Topamax, 50 mg capsules 60 pcs

The drug belongs 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.

The drug increases the activity of GABA (GABA) against some subtypes of GABA receptors (including GABAA-receptors) and modulates the activity of GABAA-receptors themselves, also inhibits kainate/AMPK (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptor subtype sensitivity to glutamate, and has no effect on NMDA activity with respect to NMDA-receptor subtype. The efficacy of the drug is dose-dependent at plasma concentrations of topiramate between 1 μmol and 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, the known carbonic anhydrase inhibitor, in terms of the severity of this pharmacological effect, so that this activity of topiramate is not the main component of its antiepileptic activity.

Pharmacokinetics

Intake

After oral administration, topiramate is rapidly and effectively absorbed from the GI tract. Bioavailability is 81%. Food intake has no clinically significant effect on the bioavailability of the drug.

The pharmacokinetics of topiramate are linear; plasma clearance remains constant and AUC in dose range from 100 mg to 400 mg increases in proportion to dose.

After multiple oral doses of 100 mg twice daily, Cmax averages 6.76 mcg/ml.

Distribution

The binding to plasma proteins is 13-17%.

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

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

Metabolism

About 20% of the dose is metabolized after oral administration.

Six virtually inactive metabolites have been isolated and identified from human plasma, urine, and feces.

Excretion

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

After oral administration, the plasma clearance of the drug is 20-30 ml/min.

After multiple doses of the drug at 50 mg and 100 mg 2 times/day, the average T1/2 was on average 21 hours.

Pharmacokinetics in special clinical cases

The renal excretion rate of topiramate is dependent on renal function and is independent of age.

In patients with moderate to severe renal dysfunction (CK ≤ 70 mL/min), renal and plasma clearance of topiramate is decreased and, as a consequence, plasma Css of topiramate may be increased compared to patients with normal renal function. The time to reach plasma Css of topiramate in patients with moderate to severe renal impairment is 10 to 15 days. For patients with moderate to severe renal impairment, half the recommended initial and maintenance doses are recommended.

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

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

Topiramate is effectively excreted by hemodialysis. Prolonged hemodialysis may cause blood concentrations of topiramate to fall below the amount required to maintain anticonvulsant activity. An additional dose of Topamax® may need to be administered to avoid a rapid drop in plasma concentrations of topiramate during hemodialysis. When adjusting the dose, consideration should be given to:

1) the duration of hemodialysis;

2) the clearance rate of the hemodialysis system used;

3) the effective renal clearance of topiramate in the patient on dialysis.

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.

In children under 12 years of age, the pharmacokinetic parameters of topiramate, as well as in adults receiving the drug as adjuvant therapy, are linear, with its clearance independent of the dose, and Css in plasma increases in proportion to increasing the dose. Note that in children, topiramate clearance is increased and its T1/2 is shorter.

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 hepatic enzymes cause lower plasma concentrations of topiramate.

Indications

Epilepsy:

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

Pharmacological effect

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

Topiramate blocks sodium channels and suppresses the occurrence of repeated action potentials against the background of prolonged depolarization of the neuron membrane.

The drug increases the activity of GABA (GABA) in relation to certain subtypes of GABA receptors (including GABAA receptors) and modulates the activity of the GABAA receptors themselves, also prevents the activation by kainate of the sensitivity of the subtype kainate/AMPK (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptors to glutamate, does not affect the activity of NMDA in relation to NMDA receptor subtype. The effectiveness of the drug is dose-dependent with plasma concentrations of topiramate ranging from 1 µmol to 200 µmol, with minimal activity ranging from 1 µmol to 10 µmol.

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

Pharmacokinetics

Suction

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

The pharmacokinetics of topiramate 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 oral administration at a dose of 100 mg 2 times/day, Cmax averages 6.76 mcg/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. The value of Vd depends on gender. In women, the 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 reach steady state.

Metabolism

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

Six practically inactive metabolites were isolated and identified from human plasma, urine and feces.

Removal

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

After oral administration, plasma clearance of the drug is 20-30 ml/min.

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

Pharmacokinetics in special clinical situations

The rate of renal excretion of topiramate depends on renal function and is independent of age.

In patients with moderate to severe renal impairment (creatinine clearance ≤ 70 ml/min), the renal and plasma clearance of topiramate is reduced, as a result of which the Css of topiramate in the blood plasma may increase compared to patients with normal renal function. The time to reach Css of topiramate in the blood plasma in patients with moderate or severe renal impairment ranges from 10 to 15 days. In patients with moderate or severe renal impairment, half the recommended initial and maintenance dose is recommended.

