Topamax capsules 50mg №60

Capsules

Composition

1 capsule contains: topiramate 50 mg.
Excipients: sugar grits (sucrose, starch syrup), povidone, cellulose acetate.
The composition of the shell of the capsule: gelatin, purified water, silicon dioxide, sodium lauryl sulfate, titanium dioxide, opacode black ink S-1-17822 / 23 (containing iron oxide (E172)).

In a polyethylene bottle 60 capsules. In a carton one bottle.

Mechanism of action

Topamax - an antiepileptic drug, belongs to the class of sulfate-substituted monosaccharides. Topiramate blocks sodium channels and suppresses the occurrence of repeated action potentials against the background of long-term depolarization of the neuron membrane. Topiramate increases the activity of GABA in relation to certain subtypes of GABA receptors (including GABA A receptors), and also modulates the activity of the GABA A receptors themselves, inhibits the activation of kainate / AMPK (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 when plasma topiramate concentration is 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.

Indications and usage

Epilepsy:
- As monotherapy in adults and children older than 2 years (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.
Caution should be used when:
- Renal or hepatic failure.
- Nefururolithiasis (including in the past or in the family history).
- Hypercalciuria.

Pregnancy and Breastfeeding

Studies of the safety of the drug Topamax in pregnant women have not been conducted. However, it is possible to use Topamax during pregnancy only in cases where the intended benefit to the mother outweighs the potential risk to the fetus. A limited number of observations suggests that topiramate is excreted in breast milk.If necessary, the use of the drug Topamax during lactation should decide on the termination of breastfeeding.

Dosage and administration

The drug is taken orally, regardless of the meal. The 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.
Epilepsy: in order to achieve optimal control of epileptic seizures in adults and children, it is recommended to begin treatment by taking the drug in low doses, followed by titration to an effective dose. Capsules are intended for patients who have difficulty swallowing pills (for example, in children and elderly patients).
When conducting monotherapy: adults, including elderly patients with normal renal function, at the beginning of treatment, Topamax is prescribed 25 mg 1 time / day at bedtime for 1 week. Then the dose is increased with an interval of 1-2 weeks at 25-50 mg / day in 2 doses. In case of intolerance to such a treatment regimen, the dose is increased by a smaller amount or at long intervals. The criterion for the selection of the dose is the clinical effect. The initial dose is 100 mg / day, the maximum daily dose is 500 mg. In some cases, with a refractory form of epilepsy, patients tolerate monotherapy with Topamax at doses up to 1 g / day.For children older than 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, the daily dose is divided into 2 doses. In case of intolerance to such a regimen, the dose can be increased by a smaller amount or at large intervals. The magnitude of the dose and the rate of its increase are determined by the clinical efficacy of therapy. The recommended dose range for monotherapy with topiramate in children older than 2 years is 3-6 mg / kg / day. With newly diagnosed partial seizures, the dose can be up to 500 mg / day.
When using the drug Topamax as part of combination therapy with other anticonvulsants: in adults, including elderly patients with normal renal function, the minimum effective dose is 200 mg / day. The average daily dose is 200-400 mg, the multiplicity of reception - 2 times / day. Selection of the dose begins with 25-50 mg 1 time / day at night, the drug is taken within 1 week. Further, the dose should be increased by 25-50 mg at intervals of 1 or 2 weeks prior to the selection of the effective dose; a frequency rate of reception - 2 times / days. If necessary, you can increase the daily dose to the maximum - 1600 mg. The criterion for the selection of the dose is the clinical effect. In some patients, the effect is 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. In children older than 2 years, the recommended total daily dose is from 5 to 9 mg / kg, the frequency of administration is 2 times / day.The selection of the dose begins with 25 mg / day (or less, at the rate of 1-3 mg / kg body weight / day), the drug is taken overnight for 1 week. In the future, with weekly or two-week intervals, the dose can be increased by 1-3 mg / kg and take the drug in 2 doses. When selecting the dose should be guided by the clinical effect. A daily dose of up to 30 mg / kg body weight is generally well tolerated.
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 the concomitant anticonvulsant drug for safety reasons, it is recommended to reduce their dose gradually, reducing the dose of the concomitant anti-epileptic drug by one third every 2 weeks. With the abolition of drugs that are inducers of liver 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.
For the prevention of migraine attacksThe daily dose of topiramata 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 treatment regimen, 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.

