Each film-coated tablet contains 25 and 50 mg of topiramate.
Pharmacologic category: Anticonvulsant. ATC code: N03AX112.
Pharmacology: Pharmacodynamics: Mechanism of action: Topiramate is a sulfamate-substituted monosaccharide. The precise mechanisms by which topiramate exerts its anticonvulsant and migraine prophylaxis effects are unknown; however, data from electrophysiologic and biochemical studies have revealed 4 properties of topiramate e.g., blocks voltage-dependent sodium channels, augments the activity of the neurotransmitter γ-aminobutyrate at GABAA acitivity, antagonizes the AMPA/kainate subtype of the glutamate receptor and weakly inhibits carbonic anhydrase.
Pharmacokinetics: Absorption: Topiramate is readily absorbed after oral dose, with peak plasma concentrations occurring after about 2 hours. Bioavailability is not affected by the affected food.
Distribution: Protein binding is about 9 to 17%. The volume of distribution (Vd) is 0.6 to 0.8 L/kg and Vd in women is about half that in men.
Metabolism: In the healthy subjects topiramate is not extensively metabolized in liver via hydroxylation, hydrolysis and glucuronidation; six minor metabolites have been identified, none of which constitutes more than 5% of an administered dose. However, up to 50% of a dose may undergo metabolism in the liver in patients also receiving enzyme inducing drugs.
Excretion: Topiramate is eliminated chiefly in urine, as unchanged drug and metabolites (Approximately 70%); mean plasma elimination half-life is about 21 hours. Steady-state concentrations occur after about 4 to 8 days in patients with normal renal function.
Epilepsy: Topiramate is used as initial monotherapy in adult and children (≥ 2 years of age) for newly diagnosed epilepsy patients or patients who previously received a regimen of other anticonvulsant agents.
Topiramate is used as adjunctive therapy for management in adults and children (≥ 2 years of age ) with partial onset seizures, generalized tonic-clonic seizures and seizures associated with Lennox-Gastaut Syndrome.
Migraine: Topiramate is used in the prophylaxis of migraine headache; efficacy of the drug in the acute treatment of migraine headache has not been established.
Recommended Dose: Dosage of topiramate must be adjusted carefully and individualized according to patient response and tolerance and the condition being treated. Small increments or longer intervals between increments may be necessary if patients cannot tolerate the above regimens.
It is not necessary to monitor plasma topiramate concentrations to achieve optimal clinical effect with the drug when it is added to an existing anticonvualsant regimen. However, the addition of topiramate to phenytoin may require an adjustment of the phenytoin dose to achieve optimal clinical outcome. Addition or withdrawal of phenytoin and/or carbamazepine during adjunctive therapy with topiramate may require adjustment of the topiramate dose.
Epilepsy: Monotherapy: Adults: The initial oral dose of topiramate is 25 to 50 mg at night for 1 week increased thereafter by increments of 25 or 50 mg at intervals of 1 to 2 weeks until the effective dose is reached. Daily doses of more than 25 mg should be taken in 2 divided doses. When used as monotherapy, usual doses range from 100 mg daily to a maximum of 500 mg daily.
Children ≥ 6 years: The initial daily oral dose is 0.5 to 1.0 mg/kg at night for the first week, increased thereafter by 0.5 to 1 mg/kg every 1 or 2 weeks, daily in 2 divided doses.
Adjunctive therapy: Adults: The initial oral dose of topiramate is 25 to 50 mg at night for 1 week increased thereafter by increments of 25 or 50 mg at intervals of 1 to 2 weeks until the effective dose is reached. Daily doses of more than 25 mg should be taken in 2 divided doses. The usual daily dose is 200-400 mg.
Children ≥ 2 years: The initial for oral dose is 25 mg. This is given as a single dose at night for 1 week, then increased by 1 to 3 mg/kg every 1 or 2 weeks until the effective dose is reached; these higher daily doses are divided and given twice daily. About 5 to 9 mg/kg daily is usually required.
Migraine: Adults: Topiramate is given orally in initial doses of 25 mg at night for 1 week, increased by 25 mg increments every week, to a usual dose of 50 mg twice daily.
Special Population: Renal impairment: In patients with moderate to severe renal impairment (CrCl< 70 ml/min/1.73 m2), one-half of the usual adult dose of topiramate is recommended. For patients undergoing hemodialysis a supplemental dose equal to about one-half of the daily dose should be given in divided doses (at the start and finish of the procedure).
Hepatic impairment: Topiramate should be used with caution in patients with hepatic impairment.
