Topiramate-ALSI, 100 mg 30 pcs

Pharmacotherapeutic group: Antiepileptic drug.

ATX code: N03AX11

Pharmacological properties

Pharmacodynamics

Topyramate 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 neuron 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 from 1 µmol to
200 µmol, with minimal activity between 1 µmol and 10 µmol.

In addition, topiramate inhibits the activity of some carboanhydrase isoenzymes. Topiramate is considerably inferior to acetazolamide, a known carbonic 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

absorption

Topiramate is absorbed rapidly 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 taken 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%.

Elimation

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

Kidney function 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. In 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. When adjusting the dose, consideration should be given to:

• length of hemodialysis;
• the clearance rate of the hemodialysis system used;
• the effective renal clearance of topiramate in the patient on dialysis.

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

In elderly patients without renal disease, the plasma clearance of topiramate is not altered.

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 the dose and equilibrium plasma concentrations increasing in proportion to increasing the 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 of 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

By monotherapy:

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

In complex therapy:

In adults and children over 3 years of age with partial or generalized tonic-clonic seizures, and for the treatment of seizures in 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:
Active substance: topiramate – 25.0 mg or 100.0 mg;
auxiliary substances: microcrystalline cellulose – 31.4/125.6 mg, pregelatinized starch – 23.0/92.0 mg, magnesium stearate – 0.4/1.6 mg, colloidal silicon dioxide (aerosil) – 0.2/0.8 mg,
Pill coating: Opadray II Yellow (85F32830) – 3.2/12.8 mg (polyvinyl alcohol – 1.28/5.12 mg, macrogol (polyethylene glycol) – 0.65/2.60 mg, talc – 0.47/1.89 mg, titanium dioxide – 0.23/0.93 mg, quinoline yellow aluminum dye – 0.53/2.10 mg and sunset yellow aluminum dye – 0.04/0.16 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 followed by gradual titration to an effective dose.

Parcial or generalized tonic-clonic seizures and seizures against the background of Lennox-Gastaud syndrome.

Use 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 effect.

The given dose recommendations are applicable to all adult patients, including the elderly, in the absence of renal disease (see section “Special Indications.

These dose recommendations apply to all adult patients, including the elderly, without renal disease (see section on Special Precautions).

Combined anticonvulsant therapy in children over 3 years

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. Daily doses up to 30 mg/kg are usually well tolerated.

Epilepsy (including newly diagnosed)

Monotherapy: General Provisions

When withdrawing concomitant anticonvulsant medications for the purpose of topiramate monotherapy, the possible effect of this step on seizure frequency must be considered. When 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 can be increased, or the dose can 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

Children over 3 years of age should be given topiramate at a dose of 0.5-1 mg/kg body weight before bedtime during 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 increase should be determined by clinical outcome.

The recommended dose range for monotherapy with topiramate 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 a 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.

Special patient groups

Patients with moderate to severe renal impairment may need a reduced 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

Influence of topiramate on concentrations of other antiepileptic drugs (PEDs)

.Concomitant administration 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 cause increased plasma phenytoin 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.

Effects 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.

The results of these interactions are summarized in the following table:

PEP added

Concentration of PEP

Concentration of the drug Topiramate-ALSI

Phenytoin

↔**

↓ (48%)

Carbamazepine

↔

↓ (40%)

Valproic acid

↔

↔

Phenobarbital

↔

NI

Primidone

↔

NI

↔ = no effect;

** = increased concentration in single patients;

↓ = decreased plasma concentration;

NI = not investigated;

PEP = antiepileptic drug.

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 at the same time. The clinical significance of this observation is unclear. Special attention should be paid to monitoring serum digoxin concentrations when prescribing or withdrawing Topiramate-ALSI in patients taking digoxin.

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

St. John’s Wort

Topiramate and preparations based on Hypericum perforatum (Hypericum perforatum L.) may decrease the plasma concentration of topiramate and, as a consequence, the effectiveness of the drug may also decrease. There have been no clinical studies of interaction between the drug Topiramate-ALSI and preparations based on Hypericum perforatum.

Peroral 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 topiramate doses
200-800 mg daily. 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. Contraceptive efficacy may be reduced even in the absence of “breakthrough” bleeding.

Lithium: In healthy volunteers, an 18% reduction in the AUC of lithium was observed when topiramate was taken concomitantly 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
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-hydroxysperidone and topiramate was not clinically significant, and this interaction is unlikely to be clinically relevant.

