Epimate-50

Topiramate (Epimate-50) 50 mg Tablet is a yellow colored, round, biconvex, film coated tablet debossed with breakline on both sides, separating '10' and '32' on one side and '50' on other side.
Each film-coated tablet contains: Topiramate 50 mg.

Pharmacology: Pharmacodynamics: Mechanism of Action: The precise mechanism by which topiramate exerts its antiseizure effect is unknown; however, electrophysiological and biochemical studies of the effects of topiramate on cultured neurons have revealed three properties that may contribute to topiramate's antiepileptic efficacy. First, action potentials elicited repetitively by a sustained depolarization of the neurons are blocked by topiramate in a time-dependent manner, suggestive of a state-dependent sodium channel blocking action. Second, topiramate increases the frequency at which γ-aminobutyrate (GABA) activates GABAA receptors, and enhances the ability of GABA to induce a flux of chloride ions into neurons, suggesting that topiramate potentiates the activity of this inhibitory neurotransmitter. This effect was not blocked by flumazenil, a benzodiazepine antagonist, nor did topiramate increase the duration of the channel open time, differentiating topiramate from barbiturates that modulate GABAA receptors. Third, topiramate antagonizes the ability of kainate to activate the kainate/AMPA (α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid; non-NMDA) subtype of excitatory amino acid (glutamate) receptor, but has no apparent effect on the activity of N-methyl-D-aspartate (NMDA) at the NMDA receptor subtype. These effects of topiramate are concentration-dependent within the range of 1 μM to 200 μM.
Topiramate also inhibits some isoenzymes of carbonic anhydrase (CA-II and CA-IV). This pharmacologic effect is generally weaker than that of acetazolamide, a known carbonic anhydrase inhibitor, and is not thought to be a major contributing factor to topiramate's antiepileptic activity.
Topiramate has anticonvulsant activity in rat and mouse maximal electroshock seizure (MES) tests. Topiramate is only weakly effective in blocking clonic seizures induced by the GABAA receptor antagonist, pentylenetetrazole. Topiramate is also effective in rodent models of epilepsy, which include tonic and absence-like seizures in the spontaneous epileptic rat (SER) and tonic and clonic seizures induced in rats by kindling of the amygdala or by global ischemia.
Pharmacokinetics: Topiramate is readily absorbed after oral doses, with peak plasma concentrations achieved after 2 hours. Bioavailability is not affected by the presence of food. Protein binding is about 9 to 17%. The volume of distribution in women is approximately half that in men. Topiramate crosses placental barrier and is distributed in breast milk.
In healthy subjects topiramate is not extensively metabolized; however, up to 50% of a dose may undergo metabolism in the liver in patients receiving enzyme-inducing drug concomitantly. It is eliminated chiefly in urine; as unchanged drug and metabolites; mean plasma elimination half-life is about 21 hours. Steady-state concentrations are achieved after 4 to 8 days in patients with normal renal function. Clearance is decreased in patients with impaired renal or hepatic function, and steady-state plasma concentrations may not be achieved for 10 to 15 days in the former. Children exhibit a higher clearance and shorter elimination half-life than adults.
The pharmacokinetics of topiramate may be affected by concurrent administration of other antiepileptics.

Monotherapy in adults and children with newly diagnosed epilepsy. Adjunctive therapy in adults and children under 2 years for refractory partial seizures with or without secondary generalization, seizures associated with Lennox-Gastaut Syndrome and primary generalized tonic-clonic seizures. Also used for the treatment and prophylaxis of migraine headache in adults.