Method of Administration: Topiramate tablets can be taken without regard to meals. Because of the bitter taste, immediate-release tablets or topiramate preferably should be swallowed intact and not broken or chewed.
Signs and Symptoms: Overdoses of topiramate have been reported. Signs and symptoms included convulsions, drowsiness, speech disturbance, blurred vision, diplopia, impaired mentation, lethargy, abnormal coordination, stupor, hypotension, abdominal pain, agitation, dizziness and depression. The clinical consequences were not severe in most cases, but death have been reported after overdoses involving topiramate. Topiramate overdose has resulted in severe metabolic acidosis.
Treatment: In acute topiramate overdose, if the ingestion is recent, the stomach should be emptied immediately by lavage or by induction of emesis. Activated charcoal has been shown to adsorb topiramate in vitro. Hemodialysis is an effective means of removing topiramate from the body.
Hypersensitivity to the active substance or to any the excipients.
Acute Myopia and Secondary Angle Closure Glaucoma: A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients receiving topiramate. Symptoms include acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings can include myopia, anterior chamber shallowing, ocular hyperemia (redness), and increased intraocular pressure. Mydriasis may or may not be present. This syndrome may be associated with supraciliary effusion resulting in anterior displacement of the lens and iris, with secondary angle closure glaucoma. Symptoms typically occur within 1 month of initiating topiramate therapy. In contrast to primary narrow angle glaucoma, which is rare under 40 years of age, secondary angle closure glaucoma associated with topiramate has been reported in pediatric patients as well as adults. The primary treatment to reverse symptoms is discontinuation of topiramate as rapidly as possible, according to the judgment of the treating physician. (Elevated intraocular pressure of any etiology, if left untreated, can lead to serious sequelae including permanent vision loss.)
Visual Field Defects: Visual field defects (independent of elevated intraocular pressure) have been reported in patients receiving topiramate. In clinical trials, most of these events were reversible after topiramate discontinuation. If visual problems occur at any time during topiramate treatment, consideration should be given to discontinuing the drug.
Oligohidrosis and Hyperthermia: Oligohidrosis (decrease sweating) has been reported in association with topiramate use. Decrease sweating and an elevation in body temperature above normal characterized these cases. Some of the cases were reported after exposure to elevated environmental temperatures. The majority of the reports have been in pediatric patients. Patients (especially pediatric patients) treat with topiramate should be monitored closely for evidence of decreased sweating and increased body temperature, especially in hot weather. Caution should be used when topiramate is given with other drugs that predispose patients to heat-related disorders; these drugs include, but are not limited to, other carbonic anhydrase inhibitor and drugs with anticholinergic activity.
Metabolic Acidosis: Topiramate can cause hyperchloremic, non-anion gap, metabolic acidosis (i.e., decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis). This metabolic acidosis is caused by renal bicarbonate loss due to carbonic anhydrase inhibition by topiramate. Topiramate-induced metabolic acidosis can occur at anytime during treatment.
Bicarbonate decrements are usually mild-moderate (average decrease of 4 mEq/L at daily doses of 400 mg in adults and at approximately 6 mg/kg/day in pediatric patients); rarely, patients can experience severe decrements to values below 10 mEq/L. Conditions or therapies that predispose patients to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhea, ketogenic diet, or specific drugs) may be additive to the bicarbonate lowering effects of topiramate. Chronic metabolic acidosis in pediatric patients may also reduce growths rates. The effect of topiramate on growth and bone-related sequelae has not been systematically investigated in long-term study. Measurement of baseline and periodic serum bicarbonate during topiramate treatment is recommended. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing topiramate (using dose tapering).
Suicidal Behavior and Ideation: Antiepileptic drugs (AEDs), including topiramate, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusal changes in mood or behavior.
Discontinuous topiramate: In patients with or without a history of seizures or epilepsy, antiepileptic drugs, including topiramate, should be gradually withdrawn to minimize the potential for seizures or increased seizure frequency. In situations where rapid withdrawal of topiramate is medically required, appropriate monitoring is recommended.
Hyperammonemia and Encephalopathy: Topiramate treatment can cause hyperammonemia with or with out encephalopathy. The risk for hyperammonemia with topiramate appears dose-related. Hyperammonemia has been reported more frequently when topiramate is used concomitantly with valproic acid. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy and/or vomiting. In most cases, hyperammonemic encephalopathy abated with discontinuation of treatment. In patients who develop unexplained lethargy, vomiting or changes in mental status associated with any topiramate treatment, hyperammonemic encephalopathy should be considered and an ammonia level should be measured.
