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Active Ingredient: Topiramate.

Topamax is used for treating seizures in certain patients.

Other names for this medication:
Bipomax, Epimaxan, Epiramat, Epitomax, Erravia, Letop, Neutop, Piramax, Symtopiram, Talopam, Tidian, Tiramat, Topamac, Topibrain, Topictal, Topiegis, Topifar, Topigen, Topilek, Topilep, Topilex, Topimark, Topimatil, Topimax, Topina, Topinmate, Topira-q, Topiragamma, Topiramat, Topiramato, Topiramatum, Topiramed, Topirat, Topirax, Topirol, Topistad, Toplep, Toprel, Toramat, Zidoxer.

Clinico-pharmacological group
Anticonvulsant drug

Pharmachologic effect
Antiepileptic drug belongs to the class of sulphamate-substituted monosaccharides.

Topiramate blocks sodium channels and suppresses the occurrence of repeated action potentials against the background of prolonged depolarization of the neuron membrane. Topiramate increases the activity of GABA (GABA) with respect to certain subtypes of GABA receptors (including GABAA receptors), and also modulates the activity of the GABAA receptors themselves, and prevents the kainate / AMPK sensitivity to be activated by the kainate (alpha-amino-3-hydroxy -5-methylisoxazole-4-propionic acid) glutamate receptors, does not affect the activity of NMDA in relation to the NMDA receptor subtype. These effects of the drug are dose-dependent at plasma concentrations of topiramate from 1 μmol to 200 μmol, with a minimum activity ranging from 1 μmol to 10 μmol.

In addition, topiramate inhibits the activity of some isoenzymes of carbonic anhydrase. In terms of the severity of this pharmacological effect, topiramate is significantly inferior to acetazolamide, a known inhibitor of carbonic anhydrase, therefore this activity of topiramate is not the main component of its antiepileptic activity.

Pharmacokinetics
Suction

After taking the drug inside topiramate is quickly and effectively absorbed from the gastrointestinal tract. Bioavailability is 81%. Eating does not have a clinically significant effect on the bioavailability of the drug.

Topramata pharmacokinetics is linear, plasma clearance remains constant, and AUC in the dose range from 100 mg to 400 mg increases in proportion to the dose.

After repeated ingestion in a dose of 100 mg 2 times / day, Cmax averages 6.76 µg / ml.

Distribution

Plasma protein binding is 13-17%.

After a single oral dose of up to 1200 mg, the average Vd is 0.55-0.8 l / kg. Vd value depends on gender. In women, values ​​are approximately 50% of the values ​​observed in men, which is associated with a higher content of adipose tissue in the body of women.

In patients with normal renal function, it may take 4 to 8 days to achieve an equilibrium.

Metabolism

After ingestion, about 20% of the dose is metabolized.

From the human plasma, urine and feces, 6 practically inactive metabolites were isolated and identified.

Removal

Topiramate (70%) and its metabolites are excreted mainly by the kidneys.

After ingestion of plasma clearance of the drug is 20-30 ml / min.

After repeated administration of the drug in 50 mg and 100 mg 2 times / day, the average T1 / 2 averaged 21 hours.

Pharmacokinetics in special clinical situations

The rate of elimination of topiramate by the kidneys depends on the function of the kidneys and does not depend on age.

In patients with impaired renal function of moderate and severe (CK ≤ 70 ml / min), the renal and plasma clearance of topiramate decreases, resulting in an increase in plasma Css of topiramate in blood plasma compared with patients with normal renal function. The time to Css topiramate in plasma in patients with moderate or severe impaired renal function is from 10 to 15 days. Patients with moderate to severe renal failure are recommended to use half of the recommended initial and maintenance dose.

In the elderly, not suffering from kidney disease, plasma clearance of topiramate does not change.

In patients receiving concomitant therapy with antiepileptic drugs that induce enzymes involved in the metabolism of drugs, topiramate metabolism increased by 50%.

