PACKAGE LABEL.PRINCIPAL DISPLAY PANEL 100 MG


17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Eye Disorders

Instruct patients taking topiramate to seek immediate medical attention if they experience blurred vision, visual disturbances, or periorbital pain [see Warnings and Precautions (5.1, 5.2)].

Oligohidrosis and Hyperthermia

Closely monitor topiramate-treated patients, especially pediatric patients, for evidence of decreased sweating and increased body temperature, especially in hot weather. Counsel patients to contact their healthcare professionals immediately if they develop a high or persistent fever, or decreased sweating [see Warnings and Precautions (5.3)].

Metabolic Acidosis

Warn patients about the potential significant risk for metabolic acidosis that may be asymptomatic and may be associated with adverse effects on kidneys (e.g., kidney stones, nephrocalcinosis), bones (e.g., osteoporosis, osteomalacia, and/or rickets in children), and growth (e.g., growth delay/retardation) in pediatric patients, and on the fetus [see Warnings and Precautions (5.4), Use in Specific Populations (8.1)].

Suicidal Behavior and Ideation

Counsel patients, their caregivers, and families that AEDs, including topiramate, may increase the risk of suicidal thoughts and behavior, and advise of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior or the emergence of suicidal thoughts, or behavior or thoughts about self-harm. Instruct patients to immediately report behaviors of concern to their healthcare providers [see Warnings and Precautions (5.5)].

Interference with Cognitive and Motor Performance

Warn patients about the potential for somnolence, dizziness, confusion, difficulty concentrating, or visual effects, and advise patients not to drive or operate machinery until they have gained sufficient experience on topiramate to gauge whether it adversely affects their mental performance, motor performance, and/or vision [see Warnings and Precautions (5.6)].

Even when taking topiramate or other anticonvulsants, some patients with epilepsy will continue to have unpredictable seizures. Therefore, advise all patients taking topiramate for epilepsy to exercise appropriate caution when engaging in any activities where loss of consciousness could result in serious danger to themselves or those around them (including swimming, driving a car, climbing in high places, etc.). Some patients with refractory epilepsy will need to avoid such activities altogether. Discuss the appropriate level of caution with patients, before patients with epilepsy engage in such activities.

Fetal Toxicity

Inform pregnant women and women of childbearing potential that use of topiramate during pregnancy can cause fetal harm, including an increased risk for cleft lip and/or cleft palate (oral clefts), which occur early in pregnancy before many women know they are pregnant. Also inform patients that infants exposed to topiramate monotherapy in utero may be SGA [see Use in Specific Populations (8.1)]. There may also be risks to the fetus from chronic metabolic acidosis with use of topiramate during pregnancy [see Warnings and Precautions (5.7), Use in Specific Populations (8.1)]. When appropriate, counsel pregnant women and women of childbearing potential about alternative therapeutic options.

Advise women of childbearing potential who are not planning a pregnancy to use effective contraception while using topiramate, keeping in mind that there is a potential for decreased contraceptive efficacy when using estrogen- containing birth control with topiramate [see Drug Interactions (7.4)].

Encourage pregnant women using topiramate, to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. The registry is collecting information about the safety of antiepileptic drugs during pregnancy [see Use in Specific Populations (8.1)].

Hyperammonemia and Encephalopathy

Warn patients about the possible development of hyperammonemia with or without encephalopathy. Although hyperammonemia may be asymptomatic, clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy and/or vomiting. This hyperammonemia and encephalopathy can develop with topiramate treatment alone or with topiramate treatment with concomitant valproic acid (VPA).

Instruct patients to contact their physician if they develop unexplained lethargy, vomiting, or changes in mental status [see Warnings and Precautions (5.9)].

Kidney Stones

Instruct patients, particularly those with predisposing factors, to maintain an adequate fluid intake in order to minimize the risk of kidney stone formation [see Warnings and Precautions (5.10)].

Instructions for a Missing Dose

Instruct patients that if they miss a single dose of topiramate, it should be taken as soon as possible. However, if a patient is within 6 hours of taking the next scheduled dose, tell the patient to wait until then to take the usual dose of topiramate, and to skip the missed dose. Tell patients that they should not take a double dose in the event of a missed dose. Advise patients to contact their healthcare provider if they have missed more than one dose.

Medication Guide available at:

www.glenmarkpharma-us.com/medguides

Manufactured by:

Glenmark Pharmaceuticals Ltd.

