawn gradually to minimize the possibility of increased seizure frequency. To reduce the dose by 25-50 mg, use Topiramate-ALSI at a dose of 25 mg. In clinical trials, doses have been reduced by 50-100 mg at weekly intervals for adults on epilepsy therapy and by 25-50 mg in adults receiving 100 mg of Topiramate-ALSI daily for migraine prophylaxis. If a rapid withdrawal of topiramate is medically necessary, appropriate monitoring of the patient is recommended.

As with other antiepileptic drugs, some patients taking topiramate experience increased frequency of seizures or new types of seizures. This phenomenon may be a consequence of overdose, decreased concentrations of co-administered antiepileptic drugs, disease progression, or paradoxical effects. The rate of excretion through the kidneys depends on renal function and is independent of age. In patients with moderate to severe renal dysfunction, it may take 10 to 15 days to reach stable plasma concentrations, in contrast to 4 to 8 days in patients with normal renal function.

As with any disease, the dosing regimen should be guided by clinical effect (i.e., degree of seizure control, no side effects) and take into account that in patients with impaired renal function, it may take longer for each dose to establish stable plasma concentrations.

In therapy with topiramate, oligohidrosis (reduced sweating) and anhidrosis may occur. Reduced sweating and hyperthermia (increase in body temperature) may occur in children exposed to high ambient temperatures. Therefore, adequate increase in fluid intake is very important during therapy with topiramate, which can reduce the risk of nephrolithiasis, as well as side effects that may occur with physical activity or elevated temperatures.

Mood disorders/depression

There is an increased incidence of mood disorders and depression when treated with topiramate.

Suicidal attempts

The use of antiepileptic drugs, including Topiramate-ALSI, increases the risk of suicidal ideation and suicidal behavior in patients taking these drugs for any of the indications.

In double-blind clinical trials, the incidence of suicidal events (suicidal thoughts, suicide attempts, suicide) was 0.5% in patients receiving topiramate (in 46 of 8,652), about 3 times higher than in patients receiving placebo (0.2%: in 8 of 4,045). One case of suicide was reported in a double-blind study of bipolar disorder in a patient receiving topiramate.

Hence, patients should be monitored for signs of suicidal ideation and appropriate treatment should be prescribed. Patients (and their caregivers, if necessary) should be advised to seek immediate medical attention if they show signs of suicidal ideation or suicidal behavior.

Nephrolithiasis

In some patients, particularly those with a predisposition to nephrolithiasis, there may be an increased risk of kidney stones and associated symptoms such as renal colic, kidney pain, and pain in the side. To reduce this risk, an adequate increase in fluid intake is necessary. Risk factors for nephrolithiasis include a history of nephrolithiasis (including a family history), hypercalciuria, and concomitant therapy with drugs that promote nephrolithiasis.

Renal dysfunction

Caution should be exercised when prescribing topiramate in patients with renal impairment (creatinine clearance < 70 ml/min). This is because in these patients the clearance of the drug is decreased.

Hepatic impairment

In patients with hepatic impairment, topiramate should be used with caution because of the possible decreased clearance of this drug.

Myopia and secondary closed-angle glaucoma

A syndrome has been described with topiramate including acute myopia with concomitant secondary closed-angle glaucoma. Symptoms include acute decrease in visual acuity and/or pain in the eye. Ophthalmologic examination may reveal myopia, flattening of the anterior chamber of the eye, hyperemia (redness) of the eyeball, and increased intraocular pressure. Mydriasis may be observed. This syndrome may be accompanied by fluid secretion, resulting in forward displacement of the lens and iris with the development of secondary closed-angle glaucoma. Symptoms usually appear 1 month after initiation of Topiramate-ALSI. Unlike primary open-angle glaucoma, which is rarely seen in patients under 40 years of age, secondary closed-angle glaucoma is seen with topiramate use in both adults and children. When a syndrome involving myopia associated with closed-angle glaucoma occurs, treatment includes discontinuation of Topiramate-ALSI as soon as the treating physician considers it possible and appropriate measures to lower intraocular pressure. Usually, these measures lead to normalization of intraocular pressure.