Topiramate is effectively eliminated by hemodialysis. Prolonged hemodialysis can lead to a decrease in the concentration of topiramate in the blood below the amount required to maintain anticonvulsant activity. To avoid a rapid drop in plasma topiramate concentration during hemodialysis, it may be necessary to prescribe an additional dose of Topamax.

Dose adjustment should take into account:

1) duration of hemodialysis;

2) the amount of clearance of the used hemodialysis system;

3) effective renal clearance of topiramat in a dialysis patient.

Plasma clearance of topiramate is reduced by an average of 26% in patients with moderate to severe liver failure. Therefore, patients with hepatic insufficiency should use topiramate with caution.

In children under the age of 12, the pharmacokinetic parameters of topiramate as well as in adults receiving the drug as an adjunct therapy are linear, while its clearance does not depend on the dose, and Css in plasma increases in proportion to the dose increase. It should be borne in mind that in children the clearance of topiramata is increased, and its T1 / 2 is shorter. Therefore, at the same dose per 1 kg of body weight, plasma topiramate concentrations in children may be lower than in adults. In children, as in adults, antiepileptic drugs that induce hepatic enzymes, cause a decrease in the concentration of topiramate in the blood plasma.

Indications
Epilepsy:

  • as monotherapy in adults and children over 2 years of age with epilepsy (including in patients with newly diagnosed epilepsy);
  • as part of complex therapy in adults and children over 2 years old with partial or generalized tonic-clonic seizures, as well as for the treatment of seizures in the presence of Lennox-Gastaut syndrome.

Migraine:

  • prevention of migraine attacks in adults (the use of Topamax for the treatment of acute migraine attacks has not been studied).

Contraindications

  • children’s age up to 2 years;
  • Hypersensitivity to the drug.

It should be used with caution in case of renal or hepatic insufficiency, nephroluritiasis (including in the past or in the family history), with hypercalciuria.

Dosage
The drug is taken orally, regardless of the meal.

Capsules should be carefully opened, mix their contents with a small amount (about 1 teaspoon) of any soft food. This mixture should be swallowed immediately, without chewing. Do not store the drug mixed with food until the next dose. Capsules Topamax can be swallowed whole.

To achieve optimal control of epileptic seizures in adults and children, it is recommended to begin treatment with the use of the drug in low doses, followed by titration to an effective dose.

Capsules are intended for patients who have difficulty swallowing tablets (for example, in children and elderly patients).

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

Combined anticonvulsant therapy in adults. The minimum effective dose is 200 mg / day. Typically, the total daily dose ranges from 200 mg to 400 mg and is taken in 2 divided 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 gradual selection of an effective dose. Selection of the dose begins with 25-50 mg, taking them overnight for 1 week. In the future, at intervals of 1-2 weeks, the dose can be increased by 25-50 mg and take it in 2 doses. The selection of the dose should be guided by the clinical effect. In some patients, the effect can be achieved when taking the drug 1 time / day. To achieve the optimal effect of treatment with Topamax, it is not necessary to control its plasma concentration.

These dose recommendations apply to all adult patients, including elderly patients, in the absence of kidney disease.

Combined anticonvulsant therapy in children older than 2 years. The recommended total daily dose of Topamax as an additional therapy is from 5 to 9 mg / kg and is taken in 2 divided doses. Selection of the dose should be started with 25 mg (or less, based on the initial dose of 1 to 3 mg / kg / day) at night for 1 week. In the future, the dose can be increased with an interval of 1-2 weeks for 1-3 mg / kg and take it in 2 doses. The selection of the dose should be guided by the clinical effect. Daily dosages up to 30 mg / kg are usually well tolerated.

Epilepsy (including first diagnosed)

When canceling concomitant anticonvulsant drugs for the purpose of monotherapy with topiramate, it is necessary to consider the possible influence of this step on the frequency of seizures. In cases where there is no need to abruptly cancel concomitant anticonvulsant drugs for safety reasons, it is recommended to reduce their doses gradually, reducing the dose of concomitant anti-epileptic drugs by 1/3 every 2 weeks.