India

Manufactured for :


Glenmark Pharmaceuticals Inc., USA

Mahwah, NJ 07430

Questions? 1 (888) 721-7115

www.glenmarkpharma-us.com

June 2019

MEDICATION GUIDE

Topiramate (TOE-pee-rah-mate)

Tablets

What is the most important information I should know about topiramate tablets?

**Topiramate tablets 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, including any new problems with your vision.

**Topiramate tablets 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. If a high fever, a fever that does not go away, or decreased sweating develops, call your healthcare provider right away .

**Topiramate tablets 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 tablets. If you are pregnant, you should talk to your healthcare provider about whether you have metabolic acidosis.

Like other antiepileptic drugs, topiramate tablets 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 tablets without first talking to a healthcare provider.

• Stopping topiramate tablets 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.

How can I 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 tablets can harm your unborn baby.

• If you take topiramate tablets during pregnancy, your baby has a higher risk for birth defects called cleft lip and cleft palate. These defects can begin early in pregnancy, even before you know you are pregnant.
• Cleft lip and cleft palate may happen even in children born to women who are not taking any medicines and do not have other risk factors.
• There may be other medicines to treat your condition that have a lower chance of birth defects.
• All women of childbearing age should talk to their healthcare providers about using other possible treatments instead of topiramate tablets. If the decision is made to use topiramate tablets, you should use effective birth control (contraception) unless you are planning to become pregnant. You should talk to your doctor about the best kind of birth control to use while you are taking topiramate tablets.
• Tell your healthcare provider right away if you become pregnant while taking topiramate tablets. You and your healthcare provider should decide if you will continue to take topiramate tablets while you are pregnant.
• If you take topiramate tablets during pregnancy, your baby may be smaller than expected at birth. The long-term effects of this are not known. Talk to your healthcare provider if you have questions about this risk during pregnancy.
• Metabolic acidosis may have harmful effects on your baby. Talk to your healthcare provider if topiramate tablets has caused metabolic acidosis during your pregnancy.
• Pregnancy Registry: If you become pregnant while taking topiramate tablets, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of topiramate tablets and other antiepileptic drugs during pregnancy.

What is topiramate tablets?

Topiramate tablets are 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 adolescents 12 years and older.

Before taking topiramate tablets, tell your healthcare provider about all of your medical conditions, including if you:

• have or have had depression, mood problems, or suicidal thoughts or behavior.
• have kidney problems, have kidney stones, or are getting kidney dialysis.
• have a history of metabolic acidosis (too much acid in the blood).
• have liver problems.
• have weak, brittle, or soft bones (osteomalacia, osteoporosis, osteopenia, or decreased bone density).
• have lung or breathing problems.
• have eye problems, especially glaucoma.
• have diarrhea.
• have a growth problem.
• are on a diet high in fat and low in carbohydrates, which is called a ketogenic diet.
• are having surgery.
• are pregnant or plan to become pregnant.
• are breastfeeding or plan to breastfeed. Topiramate passes into breast milk. Breastfed babies may be sleepy or have diarrhea. It is not known if the topiramate that passes into breast milk can cause other serious harm to your baby. Talk to your healthcare provider about the best way to feed your baby if you take topiramate tablets..

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Topiramate tablets and other medicines may affect each other causing side effects.

Especially tell your healthcare provider if you take:

• Valproic acid (such as DEPAKENE or DEPAKOTE).
• any medicines that impair or decrease your thinking, concentration, or muscle coordination.
• birth control pills. Topiramate tablets may make your birth control pills less effective. Tell your healthcare provider if your menstrual bleeding changes while you are taking birth control pills and topiramate tablets.

Ask your healthcare provider if you are not sure if your medicine is listed above.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist each time you get a new medicine. Do not start a new medicine without talking with your healthcare provider.

How should I take topiramate tablets?

