Topiragen

Name: Topiragen

Uses of Topiragen

Topiramate is a prescription medicine used:

  • to treat certain types of seizures (partial onset seizures and primary generalized tonic-clonic seizures) in adults and children 2 years and older
  • with other medicines to treat certain types of seizures (partial onset seizures, primary generalized tonic-clonic seizures, and seizures associated with Lennox-Gastaut syndrome) in adults and children 2 years and older
  • to prevent migraine headaches in adults and in adolescents ages 12 to 17

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Side Effects of Topiragen

Topiramate may cause serious side effects including:

See "Drug Precautions".

  • Metabolic acidosis. Metabolic acidosis can cause:
    • tiredness
    • loss of appetite
    • irregular heartbeat
    • impaired consciousness
  • High blood ammonia levels. High ammonia in the blood can affect your mental activities, slow your alertness, make you feel tired, or cause vomiting. This has happened when topiramate is taken with a medicine called valproic acid (Depakene and Depakote).
  • Low body temperature. Taking topiramate when you are also taking valproic acid can cause a drop in body temperature to less than 95°F, feeling tired, confusion, or coma.
  • Kidney stones. Drink plenty of fluids when taking topiramate to decrease your chances of getting kidney stones.
  • Effects on thinking and alertness. Topiramate may affect how you think and cause confusion, problems with concentration, attention, memory, or speech. Topiramate may cause depression or mood problems, tiredness, and sleepiness.
  • Dizziness or loss of muscle coordination.

Call your healthcare provider right away if you have any of the symptoms above.

The most common side effects of topiramate include:

  • tingling of the arms and legs (paresthesia)
  • not feeling hungry
  • nausea
  • a change in the way foods taste
  • diarrhea
  • weight loss
  • nervousness
  • upper respiratory tract infection

Tell your healthcare provider about any side effect that bothers you or that does not go away.

These are not all the possible side effects of topiramate. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects.

Topiragen Precautions

Topiramate may cause eye problems. Serious eye problems include:

  • any sudden decrease in vision with or without eye pain and redness
  • a blockage of fluid in the eye causing increased pressure in the eye (secondary angle closure glaucoma)

These eye problems can lead to permanent loss of vision if not treated. You should call your healthcare provider right away if you have any new eye symptoms.

Topiramate may cause decreased sweating and increased body temperature (fever). People, especially children, should be watched for signs of decreased sweating and fever, especially in hot temperatures. Some people may need to be hospitalized for this condition. Call your healthcare provider right away if you have a fever or decreased sweating.

Topiramate can increase the level of acid in your blood (metabolic acidosis). If left untreated, metabolic acidosis can cause brittle or soft bones (osteoporosis, osteomalacia, osteopenia), kidney stones, can slow the rate of growth in children, and may possibly harm your baby if you are pregnant. Metabolic acidosis can happen with or without symptoms.

Sometimes people with metabolic acidosis will:

  • feel tired
  • not feel hungry (loss of appetite)
  • feel changes in heartbeat
  • have trouble thinking clearly

Your healthcare provider should do a blood test to measure the level of acid in your blood before and during your treatment with topiramate. If you are pregnant, you should talk to your healthcare provider about whether you have metabolic acidosis.

Topiramate may cause suicidal thoughts or actions in a very small number of people, about 1 in 500.

Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:

  • thoughts about suicide or dying
  • attempts to commit suicide
  • new or worse depression
  • new or worse anxiety
  • feeling agitated or restless
  • panic attacks
  • trouble sleeping (insomnia)
  • new or worse irritability
  • acting aggressive, being angry, or violent
  • acting on dangerous impulses
  • an extreme increase in activity and talking (mania)
  • other unusual changes in behavior or mood

Do not stop topiramate without first talking to a healthcare provider.

  • Stopping topiramate suddenly can cause serious problems.
  • Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.

Watch for early symptoms of suicidal thoughts and actions.

  • Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.
  • Keep all follow-up visits with your healthcare provider as scheduled.
  • Call your healthcare provider between visits as needed, especially if you are worried about symptoms.

Topiramate can harm your unborn baby (see "Pregnant Section").

  • Do not drink alcohol while taking topiramate. Topiramate and alcohol can affect each other causing side effects such as sleepiness and dizziness.
  • Do not drive a car or operate heavy machinery until you know how topiramate affects you. Topiramate can slow your thinking and motor skills, and may affect vision.

Before Using Topiragen

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of topiramate capsules or tablets, or Qudexy® extended-release capsules for the treatment of seizures in children younger than 2 years of age (when used alone or together with other medicines). Safety and efficacy have not been established.

Appropriate studies have not been performed on the relationship of age to the effects of Trokendi™ extended-release capsules for the treatment of seizures in children younger than 6 years of age.

Appropriate studies have not been performed on the relationship of age to the effects of topiramate capsules, extended-release capsules, or tablets for the prevention of migraine headaches in children younger than 12 years of age. Safety and efficacy have not been established.

Geriatric

Although appropriate studies on the relationship of age to the effects of topiramate have not been performed in the geriatric population, geriatric-specific problems are not expected to limit the usefulness of topiramate in the elderly. However, elderly patients are more likely to have age-related kidney problems, which may require caution and an adjustment in the dose for patients receiving topiramate.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

  • Alfentanil
  • Bromazepam
  • Buprenorphine
  • Butorphanol
  • Calcifediol
  • Carbinoxamine
  • Citalopram
  • Codeine
  • Desogestrel
  • Dienogest
  • Dihydrocodeine
  • Doxylamine
  • Drospirenone
  • Estradiol
  • Ethinyl Estradiol
  • Ethynodiol
  • Etonogestrel
  • Fentanyl
  • Flibanserin
  • Gestodene
  • Hydrocodone
  • Hydromorphone
  • Levonorgestrel
  • Levorphanol
  • Meperidine
  • Mestranol
  • Methadone
  • Morphine
  • Morphine Sulfate Liposome
  • Nalbuphine
  • Nifedipine
  • Norethindrone
  • Norgestimate
  • Norgestrel
  • Orlistat
  • Oxycodone
  • Oxymorphone
  • Pentazocine
  • Periciazine
  • Piperaquine
  • Remifentanil
  • Sodium Oxybate
  • Sufentanil
  • Tapentadol
  • Tramadol
  • Ulipristal
  • Zolpidem

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

  • Carbamazepine
  • Fosphenytoin
  • Ginkgo
  • Hydrochlorothiazide
  • Phenobarbital
  • Phenytoin
  • Pioglitazone
  • Posaconazole
  • Valproic Acid

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following is not recommended. Your doctor may decide not to treat you with this medication, change some of the other medicines you take, or give you special instructions about the use of food, alcohol, or tobacco.

  • Ethanol

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

  • Depression, history of or
  • Eye or vision problems (eg, glaucoma) or
  • Mood disorder, history of or
  • Metabolic acidosis (too much acid in the blood), or history of or
  • Osteoporosis (weak bones)—Use with caution. May make these conditions worse.
  • Diarrhea or
  • Lung or breathing problems or
  • Patients on ketogenic diet—May increase risk for metabolic acidosis.
  • Kidney disease or
  • Liver disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body.
  • Patients with metabolic acidosis who are also taking metformin—Should not be used in patients with this condition.

Proper Use of topiramate

This section provides information on the proper use of a number of products that contain topiramate. It may not be specific to Topiragen. Please read with care.

Take this medicine only as directed by your doctor. Do not use more of it, do not use it more often, and do not use it for a longer time than your doctor ordered.

This medicine comes with a Medication Guide. Read and follow the instructions carefully. Ask your doctor if you have any questions.

Topiramate may be taken with or without food.

Swallow the Trokendi XR™ extended-release capsule whole. Do not open, crush, or chew the capsule.

