Topiram

Uses

This drug is used to treat epilepsy in both children and adults. In children it is also used for treatment of Lennox-Gastaut syndrome (a disorder that causes seizures and developmental delay). It is now most frequently prescribed for the prevention of migraines. It has been used by psychiatrists to treat bipolar disorder and alcoholism.

The drug is also used to treat Post Traumatic Stress Disorder. Studies suggest that Topiram is effective against infantile spasms.

Monotherapy in Epilepsy: Topiram is used for initial monotherapy in patients of 10 years of age and older with partial onset or primary generalized tonic-clonic seizures.

Adjunctive Therapyin Epilepsy: Topiram is used for adjunctive therapy for adults and pediatric patients ages 2-16 years with partial onset seizures, or primary generalized tonic-clonic seizures, and in patients 2 years of age and older with seizures associated with Lennox-Gastaut syndrome.

Migraine: Topiram is used for adults for the prophylaxis of migraine headache.

Topiram is also used to associated treatment for these conditions: Alcohol Dependency, Grand mal Generalized tonic-clonic seizure, Lennox-Gastaut Syndrome (LGS), Migraine, Moods Disorders, Partial-Onset Seizures, Weight, Primary generalized tonic-clonic seizure Epilepsy, Weight Reduction

How Topiram works

A seizure is an abnormal and unregulated electrical discharge occurring in the brain. This leads to transient interruption in brain function, manifested by reduced alertness, abnormal sensations, and focal involuntary movements or convulsions. Several types of seizures exist, with common types including tonic-clonic seizures and partial onset seizures.

The exact mechanisms by which topiramate exerts pharmacological actions on seizures and migraines are currently not fully characterized. Several properties of this drug, however, are likely to contribute to its therapeutic effects. Topiram has been observed to exert actions on voltage-dependent sodium channels, GABA receptors, and glutamate receptors.

Topiram stimulates GABA-A receptor activity at brain non-benzodiazepine receptor sites and reduces glutamate activity at both AMPA and kainate receptors. Normally, GABA-A receptors are inhibitory and glutaminergic receptors are stimulatory for neuronal activity. By increasing GABA activity and inhibiting glutamate activity, topiramate blocks neuronal excitability, preventing seizures and migraines. Additionally, it blocks the voltage-dependent sodium channels, further blocking seizure activity. Topiram has been shown to inhibit various carbonic anhydrase isozymes, but the clinical significance of this is unknown at this time.

Dosage

Topiram dosage

The initial dose normally is low and increased in slow steps.The usual initial dose is 25 to 50 mg daily in 2 single doses. Recommended increments are 25 to 50 mg every 1 or 2 weeks. Common doses for maintenance treatment are 100 to 200 mg daily. The highest dose possible is 1,000 mg daily in divided doses.

Monotherapy Use: The recommended maximum dose for Topiram monotherapy in adults and children 10 years of age and older is 400 mg/day in two divided doses.

Adjunctive Therapy Use Adults (17 Years of Age and Over): The recommended total daily dose of Topiram is 400 mg/day in Partial Seizures or Primary Generalized Tonic-Clonic Seizures. Daily doses above 1600 mg have not been studied.

Pediatric Patients (Ages 2 to 16 Years): Partial Seizures or Primary Generalized Tonic-Clonic Seizures The recommended total daily dose of Topiram tablets as adjunctive therapy for patients with partial seizures or primary generalized tonic-clonic seizures is approximately 5 to 9 mg/kg/day in two divided doses.Titration should begin at 25 mg (or less, based on a range of 1 to 3 mg/kg/day) nightly for the first week. The dosage should then be increased at 1 or 2 week intervals by increments of 1 to 3 mg/kg/day (administered in two divided doses), to achieve optimal clinical response. Dose titration should be guided by clinical outcome.

Topiram tablets can be taken without regards to meals.

Side Effects

The most common side effects include a change in taste and feelings of pins and needles in the head and extremities. Less common side effects include cognitive deficiency (particularly word-finding difficulty); difficulty in understanding, grogginess, lethargy, renal (kidney) stones, vision abnormality, weight loss, breast pain, abdominal pain, intense sweating, menstrual disorder and dry mouth.

Toxicity

The LD50 of intraperitoneal topiramate in the rat is above 1500 mg/kg.

Overdose information

In a study of 4 healthy adult women taking topiramate, the severity of clinical effects following an overdose ranged from asymptomatic to severe, with no deaths reported. According to the FDA prescribing information for topiramate, an overdose may cause hypotension, severe metabolic acidosis, coma, abdominal pain, visual disturbances, convulsions, drowsiness, speech abnormalities, impaired mentation and coordination, stupor, agitation, dizziness, as well as depression.