Adverse reactions

Nervous system: very often - drowsiness, dizziness, paresthesias, in children - apathy, impaired attention; often - incoordination, nystagmus, lethargy, impaired memory, impaired concentration, tremor, amnesia, irregular gait, hypoesthesia, taste perversion, impaired thinking, speech disorder, dysarthria, cognitive disorders, apathy, mental impairment, psychomotor disorders, sedative effect; sometimes - loss of taste sensitivity, akinesia, loss of smell, aphasia, burning sensation (mainly on the face and limbs), cerebellar syndrome, circadian sleep rhythm disturbance, awkward movements, postural dizziness, increased salivation, dysesthesia, dysgraphia, dyskinesia, dysphasia, feeling goose bumps "through the body, hyperesthesia, hypogemia, hypokinesia, hyposmia, peripheral neuropathy, parosmia, pre-unconscious states, repeated speech, impaired touch, stupor, syncope, lack of response to stimuli, in children d - psychomotor hyperactivity.
Mental disorders: often - slow thinking, confusion, depression, insomnia, aggressive reactions, agitation, irritability, disorientation, emotional lability, erectile dysfunction, in children - behavior change; sometimes - anorgasmia, sexual dysfunction, crying, violation of sexual arousal, dysfemia, early waking up in the morning, euphoric mood,auditory and visual hallucinations, hypomania states, decreased libido, mania, panic state, paranoid states, perseveration of thinking, impaired reading skills, restlessness, sleep disorders, suicidal ideas or attempts, tearfulness; very rarely - a sense of hopelessness.
From the digestive system: very often - decrease in appetite, anorexia; often - nausea, diarrhea; sometimes - abdominal pain, constipation, dry mouth, impaired sensitivity in the mouth, gastritis, gastroesophageal reflux, bleeding gums, bad breath, flatulence, glossy, oral pain, thirst, dyspeptic symptoms (stomach discomfort, 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, arthralgia; sometimes - pain in the side, stiffness of the muscles; very rarely - swelling of the joints, discomfort in the limbs.
Since the cardiovascular system: sometimes - bradycardia, heart palpitations, flushing, orthostatic hypotension, Raynaud's phenomenon.
On the part of the organ of vision: often - diplopia, blurred vision, dry eyes; sometimes - disturbance of accommodation, amblyopia, blepharospasm, transient blindness, unilateral blindness, increased tearing, mydriasis, night blindness, photopsia, presbyopia, atrial scotoma, scotoma, reduction of visual acuity; very rarely - angle-closure glaucoma, impaired eye movements, eyelid edema, myopia, conjunctival edema.
From the organ of hearing: often - pain in the ears, ringing in the ears, in children - vertigo; sometimes - deafness, neurosensory deafness, unilateral deafness, discomfort in the ears, hearing impairment.
On the part of the respiratory system: often - shortness of breath, nosebleeds; sometimes hoarseness, shortness of breath on exertion, nasal congestion, hypersecretion in the paranasal sinuses, in children rhinorrhea; very rarely - nasopharyngitis.
Dermatological reactions: often - a rash, alopecia, itching, decrease in sensitivity of the face; sometimes - lack of sweating, allergic dermatitis, redness of the skin, impaired skin pigmentation, swelling of the face, unpleasant smell of the skin, urticaria; very rarely - erythema multiforme, paraorbital edema, Stevens-Johnson syndrome, toxic epidermal necrolysis.
From the urinary system: often - nephrolithiasis, dysuria, pollakiuria; sometimes - urolithiasis, hematuria, urinary incontinence, frequent urination, renal colic, pain in the kidneys; very rarely - renal tubular acidosis.
From the hemopoietic system: often anemia; sometimes - leukopenia, lymphadenopathy, thrombocytopenia, in children - eosinophilia; very rarely - neutropenia.
Laboratory values: sometimes - a decrease in the content of bicarbonates 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 violations: very often - fatigue, irritability,weight loss; often - asthenia, anxiety, in children - fever; infrequently - swelling of the face, allergic reactions, cold extremities; very rarely - generalized edema, flu-like illness, allergic edema, weight gain.