Avoid drinking alcohol with Qudexy® XR or Topamax®, or avoid for 6 hours before and 6 hours after taking the Trokendi XR™ capsule.

Swallow the tablet whole. Do not break, crush, or chew it. The tablet may taste bitter if it is held in the mouth or chewed.

The Topamax® sprinkle capsule or Qudexy® XR extended-release capsule may be swallowed whole or opened and sprinkled on a small amount (1 teaspoon) of soft food like applesauce. Swallow the food mixture immediately without chewing. Do not store the mixture for use at a later time.

Drink extra water with this medicine to help prevent kidney stones.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

  • For oral dosage form (extended-release capsules):
    • For seizures (taken with other medicines):
      • Adults—At first, 25 to 50 milligrams (mg) once a day. Your doctor may adjust the dose as needed. However, the dose is usually not more than 400 mg per day.
      • Children—
        • Qudexy®:
          • Children 2 years of age and older—Dose is based on body weight and must be determined by your doctor. The usual starting dose is 25 milligrams (mg) once a day in the evening. Your doctor may adjust the dose as needed. However, the dose is usually not more than 5 to 9 mg per kilogram (kg) of body weight per day.
          • Children younger than 2 years of age—Use is not recommended.
        • Trokendi™:
          • Children 6 years of age and older—At first, 25 milligrams (mg) once a day in the evening. Your doctor may adjust the dose as needed. However, the dose is usually not more than 5 to 9 mg per kilogram (kg) of body weight per day.
          • Children younger than 6 years of age—Use is not recommended.
    • For seizures (taken alone):
      • Qudexy®:
        • Adults and children 10 years of age and older—At first, 50 milligrams (mg) once a day. Your doctor may increase the dose as needed. However, the dose is usually not more than 400 mg per day.
        • Children 2 to 10 years of age—Dose is based on body weight and must be determined by your doctor. The starting dose is usually 25 mg once a day, in the evening. Your doctor may increase the dose as needed and tolerated. However, the dose is usually not more than 400 mg per day.
        • Children younger than 2 years of age—Use and dose must be determined by your doctor.
      • Trokendi™:
        • Adults and children 10 years of age and older—At first, 50 milligrams (mg) once a day. Your doctor may adjust the dose as needed. However, the dose is usually not more than 400 mg per day.
        • Children younger than 10 years of age—Use and dose must be determined by your doctor.
    • For migraine headaches:
      • Adults and children 12 years of age and older—At first, 25 milligrams (mg) once a day. Your doctor may adjust the dose as needed. However, the dose is usually not more than 100 mg per day.
      • Children younger than 12 years of age—Use and dose must be determined by your doctor.
  • For oral dosage forms (capsules or tablets):
    • For seizures (taken with other medicines):
      • Adults and children 17 years of age and older—At first, 25 or 50 milligrams (mg) once a day. Your doctor may adjust the dose as needed. However, the dose is usually not more than 400 mg per day.
      • Children 2 to 16 years of age—Dose is based on body weight and must be determined by your child's doctor. The starting dose is usually 25 milligrams (mg) once a day in the evening. The doctor may adjust the dose as needed.
      • Children younger than 2 years of age—Use and dose must be determined by your doctor.
    • For seizures (taken alone):
      • Adults and children 10 years of age and older—At first, 50 milligrams (mg) per day, divided and taken as 2 doses. Your doctor may adjust the dose as needed. However, the dose is usually not more than 400 mg per day.
      • Children 2 to less than 10 years of age—Dose is based on body weight and must be determined by your child's doctor. The starting dose is usually 25 milligrams (mg) once a day in the evening. The doctor may adjust the dose as needed. However, the dose is usually not more than 250 to 400 mg per day.
      • Children younger than 2 years of age—Use and dose must be determined by your doctor.
    • For migraine headaches:
      • Adults and children 12 years of age and older—At first, 25 milligrams (mg) once a day in the evening. Your doctor may adjust the dose as needed. However, the dose is usually not more than 100 mg per day.
      • Children younger than 12 years of age—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

If you miss a dose or forget to use your medicine, use it as soon as you can. If your next regular dose of Topamax® capsule or tablet is less than 6 hours away, wait until then to use the medicine and skip the missed dose.