With the abolition of drugs that are inducers of liver microsomal enzymes, the concentration of topiramate in the blood will increase. In such situations, in the presence of clinical indications, the dose of Topamax can be reduced.

When monotherapy in adults at the beginning of treatment, Topamax is prescribed at a dose of 25 mg at bedtime for 1 week. Then the dose is increased with an interval of 1-2 weeks by 25 mg or 50 mg in 2 doses. If the patient does not tolerate such a mode of increasing the dose, you can increase the intervals between dose increases, or increase the dose more smoothly. The selection of the dose should be guided by the clinical effect. The initial dose for monotherapy with topiramate in adults is 100 mg / day, and the maximum daily dose should not exceed 500 mg. Some patients with refractory forms of epilepsy tolerate monotherapy with topiramate in doses up to 1000 mg / day. These dosing recommendations apply to all adults, including elderly patients without kidney disease.

When monotherapy for children over the age of 2 years in the first week of treatment, Topamax is prescribed at a dose of 0.5-1 mg / kg of body weight at bedtime. Then the dose is increased with an interval of 1-2 weeks by 0.5-1 mg / kg / day in 2 doses. If the child does not tolerate such a mode of increasing the dose, it is possible to increase the dose more smoothly or increase the intervals between dose increases. The magnitude of the dose and the rate of its increase depends on the clinical effect. The recommended dose range for monotherapy with topiramate in children over the age of 2 years is 100-400 mg / day. Children with newly diagnosed partial seizures can be given up to 500 mg / day.

Migraine

For the prevention of migraine attacks, the recommended daily dose of topiramate is 100 mg in 2 divided doses. At the beginning of treatment, 25 mg is prescribed at bedtime for 1 week. Then the dose is increased by 25 mg / day with an interval of 1 week. In case of intolerance to such a regimen of therapy, the dose is increased by a smaller amount or at long intervals. The dose is selected depending on the clinical effect. In some cases, a positive result is achieved with a daily dose of topiramate 50 mg. In clinical studies, patients received various doses of topiramate, but not more than 200 mg / day.

Special patient groups

Patients with moderate to severe renal insufficiency may need a dose reduction. The use of half the recommended initial and maintenance dose is recommended.

Hemodialysis: since topiramate is removed from plasma during hemodialysis, on the days of hemodialysis, an additional dose of Topamax should be administered, equal to about half the daily dose. The additional dose should be divided into two doses taken at the beginning and after completion of the hemodialysis procedure. The additional dose may vary depending on the characteristics of the equipment used during hemodialysis.

In patients with hepatic insufficiency, topiramate should be used with caution.

Side effects
Determination of the frequency of side effects: very often (≥1 / 10), often (≥1 / 100, <1/10), infrequently (≥1 / 1000 and <1/100), rarely (≥1 / 10 000 and <1 / 1000) and very rarely (<1/10 000).

From the side of the central nervous system: very often – drowsiness, dizziness, paresthesias, in children – apathy, impaired attention; often – impaired motor coordination, nystagmus, lethargy, impaired memory, tremor, amnesia, abnormal gait, hypoesthesia, taste perversion, impaired thinking, cognitive disorders, apathy, mental decline, psychomotor disorders, sedative action; infrequently – loss of taste sensitivity, akinesia, loss of smell, aphasia, apraxia, aura, burning sensation in the limbs or on the face, cerebellar syndrome, circadian rhythm sleep disorder, complex partial seizures, convulsions, postural dizziness, dysesthesia, sensitivity disorder, dysography, dyskinesia , dysphasia, dystonia, tingling sensation in the body, tonic-clonic seizures of grand mal type, hyperesthesia, hypogemia, hypokinesia, hyposmia, peripheral neuropathy, parosmia, pre-fainting states, repetitive p To treat, violation of touch, stupor, fainting, lack of response to stimuli, in children – psychomotor hyperactivity.