Hydrochlorothiazide: Drug interactions were evaluated in healthy volunteers with separate and combined use of hydrochlorothiazide (25 mg) and topiramate (96 mg). The 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 AUC curve of topiramate. The clinical relevance 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. 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. Clearance of topiramate 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 were evaluated in healthy volunteers with separate and simultaneous use of pioglitazone and topiramate. A 15% decrease in the area under the AUC curve of pioglitazone was found, with no change in maximum drug concentration. 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 stones. The use of nephrolithiasis-predisposing drugs should be avoided during treatment with Topiramate-ALSI because they may cause physiologic changes that contribute to nephrolithiasis.

Valproic acid: Combined use of topiramate and valproic acid in patients who tolerate each drug alone is accompanied by hyperammonemia with or without encephalopathy. In most cases, the symptoms and signs disappear after withdrawal of one of the drugs (see section “Special Precautions” and “Side effects”). This adverse reaction is not due to a pharmacokinetic interaction.

Hypothermia (an unintended drop in body temperature below 35°C) may occur when topiramate and valproic acid are taken together, in combination 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: Several clinical studies have been conducted to evaluate potential drug interactions between topiramate and other medications.

The results of these interactions are summarized in the following table:

Drug to be added

.Concentration of drug to be addeda

Concentration of topiramatea

Amitriptyline

increased maximum concentration and AUC of nortriptyline metabolite by 20%

/td>

not investigated

Dihydroergotamine
(oral and subcutaneous)

↔

↔

Haloperidol

increased AUC of the metabolite by 31%

not investigated

Propranololol

17% increase in maximum concentration for 4-OH propranololol (topiramate 50 mg)

increase in maximum concentration by 9% and 16%, increase in AUC by 9% and 17%, respectively (for propranololol 40 mg and 80 mg every 12 hours)

Sumatriptan
(oral and subcutaneous)

↔

not investigated

/p>

Pisotifen

↔

↔

↔ = no change in maximum plasma concentration and AUC (≤ 15% of baseline);

b = a 14% increase in AUC was observed with repeated administration of flunarizine alone, which may be due to accumulation of the drug during equilibrium state achievement.

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 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 seizure frequency or new types of seizures. This phenomenon may be a consequence of overdose, lower concentrations of co-administered antiepileptic drugs, disease progression, or a paradoxical effect. The rate of excretion through the kidneys depends on renal function and is independent of age. In patients with moderate or severe renal dysfunction, it may take 10 to 15 days to reach stable plasma concentrations, as opposed 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 consider that in patients with impaired renal function, it may take longer for each dose to establish stable plasma concentrations.

In therapy with topiramate, oligohidrosis (decreased 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

Treatment with topiramate has an increased incidence of mood disorders and depression.

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 suicide-related 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 4045). 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 prescribed. Patients (and their caregivers, if necessary) should be advised to seek immediate medical attention if they show signs of suicidal thoughts or suicidal behavior.

Nephrolithiasis

Some patients, especially those with a predisposition to nephrolithiasis, may have an increased risk of kidney stone formation 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.

Kidney function impairment

Caution should be exercised when prescribing topiramate to 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 decrease in clearance of this drug.

Myopia and secondary closed-angle glaucoma

A syndrome involving acute myopia with concomitant secondary closed-angle glaucoma has been described with topiramate. 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 normalize the intraocular pressure.

Elevated intraocular pressure of any etiology can lead to serious complications, including loss of vision, 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 must 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 trials, most of these cases were reversible, and visual field defects disappeared after withdrawal of topiramate therapy. If vision problems occur while taking topiramate, discontinuation of therapy should be considered.

Metabolic acidosis

Hyperchloremic, unrelated to anion deficiency, metabolic acidosis may occur with topiramate (e.g., a decrease in 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 (average value is 4 mmol/L when used in adult patients at a dose above
100 mg per day and about 6 mg per day per kg body weight when used in pediatric practice). Rarely, patients have had decreases in hydrocarbonate concentrations below 10 mmol/L. Certain diseases or treatments that predispose to acidosis (e.g., kidney disease, severe respiratory disease, epileptic status, diarrhea, surgery, ketogenic diet, taking certain medications) may be additional factors that enhance 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 hydrocarbonate 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 caused by 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 effects 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.

Strengthened nutrition

If a patient loses body weight while being treated with Topiramate-ALSI, consideration should be given to the appropriateness of enhanced nutrition.