In elderly people who do not suffer from kidney disease, the plasma clearance of topiramate does not change.

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

Topiramate is effectively eliminated by hemodialysis. Long-term hemodialysis may result in a decrease in blood concentrations of topiramate below the amount required to maintain anticonvulsant activity. To avoid a rapid fall in plasma concentrations of topiramate during hemodialysis, an additional dose of Topamax may be required. When adjusting the dose, you should take into account:

1) duration of hemodialysis;

2) the clearance value of the hemodialysis system used;

3) effective renal clearance of topiramate in a patient on dialysis.

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

In children under the age of 12 years, the pharmacokinetic parameters of topiramate, as well as in adults receiving the drug as adjuvant therapy, are linear, while its clearance does not depend on the dose, and Css in plasma increases in proportion to the dose. It should be taken into account that in children the clearance of topiramate is increased and its T1/2 is shorter.

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 liver enzymes cause a decrease in the concentration of topiramate in the blood plasma.

Special instructions

Topamax® (like other antiepileptic drugs) should be discontinued gradually to minimize the possibility of an increase in the frequency of seizures. In clinical studies, the dose of the drug was reduced by 50-100 mg once a week – for adults during the treatment of epilepsy and by 25-50 mg – in adults receiving Topamax® at a dose of 100 mg / day for the prevention of migraine.

In children in clinical studies, Topamax® was gradually withdrawn over 2-8 weeks. If, for medical reasons, rapid discontinuation of Topamax® is necessary, it is recommended to appropriately monitor the patient’s condition.

As with any disease, dosing schedules should be based on clinical response (i.e., degree of seizure control, absence of side effects) and take into account that in patients with renal impairment, a longer time may be required to establish stable plasma concentrations for each dose.

During therapy with topiramate, oligohidrosis (decreased sweating) and anhidrosis may occur. Decreased sweating and hyperthermia (increased body temperature) may occur in children exposed to high ambient temperatures. When treating with topiramate, it is very important to adequately increase the volume of fluid intake, which helps reduce the risk of developing nephrolithiasis, as well as side effects that may occur under the influence of physical activity or elevated temperatures.

An increased incidence of mood disorders and depression has been observed during treatment with topiramate.

When using antiepileptic drugs, including Topamax®, the risk of suicidal thoughts and behavior increases in patients taking these drugs for any indication.

In double-blind clinical studies, the incidence of suicide-related events (suicidal ideation, suicide attempts, suicide) was 0.5% in patients receiving topiramate (46 of 8652 people), which is approximately 3 times higher than in patients receiving placebo (0.2%; 8 of 4045 people). One case of suicide was reported in a double-blind study of bipolar disorder in a patient receiving topiramate.

Thus, it is necessary to monitor patients for signs of suicidal ideation and prescribe appropriate treatment. Patients (and, if appropriate, caregivers) should be advised to seek immediate medical attention if signs of suicidal thoughts or behavior occur.

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

Caution should be exercised when prescribing Topamax® to patients with renal failure.

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

When using the drug Topamax®, a syndrome has been described that includes acute myopia with concomitant secondary angle-closure glaucoma. Symptoms include acute loss of visual acuity and/or eye pain. An ophthalmological examination may reveal 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 fluid secretion, leading to forward displacement of the lens and iris with the development of secondary angle-closure glaucoma. Symptoms usually appear 1 month after starting Topamax®.

Unlike primary open-angle glaucoma, which is rarely observed in patients under 40 years of age, secondary angle-closure glaucoma is observed with the use of topiramate in both adults and children. If a syndrome involving myopia associated with angle-closure glaucoma occurs, treatment includes discontinuation of Topamax® as soon as deemed possible by the attending physician and appropriate measures aimed at lowering intraocular pressure. Typically, these measures lead to 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 topiramate is used, hyperchloremic, non-anion deficiency, metabolic acidosis (eg, a decrease in plasma bicarbonate concentrations below normal levels in the absence of respiratory alkalosis) may occur. This decrease in serum bicarbonate concentrations is a consequence of the inhibitory effect of topiramate on renal carbonic anhydrase. In most cases, a decrease in bicarbonate concentrations occurs at the beginning of the drug, although this effect can occur at any time during treatment with topiramate.

The level of decrease in concentration is usually weak 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 experienced a decrease in concentration below 10 mmol/l. Certain medical conditions or treatments that predispose to the development of acidosis (eg, kidney disease, severe respiratory disease, status epilepticus, diarrhea, surgery, ketogenic diet, certain medications) may be additive factors that enhance the bicarbonate-lowering effect of topiramate.