Epilepsy: Adult: 25 mg once daily by mouth for one week increased thereafter by increments of 25 to 50 mg at intervals of one to two weeks. Daily dose of more than 25 mg should be taken in 2 divided doses.
Adjunctive Therapy: The usual dose for adjunctive therapy is 200 to 400 mg, although some patients may require up to 800 mg daily.
Monotherapy: Usual ranges range from 100 mg to a maximum of 400 mg daily.
Children: Adjunctive Therapy: Children aged 2 to 16 years is 25 mg nightly for the first week, increased at intervals of one to two weeks by increments of 1 to 3 mg/kg/day. The recommended dose thereafter is about 5 to 9 mg/kg/day given in 2 divided doses, though up to 30 mg/kg/day may be given.
Monotherapy: Children aged 6 years and over may be started on 0.5 to 1 mg/kg at night for the first week, increased at intervals of one to two weeks by increments of 0.5 to 1 mg/kg/day. The usual dose is 3 to 6 mg/kg/day in 2 divided doses, although higher doses have been tolerated.
Migraine: Adult: 25 mg per day administered nightly for the first week and increased thereafter by increments of 25 mg. Dosage of more than 25 mg should be taken in 2 divided doses. Usual dose is 100 mg. Dose and titration should be guided by clinical outcome.
Administration in Patients with Renal Impairment: In renally impaired patients (creatinine clearance less than 70 mL/min/1.73 m²), one half of the adult dose is recommended.
Patients Undergoing Hemodialysis: Topiramate is cleared by hemodialysis, a prolonged period of dialysis may cause topiramate concentration to fall below that of required to maintain an anti-seizure effect. Thus, in 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).
Topiramate tablets may be taken with or without food. Swallow whole, do not chew or crush.

Overdoses of topiramate have been reported. Signs and symptoms included convulsions, drowsiness, speech disturbance, blurred vision, diplopia, mentation impaired, lethargy, metabolic acidosis, abnormal coordination, stupor, hypotension, abdominal pain, agitation, dizziness and depression. The clinical consequences were not severe in most cases, but deaths have been reported after poly-drug overdoses involving topiramate.
A patient who ingested a dose between 96 and 110 g topiramate was admitted to hospital with coma lasting 20-24 hours followed by full recovery after 3 to 4 days.
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. Treatment should be appropriately supportive. Hemodialysis is an effective means of removing topiramate from the body.

Topiramate is contraindicated in patients with a history of hypersensitivity to any component of this product.

Patient should observe adequate hydration during treatment of topiramate to reduce the risk of nephrolithiasis. Proper hydration prior to and during activities (e.g., exposure to warm temperatures and exercise) may reduce risk of heat-related adverse events. Topiramate should be gradually withdrawn to minimize the potential for seizure or increased seizure frequency in patients with or without a history of epilepsy/seizure. Daily dosage can be decreased in weekly interval by 50-100 mg in adults with epilepsy and by 25-50 mg in adults receiving topiramate at doses up to 100 mg/day for migraine prophylaxis. Gradual withdrawal in children is also recommended over 2-8 weeks period. In cases where rapid withdrawal is medically required, monitoring is recommended.
Mood Disturbances/Depression: During treatment with topiramate, mood disturbances and/or depression may occur.
Suicidal Ideation/Suicide: Although the mechanism of this risk is unknown, increased risk of suicidal thoughts or behavior in patients taking topiramate were observed. Patients and caregivers should seek immediate medical advice if signs and symptoms occur.
Nephrolithiasis: Topiramate may increase the risk for renal stone formation in some patients with predisposing risk factors to nephrolithiasis, with family history of nephrolithiasis and patients with hypercalciuria. Risk factors (e.g., renal colic, renal pain or flank pain) cannot reliably predict stone formation.
Acute Myopia and Secondary Angle-Closure Glaucoma: There have been rare reports of acute myopia with secondary angle-closure glaucoma in adults and children receiving topiramate. Symptoms include decreased visual acuity and ocular pain which generally appear within one month of starting treatment; hyperaemia and raised intra-ocular pressure may be present with or without mydriasis. Choroidal effusions resulting in anterior displacement of lens and iris have been reported. Appropriate measures to reduce intra-ocular pressure should be taken, and discontinuation of topiramate as rapidly as possible to reverse the symptoms. Elevated intra-ocular pressure of any etiology, if left untreated, can lead to serious sequelae including permanent vision loss.
Metabolic Acidosis: Metabolic acidosis has been associated with topiramate treatment. Generally, the decreases in serum bicarbonate are mild to moderate and occur as soon after starting topiramate. Clinical signs such as hyperventilation may develop. Baseline and periodic serum bicarbonate levels should be monitored during topiramate treatment. If metabolic acidosis develops or persists, it may be necessary to reduce the dose or discontinue topiramate although, in some cases, correcting the acidosis with alkali therapy may be appropriate.
Hepatic Impairment: Topiramate should be administered with caution in patients with hepatic impairment as the clearance of topiramate may be decreased.
Effects on the Ability to Drive and Use Machines: Topiramate acts on the central nervous system and may cause dizziness, drowsiness and other related symptoms. It may also cause visual disturbances and/or blurred vision. These adverse events may potentially be dangerous in patients driving a vehicle or operating machinery.