• Take topiramate tablets exactly as prescribed.
• Your healthcare provider may change your dose.Do not change your dose without talking to your healthcare provider.
• Take topiramate tablets whole.Do not chew the tablets. They may leave a bitter taste. *Do not store any medicine and food mixture for later use.
• Topiramate tablets can be taken before, during, or after a meal. Drink plenty of fluids during the day. This may help prevent kidney stones while taking topiramate tablets.
• If you take too many topiramate tablets, call your healthcare provider right away or go to the nearest emergency room.
• If you miss a single dose of topiramate tablets, take it as soon as you can. However, if you are within 6 hours of taking your next scheduled dose, wait until then to take your usual dose of topiramate tablets, and skip the missed dose.Do not double your dose. If you have missed more than one dose, you should call your healthcare provider for advice. *Do not stop taking topiramate tablets without talking to your healthcare provider. Stopping topiramate tablets suddenly may cause serious problems. If you have epilepsy and you stop taking topiramate tablets suddenly, you may have seizures that do not stop. Your healthcare provider will tell you how to stop taking topiramate tablets slowly.

Your healthcare provider may do blood tests while you take topiramate tablets.

What should I avoid while taking topiramate tablets?

• You should not drink alcohol while taking topiramate tablets. Topiramate tablets and alcohol can affect each other causing side effects such as sleepiness and dizziness.

Do not drive a car or operate machinery until you know how topiramate tablets affects you. Topiramate tablets can slow your thinking and motor skills, and may affect vision.

What are the possible side effects of topiramate tablets?

Topiramate tablets may cause serious side effects including:

See**"What is the most important information I should know about topiramate tablets?"**

*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 tablets are taken with a medicine called valproic acid (DEPAKENE and DEPAKOTE). ***Effects on thinking and alertness.**Topiramate tablets may affect how you think and cause confusion, problems with concentration, attention, memory, or speech. Topiramate tablets may cause depression or mood problems, tiredness, and sleepiness. *Dizziness or loss of muscle coordination. *Kidney stones. Drink plenty of fluids when taking topiramate tablets to decrease your chances of getting kidney stones. *Low body temperature. Taking topiramate tablets when you are also taking valproic acid can cause a drop in body temperature to less than 95oF, or can cause tiredness, confusion, or coma.

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

The most common side effects of topiramate tablets 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 speech problems tiredness dizziness sleepiness/drowsiness

slow reactions difficulty with memory pain in the abdomen fever abnormal vision decreased feeling or sensitivity, especially in the skin

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 tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Glenmark Pharmaceuticals Inc., USA at 1(888)721-7115.

How should I store topiramate tablets?

• Store topiramate tablets at room temperature, 20°C to 25°C (68°F to 77°F).
• Keep topiramate tablets in a tightly closed container.
• Keep topiramate tablets dry and away from moisture.

Keep topiramate tablets and all medicines out of the reach of children.

**General information about the safe and effective use of topiramate tablets. **

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use topiramate tablets for a condition for which it was not prescribed. Do not give topiramate tablets to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about topiramate tablets that is written for health professionals.

What are the ingredients in topiramate tablets?

**Active ingredient:**topiramate, USP

**Inactive ingredients:**hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch, polyethylene glycol, polysorbate 80, sodium starch glycolate, and titanium dioxide. The 50 mg tablets also contain FD&C yellow# 6 and iron oxide yellow for color. The 100 mg and 200 mg tablets also contain iron oxide red and iron oxide yellow for color.

Trademarks are the property of their respective owners.

This Medication Guide has been approved by the U.S. Food and Drug Administration

Medication Guide available at:

www.glenmarkpharma-us.com/medguides

Manufactured by:

Glenmark Pharmaceuticals Ltd.

India

Manufactured for:


Glenmark Pharmaceuticals Inc., USA

Mahwah, NJ 07430

Questions? 1 (888) 721-7115

www.glenmarkpharma-us.com

June 2019

PE521660519-1

14 CLINICAL STUDIES

The studies described in the following sections were conducted using topiramate tablets.

14.1 Monotherapy Epilepsy

Patients with Partial-Onset or Primary Generalized Tonic-Clonic Seizures

Adults and Pediatric Patients 10 Years of Age and Older

The effectiveness of topiramate as initial monotherapy in adults and pediatric patients 10 years of age and older with partial-onset or primary generalized tonic-clonic seizures was established in a multicenter, randomized, double- blind, parallel-group trial (Study 1).

