Topiramate - Uses, Dosage, and Side Effects

Overview

Topiramate is an anticonvulsant drug used to control epilepsy. The anti-epileptic is also used in the prevention and treatment of migraine. Topiramate is Food and Drug Administration (FDA) approved medicine for preventing adult migraines. The extended-release Topiramate formulation and Phentermine are approved for chronic weight management in adults.

How Does Topiramate Work?

Topiramate works inside the brain by interfering with the brain signals used to communicate with the rest of the body. It works by helping in preventing nerve cells from sending signals and reduces bursts of electrical activity in the brain. Topiramate also blocks the voltage-dependent sodium channels resulting in reduced seizure activity.

Uses of Topiramate:

• Topiramate is used alone or with other medicines to treat certain kinds of seizures, such as primary generalized tonic-clonic seizures involving the entire body and partial onset seizures involving only one part of the brain.

• The drug helps control seizures in individuals with Lennox-Gastaut syndrome, characterized by seizures with developmental delays and affects young children.

• Topiramate is prescribed to prevent migraine headaches.

• It may be used for the management of alcohol dependence.

Limitations:

• Topiramate is used to prevent migraine headaches but does not relieve the pain of migraine headaches when they occur.

• Topiramate causes long-term and permanent damage to the eyes and eye side effects, such as glaucoma (a condition caused due to damage to the optic nerve in the eye).

• Topiramate needs to be taken for many years, even when the epilepsy is under control.

Route of Administration - Oral and injectable.

Dosage Strengths-

Tablets -

• 25 milligrams.

• 50 milligrams.

• 100 milligrams.

• 200 milligrams.

Capsule (sprinkles)-

• 15 milligrams.

• 25 milligrams.

Extended-release Capsules -

• 25 milligrams.

• 50 milligrams.

• 100 milligrams.

• 150 milligrams.

• 200 milligrams.

Oral Solution - 25 milligrams per milliliter.

Typical Dosage -

The recommended dose for Topiramate in adults and pediatric patients is 400 milligrams.

The dosage of Topiramate should not exceed 200 milligrams to 400 milligrams per day. The adult dosage is as given below:

• Monotherapy Partial-Onset or Primary Generalized Tonic-Clonic: 25 milligrams twice a day initially and increased by 50 milligrams per day at weekly intervals.

• Adjunctive Partial-Onset or Primary Generalized Tonic-Clonic Seizure: 25 to 50 milligrams per day.

• Lennox-Gastaut Syndrome: 25 milligrams to 50 milligrams, initially increased to 25 to 50 milligrams at weekly intervals.

• Migraine Headache: 50 milligrams taken twice a day and gradually increased at weekly intervals.

Special Considerations

• Pregnancy and Lactation- It is a pregnancy category D drug. Topiramate can increase the incidence of cleft lip and palate (splits between the upper lip, roof of the mouth, and palate) in the baby and should be given if the benefits outweigh the risk to the fetus.

• Allergy - Topiramate can cause serious allergic reactions, such as hives (a skin rash), breathing difficulty, or throat and tongue swelling.

• Activities Requiring Mental Alertness - Topiramate can cause drowsiness, dizziness, confusion, and inability to concentrate. The drug should be avoided while driving or operating heavy machinery until one knows how the medication affects them.

• Elderly - Older patients are more susceptible to side effects, especially neurotoxic effects, and should be administered cautiously in these patients.

• Children - Topiramate is approved to treat children above six.

Warnings and Contraindications:

• Hypersensitivity - Topiramate should be avoided in patients with a proven history of allergy to the drug.

• Metabolic Acidosis - Topiramate can precipitate metabolic anhydrase development and is contraindicated in individuals with metabolic acidosis or those prone to metabolic acidosis.

• Alcohol - Topiramate is contraindicated in people for at least six hours before and after alcohol use. When taken together, there can be an increase in the severity of the side effects, such as sleepiness, dizziness, confusion, difficulty in concentration, loss of consciousness, or coma.

• Severe Liver Disease - Topiramate is contraindicated in patients with liver disease or cirrhosis as it increases the risk of developing hepatic encephalopathy. A dose reduction and monitoring of liver function are recommended in patients with mild to moderate liver disease.

• Suicidal Tendency - Anti-epileptic drugs, such as Topiramate, are analogous to increased suicidal thoughts or behavior. These patients should be carefully assessed against the risk of untreated illness.

• Renal Dysfunction - Topiramate is mainly eliminated through the kidneys. The drug should be administered cautiously in patients with reduced renal function who may require dose adjustment.