Influence on ability to drive vehicles, machinery

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

Synopsis

Contraindications

With caution

With caution in renal and hepatic failure, 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 disorders, nystagmus, paresthesia, sleepiness, tremor, diplopia, blurred vision, diarrhea, nausea, fatigue, irritability and decreased body weight.

Infectious and parasitic diseases: very often, nasopharyngitis*.

Blood and lymphatic system disorders: frequently – anemia; infrequently – leukopenia, lymphadenopathy, thrombocytopenia, eosinophilia; rarely – neutropenia*.

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

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

Mental 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, disrupted 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: common – vertigo, tinnitus, ear pain; infrequent – deafness, unilateral deafness, neurosensory deafness, discomfort in the ear, hearing loss.

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

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

Relatory system, thorax and mediastinum disorders: frequently – shortness of breath, nasal bleeding, nasal congestion, rhinorrhea, cough*; infrequently – shortness of breath on exercise, hypersecretion in the sinuses, dysphonia.

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

Hepatic and biliary tract disorders: rare – hepatitis, liver failure.

Skin and subcutaneous tissue disorders: Frequent – alopecia, rash, itching; infrequent – angidrosis, facial sensitivity disorders, 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: Frequent – arthralgia, muscle cramps, myalgia, muscle cramps, muscle weakness, skeletal-muscular pain in the chest; infrequent – swollen joints*, muscle stiffness, pain in the side, muscle fatigue; rare – 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*.

Genital and breast disorders: infrequent – erectile dysfunction, sexual dysfunction.

General disorders and disorders at the site of administration: very common – fatigue; common – elevated body temperature, asthenia, irritability, gait disturbances, malaise, restlessness; infrequent – hyperthermia, thirst, flu-like syndrome*, slowness, coldness of extremities, feeling intoxicated, feeling restless; rare – facial edema, calcinosis.

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

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

* – an adverse reaction was registered in the post-registration period from spontaneous reports. The frequency is calculated on the basis of data from clinical studies.

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 only been reported in children in controlled clinical trials: eosinophilia, psychomotor hyperactivity, vertigo, vomiting, hyperthermia, pyrexia, learning disability.

Overdose

Pregnancy use

Pregnancy

Topiramate showed teratogenic properties in mice, rats and rabbits. In rats, topiramate penetrated the placental barrier.

There have been no specific controlled studies in which topiramate has been used to treat pregnant women. Topiramate may cause fetal harm when used in pregnant women. Pregnancy records show that infants who have had intrauterine exposure to topiramate during the first trimester of pregnancy have an increased risk of birth defects (e.g., craniofacial defects such as cleft lip or palate, hypospadias, and abnormal development of various body systems). These malformations have been documented with both topiramate monotherapy and with its use in polytherapy.

Data from one pregnancy registry showed that topiramate monotherapy increased the incidence of significant birth defects by approximately 3 times that of the comparison group who did not take antiepileptic drugs.

In addition, the risk of teratogenic effects associated with taking antiepileptic drugs has been shown to be higher with combination therapy than with monotherapy.

In comparison with the group of patients not taking antiepileptic drugs, pregnancy registries for topiramate monotherapy show an increased likelihood of low birth weight babies (less than 2500 g). One pregnancy registry showed an increase in the relative number of infants underweight for their gestational age (UWB; defined as birth weight below the 10th percentile, adjusted for gestational age and stratified by sex) among infants who were exposed to topiramate in utero. The long-term effects of NGV have not been determined. The cause of decreased birth weight and OHV has not been determined.

Women of preserved childbearing potential should use reliable contraception during topiramate therapy.

The use of topiramate in pregnancy in women with uncontrolled epilepsy is justified only when the potential benefit of the drug to the mother exceeds the possible risk to the fetus. Topiramate use for prevention of migraine attacks is contraindicated during pregnancy, as well as in women of preserved childbearing potential who do not use reliable contraceptive methods.

When treating and consulting women of childbearing potential, the treating doctor should weigh the balance of benefits and risks of treatment and consider alternative treatment options. If topiramate is used during pregnancy, or if a patient becomes pregnant while taking this medication, she should be warned of the potential risk to the fetus.

Breastfeeding

Limited patient observations suggest that topiramate is excreted with breast milk in women, so the physician should decide not to breastfeed or to stop taking the drug.

Fertility

Topiramate has not been shown to affect fertility in animals. The effect of topiramate on fertility in humans has not been established.

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