Study 1 was conducted in 487 patients diagnosed with epilepsy (6 to 83 years of age) who had 1 or 2 well-documented seizures during the 3-month retrospective baseline phase who then entered the study and received topiramate 25 mg/day for 7 days in an open-label fashion. Forty-nine percent of patients had no prior AED treatment and 17% had a diagnosis of epilepsy for greater than 24 months. Any AED therapy used for temporary or emergency purposes was discontinued prior to randomization. In the double-blind phase, 470 patients were randomized to titrate up to 50 mg/day or 400 mg/day. If the target dose could not be achieved, patients were maintained on the maximum tolerated dose. Fifty-eight percent of patients achieved the maximal dose of 400 mg/day for >2 weeks, and patients who did not tolerate 150 mg/day were discontinued.

The primary efficacy assessment was a between-group comparison of time to first seizure during the double-blind phase. Comparison of the Kaplan-Meier survival curves of time to first seizure favored the topiramate 400 mg/day group over the topiramate 50 mg/day group (Figure 1). The treatment effects with respect to time to first seizure were consistent across various patient subgroups defined by age, sex, geographic region, baseline body weight, baseline seizure type, time since diagnosis, and baseline AED use.

Figure 1: Kaplan-Meier Estimates of Cumulative Rates for Time to First Seizure in Study 1


Pediatric Patients 2 to 9 Years of Age

The conclusion that topiramate is effective as initial monotherapy in pediatric patients 2 to 9 years of age with partial-onset or primary generalized tonic-clonic seizures was based on a pharmacometric bridging approach using data from the controlled epilepsy trials described in labeling. This approach consisted of first showing a similar exposure response relationship between pediatric patients down to 2 years of age and adults when topiramate was given as adjunctive therapy. Similarity of exposure-response was also demonstrated in pediatric patients 6 to less than 16 years of age and adults when topiramate was given as initial monotherapy. Specific dosing in pediatric patients 2 to 9 years of age was derived from simulations utilizing plasma exposure ranges observed in pediatric and adult patients treated with topiramate initial monotherapy [see Dosage and Administration (2.1)].

14.2 Adjunctive Therapy Epilepsy

Adult Patients With Partial-Onset Seizures

The effectiveness of topiramate as an adjunctive treatment for adults with partial-onset seizures was established in six multicenter, randomized, double- blind, placebo-controlled trials (Studies 2, 3, 4, 5, 6 and 7), two comparing several dosages of topiramate and placebo and four comparing a single dosage with placebo, in patients with a history of partial-onset seizures, with or without secondarily generalized seizures.

Patients in these studies were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate tablets or placebo. In each study, patients were stabilized on optimum dosages of their concomitant AEDs during baseline phase lasting between 4 and 12 weeks. Patients who experienced a pre-specified minimum number of partial-onset seizures, with or without secondary generalization, during the baseline phase (12 seizures for 12-week baseline, 8 for 8-week baseline or 3 for 4-week baseline) were randomly assigned to placebo or a specified dose of topiramate tablets in addition to their other AEDs.

Following randomization, patients began the double-blind phase of treatment. In five of the six studies, patients received active drug beginning at 100 mg per day; the dose was then increased by 100 mg or 200 mg/day increments weekly or every other week until the assigned dose was reached, unless intolerance prevented increases. In the sixth study (Study 7), the 25 or 50 mg/day initial doses of topiramate were followed by respective weekly increments of 25 or 50 mg/day until the target dose of 200 mg/day was reached. After titration, patients entered a 4, 8 or 12-week stabilization period. The numbers of patients randomized to each dose and the actual mean and median doses in the stabilization period are shown in Table 11.

Pediatric Patients 2 to 16 Years of Age with Partial-Onset Seizures

The effectiveness of topiramate as an adjunctive treatment for pediatric patients 2 to 16 years of age with partial-onset seizures was established in a multicenter, randomized, double-blind, placebo-controlled trial (Study 8), comparing topiramate and placebo in patients with a history of partial-onset seizures, with or without secondarily generalized seizures (see Table 12).

Patients in this study were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate tablets or placebo. In this study, patients were stabilized on optimum dosages of their concomitant AEDs during an 8-week baseline phase. Patients who experienced at least six partial-onset seizures, with or without secondarily generalized seizures, during the baseline phase were randomly assigned to placebo or topiramate tablets in addition to their other AEDs.

Following randomization, patients began the double-blind phase of treatment. Patients received active drug beginning at 25 or 50 mg/day; the dose was then increased by 25 mg to 150 mg/day increments every other week until the assigned dosage of 125, 175, 225, or 400 mg/day based on patients' weight to approximate a dosage of 6 mg/kg/day was reached, unless intolerance prevented increases. After titration, patients entered an 8-week stabilization period.