Elevated intraocular pressure of any etiology can lead to serious complications, including vision loss, if not treated appropriately.

When prescribing topiramate to patients with a history of eye disease, the ratio of expected benefit to possible risk of use should be evaluated.

Visual field defects

Visual field defects have been observed in patients taking topiramate regardless of the presence of elevated intraocular pressure. In clinical studies, most of these cases were reversible, and visual field defects disappeared after discontinuation of topiramate therapy. If vision problems occur while taking topiramate, consideration should be given to discontinuing therapy.

Metabolic acidosis

Hyperchloremic metabolic acidosis, not related to anion deficiency, can occur with topiramate (e.g., decreased plasma hydrocarbonate concentrations below normal levels in the absence of respiratory alkalosis). This decrease in serum hydrocarbonate concentration is a consequence of the inhibitory effect of topiramate on renal carboanhydrase. In most cases, the decrease in bicarbonate concentrations occurs at the beginning of drug administration, although this effect may occur at any time during treatment with topiramate. The degree of decrease in concentration is usually mild to moderate (the average is 4 mmol/L when used in adult patients at a dose above

100 mg per day and about 6 mg per kg body weight when used in pediatric practice). Rarely, patients have had decreases in hydrocarbonate concentrations below 10 mmol/L. Certain conditions or treatments that predispose to the development of acidosis (e.g., renal disease, severe respiratory disease, epileptic status, diarrhea, surgery, ketogenic diet, taking certain medications) may be additional factors that increase the hydrocarbonate-lowering effect of topiramate.

In children, chronic metabolic acidosis can lead to growth retardation. The effects of topiramate on growth and possible bone-related complications have not been systematically studied in children and adults.

In view of the above, it is recommended that necessary studies, including determination of serum bicarbonate concentrations, be performed when treating with topiramate. If symptoms of metabolic acidosis (e.g., deep Cussmaulian breathing, dyspnea, anorexia, nausea, vomiting, increased fatigue, tachycardia or arrhythmia) occur, serum hydrocarbonate concentration determination is recommended. If metabolic acidosis occurs and persists, it is recommended to reduce the dose or discontinue topiramate.

Cognitive impairment

Cognitive impairment in epilepsy is multifactorial in nature and may be due to the underlying disease, epilepsy itself, or antiepileptic therapy. Cognitive impairment has been reported in adult patients taking topiramate, requiring dose reduction or discontinuation of therapy. Data on the effect of topiramate on cognitive function in children are insufficient, and its effects require further study.

Hyperammonemia and encephalopathy

Hyperammonemia with or without encephalopathy has been reported with topiramate (see section “Adverse effects”). The risk of hyperammonemia with topiramate is dose-dependent. Hyperammonemia is more common with concomitant use of topiramate and valproic acid (see section “Other drug interactions”).

The clinical symptoms of hyperammonemic encephalopathy are often acute impairment of consciousness and/or cognitive function and lethargy. In most cases, hyperammonium encephalopathy regresses when therapy is withdrawn. In patients with lethargy or mental status changes of unclear genesis receiving topiramate as monotherapy or as part of combination therapy, it is recommended to consider the possibility of hyperammonium encephalopathy and determine blood ammonia levels.

If the patient is losing weight while being treated with Topiramate-ALSI, then consideration should be given to whether enhanced nutrition is appropriate.

The effect on driving, operating machinery

Topiramate-ALSI acts on the central nervous system and may cause drowsiness, dizziness, and other symptoms. It can also cause visual disturbances. These adverse events may pose a danger to patients driving cars and moving machinery, especially while the patient’s response to the drug is pending.

Contraindications

Cautions

We should use with caution in renal and hepatic impairment, nephrourolithiasis (including past or family history), hypercalciuria.

Side effects

Unwanted reactions are listed with frequency and organ system distributions. The frequency of adverse reactions was classified as follows: very common (≥1/10); common (≥1/100 to < 1/10); infrequent (≥1/1,000 to < 1/100); rare (≥1/10,000 to < 1/1,000); very rare (< 1/10,000, including individual cases) and frequency unknown (frequency cannot be estimated from available data).