Caution should be usedwith liver failure. In patients with moderately severe and severely impaired liver function, plasma clearance is reduced.
When prescribing the drugpatients with moderate or severe renal impairment 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, as opposed to 4-8 days in patients with normal renal function. Since topiramate is removed from the 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.
Cancel Topamax should gradually to minimize the possibility of increasing the frequency of seizures. When conducting clinical trials, the dose of the drug was reduced by 50-100 mg 1 time per week - for adults during the treatment of epilepsy and 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 canceled over a period of 2–8 weeks.If, for medical reasons, rapid discontinuation of Topamax is necessary, then it is recommended to carry out appropriate monitoring of the patient's condition. In some patients, the abolition of the drug was accelerated and passed without complications.
As with any disease, the dose selection scheme should be established in accordance with the clinical effect (i.e., the degree of control of seizures, no side effects) and take into account that in patients with impaired renal function to establish a stable plasma concentration, each dose may be needed longer time.
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 topiramate, there is an increased incidence of mood disorders and depression.
When conducting double-blind clinical studies using topiramate according to the approved and studied indications, suicide attempts occurred with a frequency of 0.003 when taking topiramate (13 cases among 3999 patients), while taking placebo - with a frequency of 0 (0 cases among 430 patients). One completed suicide attempt was noted during a clinical study on the use of the drug in bipolar disorders.
The use of Topamax may increase the risk of kidney stones and associated symptoms, such as renal colic, especially in patients with a predisposition to nephrolithiasis.Risk factors for nephrolithiasis are nephrolithiasis in history (including family), hypercalciuria, concomitant therapy with other drugs that contribute to the development of nephrolithiasis.
When using the drug Topamax described syndrome, including acute myopia with concomitant secondary angle-closure glaucoma. Symptoms include acute reduction in 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, increased intraocular pressure. Mydriasis may occur. This syndrome may be accompanied by the 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 plasma bicarbonate concentration below the normal level 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 the concentration of bicarbonates occurs at the beginning of the drug intake, although this effect may appear in any period of treatment with topiramate. The level of reduction 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 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 increase 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, while taking the drug Topamax, the patient's body weight decreases, then the question of the advisability of enhanced nutrition should be considered.
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.

The effect of Topamax on the concentrations of other antiepileptic drugs (AEP):simultaneous administration of Topamax with other PEP (phenytoin, Carbamazepine , valproic acid, phenobarbital, primidone) does not affect the values ​​of their stable plasma concentrations. The simultaneous use of the drug Topamax has led in some cases to an increase in the concentration of phenytoin, which is connected, apparently, with the inhibition of the isoenzyme (CYP2C meph). Therefore, in the development of toxic symptoms 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 C ss of the latter in the blood plasma at doses of topiramate 100-400 mg / day. During and after the abolition of lamotrigine (the average dose of 327 mg / day), the equilibrium concentration of 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 change in the dose 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.
Interaction with other drugs: in studies with the 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 discontinuing 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 Topamax with drugs that inhibit the functions of the central nervous system, as well as with ethanol, have not been studied.The combined use of the drug with drugs that have a depressant effect on the central nervous system, and with ethanol is not recommended.
With simultaneous use of oral contraceptive containing norethisterone (1 mg) and ethinyl estradiol (35 mcg), Topamax in doses of 50-800 mg / day had no significant effect on the effectiveness of norethisterone and in doses of 50-200 mg / day - on the effectiveness of ethinyl estradiol. The clinical significance of the described changes is not clear. A significant dose-dependent decrease in the efficacy of ethinyl estradiol was observed at doses of the drug Topamax 200-800 mg / day. 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 /), 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 can hardly 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 C max 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. No significant changes in the pharmacokinetic parameters of hydrochlorothiazide were observed with concomitant therapy with topiramate.
Drug interactions have been studied in healthy volunteers who received Metformin or a combination of metformin and topiramate.Studies have shown that while taking topiramate and metformin, C max and AUC of metformin increase by 18% and 25%, respectively, while clearance of metformin while being administered simultaneously with topiramate was reduced by 20%. Topiramate had no effect on T max in plasma metformin. 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 the pharmacokinetics of topiramate is not clear. In the case of the addition or withdrawal of Topamax ® in patients receiving metformin, special attention should be paid to a thorough study of the diabetic status of these patients.
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 C max drug. These changes were not statistically significant. Also for the active hydroxymetabolite pioglitazone, a decrease in C max and AUC was detected by 13% and 16%, respectively, and for active ketometabolite, a decrease in both C max and AUC by 60% was found. The clinical significance of this data has not been elucidated. When patients are jointly prescribed Topamax and pioglitazone, special attention should be paid to a thorough study of the diabetic status of these patients.
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, the AUC of 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 reduction in the AUC of pioglitazone by 15% was found with no change in its C max. 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.
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 discontinuation 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.
Clinical studies have been conducted to evaluate potential options for drug interactions between topiramate and other drugs.

Symptoms: convulsions, drowsiness, impaired speech and vision, diplopia, disturbed thinking, lack of coordination, lethargy, stupor, hypotension, abdominal pain, dizziness, agitation and depression. In most cases, the clinical consequences were not severe, but deaths were noted after an overdose using a mixture of several drugs, including topiramate. May develop severe metabolic acidosis.
Treatment: if the patient took a meal shortly before taking an excessive dose of the drug, you should 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.

Store in a dry place at a temperature not exceeding 25 ° C.

2 years.