If you miss more than 1 dose of Topamax® capsule or tablet, contact your doctor for instructions about how to re-start it.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Topiragen Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

More common
  • Any vision problems, especially blurred vision, double vision, eye pain, or rapidly decreasing vision
  • burning, prickling, or tingling sensations
  • clumsiness or unsteadiness
  • confusion
  • continuous, uncontrolled back-and-forth or rolling eye movements
  • dizziness
  • drowsiness
  • eye redness
  • generalized slowing of mental and physical activity
  • increased eye pressure
  • memory problems
  • menstrual changes
  • menstrual pain
  • nervousness
  • speech or language problems
  • trouble in concentrating or paying attention
  • unusual tiredness or weakness
Less common
  • Abdominal or stomach pain
  • fever, chills, or sore throat
  • lessening of sensations or perception
  • loss of appetite
  • mood or mental changes, including aggression, agitation, apathy, irritability, and mental depression
  • red, irritated, or bleeding gums
  • weight loss
Rare
  • Blood in the urine
  • decrease in sexual performance or desire
  • difficult or painful urination
  • frequent urination
  • hearing loss
  • loss of bladder control
  • lower back or side pain
  • nosebleeds
  • pale skin
  • red or irritated eyes
  • ringing or buzzing in the ears
  • skin rash or itching
  • swelling
  • trouble breathing
Incidence not known
  • Blistering, peeling, or loosening of the skin
  • blisters in the mouth
  • blisters on the trunk, scalp, or other areas
  • bloating
  • clay-colored stools
  • constipation
  • cough
  • diarrhea
  • increased rate of breathing
  • joint or muscle pain
  • pain or tenderness in upper abdomen or stomach
  • red skin lesions, often with a purple center
  • sores, ulcers, or white spots in the mouth or on the lips
  • yellow eyes or skin

Get emergency help immediately if any of the following symptoms of overdose occur:

Symptoms of overdose
  • Decreased awareness or responsiveness
  • dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
  • severe sleepiness
  • unusual drowsiness, dullness, tiredness, weakness, or feeling of sluggishness

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common
  • Breast pain in women
  • tremors
Less common
  • Back pain
  • chest pain
  • constipation
  • heartburn
  • hot flushes
  • increased sweating
  • leg pain

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Clinical pharmacology

Mechanism of Action:

The precise mechanisms by which topiramate exerts its anticonvulsant effects are unknown; however, preclinical studies have revealed four properties that may contribute to topiramate's efficacy for epilepsy. Electrophysiological and biochemical evidence suggests that topiramate, at pharmacologically relevant concentrations, blocks voltage-dependent sodium channels, augments the activity of the neurotransmitter gamma-aminobutyrate at some subtypes of the GABA-A receptor, antagonizes the AMPA/kainate subtype of the glutamate receptor, and inhibits the carbonic anhydrase enzyme, particularly isozymes II and IV.

Pharmacodynamics:

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:

Absorption of topiramate is rapid, with peak plasma concentrations occurring at approximately 2 hours following a 400 mg oral dose. The relative bioavailability of topiramate from the tablet formulation is about 80% compared to a solution. The bioavailability of topiramate is not affected by food.

The pharmacokinetics of topiramate are linear with dose proportional increases in plasma concentration over the dose range studied (200 to 800 mg/day). The mean plasma elimination half-life is 21 hours after single or multiple doses. Steady state is thus reached in about 4 days in patients with normal renal function. Topiramate is 15-41% bound to human plasma proteins over the blood concentration range of 0.5-250 μg/mL. The fraction bound decreased as blood concentration increased.