In the case of a recent ingestion of topiramate, the stomach contents should be emptied through the induction of emesis or gastric lavage. Offer supportive treatment, including activated charcoal and hemodialysis.

Precaution

Concomitant administration of Topiram and valproic acid has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone. In patients who develop unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured.

Interaction

Potential interactions between Topiram and standard AEDs like Phenytoin, Carbamazepine and Valproic acid were observed during the concomitant treatment with these drugs for antiepileptic patients. Beside these. Concomitant use of Topiram, a 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. Digoxin, CNS depressants, oral contraceptives. Hydrochlorothiazide (HCTZ) may also interact with Topiram.

Food Interaction

• Avoid a ketogenic diet. This type of diet increases the risk of kidney stones.
• Take with or without food. Food slightly alters absorption but not to any clinically significant extent.

Topiram Alcohol interaction

[Moderate] GENERALLY AVOID:

Topiram, when coadministered with other CNS depressants including alcoholic beverages, may lead to excessive somnolence and other forms of nervous system depression.

The patient should be informed to avoid alcohol or to use caution if these agents are coadministered, especially if performing hazardous tasks such as driving or operating machinery.

Topiram Drug Interaction

Major: aripiprazole, diphenhydramineModerate: duloxetine, escitalopram, pregabalin, acetaminophen / hydrocodone, alprazolam, sertraline, cetirizineUnknown: amphetamine / dextroamphetamine, omega-3 polyunsaturated fatty acids, albuterol, montelukast, levothyroxine, cyanocobalamin, ascorbic acid, ergocalciferol, cholecalciferol, lisdexamfetamine, bupropion

Topiram Disease Interaction

Major: bone marrow depression/blood dyscrasias, oligohidrosis/hyperthermia, severe liver diseaseModerate: suicidal tendency, renal dysfunction, metabolic acidosis, angle closure glaucoma, hemodialysis, nephrolithiasis

Volume of Distribution

The mean apparent volume of distribution of topiramate ranges from 0.6-0.8 L/kg when doses of 100mg to 1200mg are given. Topiram readily crosses the blood-brain barrier.

Elimination Route

After a 400mg dose in one clinical trial, topiramate reached maximal concentrations within 1.8-4.3 hours and ranged from 1.73-28.7 ug/mL. Food did not significantly affect the extent of absorption, despite delaying time to peak concentration. In patients with normal creatinine clearance, steady state concentrations are reached within 4 days. The bioavailability of topiramate in tablet form is about 80% compared to a topiramate solution.

Half Life

The elimination half-life is reported to be in the range of 19-23 hours. If topiramate is given with enzyme-inducers, the half-life can be reduced to 12-15 hours because of increased metabolism.

Clearance

The mean oral plasma clearance of topiramate ranges from 22-36 mL/min while the renal clearance is 17-18 mL/min, according to one pharmacokinetic study. The FDA label for topiramate indicates a similar oral plasma clearance of approximately 20 to 30 mL/min in adults.

Elimination Route

Topiram is mainly eliminated through the kidneys. About 70-80% of the eliminated dose is found unchanged in the urine.

Pregnancy & Breastfeeding use

Topiram is pregnancy category C. So it may be given only if clearly needed and after the assessment of risk benefit ratio. It is not known whether Topiram is excreted through breast milk. So caution should be taken if it is prescribed to a breast feeding mother.

Contraindication

Topiram tablets are contraindicated in patients with a history of hypersensitivity to any component of this product.

Special Warning

Patients with Renal Impairment: In renally impaired subjects (creatinine clearance less than 70 ml/min/1.73 m2), one-half of the usual adult dose is recommended. Such patients will require a longer time to reach steady-state at each dose.

Patients Undergoing Hemodialysis: Topiram is cleared by hemodialysis at a rate that is 4 to 6 times greater than a normal individual. Accordingly, a prolonged period of dialysis may cause Topiram concentration to fall below that required to maintain an anti-seizure effect.To avoid rapid drops in Topiram plasma concentration during hemodialysis, a supplemental dose of Topiram may be required. The actual adjustment should take into account 1) the duration of dialysis period, 2) the clearance rate of the dialysis system being used, and 3) the effective renal clearance of Topiram in the patient being dialyzed.

Acute Overdose

Overdoses of Topiram includes convulsions, drowsiness, speech disturbance, blurred vision, diplopia, lethargy, abnormal coordination, stupor, hypotension, abdominal pain, agitation, dizziness and depression.The clinical consequences are not severe. Topiram overdose results in severe metabolic acidosis.

In acute Topiram overdose, if the ingestion is recent, the stomach should be emptied immediately by lavage or by induction of ernes is. Activated charcoal has been shown to adsorb Topiram in vitro. Hemodialysis is an effective means of removing Topiram from the body.

Storage Condition

Store at a cool & dry place, protected from light and moisture. Keep out of reach of the children.

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