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

In connection with the above, when treating with topiramate, it is recommended to carry out the necessary studies, including determination of the concentration of bicarbonate in the serum. If metabolic acidosis occurs and persists, it is recommended to reduce the dose or stop taking Topamax®.

If, while taking Topamax®, the patient’s body weight decreases, then the advisability of increased nutrition should be considered.

Impact on the ability to drive vehicles and operate machinery

Topamax® acts on the central nervous system and may cause drowsiness, dizziness, blurred vision and other symptoms. These adverse effects may pose a danger to patients who drive cars and operate machinery, especially until the patient’s response to the drug is established.

Active ingredient

Topiramate

Composition

Active ingredient:

topiramate 50 mg

excipients:

granulated sugar [sucrose, starch syrup] 150.00 mg,

povidone 34.733 mg,

cellulose acetate 18.076 mg.

composition of hard gelatin capsule:

gelatin 80.6-83.5 mg,

water 12.5-15.4 mg,

sorbitan laurate 0.0397 mg,

sodium lauryl sulfate 0.0397 mg,

titanium dioxide (E171) 0.99 mg,

ink Opacode Black S-1-17822/23 black (ink composition: shellac glaze solution in ethanol, black iron oxide, n-butyl alcohol, isopropyl alcohol, propylene glycol, ammonium hydroxide) 5-10 mcg.

Pregnancy

There have been no special controlled studies in which Topamax was used to treat pregnant women. Topiramate may cause fetal harm when used in pregnant women. Pregnancy data indicate that infants exposed to topiramate in utero have an increased risk of developing congenital malformations (eg, craniofacial defects such as cleft lip or palate, hypospadias, and developmental anomalies of various body systems). These malformations were recorded both during monotherapy with topiramate and when it was used as part of polytherapy.

Compared with the group of patients not taking antiepileptic drugs, data from pregnancies during monotherapy with Topamax indicate an increased likelihood of having children with low body weight (less than 2500 g). The connection between the observed phenomena and the use of the drug has not been established.

In addition, pregnancy records and the results of other studies indicate that the risk of developing teratogenic effects with combination treatment with antiepileptic drugs is higher than with monotherapy.

The use of Topamax during pregnancy is justified only if the potential benefit of the drug for the mother outweighs the possible risk to the fetus. When treating and counseling women of childbearing potential, the treating physician must weigh the benefits and risks of treatment and consider alternative treatment options. If Topamax is used during pregnancy or the patient becomes pregnant while taking this drug, she should be warned of the potential risk to the fetus.

A limited number of patient observations suggests that topiramate is excreted into breast milk in women, so the physician should decide whether to breastfeed or discontinue the drug.

Contraindications

children under 2 years of age;
hypersensitivity to the components of the drug.

Use with caution in case of renal or liver failure, nephrourolithiasis (including in the past or family history), and hypercalciuria.

Use for liver dysfunction

Use with caution in case of liver failure. In patients with moderate to severe liver dysfunction, plasma clearance is reduced.

Use for renal impairment

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

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

Side Effects

Determination of the frequency of side effects: very often (≥1/10), often (≥1/100,

From the nervous system: very often – drowsiness, dizziness, paresthesia, in children – apathy, impaired attention; often – nystagmus, lethargy, memory impairment, impaired concentration, tremor, amnesia, hypoesthesia, perversion of taste, impaired thinking, impaired speech, cognitive disorders, apathy, mental impairment, psychomotor impairment, sedative effect; uncommon – loss of taste sensitivity, akinesia, loss of smell, aphasia, apraxia, aura, burning sensation (mainly on the face and extremities), cerebellar syndrome, circadian sleep disorder, impaired motor coordination, complex partial seizures, convulsions, postural dizziness, increased salivation, dysesthesia, dysgraphia, dyskinesia, dysphasia, dystonia, sensation “goose bumps” all over the body, tonic-clonic seizures of the grand mal type, hyperesthesia, hypogeusia, hypokinesia, hyposmia, peripheral neuropathy, parosmia, presyncope, repetitive speech, disturbance of touch, stupor, fainting, lack of reactions to stimuli, in children – psychomotor hyperactivity.

Mental disorders: often – slow thinking, confusion, depression, insomnia, aggressive reactions, agitation, disorientation, emotional lability, erectile dysfunction, in children – behavioral changes; uncommon – anorgasmia, sexual dysfunction, crying, sexual arousal disorder, dysphemia, early morning awakenings, euphoric mood, auditory and visual hallucinations, hypomanic states, decreased libido, mania, state of panic, paranoid states, perseveration of thinking, impaired reading skills, restlessness, sleep disturbances, suicidal ideas or attempts, tearfulness; very rarely – a feeling of hopelessness.