Warnings and Precautions

• Bone Marrow Depression - Caution should be exercised when Topiramate is administered in patients with preexisting conditions, such as aplastic anemia, thrombocytopenia, or leukopenia. These patients should be periodically monitored with baseline CBC (complete blood count) and platelet count.

• Hyperthermia - Topiramate causes oligo hidrosis (decreased sweating) and hyperthermia in some people, especially children. Patients with fever or in hot weather should be closely monitored for body temperature while taking these drugs.

• Suicidal Tendency - Anti-epileptic drugs, such as Topiramate, are associated with an increased risk of suicidal thoughts or behavior. These patients should be carefully assessed against the risk of untreated illness.

• Renal Dysfunction - Topiramate is mainly eliminated through the kidneys. The drug should be administered cautiously in patients with reduced renal function who may require dose adjustment.

• Angle Closure Glaucoma - Patients receiving Topiramate have been reported with acute myopia associated with secondary angle closure glaucoma. It is usually reported within one month of treatment and mostly in patients with elevated intraocular pressure.

• Hemodialysis - Topiramate is cleared by hemodialysis and causes a fall in the drug plasma level. A supplemental dose may be required in patients undergoing hemodialysis.

• Nephrolithiasis - Therapy with Topiramate has been reported to be associated with the development of kidney stones. The drug should be administered cautiously in patients with a history of nephrolithiasis.

For Patients

What Is Epilepsy?

Epilepsy is characterized by seizures, which are unusual electrical discharges caused in the brain that may temporarily disrupt the brain's normal function. Seizures are classified as generalized, originating in both sides of the brain simultaneously or partially, starting in one area of the brain.

• Generalized Tonic-Clonic Seizure - Formerly known as grand mal seizure, is a seizure that has a tonic phase followed by clonic muscle contractions. It is associated with impaired awareness or complete loss of consciousness. A generalized tonic-clonic seizure can be termed a motor seizure that arises rapidly and causes violent muscle contractions. People usually do not remember the seizure afterward.

• Partial Onset Seizure - It is also known as focal onset seizure that begins in one half of the brain. Partial onset seizure is the most frequent seizure experienced by people with epilepsy. During a partial-onset seizure, the patient is aware of what has happened or may lose consciousness.

Symptoms of Seizure:

• Temporary confusion.

• Uncontrollable jerky movements.

• Fear or anxiety.

• Stiffening of the body.

• Loss of bowel or bladder control.

• Loss of consciousness.

Why Is Topiramate Prescribed for Epilepsy?

Anti-epileptic drugs, such as Topiramate, are selected based on the type of seizure. The brain cells are forced to work faster and more rapidly during a seizure. Topiramate helps prevent brain cells from working as fast as a seizure requires and restores the normal balance of nerve activity.

What Is Migraine Headache?

It is a neurological disorder associated with significant disability and impaired quality of life, affecting many people's daily activities and work-related productivity. It is caused by abnormal brain activity that temporarily affects nerve signals, chemicals, and blood vessels in the brain. It is characterized by severe throbbing pain on one side of the head. The other symptoms may include nausea, vomiting, and extreme sensitivity to light and sound. These patients require bed rest in addition to medication, such as Topiramate.

Why Is Topiramate Prescribed For Migraine Headache?

Recent studies suggest that overuse of acute medicines, such as Triptan, Ergots, or other analgesics, can lead to chronic headaches. Preventive medications, such as Topiramate, can serve an important role in treating migraine by reducing frequency and dose escalation and the potential for overuse of acute pharmacotherapies. The drug reduces the brain hyperexcitability that provokes migraine in susceptible individuals.

Facts One Should Know About Topiramate:

• The use of Topiramate increases body temperature while decreasing sweating and causes hot, dry skin.

• Topiramate can cause vision problems, if not treated, can cause a sudden decrease in vision.

• Topiramate can make people have suicidal thoughts and cause changes in mood and behavior.

• It may take up to two to four weeks for Topiramate to work fully. It may take up to three months to prevent migraine.

• Topiramate causes dizziness and should be avoided while operating heavy machinery or driving.

• Topiramate helps reduce nocturnal eating, improves sleep, and produces weight loss.

• Renal function tests and serum bicarbonate levels must be monitored periodically.

How Should One Take Topiramate?

• Topiramate is available as a tablet and a sprinkle capsule containing small beads of medicine that can be sprinkled on food), an extended-release capsule, and a solution. It can be taken with or without meals once or twice a day.

• Topiramate is taken around the same time every day.

