Topamax
Topamax is for the treatment of epilepsy. It is suitable for adults and children older than 2 years. Used for newly diagnosed epilepsy, partial or generalized tonic-clonic seizures, Lennox-Gastaut syndrome.
The composition and the form of:
Topamax capsules or coated tablets, and 28 or 60 pieces. in the package.
Topamax 1 capsule contains: topiramate 15, 25 or 50 mg.
Topamax 1 tablet contains: topiramate 25 or 100 mg.
Active-active substance: Topiramate
Properties / Action:
Topamax – antiepileptic. It belongs to a class of sulfate-substituted monosaccharides.
Antiepileptic activity of topamax side effects is caused by a number of its properties. Topamax (topiramate) blocks sodium channels and reduces the frequency of action potentials characteristic of the neuron in a state of persistent depolarization. Topiramate potentiates the activity of GABA (gamma-aminobutyric acid, GABA) in respect of certain subtypes of GABA-receptors (including GABAA-receptor), and modulates the activity itself GABAA-receptor activation prevents kainate sensitivity of kainate / AMPK-receptors for glutamate does not affect the activity of N-methyl-D-aspartate for NMDA-receptors. These effects are dose-related with Topamax topiramate concentrations in plasma from 1 mmol to 200 mmol, with minimal activity in the range from 1 mmol to 10 mmol.
In addition, Topamax (topiramate) inhibits the activity of some isozymes of carbonic anhydrase, but this effect in topiramate weaker than that of acetazolamide, and, apparently, is not central to the antiepileptic activity of topiramate.
Pharmacokinetics:
After receiving oral topiramate Topamax quickly and efficiently absorbed from the gastrointestinal tract. Bioavailability is about 80%. Eating no clinically significant effect on the bioavailability of Topamax. In healthy volunteers the average maximum plasma concentration (Cmax) after multi-dose oral Topamax 100 mg 2 times a day was 6.76 mg / ml. Plasma protein binding is 13-17%. After a single oral dose to 1200 mg of the average volume of distribution (Vd) of 0.55-0.8 l / kg. The value of Vd depends on sex. In women, the values are approximately 50% of the values observed in men, which is associated with a higher content of adipose tissue in women. After receiving a single oral Topamax topiramate pharmacokinetics is linear, the plasma clearance remained constant at 20-30 ml / min, and AUC in the range of doses from 100 mg to 400 mg increases proportionally with dose. In patients with normal renal function to achieve equilibrium may require 4 to 8 days. About 20% of topiramate biotransformed with the formation of 6 metabolites, 2 of which are essentially retain the structure of topiramate, and either do not possess anticonvulsant activity, or show it to a minimum extent. Topiramate and its metabolites are primarily in the urine (70%). After multi-dose Topamax for 50 and 100 mg 2 times a day the average T1 / 2 was 21 hours. Patients receiving concomitant therapy antiepileptic drugs that induce the enzymes responsible for the metabolism of drugs, the metabolism of topiramate increased to 50%.
Patients with impaired renal function (creatinine clearance below 60 ml / minute), renal and plasma clearance of topiramate is reduced. Time needed to reach equilibrium in patient’s c moderate to severe impaired renal function from 10 to 15 days. Topiramate effectively removed from plasma by hemodialysis. In patients with moderately and severely impaired hepatic function expressed plasma clearance topimirate reduced. In children, clearance of topiramate is elevated, and T1 / 2 – faster. At the same dose, per 1 kg of body weight, plasma concentrations of topiramate in children may be lower than in adults. Elderly patients` plasma clearance of topiramate is unchanged.
Indications:
Topamax is used in adults and children older than 2 years:
Partial or generalized tonic-clonic seizures (in combination with other anticonvulsants);
Of newly diagnosed epilepsy (monotherapy);
Seizures associated with Lennox-Gastaut syndrome (Additional therapy).
Topamax dosage and administration:
Topamax appointed interior, regardless of the meal. Tablets should not chew. Capsules are intended for patients who have difficulties with swallowing tablets (eg, children or elderly patients). In such cases, the capsule should be carefully opened, mix the contents with a small amount (1 teaspoon) of any soft food. This mixture should be swallowed immediately without chewing. Do not store medicine mixed with food until the next reception. Capsules can be swallowed whole and. To achieve optimal control of epileptic seizures in children and adults are recommended to start treatment with low doses of the drug taking, followed by gradual titration to effective dose. In determining the rate of increasing doses of Topamax and its value, the determining criterion is the clinical effect – the degree of control the seizures, the absence of side effects. To achieve optimal effect of treatment does not necessarily control topimirate concentration in blood plasma.