Kidney Stones: Topiramate increases the risk of kidney stones due to it is a carbonic anhydrase inhibitor. Carbonic anhydrase inhibitors can promote stone formation by reducing urinary citrate excretion and by increasing urinary pH. The concomitant use of topiramate with any other drug producing metabolic acidosis, or potentially in patients on a ketogenic diet, may create a physiological environmental that increases the risk of kidney stone formation, and should therefore be avoided. Increased fluid intake increases the urinary output, lowering the concentration of substances involved in stone formation. Hydration is recommended to reduce new stone formation.
Warning base on the Ministry of Public Health Announcement: This medicine may cause drowsiness, should not drive a car or operate machinery and do not drink alcohol while taking this medicine.
This medicine may cause hematological disorders.
Do not use this medicine in pregnant women because it may cause infants with disabilities.
Should use with caution in patients with hepatic or renal impairment.
This medicine may cause acute myopia and secondary angle closure glaucoma.
If visual disorders e.g., decreased visual acuity and/or ocular pain occur, stop taking this medicine and seek medical advice immediately.
Should drink enough water daily to reduce kidney stone formation.
Pregnancy: Topiramate can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in utero have an increased risk for cleft lip and/or cleft palate (oral clefts) and small gestation age. Consider the benefits and risks of topiramate when prescribing this drug to women of childbearing potential, particularly when topiramate is considered for a condition not usually associated with permanent injury or death.
Because of the risk of oral clefts to the fetus, which occur in the first trimester of pregnancy, all women of childbearing potential should be informed of the potential risk to the fetus from exposure to topiramate. Women who are planning a pregnancy should be counseled regarding the relative risks and benefits of topiramate use during pregnancy, and alternative therapeutic options should be considered for these patients.
Lactation: Topiramate is excreted in human milk. The effects of topiramate on milk production are unknown. Breastfeeding should be considered along with the mother's clinical need for topiramate and any potential adverse effects on the breastfed infant from topiramate or from the underlying maternal condition.
The adverse reactions have been identified as shown in following table. (See Table.)
Click on icon to see table/diagram/image
Antiepileptic Drugs: Concomitant administration of phenytoin or carbamazepine with topiramate resulted in a clinically significant decrease in plasma concentrations of topiramate when compared to topiramate given alone. A dosage adjustment may be needed.
Concomitant administration of valproic acid and topiramate has been associated with hypothermia and hyperammonemia with and without encephalopathy.
CNS Depressants: Concomitant administration of topiramate and alcohol or other CNS Depressant drugs has not been evaluated in clinical studies. Because of the potential of topiramate to cause CNS depression, as well as other cognitive and/or neuropsychiatric adverse reactions, topiramate should be used with extreme caution if used in combination with alcohol and other CNS depressants.
Oral Contraceptives: The possibility of decreased contraceptive efficacy and increased breakthrough bleeding may occur in patients taking combination oral contraceptive products with topiramate. Patients taking estrogen-containing contraceptives should be asked to report any change in their bleeding patterns. Contraceptive efficacy can be decreased even in the absence of breakthrough bleeding.
Lithium: An increase in systemic exposure of lithium following topiramate doses of up 600 mg/day can occur. Lithium levels should be monitored when co-administered with high-dose topiramate.
Other Carbonic Anhydrase Inhibitors: Concomitant use of topiramate, a carbonic anhydrase inhibitor, with any other carbonic anhydrase inhibitor (e.g., zonisamide or acetazolamide) may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation. Therefore, patients given topiramate concomitantly with another carbonic anhydrase inhibitor should be monitored particularly closely for the appearance or worsening of metabolic acidosis.
Hydrochlorothaizide (HCTZ): Topiramate Cmax and AUC increased when HCTZ was added to topiramate. The addition of HCTZ to topiramate may require a decrease in the topiramate dose.
Pioglitazone: When topiramate is added to pioglitazone therapy or pioglitazone is added to topiramate therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state.
Store below 30°C. Keep in the original pack and keep the container tightly closed in order to protect from moisture.
N03AX11 - topiramate ; Belongs to the class of other antiepileptics.
FC tab 25 mg (white, round, biconvex with bevel-edge, engraved with "M" on one side and "25" on the other) x 6 x 10's. 50 mg (light yellow, round, biconvex with bevel-edge, engraved with "M" on one side and "50" on the other) x 6 x 10's.