• Topiramate tablets must be swallowed whole as it has a bitter taste. Topiramate solution should be measured with a marked calibrated device to ensure the correct dose.

• Topiramate is started on a low dose and gradually increases, not more than once every week.

• Topiramate must be stored in an airtight container away from children and pets. The medication should be stored at room temperature and away from heat, moisture, and direct sunlight.

• Topiramate should not be shared with other people, especially those with a history of drug abuse or addiction.

• In case a person misses their dose, it may be taken soon after one remembers. However, do not take two tablets together at once, as it may cause adverse reactions. Always take the doses at least eight hours apart.

Information To Be Given to the Doctor Before Taking Topiramate:

• Allergy - Therapy with Topiramate should be avoided if a person has had allergic reactions such as rash, breathing difficulty, and swelling of the face to the drug.

• Pregnancy and Breastfeeding - Topiramate increases the risk of long-term problems with learning and development in the baby. Pregnant women are advised to take high doses of folic acid while taking Topiramate. It helps them in the growth of the baby. Topiramate passes into human breast milk and can make the baby sleepy and irritable.

• Fertility - Using contraception and avoiding getting pregnant while taking Topiramate is recommended.

• Renal and Hepatic Disease - Low doses are prescribed to patients with chronic kidney disease or other kidney problems. It should be cautiously administered in patients with advanced liver disease or cirrhosis.

• Children - Topiramate should be administered in low doses in children six years or older.

Safety of Topiramate:

Topiramate is a safe medication as directed by the doctor. The drug is, however, contraindicated in pregnant women and those of childbearing potential if they are not using a highly effective method of contraception. Topiramate may rarely cause serious eye problems, which, if left untreated, can lead to permanent blindness.

Effectiveness of Topiramate:

Topiramate is more effective than other anti-epileptic drugs. However, due to its relative frequency of adverse effects, other approaches to migraine prevention, such as beta-blockers, tricyclic antidepressants, or Riboflavin, should be considered first.

Side Effects Expected With Topiramate:

Topiramate may cause common side effects, including

• Drowsiness.

• Nervousness.

• Headache.

• Constipation.

• Nausea.

• Stomach pain.

• Weakness.

• Uncontrolled movements of the eyes.

• Uncontrolled shaking of one side of the body.

• Dry mouth.

• Change in ability to taste food.

• Nosebleeds.

• Missed menstrual periods or excessive bleeding.

• Pain in legs, back, or bones.

Serious side effects may include

• Blurred vision.

• Pain in the eyes.

• Confusion.

• Double vision.

• Loss of coordination.

• Difficulty in concentrating.

• Excessive tiredness.

• Diarrhea.

• Vomiting.

• Speech problems.

• Increased urge to urinate.

• Fever.

• Loss of appetite.

• Increased tendency to breaking of bones (osteoporosis in adults and rickets in children).

• The slow growth of children.

Can One Stop Taking Topiramate Suddenly Without the Doctor's Approval?

• Never stop taking medicines without talking to the doctor. The doctor will decrease the dose gradually and taper off Topiramate.

• Do not take the drug more than advised by the doctor.

• Topiramate should not be stopped even if one experiences unusual side effects, such as a change in behavior or mood.

• Abrupt stopping of Topiramate can cause severe seizures, even in people who do not have a history of seizures. It can increase the risk of more frequency of seizures or may worsen the condition.

Dietary Restrictions to Consider When Taking Topiramate:

• Alcohol - Consumption of alcohol while taking Topiramate can cause dangerous side effects or increase the frequency of seizures.

• Caffeine - Topiramate can increase caffeine excretion rate while reducing its efficacy in the body.

• Ketosis Diet - Taking a ketosis diet or using a ketogenic diet (high in fat, low in carbohydrates) while taking Topiramate should be avoided.

Storage of Topiramate:

• Keep Topiramate medicine in their original packaging and in a tightly closed container.

• Store at room temperature between 15 to 30 degrees. The sprinkle capsule should be stored at or below 25 degrees Celsius.

• Direct contact with heat, air, and light may damage the medicines. Therefore, keep the medicines away from moisture, direct light, and heat.

• Always keep the medicines out of reach of children and pets. Always lock the safety caps of the medication to protect small children from poisoning themselves.

Disposal of Topiramate Medicines:

• Do not keep outdated medicines or medicines that are no longer needed. Discard any unused portion of the solution 30 days after opening the bottle.

• Likewise, unneeded Topiramate tablets and solutions should not be disposed of by flushing or throwing them out with regular garbage.

• Dispose of the medicine through the local medicine take-back program, which can be accessed or learned more about through the local pharmacist.