From the digestive system: very often – decreased appetite, anorexia; often – nausea, diarrhea; uncommon – abdominal pain, constipation, dry mouth, decreased sensitivity in the oral cavity, pancreatitis, increased appetite, gastritis, gastroesophageal reflux, bleeding gums, bad breath, flatulence, glossodynia, pain in the oral cavity, thirst, dyspeptic symptoms (discomfort in the stomach, discomfort in the epigastric region, heaviness in the stomach), in children – vomiting.

From the musculoskeletal system: often – myalgia, muscle spasms, muscle cramps, muscle pain in the chest area, arthralgia; infrequently – pain in the side, muscle stiffness; very rarely – swelling of the joints, discomfort in the limbs.

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

From the organ of vision: often – diplopia, blurred vision, dry eyes; uncommon – disturbance of accommodation, amblyopia, blepharospasm, transient blindness, one-sided blindness, increased lacrimation, mydriasis, night blindness, photopsia, presbyopia, scotoma (including atrial fibrillation), decreased visual acuity; very rarely – angle-closure glaucoma, involuntary movements of the eyeballs, swelling of the eyelids, myopia, conjunctival edema, maculopathy.

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

From 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 skin and subcutaneous tissues: often – rash, alopecia, itching, decreased sensitivity of the face; uncommon – lack of sweating, allergic dermatitis, redness of the skin, impaired skin pigmentation, unpleasant skin odor, urticaria; very rarely – erythema multiforme, periorbital edema, Stevens-Johnson syndrome, toxic epidermal necrolysis.

From the urinary system: often – nephrolithiasis, dysuria, pollakiuria; uncommon – exacerbation of urolithiasis, hematuria, urinary incontinence, frequent urge to urinate, renal colic, pain in the kidney area; very rarely – renal tubular acidosis.

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

From the laboratory parameters: infrequently – a decrease in the content of bicarbonates in the blood (on average by 4 mmol/l), crystalluria, leukopenia, hypokalemia (a 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; uncommon – facial swelling, allergic reactions, hyperchloremic acidosis, increased appetite, metabolic acidosis, polydipsia, cold extremities, fatigue, weakness, calcinosis; very rarely – generalized edema, influenza-like illnesses, allergic edema, weight gain.

Interaction

The effect of Topamax® on the concentrations of other antiepileptic drugs (AEDs)

Concomitant use of Topamax® with other AEDs (phenytoin, carbamazepine, valproic acid, phenobarbital, primidone) does not affect their plasma Css values, with the exception of certain patients in whom the addition of Topamax® to phenytoin may cause an increase in plasma phenytoin concentrations. This may be due to the inhibition of a specific polymorphic isoform of the cytochrome P450 enzyme (CYP2Cmeph). Therefore, if symptoms of toxicity develop in patients receiving phenytoin, it is necessary to monitor the concentration of phenytoin in the blood plasma.

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

Effect of other AEDs on plasma concentrations of topiramate

Phenytoin and carbamazepine, when used simultaneously with Topamax®, reduce the concentration of topiramate in plasma. The addition or removal of phenytoin or carbamazepine during treatment with Topamax® may require a change in the dose of the latter. The dose is selected depending on the development of the desired clinical effect. The addition or removal of valproic acid does not cause clinically significant changes in the plasma concentration of topiramate and, therefore, does not require a change in the dose of Topamax®.

Added PEP PEP concentration Topiramate concentration Phenytoino no effect (increased plasma concentration in isolated cases) 48% decrease in plasma concentration Carbamazepine no effect 40% decrease in plasma concentration Valproic acid no effect no effect Phenobarbital no effect not studied Primidone no effect not studied

Interaction with other drugs

In studies conducted with the simultaneous use of Topamax® in a single dose, the AUC of digoxin decreased by 12%. The clinical significance of this effect has not been established. When prescribing or discontinuing Topamax® in patients receiving digoxin, monitoring of serum digoxin concentrations is necessary.

In clinical studies, the effects of combined use of Topamax® with drugs that depress the functions of the central nervous system, as well as with ethanol, have not been studied. The combined use of Topamax® with drugs that have a depressant effect on the central nervous system and with ethanol is not recommended.

When taking Topamax together with drugs based on St. John’s wort (Hypericum perforatum), the plasma concentration of topiramate may decrease and, as a result, the effectiveness of the drug may also decrease. Clinical studies of the interaction of Topamax® and drugs based on St. John’s wort 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 have a significant effect on 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 Topamax® 200-800 mg/day. The clinical significance of the described changes is unclear. The risk of decreased contraceptive effectiveness and increased breakthrough bleeding should be considered in patients taking oral contraceptives in combination with Topamax®. Patients taking estrogen-containing contraceptives should inform their doctor about any changes in the timing and nature of menstruation. The effectiveness of contraceptives may be reduced even in the absence of breakthrough bleeding.