Mental disorders: often – delayed thinking, pronounced speech disorders, confusion, depression, insomnia, aggressive reactions, agitation, disorientation, emotional lability, erectile dysfunction, in children – behavioral change, learning disability (difficulty reading, writing, counting); infrequently – anorgasmia, sexual dysfunction, tearfulness, disturbance of sexual arousal, dysfemia, early waking up in the morning, euphoric mood, auditory and visual hallucinations, hypomania states, decreased libido, mania, mania, panic state, paranoid states, thinking perseveration, misunderstandings, habits sleep, suicidal ideation or trying, crying; very rarely – a feeling of despair.

On the part of the digestive system: very often – reduction of appetite, anorexia; often – nausea, diarrhea; infrequently – abdominal pain, constipation, stomach discomfort, dyspepsia, dry mouth, impaired oral sensitivity, gastritis, gastroesophageal reflux, bleeding gums, heaviness in the stomach, in children – vomiting, unpleasant smell from the mouth, discomfort in the epigastric areas, flatulence, glossodynia, pain in the mouth, pancreatitis, salivary hypersecretion, thirst.

On the part of the musculoskeletal system: often – myalgia (including in the chest), muscle spasms, muscle cramps, arthralgia; infrequently – pain in the side, muscle fatigue, muscle weakness, muscle stiffness; very rarely – swelling of the joints, discomfort in the limbs.

Since the cardiovascular system: sometimes – bradycardia, rapid heartbeat, flushing, orthostatic hypotension, Raynaud’s phenomenon.

On the part of the organ of vision: often – diplopia, impaired vision, dry eyes; infrequently – disturbance of accommodation, amblyopia, blepharospasm, transient blindness, unilateral blindness, increased lacrimation, mydriasis, night blindness, photopsia, presbyopia, scotoma (including atrial), reduction of visual acuity; very rarely – discomfort in the eyes, angle-closure glaucoma, involuntary movements of the eyeballs, eyelid edema, myopia, maculopathy, conjunctival edema.

From the organ of hearing: often – pain in the ears, ringing in the ears, in children – vertigo; infrequently – deafness (including neurosensory and unilateral), discomfort in the ears, hearing impairment.

On the part of the respiratory system: often – difficulty breathing, nosebleeds; infrequently – hoarseness, shortness of breath on exertion, nasal congestion, hypersecretion in the paranasal sinuses, in children – rhinorrhea; very rarely – nasopharyngitis.

From the hemopoietic system: often – anemia; infrequently – leukopenia, lymphadenopathy, thrombocytopenia, in children – eosinophilia; very rarely – neutropenia.

On the part of the skin and subcutaneous tissues: often – a rash, alopecia, itching, decrease in the sensitivity of the skin of the face; infrequently – lack of sweating, allergic dermatitis, reddening of the skin, impaired skin pigmentation, swelling of the face, unpleasant skin odor, urticaria; very rarely – erythema multiforme, paraorbital edema, Stevens-Johnson syndrome, toxic epidermal necrolysis.

From the urinary system: often – nephrolithiasis, dysuria, pollakiuria; infrequently – exacerbation of urolithiasis, hematuria, urinary incontinence, frequent urination, renal colic, pain in the kidneys; very rarely – renal tubular acidosis.

From the laboratory indicators: infrequently – a decrease in the content of bicarbonate in the blood (on average by 4 mmol / l), crystalluria, leukopenia, hypokalemia (decrease in the level of potassium in the blood serum below 3.5 mmol / l).

General disorders: very often – fatigue, irritability, weight loss; often – asthenia, anxiety, in children – fever; infrequently – facial edema, allergic reactions, hyperchloremic acidosis, hypokalemia, increased appetite, metabolic acidosis, polydipsia, cold extremities, fatigue, weakness, calcification; very rarely – generalized edema, flu-like illness, angioedema, weight gain.

Overdose
Symptoms: convulsions, drowsiness, impaired speech and vision, diplopia, impaired thinking, impaired coordination, lethargy, stupor, arterial hypotension, abdominal pain, dizziness, agitation and depression. In most cases, the clinical consequences were not severe, but deaths were observed after an overdose using a mixture of several drugs, including topiramate. Perhaps the development of severe metabolic acidosis.