• Some people may not have access to a drug take-back program. Ask the local pharmacist about any other drug disposal options available.

Overdose:

• In case of an overdose, call the poison control helpline.

• Call the emergency services if the person has collapsed, has a seizure, or has trouble breathing.

• Overdose symptoms include seizures, drowsiness, speech problems, blurred vision, loss of coordination, pounding heartbeat, or fast, shallow breathing.

• An overdose of Topiramate may end in death if the person is not given immediate medical attention.

• Supportive treatment is initiated following the patient's clinical signs and symptoms.

For Doctors

Indications:

• Topiramate is a second-generation anti-epileptic drug used to treat epilepsy. The drug can be prescribed as monotherapy for partial-onset or primary generalized tonic-clonic seizures in patients above two years of age.

• The broad-spectrum anti-epileptic drug can be used as supportive therapy for seizures associated with Lennox-Gastaut syndrome.

• Topiramate is used to prevent headaches associated with migraines in adults and teenagers at least 12 years old.

• Doctors often prescribe Topiramate off-label as an adjunct therapy for weight management, cluster headache prevention, binge eating disorder, and mood disorders.

Pharmacology of Topiramate:

Description - Topiramate is a sulfamate-substituted monosaccharide. It appears as a white crystalline powder with a bitter taste. It is mostly soluble in alkaline solutions containing sodium hydroxide and freely soluble in acetone, chloroform, and ethanol.

Components of Tablets -

Active Ingredients - Topiramate.

Inactive Ingredients -

• Carnauba wax.

• Hypromellose.

• Lactose monohydrate.

• Magnesium stearate.

• Microcrystalline cellulose.

• Polyethylene.

• Glycol.

• Polysorbate 80.

• Pregelatinized starch.

• Purified water.

• Sodium starch glycolate.

• Synthetic iron oxide.

• Titanium dioxide.

Sprinkle capsules consist of Topiramate-coated beads in a hard gelatin capsule. The inactive ingredients are black pharmaceutical ink, cellulose acetate, gelatin, povidone, sodium lauryl sulfate, sorbitan monolaurate, sugar spheres, and titanium dioxide.

Clinical Pharmacology:

1. Mechanism of Action -

Topiramate stimulates GABA-A (gamma-aminobutyric acid) receptor activity at brain non-benzodiazepine receptor sites and reduces glutamate activity at both AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) and kainate receptors. By increasing GABA activity and inhibiting glutamate activity, Topiramate blocks neuronal excitability and prevents seizures. Topiramate also blocks the voltage-dependent sodium channels and blocks seizure activity.

2. Pharmacodynamics

Topiramte has anticonvulsant activity. Changes from the baseline in vital signs, such as systolic and diastolic blood pressure, occur more frequently in pediatric patients. The changes are dose-related.

3. Pharmacokinetics

• The mean Cmax- 1.73 to 28.7 ug/ml.

• Median Tmax- 1.8 to 4.3 hours.

[Cmax- Maximum concentration a drug achieves in the blood, cerebrospinal fluid, or target organ after administration of a dose].

[Tmax- Time taken for a drug to reach the highest concentration after administration of a dose].

• The presence of food did not significantly affect the extent of absorption.

Pharmacokinetic Changes-

A. Distribution

• Steady-state Plasma Levels - Two hours.

• Relative Bioavailability - 80 percent.

• Protein Bound - 15 to 41 percent.

• Time to Approach Steady-state Levels - Four days.

• Mean Volume of Distribution - 0.6 to 0.8 liter per kilogram.

B. Metabolism

• Metabolic Processes- The metabolism of Topiramate is characterized by the reaction of glucuronidation, hydroxylation, and hydrolysis leading to the production of six minor metabolites.

C. Elimination - Topiramate is mainly excreted through the kidneys; around 80 percent of the eliminated dose is found unchanged in the urine.

• Elimination Half-life - 19 to 23 hours.

Special Considerations

• Pregnancy - Treatment with Topiramate during pregnancy may increase the risk of oral cleft in the unborn baby. The drug may be given only after a detailed risk-benefit evaluation is done. Topiramate has been reported to cause sedation and diarrhea in breastfed infants.

• Elderly - Older adults have reduced renal function compared to young adults.

• Children - Topiramate clearance is greater in the pediatric population and, consequently, low plasma drug concentration.

• Renal Impairment - Dose adjustment may be required for people with moderate to severe renal impairment. A supplemental dose may be given during hemodialysis as dialysis may remove the drug.