Pregnancy: Category C.
Topiramate should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus. There is an increased risk for the development of cleft lip and/or cleft palate (oral clefts) in infants born to women treated with topiramate during pregnancy. Topiramate may cause serious adverse fetal effects.
Lactation: Topiramate is excreted in the breast milk. Use of topiramate while breastfeeding is not recommended.

The most common adverse event reported were fatigue, decrease in weight, paresthesia, anorexia, somnolence and mood/behavior disturbances. The safety of Topiramate for the treatment of primary generalized tonic-clonic seizures, partial onset seizures, seizures associated with Lennox-Gestaut syndrome, newly or recently diagnosed epilepsy or migraine. The table shows the adverse events reported during treatment with topiramate for both adult and pediatric population. The majority of all adverse reactions were mild to moderate in severity. (See table.)

Click on icon to see table/diagram/image

Other Antiepileptic Drugs: Concomitant administration of topiramate on other antiepileptic drugs has no effect on their steady-state plasma concentrations. Addition of topiramate to lamotrigine had no effect on the plasma concentration of lamotrigine at topiramate doses of 100-400 mg/day. Concomitant administration of topiramate and valproic acid has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone. Signs and symptoms are abated once discontinuation of either drug.
Phenytoin and Carbamazepine: Phenytoin and Carbamazepine decrease the plasma concentrations of topiramate.
Digoxin: Digoxin and topiramate co-administration may decrease plasma concentrations of digoxin. Monitoring of serum digoxin is recommended.
CNS Depressants: Concomitant administration of topiramate and other CNS depressants is not recommended because of potential to topiramate to cause CNS depression, as well as other cognitive and/or neuropsychiatric adverse events.
Oral Contraceptives: Topiramate increased plasma clearance of the estrogenic component significantly.
Carbonic Anhydrase Inhibitors: Concomitant use of topiramate, a weak carbonic anhydrase inhibitor, with other carbonic anhydrase inhibitors, e.g. Acetazolamide or dichlorphenamide, may create a physiological environment that increases the risk of renal stone formation, and should therefore be avoided.
Lithium: Lithium exposure is reduced during concomitant administration with topiramate at a dose of 200 mg/day. In patients with bipolar disorder, the pharmacokinetics of lithium were unaffected during treatment with topiramate, however an increase in Lithium exposure was observed following topiramate doses of up to 600 mg/day. Monitor Lithium levels when co-administered with topiramate.
Risperidone: When administered concomitantly with topiramate, there was a reduction in the systemic exposure of risperidone.
Metformin: An increase in the plasma concentration of metformin is observed during concomitant administration with topiramate.
Hydrochlorothiazide: Study indicates that co-administration of HCTZ and topiramate increases the concentration of topiramate.
Pioglitazone/Glyburide: A decrease in the concentration of pioglitazone was observed during treatment with topiramate. Systemic exposure of glyburide was also reduced during treatment with topiramate. Careful monitoring of patients for adequate control of their diabetic disease state is advised.

Store at temperatures not exceeding 25°C.

Anticonvulsants / Antimigraine Preparations

N03AX11 - topiramate ; Belongs to the class of other antiepileptics.

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