Combination therapy:
When using Topamax as part of combination therapy with other anticonvulsants in adult patients the minimum effective dose is 200 mg per day. Average daily dose of Topamax is 200-400 mg, number of intakes – 2 times a day. It is recommended to start treatment with doses of 25-50 mg 1 time a day at night for 1 week. This is followed by increasing the dose of 25-50 mg at intervals of 1 or 2 weeks before the selection of effective dose, number of intakes – 2 times a day. If necessary, may increase to a maximum daily dose – 1600 mg. In some patients the effect is achieved while taking Topamax 1 times per day. When using Topamax as part of combination therapy with other anticonvulsants in children older than 2 years, the recommended total daily dose is from 5 to 9 mg / kg and was adopted in 2 hours. Selection of the starting dose is 25 mg / day (or less, the rate of 1-3 mg / kg body weight per day), taken at night, for 1 week. In the future, with weekly or biweekly intervals Topamax dose can be increased by 1-3 mg / kg and take in 2 hours. The daily dose of 30 mg / kg of body weight is usually well tolerated.
Recommendations for dosage Topamax in combination therapy are all adults, including elderly patients not suffering from kidney disease.
Monotherapy:
When using Topamax as a means of monotherapy should take into account the possible impact of the abolition of concomitant anticonvulsant therapy (PST) to control the frequency of seizures. In cases where undesirable sharply cancel accompanying PST, gradually reduce the dose of drugs, reducing the dose by 1 / 3 every 2 weeks. With the abolition of drugs that are inducers of hepatic microsomal enzymes, the concentration of topiramate in plasma will increase. In such situations, if clinically indicated dose of Topamax can be reduced.
At the beginning of Topamax monotherapy adults should take 25 mg 1 time a day at bedtime for 1 week. Then increase the dose of Topamax at intervals of 1-2 weeks at 25-50 mg / day (daily dose divided into 2 admissions). In such a regime of intolerance to therapy, increase the dose of lesser value, or over large intervals. The recommended dose is 100 mg per day, maximum daily dose – 500 mg. In some cases, a single agent to treat refractory epilepsy dose of Topamax may be 1000 mg per day.
In the first week of treatment of children older than 2 years of monotherapy with Topamax is prescribed in doses of 0.5-1 mg / kg body weight per day (daily dose divided into 2 admissions). The value of dose and its rate of increase is determined by the clinical efficacy and tolerability of therapy. On average, increase the dose at intervals of 1-2 weeks to 0.5-1 mg / kg per day. The recommended dose range for monotherapy Topamax in children older than 2 years is 3-6 mg / kg per day. In newly diagnosed partial seizures dose can be up to 500 mg per day, number of intakes – 2 times a day. Recommendations for dosage Topamax in monotherapy apply to all adults, including elderly patients not suffering from kidney disease.
In appointing Topamax patients with moderately or severely impaired renal function expressed should be aware that in order to achieve the equilibrium state of this category of patients may need 10-15 days, as opposed to 4-8 days in patients with normal renal function. Since topiramate is removed from plasma during hemodialysis, in the days of the meeting should be prescribed an additional dose of Topamax, equal to half the daily dose in 2 hours (before and after the procedure).
Topamax therapy withdrawal:
Cancel Topamax should be gradual, to minimize the possibility of increasing the frequency of seizures. It is recommended each week to reduce the dosage to 100 mg.
Topamax overdose:
Symptoms: increased side effects, seizures, drowsiness, disturbances of speech and vision, diplopia, disturbances of thinking, disturbances of coordination, lethargy, stupor, hypotension, abdominal pain, dizziness, agitation and depression. In most cases the clinical consequences were not severe, but there were fatalities after an overdose with the use of a combination of several drugs, including Topamax. Overdose Topamax can cause severe metabolic acidosis. The patient, who received topiramate at a dose of 96 to 110 g, was hospitalized in a coma, which lasted 20-24 hours. After 3-4 days the patient fully recovered. Treatment: gastric lavage, if necessary, carry symptomatic therapy is recommended adequate increase in the volume of fluid intake. Application of activated carbon is not shown (not adsorb topiramate). Effective way of removing topiramate from the body is hemodialysis.
Contraindications:
Idiosyncrasy (including a history of hypersensitivity) components Topamax;
Children age 2 years (safety and efficacy not established).
Topamax is used with caution:
Renal or hepatic impairment;
Nefrourolitiaz (including past or family history);
Hypercalciuria.