A case of overdose is known, when the patient took a dose of topiramate from 96 to 110 g, which caused a coma lasting for 20-24 hours. After 3-4 days, the symptoms of overdose resolved.

Treatment: if shortly before receiving an excessive dose of the drug, the patient took food, you must immediately flush the stomach or induce vomiting. In vitro studies have shown that activated carbon adsorbs topiramate. If necessary, symptomatic therapy should be carried out. An effective way to remove topiramate from the body is hemodialysis. Patients are recommended an adequate increase in fluid intake.

Drug interaction
Effect of Topamax on concentrations of other antiepileptic drugs (AEP)

Simultaneous administration of Topamax with other PEP (phenytoin, carbamazepine, valproic acid, phenobarbital, primidon) does not affect plasma Css values, except for certain patients in whom the addition of Topamax to phenytoin may cause an increase in plasma phenytoin concentration. This may be due to the inhibition of a specific polymorphic isoform of the cytochrome P450 enzyme system (CYP2Cmeph). Therefore, when symptoms of toxicity develop in patients receiving phenytoin, it is necessary to control the concentration of phenytoin in the blood plasma.

In the study of pharmacokinetics in patients with epilepsy, the addition of topiramate to lamotrigine did not affect the Css of the latter in plasma at doses of topiramate 100-400 mg / day. During and after the abolition of lamotrigine (the average dose of 327 mg / day), Css topiramate did not change.

The effect of other probes on the concentration of topiramate in plasma

Phenytoin and carbamazepine, while used with Topamax, reduce the concentration of topiramate in the plasma. Adding or removing phenytoin or carbamazepine during treatment with Topamax may require a dose change of the latter. The dose is selected depending on the development of the required clinical effect. Addition or removal of valproic acid does not cause clinically significant changes in the concentration of topiramate in the blood plasma and, therefore, does not require a change in the dose of Topamax.

In studies conducted with simultaneous use of the drug Topamax in a single dose of AUC of digoxin was reduced by 12%. The clinical significance of this effect has not been established. When prescribing or withdrawing the drug Topamax in patients receiving digoxin, it is necessary to monitor the concentration of digoxin in the serum.

As part of clinical studies, the effects of joint use of the drug Topamax with drugs that inhibit the function of the central nervous system, as well as with ethanol, have not been studied. The combined use of the drug Topamax with drugs that have a depressant effect on the central nervous system, and with ethanol is not recommended.

When co-administering Topamax and Hypericum perforatum preparations based on Hypericum perforatum, the concentration of topiramate in the plasma may decrease and, as a result, the effectiveness of the preparation may also decrease. Clinical studies of the interaction of the drug Topamax and preparations based on Hypericum perforatum have not been conducted.

With simultaneous use of an oral contraceptive containing norethisterone (1 mg) and ethinyl estradiol (35 mcg), Topamax in doses of 50-800 mg / day did not significantly affect the effectiveness of norethisterone and in doses of 50-200 mg / day – on the effectiveness of ethinyl estradiol. A significant dose-dependent decrease in the effectiveness of ethinyl estradiol was observed at doses of the drug Topamax 200-800 mg / day. The clinical significance of the described changes is not clear. The risk of reducing the effectiveness of contraceptives and enhancing breakthrough bleeding should be considered in patients taking oral contraceptives in combination with Topamax. Patients taking estrogen-containing contraceptives should inform the doctor about any changes in the timing and nature of menstruation. The effectiveness of contraceptives can be reduced even in the absence of breakthrough bleeding.

In healthy volunteers, lithium AUC decreased by 18% while taking topiramate at a dose of 200 mg / day. In patients with manic-depressive psychosis, the use of topiramate in doses up to 200 mg / day did not affect the pharmacokinetics of lithium, but at higher doses (up to 600 mg / day), lithium AUC was increased by 26%. With the simultaneous use of topiramate and lithium should monitor the concentration of the latter in the blood plasma.