Carbamazepine and phenytoin do not alter the binding of topiramate. Sodium valproate, at 500 μg/mL (a concentration 5-10 times higher than considered therapeutic for valproate) decreased the protein binding of topiramate from 23% to 13%. Topiramate does not influence the binding of sodium valproate.

Metabolism and Excretion:

Topiramate is not extensively metabolized and is primarily eliminated unchanged in the urine (approximately 70% of an administered dose). Six metabolites have been identified in humans, none of which constitutes more than 5% of an administered dose. The metabolites are formed via hydroxylation, hydrolysis, and glucuronidation. There is evidence of renal tubular reabsorption of topiramate. In rats, given probenecid to inhibit tubular reabsorption, along with topiramate, a significant increase in renal clearance of topiramate was observed. This interaction has not been evaluated in humans. Overall, oral plasma clearance (CL/F) is approximately 20 to 30 mL/min in humans following oral administration.

Pharmacokinetic Interactions

(see also Drug Interactions):

Antiepileptic Drugs

Potential interactions between topiramate and standard AEDs were assessed in controlled clinical pharmacokinetic studies in patients with epilepsy. The effect of these interactions on mean plasma AUCs are summarized under PRECAUTIONS (Table 4).

Special Populations:

Renal Impairment:

The clearance of topiramate was reduced by 42% in moderately renally impaired (creatinine clearance 30-69 mL/min/1.73m2) and by 54% in severely renally impaired subjects (creatinine clearance <30 mL/min/1.73m2) compared to normal renal function subjects (creatinine clearance >70 mL/min/1.73m2). Since topiramate is presumed to undergo significant tubular reabsorption, it is uncertain whether this experience can be generalized to all situations of renal impairment. It is conceivable that some forms of renal disease could differentially affect glomerular filtration rate and tubular reabsorption resulting in a clearance of topiramate not predicted by creatinine clearance. In general, however, use of one-half the usual starting and maintenance dose is recommended in patients with moderate or severe renal impairment (see PRECAUTIONS: Adjustment of Dose in Renal Failure and DOSAGE AND ADMINISTRATION).

Hemodialysis:

Topiramate is cleared by hemodialysis. Using a high efficiency, counterflow, single pass-dialysate hemodialysis procedure, topiramate dialysis clearance was 120 mL/min with blood flow through the dialyzer at 400 mL/min. This high clearance (compared to 20-30 mL/min total oral clearance in healthy adults) will remove a clinically significant amount of topiramate from the patient over the hemodialysis treatment period. Therefore, a supplemental dose may be required (see DOSAGE AND ADMINISTRATION).

Hepatic Impairment:

In hepatically impaired subjects, the clearance of topiramate may be decreased; the mechanism underlying the decrease is not well understood.

Age, Gender, and Race:

The pharmacokinetics of topiramate in elderly subjects (65-85 years of age, N=16) were evaluated in a controlled clinical study. The elderly subject population had reduced renal function [creatinine clearance (-20%)] compared to young adults. Following a single oral 100 mg dose, maximum plasma concentration for elderly and young adults was achieved at approximately 1-2 hours. Reflecting the primary renal elimination of topiramate, topiramate plasma and renal clearance were reduced 21% and 19%, respectively, in elderly subjects, compared to young adults. Similarly, topiramate half-life was longer (13%) in the elderly. Reduced topiramate clearance resulted in slightly higher maximum plasma concentration (23%) and AUC (25%) in elderly subjects than observed in young adults. Topiramate clearance is decreased in the elderly only to the extent that renal function is reduced. As recommended for all patients, dosage adjustment may be indicated in the elderly patient when impaired renal function (creatinine clearance rate ≤ 70 mL/min/1.73 m2) is evident. It may be useful to monitor renal function in the elderly patient (see Special Populations: Renal Impairment, PRECAUTIONS: Adjustment of Dose in Renal Failure and DOSAGE AND ADMINISTRATION).