Topamax application during pregnancy and breastfeeding:
There are no adequate and strictly controlled clinical trials the safety of Topamax during pregnancy was conducted. Nevertheless, the use of Topamax during pregnancy is possible in the case when the anticipated benefits to the mother outweigh the potential risk to the fetus. Derivation topiramate in breast milk has not been studied in controlled trials. A limited number of observations suggest that topiramate is excreted in breast milk. If necessary, use Topamax in lactation period should settle the question of termination of breastfeeding.
Side effects:
From the side of the central nervous system and price of topamax of peripheral nervous system: ataxia, violation of concentration, fatigue, drowsiness, thought disorder, confusion, dizziness, paresthesias (often, especially during the selection of the dose), nervousness, psychomotor retardation, headaches, speech disorders and visual impairment ; children – personality disorder, hyperkinesia (possible); stimulation, emotional lability, cognitive disorders, amnesia, aphasia, depression, diplopia, nystagmus, irregular gait, apathy, psychotic symptoms, aggressive reaction (rare), suicidal ideation or attempts, have children – hallucinations (very rare). From the digestive system: diarrheal effects, nausea, abdominal pain, anorexia, diarrhea, dry mouth; in children – increased salivation (possible), taste perversion, increased hepatic transaminases (rare), hepatitis, hepatic failure (very rare). Ophthalmic: approximately 1 month after starting treatment Topamax may cause a syndrome characterized by myopia accompanied by increased intraocular pressure. It also noted a sharp decrease in visual acuity and / or pain in the eye. Manifestations include: myopia, reducing the depth of the anterior chamber of the eye, congestion of the mucous membrane of the eye and increased intraocular pressure, mydriasis (in some cases). A possible mechanism of this syndrome is an increase supratsiliarnogo effusion, which leads to a shift forward of the lens and iris, and as a result of the development of secondary angle-closure glaucoma.
Allergic and Dermatological reactions: erythema multiforme, pemphigus, Stevens-Johnson syndrome and toxic epidermal necrolysis in patients treated with Topamax in conjunction with other drugs that cause adverse reactions from the skin and mucous membrane (very rare).
Other: nephrolithiasis, weight loss, leukopenia, oligogidroz (in children), metabolic acidosis (rare).
The safety profile of Topamax is set based on the analysis of data on the application of the drug in 1800 patients and healthy volunteers. Due to the fact that Topamax mainly used in combined therapy, to establish the exact cause of adverse effects is very difficult.
Cautions and precautions:
Cancel Topamax should be gradual, to minimize the possibility of increasing the frequency of seizures. When conducting clinical trials of topamax no prescription dose was reduced by 100 mg 1 time per week.
Patients undergoing hemodialysis, in the days of the meeting must be given an additional dose of Topamax (about 1 / 2 daily dose) before and after the procedure. Speed topimirata excretion by the kidney depends on renal function and does not depend on age. In patients with moderate or severe renal impairment in order to achieve sustainable topimirata concentrations in plasma may be needed from 10 to 15 days, as opposed to 4-8 days in patients with normal renal function hypertension due to topamax. As with any disease, Topamax dose selection scheme should focus on clinical effect and take into account that patients with impaired renal function to establish a stable plasma concentration for each dose may need more time.
When using Topamax may increase the risk of kidney stones and the appearance of related symptoms (renal colic, pain in the side and in the kidneys), particularly in patients with a predisposition to nephrolithiasis (the formation of stones in the past, a family history of nephrolithiasis, hypercalciuria) and considering the use of other drugs that promote the development of nephrolithiasis. To reduce the risk of nephrolithiasis, as well as side effects that may arise under the influence of physical activity or high temperatures should increase fluid intake. If while taking Topamax patient decreases body weight, you should adjust the power regime (high-calorie diet). Patients with impaired hepatic function Topamax should be used with caution because of possible reduction in clearance topimirata.