Studies of drug interactions conducted with a single and multiple administration of topiramate to healthy volunteers and patients with manic-depressive psychosis, gave the same results. With the simultaneous use of topiratam in daily doses of 250 mg or 400 mg of AUC of risperidone taken in doses of 1-6 mg / day, reduced 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) changed insignificantly. Changes in the level of systemic exposure to risperidone / 9-hydroxyrisperidone and topiramate were not clinically significant, and this interaction is unlikely to have clinical significance.

Drug interactions were studied in healthy volunteers with separate and co-administration of hydrochlorothiazide (25 mg) and topiramate (96 mg). The research results showed that while taking topiramate and hydrochlorothiazide, there is an increase in Cmax of topiramate by 27% and its AUC by 29%. The clinical significance of these studies has not been identified. When administering hydrochlorothiazide to patients taking topiramate, dose adjustment of topiramate may be required. There were no significant changes in the pharmacokinetic parameters of hydrochlorothiazide with concomitant therapy with topiramate.

Drug interactions were studied in healthy volunteers who received metformin or a combination of metformin and topiramate. Research results showed that while taking topiramate and metformin, Cmax and AUC of metformin increased by 18% and 25%, respectively, while clearance of metformin and simultaneous administration with topiramate decreased by 20%. Topiramate had no effect on Tmax of metformin in the blood plasma. The clearance of a topiramat at joint appointment with metformin decreases. The degree of clearance changes have not been studied. The clinical significance of the effects of metformin on topiramate pharmacokinetics is not clear. In the case of the addition or withdrawal of the drug Topamax in patients receiving metformin, the condition of patients with diabetes should be monitored.

Drug interactions were studied in healthy volunteers with separate and co-administration of pioglitazone and topiramate. It was revealed a decrease in the AUC of pioglitazone by 15%, without changing the Cmax of the drug. These changes were not statistically significant. Also for the active hydroxymetabolite pioglitazone, a decrease in Cmax and AUC was detected by 13% and 16%, respectively, and for active ketometabolite, a decrease in both Cmax and AUC by 60% was found. The clinical significance of this data has not been elucidated. When patients are jointly prescribed Topamax and pioglitazone, the patient’s condition should be carefully monitored to assess the course of diabetes.

A study of drug interactions was conducted to study the pharmacokinetics of glibenclamide (5 mg / day) in an equilibrium state, used alone or simultaneously with topiramate (150 mg / day) in patients with type 2 diabetes. When using topiramate AUC glibenclamide was reduced by 25%. The level of systemic exposure to active metabolites, 4-trans-hydroxy-glibenclamide and 3-cis-hydroxy-glibenclamide, was also reduced (by 13% and 15%, respectively). Glibenclamide did not affect the pharmacokinetics of topiramate in equilibrium. A statistically insignificant decrease in the AUC of pioglitazone by 15% was found with no change in its Cmax. When administering topiramate to patients receiving glibenclamide (or prescribing glibenclamide to patients receiving topiramate), the patient’s condition should be carefully monitored to assess the course of diabetes.

With the simultaneous use of the drug Topamax with other drugs predisposing to the development of nephrolithiasis, it is possible to increase the risk of kidney stones. During the period of treatment with Topamax, the use of such drugs should be avoided, since they can cause physiological changes that contribute to the development of nephrolithiasis.

The combined use of topiramate and valproic acid in patients who tolerate each drug well separately is accompanied by hyperammonemia with or without encephalopathy. In most cases, the symptoms and signs disappear after the cancellation of one of the drugs. This adverse event is not caused by pharmacokinetic interaction. The relationship between hyperammonemia and the use of topiramate alone or in combination with other drugs has not been established.

When combined with topiramate and valproic acid, hypothermia may occur (unintended decrease in body temperature below 35 ° C) in combination with hyperammonemia or independently. This phenomenon can occur both after the start of joint administration of valproic acid and topiramate, and with an increase in the daily dose of topiramate.