Clearance of topiramate in adults was not affected by gender or race.

Pediatric Pharmacokinetics:

Pharmacokinetics of topiramate were evaluated in patients ages 4 to 17 years receiving one or two other antiepileptic drugs. Pharmacokinetic profiles were obtained after one week at doses of 1, 3, and 9 mg/kg/day. Clearance was independent of dose.

Pediatric patients have a 50% higher clearance and consequently shorter elimination half-life than adults. Consequently, the plasma concentration for the same mg/kg dose may be lower in pediatric patients compared to adults. As in adults, hepatic enzyme-inducing antiepileptic drugs decrease the steady state plasma concentrations of topiramate.

Overdosage

Overdoses of topiramate have been reported. Signs and symptoms included convulsions, drowsiness, speech disturbance, blurred vision, diplopia, mentation impaired, lethargy, 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.

Topiramate overdose has resulted in severe metabolic acidosis (see WARNINGS).

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 Topiragen™ (topiramate) Tablets 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.

Dosage and administration

Epilepsy

In the controlled add-on trials, no correlation has been demonstrated between trough plasma concentrations of topiramate and clinical efficacy. No evidence of tolerance has been demonstrated in humans. Doses above 400 mg/day (600, 800, or 1,000 mg/day) have not been shown to improve responses in dose-response studies in adults with partial onset seizures.

It is not necessary to monitor topiramate plasma concentrations to optimize Topiragen™ Tablets therapy. On occasion, the addition of Topiragen™ Tablets to phenytoin may require an adjustment of the dose of phenytoin to achieve optimal clinical outcome. Addition or withdrawal of phenytoin and/or carbamazepine during adjunctive therapy with Topiragen™ Tablets may require adjustment of the dose of Topiragen™ Tablets. Because of the bitter taste, tablets should not be broken.

Topiragen™ Tablets can be taken without regard to meals.

Monotherapy Use

The recommended dose for topiramate monotherapy in adults and children 10 years of age and older is 400 mg/day in two divided doses. Approximately 58% of patients randomized to 400 mg/day achieved this maximal dose in the monotherapy controlled trial; the mean dose achieved in the trial was 275 mg/day. The dose should be achieved by titrating according to the following schedule:

Morning Dose Evening Dose
Week 1 25 mg 25 mg
Week 2 50 mg 50 mg
Week 3 75 mg 75 mg
Week 4 100 mg 100 mg
Week 5 150 mg 150 mg
Week 6 200 mg 200 mg

Adjunctive Therapy Use

Adults (17 Years of Age and Over) – Partial Seizures, Primary Generalized Tonic-Clonic Seizures, or Lennox-Gastaut Syndrome

The recommended total daily dose of Topiragen™ Tablets as adjunctive therapy in adults with partial seizures is 200-400 mg/day in two divided doses, and 400 mg/day in two divided doses as adjunctive treatment in adults with primary generalized tonic-clonic seizures. It is recommended that therapy be initiated at 25 - 50 mg/day followed by titration to an effective dose in increments of 25 - 50 mg/week. Titrating in increments of 25 mg/week may delay the time to reach an effective dose. Daily doses above 1,600 mg have not been studied.

In the study of primary generalized tonic-clonic seizures the initial titration rate was slower than in previous studies; the assigned dose was reached at the end of 8 weeks (see CLINICAL STUDIES, Adjunctive Therapy Controlled Trials in Patients With Primary Generalized Tonic-Clonic Seizures).

Pediatric Patients (Ages 2-16 Years) - Partial Seizures, Primary Generalized Tonic-Clonic Seizures, or Lennox-Gastaut Syndrome

The recommended total daily dose of Topiragen™ Tablets as adjunctive therapy for patients with partial seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome 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.

In the study of primary generalized tonic-clonic seizures the initial titration rate was slower than in previous studies; the assigned dose of 6 mg/kg/day was reached at the end of 8 weeks (see CLINICAL STUDIES, Adjunctive Therapy Controlled Trials in Patients With Primary Generalized Tonic-Clonic Seizures ).