The most common adverse reactions (the incidence of which was greater than 5% and higher than that of the placebo group for at least one indication in controlled clinical trials of topiramate) are: Anorexia, decreased appetite, slowed thinking, depression, impaired free speech, insomnia, movement coordination disorders, impaired concentration, dizziness, dysarthria, dysgeusia, hypoesthesia, lethargy, memory disturbances, nystagmus, paresthesia, sleepiness, tremor, diplopia, blurred vision, diarrhea, nausea, fatigue, irritability and decreased body weight.

Infectious and parasitic diseases: very common – nasopharyngitis*.

Disorders of the blood and lymphatic system: frequently – anemia; infrequently – leukopenia, lymphadenopathy, thrombocytopenia, eosinophilia; rarely – neutropenia*.

Immune system disorders: frequently – hypersensitivity; frequently unknown – allergic edema*, conjunctival edema*.

Mechanism and nutrition disorders: frequent – anorexia, decreased appetite; infrequent – metabolic acidosis, hypokalemia, increased appetite, polydipsia; rare – hyperchloremic acidosis, hyperammonemia, hyperammonemic encephalopathy.

Psychiatric disorders: very common – depression; common – delayed thinking, insomnia, impaired free speech, anxiety, confusion, disorientation, aggressive reactions, mood disorders, agitation, emotional lability, depressed mood, anger, behavior disorders; infrequent – suicidal ideation, suicide attempts, hallucinations, psychotic disorders, auditory hallucinations, visual hallucinations, apathy, speech difficulties, sleep disorders, affective lability, decreased libido, agitation, crying, dysphemia, euphoric mood, paranoia, perseveration of thought, panic attacks, tearfulness, impaired reading skills, impaired falling asleep, flattening of emotions, pathological thinking, loss of libido, lethargy, intrasomniac disorder, distractedness, early waking in the morning, panic reactions, elevated mood; Rarely, mania, panic disorder, feelings of hopelessness*, hypomania.

Nervous system disorders: very common – paresthesias, somnolence, dizziness; common – impaired concentration, memory impairment, amnesia, cognitive disorders, thinking disorders, psychomotor disorders, seizures, movement coordination disorders, tremor, lethargy, hypoesthesia, nystagmus, dysgeusia, impaired sense of balance, dysarthria, intensional tremor, sedation; infrequent – depressed consciousness, tonic-clonic grand mal seizures, visual field impairment, complex partial seizures, speech impairment, psychomotor hyperactivity, syncope, sensory disturbances, salivation, hypersomnia, aphasia, repetitive speech, hypokinesia, dyskinesia Postural dizziness, poor quality of sleep, burning sensation, loss of sensation, parosmia, cerebral syndrome, dysesthesia, hypogeusia, stupor, clumsiness, aura, agueusia, dysraphia, dysphasia, peripheral neuropathy, preconsciousness, dystonia, feeling “goose bumps” on the body rarely – apraxia, disruption of circadian rhythm of sleep, hyperesthesia, hyposmia, anosmia, essential tremor, akinesia, lack of response to stimuli.

Visual disorders: frequent – blurred vision, diplopia, visual disturbances; infrequent – decreased visual acuity, scotoma, myopia*, strange sensations in the eyes*, dry eyes, photophobia, blepharospasm, increased lacrimation, photopsia, mydriasis, presbyopia; rarely – unilateral blindness, transient blindness, glaucoma, accommodation disorder, visual spatial perception disorder, scotoma scotoma, eyelid edema*, night blindness, amblyopia; frequency not known – closed-angle glaucoma*, maculopathy*, eye movement disorders*.

Hearing and labyrinth disorders: frequent – vertigo, tinnitus, ear pain; infrequent – deafness, unilateral deafness, neurosensory deafness, discomfort in the ear, hearing loss.

Chronic disorders: infrequent – bradycardia, sinus bradycardia, palpitations.

Vascular disorders: infrequent – hypotension, orthostatic hypotension, hot flushes, hot flushes; rarely – Raynaud’s phenomenon.

Respiratory system, thoracic and mediastinal disorders: frequently – shortness of breath, nasal bleeding, nasal congestion, rhinorrhea, cough*; infrequently – shortness of breath on exertion, hypersecretion in the sinuses, dysphonia.