Special instructions
Cancel Topamax (like other anti-epileptic drugs) should be gradually, to minimize the possibility of increasing the frequency of seizures. To reduce the dose by 25-50 mg, Topamax is used in the form of capsules in a dosage of 15 mg or 25 mg. In clinical studies, the dose of the drug was reduced by 50-100 mg 1 time per week – for adults with epilepsy therapy and 25-50 mg – for adults receiving Topamax at a dose of 100 mg / day for the prevention of migraine. In children in clinical studies, Topamax was gradually canceled over a period of 2-8 weeks. If, for medical reasons, rapid withdrawal of Topamax is necessary, then it is recommended that the patient be monitored accordingly.

As with any disease, the dosage regimen should be set in accordance with the clinical effect (i.e., the degree of seizure control, no side effects) and take into account the fact that in patients with impaired renal function to establish a stable plasma concentration for each dose need a longer time.

With topiramate therapy, oligohydrosis (reduced sweating) and anhidrosis can occur. Reduction of sweating and hyperthermia (increased body temperature) may occur in children exposed to high ambient temperatures. During therapy with topiramate, it is very important to adequately increase the volume of fluid consumed, which helps reduce the risk of developing nephrolithiasis, as well as side effects that may occur under the influence of physical exertion or elevated temperatures.

When treating with topiramate, there is an increased incidence of mood disorders and depression.

The use of antiepileptic drugs, including Topamax, increases the risk of suicidal thoughts and suicidal behavior in patients taking these drugs for any of the indications.

In double-blind clinical studies, the incidence of phenomena associated with suicide (suicidal thoughts, attempted suicide, suicide) was 0.5% in patients treated with topiramate (46 people out of 8652), which is about 3 times higher than in patients placebo (0.2%; 8 people out of 4045). One case of suicide was recorded in a double-blind study of bipolar disorder in a patient receiving topiramate.

Thus, it is necessary to monitor the condition of patients in order to identify signs of suicidal thoughts and prescribe appropriate treatment. Patients (and, if necessary, caregivers) should be advised to immediately seek medical attention if they show signs of suicidal thoughts or suicidal behavior.

Some patients, especially those with a predisposition to nephrolithiasis, may have an increased risk of kidney stones and associated symptoms, such as renal colic. To reduce this risk, an adequate increase in fluid intake is needed. Risk factors for nephrolithiasis are nephrolithiasis in history (including family), hypercalciuria, concomitant therapy with other drugs that contribute to the development of nephrolithiasis.

Caution must be exercised in the appointment of Topamax to patients with renal insufficiency (CC <70 ml / min). This is due to the fact that in such patients the clearance of the drug is lowered.

In patients with impaired liver function, Topamax should be used with caution because of a possible decrease in clearance of topiramate.

When using the drug Topamax described syndrome, including acute myopia with concomitant secondary angle-closure glaucoma. Symptoms include acute reduction of visual acuity and / or pain in the eye. Ophthalmologic examination may show myopia, flattening of the anterior chamber of the eye, hyperemia (redness) of the eyeball, and increased intraocular pressure. Mydriasis may occur. This syndrome may be accompanied by secretion of fluid, leading to the displacement of the lens and the iris forward with the development of secondary angle-closure glaucoma. Symptoms usually appear 1 month after starting Topamax. Unlike primary open-angle glaucoma, which is rarely seen in patients under 40 years of age, secondary angle-closure glaucoma is observed with the use of topiramate in both adults and children. In the event of a syndrome involving myopia associated with angle-closure glaucoma, treatment includes discontinuing Topamax as soon as the attending physician considers it possible, and appropriate measures aimed at lowering intraocular pressure. Usually these measures lead to the normalization of intraocular pressure.

Increased intraocular pressure of any etiology in the absence of adequate treatment can lead to serious complications, including loss of vision.