• Hepatic Impairment - Topiramate plasma concentration may be increased in patients with hepatic impairment. However, no dose adjustment is generally suggested.

Drug Interactions:

Certain prescription drugs and over-the-counter drugs may interact with Topiramate. These may include:

• Anti-epileptic Drugs - Combining Topiramate with other anti-epileptic drugs, such as Phenytoin or Carbamazepine, can make the drug less effective.

• Oral Contraceptives - Combining Topiramate with oral contraceptives, like Norethindrone e Estradiol, can make oral contraceptives less effective.

• HIV Medications - Taking Topiramate with HIV (human immunodeficiency virus) drugs, such as Atazanavir or Dolutegravir, can affect the efficacy of the HIV medications, making them less effective.

• Central Nervous System Depressants - Medications like Oxycodone, Phenobarbital, or Zolpidem can increase the risk of side effects of Topiramate and slow down brain activity.

• Amphetamine - Theuse of Amphetamine or Lisdexamfetamine (central nervous system stimulants) can make Topiramate less effective at managing seizures and also increase the risk of side effects of Amphetamine.

• Anticholinergic Drugs - Oxybutynin, Benztropine, or Tiotropium, are anticholinergic drugs that interact with Topiramate and increase the risk of side effects.

• Antiplatelets or Blood Thinners - Coadministration of Topiramate and antiplatelets, like Aspirin, Warfarin, and Apixaban, increase the risk of side effects of both drugs.

• NSAIDs - Taking nonsteroidal anti-inflammatory drugs (NSAIDs) with Topiramate increases the severity of the side effects of both drugs.

• Selective Serotonin Reuptake Inhibitors - Topiramate interacts with Sertraline and Fluoxetine, selective serotonin reuptake inhibitors (SSRIs), causing increased side effects, like bleeding.

What Have Clinical Trials Shown About Topiramate?

Trial 1:

Objective - To assess the effectiveness and safety of Topiramate for migraine prevention.

• A 26-week, randomized, double-blind, placebo-controlled study was conducted during outpatient treatment.

• 483 patients aged 12 to 65 years having a six-month history of migraine (but no more than 15 headache days in a month) were selected during a 28-day prospective baseline phase.

• The month of onset of preventive treatment action was assessed.

• Primary Outcome Measure - Change from baseline in mean monthly migraine frequency.

• Secondary Outcome Measure - Response rate in monthly migraine frequency, reduction in the mean number of monthly migraine days, severity, duration, and days that require medication.

• Results - Mean monthly migraine frequency decreased significantly for patients receiving Topiramate at 100 and 200 milligrams compared to placebo. Statistically, a significant reduction occurred within the first month. The response rate and reduction in migraine days were greater in Topiramate versus placebo. Also, rescue medication use was reduced in the 100 milligrams and 200 milligrams of the Topiramate group.

Trial 2:

Objective - To study Topiramate's efficacy and safety in treating patients with difficult epilepsy taking one or more standard anti-epileptic drugs.

• A double-blind, placebo-controlled study was conducted, including baseline and treatment phases.

• During the baseline phase (12 weeks), n178 patients received one of the standard anti-epilepsy drugs, such as Phenytoin or Carbamazepine. Patients continued to have seizures during this period.

• Patients receive a placebo or Topiramate 100 milligrams once daily, increasing to twice daily in week 16 while continuing with the legal regime.

• Primary Outcome Measure - Percent reduction in the average monthly seizure rate from baseline to the end of the treatment.

• Secondary Outcome Measure - Percent of patients responding to treatment and assessing the incidence of adverse events throughout the study.

• Results - Topiramate, when taken as an add-on therapy with standard anti-epileptic drugs, significantly reduces seizure frequency compared to placebo in patients with refractory partial epilepsy and is well-tolerated.

Complications or Side Effects:

• Drowsiness - Consuming alcohol with Topiramate should be avoided, as it can tire one. Avoid driving and operating heavy machinery, as Topiramate can make a person tired or sleepy.

• Dizziness - Initial doses of Topiramate may make one feel dizzy. The problem wears off when one gets used to the medicine. Avoid standing up suddenly after a long-time sitting or lying position. Wait until the dizziness subsides.

• Rash - Topiramate can cause rashes and allergic reactions, which may require the person to take antihistamines.

• Suicidal Behavior - Topiramate increases the risk of suicidal thoughts and behavior. The caregivers should be counseled to be alert for the emergence or worsening of signs and symptoms of depression.

• Kidney Stones - Topiramate increases the risk of kidney stones, especially in males, by reducing urinary citrate excretion and increasing urinary pH.