Gastrointestinal disorders: very common – nausea, diarrhea; common – vomiting, constipation, epigastric pain, dyspepsia, abdominal pain, dry mouth, gastric discomfort, oral sensitivity disorders, gastritis, abdominal discomfort; infrequent – pancreatitis, flatulence, gastroesophageal reflux, lower abdominal pain, decreased oral sensitivity, bleeding gums, bloating, epigastric discomfort, abdominal sensitivity, hypersalivation, oral pain, bad breath, glossodynia.

Liver and biliary tract disorders: rarely hepatitis and liver failure.

Skin and subcutaneous tissue disorders: frequent – alopecia, rash, itching; infrequent – angidrosis, facial sensitivity disorder, urticaria, erythema, generalized itching, macular rash, skin pigmentation disorders, allergic dermatitis, facial swelling; infrequent – Stevens-Johnson syndrome*, erythema multiforme*, skin odor changes, para-orbital edema*, localized urticaria; frequency unknown – toxic epidermal necrolysis*.

Muscular and connective tissue disorders: frequently – arthralgia, muscle cramps, myalgia, muscle cramps, muscle weakness, skeletal muscle pain in the chest; infrequently – swollen joints*, muscle stiffness, pain in the side, muscle fatigue; rarely – discomfort in the extremities*.

Kidney and urinary tract disorders: frequent – nephrolithiasis, pollakiuria, dysuria; infrequent – exacerbation of urolithiasis (kidney stones), stress urinary incontinence, hematuria, urinary incontinence, frequent urge to urinate, renal colic, renal pain; rare – exacerbation of urethral stones, renal tubular acidosis*.

Gender and mammary gland disorders: infrequent – erectile dysfunction, sexual dysfunction.

General disorders and disorders at the site of administration: very often – fatigue; often – elevated body temperature, asthenia, irritability, gait disturbances, malaise, anxiety; infrequently – hyperthermia, thirst, flu-like syndrome*, slowness, coldness of limbs, feeling intoxicated, feeling anxious; rarely – facial edema, calcinosis.

Impact on the results of laboratory and instrumental studies: very often – weight loss; often – weight gain*; infrequently – crystalluria, abnormal tandem walk test result, leukopenia, increased liver enzymes activity in serum; rarely – decrease in blood hydrocarbonate content.

Impact on social factors: infrequent – impairment of learning ability.

* – an adverse reaction is registered in the post-registration period from spontaneous reports. Frequency is calculated on the basis of data from clinical trials.

Special groups:

Children:

The following is a list of adverse reactions that have been reported 2 or more times more frequently in children than in adults in controlled clinical trials: decreased appetite, increased appetite, hyperchloremic acidosis, hypokalemia, behavioral disorders, aggressive reactions, apathy, trouble falling asleep, suicidal ideation, impaired concentration, lethargy, circadian sleep disturbance, poor sleep quality, increased lacrimation, sinus bradycardia, poor well-being, gait disturbances.

The following is a list of adverse reactions that have been reported only in children in controlled clinical studies: eosinophilia, psychosis, and psychosis.

Overdose

Symptoms

The signs and symptoms of topiramate overdose include seizures, drowsiness, speech and vision disturbances, diplopia, thinking disorders, impaired coordination of movements, lethargy, stupor, arterial hypotension, abdominal pain, dizziness, agitation and depression. In most cases, the clinical consequences were not severe, but fatalities have been reported following overdoses involving a mixture of several medications, including topiramate. Topiramate overdose can cause severe metabolic acidosis (see section “Special Precautions”).

There was a known case of an overdose when a patient took a dose of 96 to 110 g of topiramate that resulted in a coma lasting 20 to 24 hours. The patient returned to normal 3-4 days later.

Treatment

In an acute overdose of topiramate, if the patient had eaten shortly before, it is necessary to flush the stomach or induce vomiting immediately. In in vitro studies it has been shown that activated charcoal adsorbs topiramate. If necessary, symptomatic therapy should be carried out. Hemodialysis is an effective way to eliminate topiramate from the body. Patients are advised to increase their fluid intake adequately.

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