Patients with Renal Impairment:

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

Geriatric Patients (Ages 65 Years and Over):

Dosage adjustment may be indicated in the elderly patient when impaired renal function (creatinine clearance rate ≤ 70 mL/min/1.73 m2) is evident (see DOSAGE AND ADMINISTRATION: Patients with Renal Impairment and CLINICAL PHARMACOLOGY: Special Populations: Age, Gender, and Race).

Patients Undergoing Hemodialysis:

Topiramate 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 topiramate concentration to fall below that required to maintain an anti-seizure effect. To avoid rapid drops in topiramate plasma concentration during hemodialysis, a supplemental dose of topiramate 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 topiramate in the patient being dialyzed.

Patients with Hepatic Disease:

In hepatically impaired patients topiramate plasma concentrations may be increased. The mechanism is not well understood.

For Healthcare Professionals

Applies to topiramate: oral capsule, oral capsule extended release, oral tablet

Cardiovascular

Uncommon (0.1% to 1%): Bradycardia, sinus bradycardia, palpitations, hypotension, orthostatic hypotension, flushing, hot flush
Rare (less than 0.1%): Raynaud's phenomenon[Ref]

Dermatologic

Common (1% to 10%): Alopecia, rash, pruritus
Uncommon (0.1% to 1%): Anhidrosis, hypoesthesia facial, urticaria, erythema, pruritus generalized, rash macular, skin discoloration, dermatitis allergic, swelling face
Rare (less than 0.1%): Stevens-Johnson syndrome, erythema multiforme, skin odor abnormal, periorbital edema, urticaria localized
Frequency not reported: Toxic epidermal necrolysis[Ref]

Gastrointestinal

Very common (10% or more): Nausea, diarrhea
Common (1% to 10%): Vomiting, constipation, abdominal pain upper, dyspepsia, abdominal pain, dry mouth, stomach discomfort, paresthesia oral, gastritis, abdominal discomfort
Uncommon (0.1% to 1%): Pancreatitis, flatulence, gastroesophageal reflux disease, abdominal pain lower, hypoesthesia oral, gingival bleeding, abdominal distension, epigastric discomfort, abdominal tenderness, salivary hypersecretion, oral pain, breath odor, glossodynia[Ref]

Genitourinary

Uncommon (0.1% to 1%): Erectile dysfunction, sexual dysfunction, renal calculus, intermenstrual bleeding, leucorrhoea, menorrhagia, vaginitis, amenorrhea, urinary tract infections, micturition frequency, urinary incontinence, dysuria[Ref]

Hematologic

Common (1% to 10%): Anemia, epistaxis
Uncommon (0.1% to 1%): Leucopenia, thrombocytopenia lymphadenopathy, white blood cell count decreased, eosinophilia
Rare (less than 0.1%): Neutropenia[Ref]

Hepatic

Rare (less than 0.1%): Hepatitis, hepatic failure, increase in liver enzymes[Ref]

Hypersensitivity

Common (1% to 10%): Hypersensitivity
Frequency not reported: Allergic edema, conjunctival edema[Ref]

Immunologic

Very common (10% or more): Nasopharyngitis
Frequency not reported: Genital moniliasis[Ref]

Metabolic

Very common (10% or more): Weight decreased
Common (1% to 10%): Anorexia, decreased appetite, weight increased
Uncommon (0.1% to 1%): Metabolic acidosis, hypokalemia, increased appetite, polydipsia
Rare (less than 0.1%): Acidosis hyperchloremic, blood bicarbonate decreased[Ref]

Musculoskeletal

Common (1% to 10%): Arthralgia, muscle spasms, myalgia, muscle twitching, muscular weakness, musculoskeletal chest pain
Uncommon (0.1% to 1%): Joint swelling, musculoskeletal stiffness, flank pain, muscle fatigue
Rare (less than 0.1%): Limb discomfort[Ref]