There may be cases of secondary angle-closure glaucoma in children and adults. Treatment includes possible discontinuation of and measures aimed at lowering intraocular pressure. Elevated intraocular pressure of any etiology in the absence of adequate treatment may lead to serious complications, even blindness. In the treatment Topamax observed an increased incidence of mood disorders and depression. In conducting double-blind clinical trials with topiramate use, suicide attempts occurred at a frequency of 0.3% while taking topiramate and 0% for placebo. In applying Topamax may occur hyperchloraemic not associated with a deficit of anions, metabolic acidosis (eg, reducing the concentration of bicarbonate in plasma below the normal level in the absence of respiratory alkalosis). This decrease in concentration of serum bicarbonate is a consequence of inhibitory effect of topiramate on renal. In most cases, reducing the concentration of bicarbonate occurs at the beginning of the reception Topamax, although this effect may occur in any period of treatment to topamax warningsbuy topamax usa. The level of concentration reduction is usually weak or moderate. Some diseases or treatments that predispose to the development of acidosis (renal disease, severe respiratory diseases, status epilepticus, diarrhea, surgery, ketogenic diet, and certain medications) may be additional factors contributing to bicarbonate-lowering effect of topiramate. In children, chronic metabolic acidosis can lead to slower growth. Effect of topiramate on growth and possible complications associated with the skeletal system have not been studied systematically in children and adults. Therefore, the treatment Topamax is recommended to determine the concentration of bicarbonate in serum. In the event of metabolic acidosis and its persistence, it is recommended to reduce the dose or stop taking Topamax. Topamax approved for use in children older than 2 years, does topamax cause weight loss?
Effects on ability to drive vehicles and management mechanisms:
Should not assign Topamax patients involved in potentially hazardous activities that require increased attention and quickness of psychomotor reactions, because Topamax can cause drowsiness and dizziness.
Drug Interactions:
With simultaneous use of Topamax with carbamazepine, valproic acid, phenobarbital, primidone topimirat no effect on the values of their equilibrium concentrations in plasma. For some patients the simultaneous application led to increased concentrations of phenytoin, which is connected, apparently, with inhibition of isoenzyme CYP 2Cmeph. Patients receiving phenytoin and who developed clinical signs or symptoms of toxicity, it is necessary to monitor the concentration of phenytoin in plasma.
Phenytoin and carbamazepine while applicated with Topamax, reduce the concentration of topiramate in plasma. Addition or removal of phenytoin or carbamazepine on the background of treatment Topamax may require changes in dose of the latter. With simultaneous use of Topamax with valproic acid does not require a change in dose of topamax weight loss, because the concentration of topiramate in plasma did not actually change. In the study on simultaneous application of a single dose Topamax AUC of digoxin decreased by 12%. In the appointment or termination of Topamax patients taking digoxin, special attention should be paid to monitoring the concentration of digoxin in serum. In an application with Topamax oral contraceptive containing norethindrone and ethinyl estradiol, topimirat had no significant effect on the clearance of norethindrone, but the plasma clearance estrogen component increases significantly. Thus, while receiving Topamax with oral contraceptives (non-ovlon, rigevidon, marvelon, silest, lindinet, etc.), their effectiveness may be reduced. Risk reducing the effectiveness of contraceptives and increased breakthrough bleeding should be considered in patients taking oral contraceptives in combination with Topamax. Patients receiving estrogen contraceptives should report any changes in the timing and nature of menstruation. At the same time metformin and generic topamax average Cmax and AUC of metformin increased (by 18% and 25%), while the average clearance is reduced by 20%. In this case the plasma clearance of topiramate is reduced. It showed a reduction in AUC pioglitazone (15%), Cmax and AUC of active gidroksimetabolita (13% and 16%) and Cmax and AUC of active ketometabolita (60%) pioglitazone. The clinical significance of this interaction is unclear.
The clinical significance of this interaction is unclear. In the appointment or termination of Topamax patients taking metformin or pioglitazone, you need to pay special attention to regular monitoring of the state of carbohydrate metabolism. The results showed that while receiving topiramate and hydrochlorothiazide is an increase in Cmax and AUC topiramate (27% and 29%). The clinical significance of this interaction is unclear. Appointment of hydrochlorothiazide in patients taking Topamax, may require a dosage adjustment Topamax. Pharmacokinetic parameters of hydrochlorothiazide have not been significant change with concomitant therapy Topamax. Patients taking Topamax should abstain from alcohol. During treatment Topamax does not recommend the use of other drugs that have an inhibitory effect on the CNS. With simultaneous use of Topamax with drugs predisposing to nephrolithiasis, may increase the risk of stone formation in kidneys. With amitriptyline: an increase in Cmax and AUC by 20% for nortriptyline (metabolite amitriptillina).
Haloperidol: an increase in AUC of 31% for the metabolite of haloperidol.
With propranolol: an increase in Cmax by 17% for 4-OH propranolol (a metabolite of propranolol) increased Cmax by 16% for topiramate.
Storage:
List B. Store in a dry place at temperatures not above 25 ° C.
Expiration: tablets – 3 years; capsules – 2 years.
Condition of supply of topamax for obesity is prescription.
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