When using topiramate, hyperchloremic, not associated with anion deficiency, metabolic acidosis can occur (for example, a decrease in blood bicarbonate concentration by an average of 4 mmol / l in the absence of respiratory alkalosis). Such a decrease in serum bicarbonate concentration is a consequence of the inhibitory effect of topiramate on renal carbonic anhydrase. In most cases, a decrease in bicarbonate concentration occurs at the beginning of the drug intake, although this effect may occur during any period of treatment with topiramate. The level of reduction is usually mild or moderate (the average value is 4 mmol / l when used in adult patients at a dose of more than 100 mg / day and about 6 mg / kg / day when used in pediatric practice). In rare cases, patients had a decrease in concentration below 10 mmol / l. Some diseases or treatments that predispose to the development of acidosis (for example, kidney disease, severe respiratory diseases, status epilepticus, diarrhea, surgical interventions, ketogenic diet, taking certain medications) can be additional factors that enhance the bicarbonate-reducing effect of topiramate.

In children, chronic metabolic acidosis can lead to stunted growth. The effect of topiramate on growth and possible complications associated with the skeletal system have not been systematically studied in children and adults.

In connection with the foregoing, in the treatment with topiramate it is recommended to conduct the necessary studies, including the determination of the concentration of bicarbonate in serum. If metabolic acidosis occurs and persists, it is recommended to reduce the dose or stop taking Topamax.

If, against the background of taking the drug Topamax, the patient’s body weight decreases, then the question of the expediency of enhanced nutrition should be considered.

Laboratory values

Hypokalemia, defined as a decrease in serum potassium concentration below 3.5 mmol / l, was observed in 0.4% of patients receiving topiramate.

Influence on ability to drive motor transport and control mechanisms

Topamax acts on the central nervous system and may cause drowsiness, dizziness, blurred vision and other symptoms. These adverse effects can be dangerous for patients driving a car and moving machinery, especially during the period until the patient’s reaction to the drug is established.

Pregnancy and lactation
Special controlled studies in which Topamax was used to treat pregnant women have not been conducted. Pregnancy records show a possible link between the use of Topamax during pregnancy and congenital malformations (for example, craniofacial defects such as cleft lip / cleft palate, hypospadias and abnormalities in the development of various body systems). These malformations were recorded both in monotherapy with topiramate and in its use in the framework of polytherapy. Compared with the group of patients not taking antiepileptic drugs, the records of pregnancies with monotherapy with Topamax indicate the likelihood of the birth of children with low body weight (less than 2500 g). The relationship of the observed phenomena with the drug is not installed.

In addition, the records of pregnancies and the results of other studies suggest that the risk of teratogenic effects in the combined treatment of antiepileptic drugs may be higher than in monotherapy. Use of the drug Topamax during pregnancy is justified only in the case when the potential benefits of therapy for the mother outweigh the possible risk to the fetus.

When treating and consulting women with childbearing potential, the attending physician should weigh the ratio of benefits and risks of treatment and consider alternative treatment options. If Topamax is used during pregnancy, or if the patient became pregnant while taking this drug, it should be warned of the potential risk to the fetus.

A limited number of observations suggests that topiramate is excreted in breast milk in women. If necessary, the use of the drug Topamax during lactation should decide on the termination of breastfeeding.

Use in childhood
The drug is contraindicated for use in children under 2 years.

In case of impaired renal function
When prescribing the drug to patients with moderately or severely impaired renal function, it should be borne in mind that in order to achieve an equilibrium state in this category of patients, it may take 10-15 days, in contrast to 4-8 days in patients with normal renal function. Since topiramate is removed from plasma during hemodialysis, on the days of its holding, an additional dose of the drug equal to half the daily dose should be administered in 2 doses (before and after the procedure).

It should be used with caution in renal failure, nephroluritiasis (including in the past or in family history), and in hypercalciuria.

With abnormal liver function
Caution should be used when liver failure. In patients with moderately severe and severely impaired liver function, plasma clearance is reduced.

Terms and conditions of storage
The drug should be stored out of the reach of children, in a dry place at a temperature not exceeding 25 ° C. Shelf life – 2 years.