In healthy volunteers, a decrease in lithium AUC by 18% was observed 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, however, at higher doses (up to 600 mg/day), the AUC of lithium was increased by 26%. When using topiramate and lithium simultaneously, the concentration of the latter in the blood plasma should be monitored.

Drug interaction studies conducted with single and multiple doses of topiramate in healthy volunteers and patients with bipolar disorder yielded similar results. With simultaneous use of topiratam in daily doses of 250 mg or 400 mg, the AUC of risperidone, taken in doses of 1-6 mg/day, is 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 slightly. The change in systemic exposure of risperidone/9-hydroxyrisperidone and topiramate was not clinically significant and this interaction is unlikely to be of clinical significance.

Drug interactions were studied in healthy volunteers with the separate and combined administration of hydrochlorothiazide (25 mg) and topiramate (96 mg). The results of the study showed that when topiramate and hydrochlorothiazide were taken simultaneously, the Cmax of topiramate increased by 27% and its AUC by 29%. The clinical significance of these studies has not been established. When prescribing hydrochlorothiazide to patients taking topiramate, a dose adjustment of topiramate may be required. There were no significant changes in the pharmacokinetic parameters of hydrochlorothiazide during concomitant therapy with topiramate.

Drug interactions were studied in healthy volunteers receiving metformin or a combination of metformin and topiramate. Study results showed that when topiramate and metformin were co-administered, the Cmax and AUC of metformin increased by 18% and 25%, respectively, while the clearance of metformin when co-administered with topiramate decreased by 20%. Topiramate had no effect on plasma Tmax of metformin. The clearance of topiramate when co-administered with metformin is reduced. The extent of the observed changes in clearance has not been studied. The clinical significance of the effect of metformin on the pharmacokinetics of topiramate is unclear. If Topamax® is added or discontinued in patients receiving metformin, the condition of patients with diabetes mellitus should be monitored.

Drug interactions were studied in healthy volunteers with the separate and combined administration of pioglitazone and topiramate. A decrease in the AUC of pioglitazone by 15% was detected, 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 by 16%, respectively, and for the active ketometabolite, a decrease in both Cmax and AUC was detected by 60%. The clinical significance of these data is unclear. When patients are co-administered Topamax® and pioglitazone, the patient’s condition should be carefully monitored to assess the course of diabetes mellitus.

A drug interaction study was conducted to examine the pharmacokinetics of glibenclamide (5 mg/day) at steady state, administered alone or concomitantly with topiramate (150 mg/day) in patients with type 2 diabetes mellitus. When topiramate was used, the AUC of glibenclamide decreased 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 at steady state. A statistically unreliable decrease in the AUC of pioglitazone by 15% was found in the absence of a change in its Cmax. When prescribing 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 mellitus.

When using Topamax® simultaneously with other drugs that predispose to the development of nephrolithiasis, the risk of kidney stones may increase. During treatment with Topamax®, the use of such drugs should be avoided, as 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 separately is accompanied by hyperammonemia with or without encephalopathy. In most cases, symptoms and signs disappear after stopping one of the medications. This adverse event is not due to a pharmacokinetic interaction. The relationship between hyperammonemia and the use of topiramate alone or in combination with other drugs has not been established.

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

Overdose

Symptoms: convulsions, drowsiness, speech and vision disorders, diplopia, thinking disorders, coordination problems, lethargy, stupor, hypotension, abdominal pain, dizziness, agitation and depression. In most cases, the clinical consequences were not severe, but deaths have been reported after overdose using a mixture of several drugs, including topiramate. Severe metabolic acidosis may develop.

There is a known case of overdose when the patient took a dose of topiramate from 96 to 110 g, which resulted in a coma that lasted 20-24 hours. After 3-4 days, the overdose symptoms resolved.

Treatment: if the patient ate food shortly before taking an excessive dose of the drug, it is necessary to immediately rinse the stomach or induce vomiting. Activated carbon has been shown to adsorb topiramate in in vitro studies. If necessary, symptomatic therapy should be carried out. An effective way to remove topiramate from the body is hemodialysis. Patients are advised to adequately increase their fluid intake.

Storage conditions

In a dry place, at a temperature not exceeding 25 °C

Shelf life

2 years

Manufacturer

Janssen Ortho LLC, Puerto Rico