Nervous system

Very common (10% or more): Paraesthesia, somnolence, dizziness
Common (1% to 10%): Disturbance in attention, memory impairment, amnesia, cognitive disorder, mental impairment, psychomotor skills impaired, convulsion, coordination abnormal, tremor, lethargy, hypethesia, nystagmus, dysgeusia, balance disorder, dysarthria, intention tremor, sedation
Uncommon (0.1% to 1%): Depressed level of consciousness, grand mal convulsion, visual field defect, complex partial seizures, speech disorder, psychomotor hyperactivity, syncope, sensory disturbance, drooling, hypersomnia, aphasia, repetitive speech, hypokinesia, dyskinesia, dizziness postural, poor quality sleep, burning sensation, sensory loss, parosmia, cerebellar syndrome, dysesthesia, hypogeusia, stupor, clumsiness, aura, ageusia, dysgraphia, dysphasia, neuropathy peripheral, presyncope, dystonia, formication
Rare (less than 0.1%): Apraxia, circadian rhythm sleep disorder, hyperesthesia, hyposmia, anosmia, essential tremor, akinesia, unresponsive to stimuli[Ref]

Ocular

Common (1% to 10%): Vision blurred, diplopia, visual disturbance
Uncommon (0.1% to 1%): Visual acuity reduced, scotoma, myopia, abnormal sensation in eye, dry eye, photophobia, blepharospasm, lacrimation increased, photopsia, mydriasis, presbyopia
Rare (less than 0.1%): Blindness unilateral, blindness transient, glaucoma, accommodation disorder, altered visual depth perception, scintillating scotoma, eyelid edema, night blindness, amblyopia
Frequency not reported: Angle closure glaucoma, maculopathy, eye movement disorder[Ref]

Other

Very common (10% or more): Fatigue
Common (1% to 10%): Vertigo, tinnitus, ear pain pyrexia, asthenia, irritability, gait disturbance, feeling abnormal, malaise
Uncommon (0.1% to 1%): Deafness, deafness unilateral, deafness neurosensory, ear discomfort, hearing impaired, hyperthermia, thirst, influenza like illness, sluggishness, peripheral coldness, feeling drunk, feeling jittery, tandem gait test abnormal
Rare (less than 0.1%): Face edema, calcinosis, learning disability[Ref]

Psychiatric

Very common (10% or more): Somnolence (15%), memory loss (10%), depression
Common (1% to 10%): Depression, difficulty with concentration/attention, anxiety psychomotor slowing, altered mood, confusion, cognitive difficulty, bradyphrenia, decreased libido, expressive language disorder, disorientation, aggression, aggression, anger, abnormal behavior
Uncommon (0.1% to 1%): Suicidal ideation, suicide attempt, hallucination, psychotic disorder, hallucination auditory, hallucination visual, apathy, lack of spontaneous speech, sleep disorder, affect lability, restlessness, crying, dysphemia, euphoria, paranoia, perseveration, panic attack, tearfulness, reading disorder, flat affect, thinking abnormal, listlessness, middle insomnia, distractibility, early morning awakening, panic reaction, elevated mood
Rare (less than 0.1%): Mania, panic disorder, feelings of despair, hypomania[Ref]

Renal

Common (1% to 10%): Nephrolithiasis, pollakiuria, dysuria
Uncommon (0.1% to 1%): Calculus urinary, urinary incontinence, hematuria, incontinence, micturition urgency, renal colic, renal pain
Rare (less than 0.1%): Calculus ureteric, renal tubular acidosis[Ref]

Respiratory

Common (1% to 10%): Bronchitis, rhinitis, dyspnea, epistaxis, nasal congestion, rhinorrhea, cough
Uncommon (0.1% to 1%): Dyspnea exertional, paranasal sinus hypersecretion, dysphonia[Ref]

Some side effects of Topiragen may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

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