Patients With Primary Generalized Tonic-Clonic Seizures

The effectiveness of topiramate as an adjunctive treatment for primary generalized tonic-clonic seizures in patients 2 years of age and older was established in a multicenter, randomized, double-blind, placebo-controlled trial (Study 9), comparing a single dosage of topiramate and placebo (see Table 12).

Patients in Study 9 were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate or placebo. Patients were stabilized on optimum dosages of their concomitant AEDs during an 8-week baseline phase. Patients who experienced at least three primary generalized tonic-clonic seizures during the baseline phase were randomly assigned to placebo or topiramate in addition to their other AEDs.

Following randomization, patients began the double-blind phase of treatment. Patients received active drug beginning at 50 mg/day for four weeks; the dose was then increased by 50 mg to 150 mg/day increments every other week until the assigned dose of 175, 225, or 400 mg/day based on patients' body weight to approximate a dosage of 6 mg/kg/day was reached, unless intolerance prevented increases. After titration, patients entered a 12-week stabilization period.

Patients With Lennox-Gastaut Syndrome

The effectiveness of topiramate as an adjunctive treatment for seizures associated with Lennox-Gastaut syndrome was established in a multicenter, randomized, double-blind, placebo-controlled trial (Study 10) comparing a single dosage of topiramate with placebo in patients 2 years of age and older (see Table 12).

Patients in Study 10 were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate or placebo. Patients who were experiencing at least 60 seizures per month before study entry were stabilized on optimum dosages of their concomitant AEDs during a 4-week baseline phase. Following baseline, patients were randomly assigned to placebo or topiramate in addition to their other AEDs. Active drug was titrated beginning at 1 mg/kg/day for a week; the dose was then increased to 3 mg/kg/day for one week, then to 6 mg/kg/day. After titration, patients entered an 8-week stabilization period.

The primary measures of effectiveness were the percent reduction in drop attacks and a parental global rating of seizure severity.

Table 11: Topiramate Dose Summary During the Stabilization Periods of Each of Six Double-Blind, Placebo-Controlled, Adjunctive Trials in Adults with Partial-Onset Seizuresa

a Dose-response studies were not conducted for other indications or pediatric partial-onset seizures. b Placebo dosages are given as the number of tablets. Placebo target dosages were as follows: Study 3, 4 tablets/day; Study 1 and 4, 6 tablets/day; Study 5 and 6, 8 tablets/day; Study 2, 10 tablets/day.
Target Topiramate Dosage (mg/day)
Study	Stabilization Dose	Placebo****b	200	400	600	800	1,000
2	N	42	42	40	41	--	--
Mean Dose	5.9	200	390	556	--	--
Median Dose	6	200	400	600	--	--
3	N	44	--	--	40	45	40
Mean Dose	9.7	--	--	544	739	796
Median Dose	10	--	--	600	800	1,000
4	N	23	--	19	--	--	--
Mean Dose	3.8	--	395	--	--	--
Median Dose	4	--	400	--	--	--
5	N	30	--	--	28	--	--
Mean Dose	5.7	--	--	522	--	--
Median Dose	6	--	--	600	--	--
6	N	28	--	--	--	25	--
Mean Dose	7.9	--	--	--	568	--
Median Dose	8	--	--	--	600	--
7	N	90	157	--	--	--	--
Mean Dose	8	200	--	--	--	--
Median Dose	8	200	--	--	--	--

In all adjunctive trials, the reduction in seizure rate from baseline during the entire double-blind phase was measured. The median percent reductions in seizure rates and the responder rates (fraction of patients with at least a 50% reduction) by treatment group for each study are shown below in Table 12. As described above, a global improvement in seizure severity was also assessed in the Lennox-Gastaut trial.

Table 12: Efficacy Results in Double-Blind, Placebo-Controlled, Adjunctive Epilepsy Trials

Target topiramate Dosage (mg per day)
Study #		Placebo	200	400	600	800	1,000	≈6 mg/kg/day*
Partial-Onset Seizures Studies in Adults
2	N	45	45	45	46	--	--	--
Median % Reduction	12	27a	48b	45c	--	--	--
% Responders	18	24	44d	46d	--	--	--
3	N	47	--	--	48	48	47	--
Median % Reduction	2	--	--	41c	41c	36c	--
% Responders	9	--	--	40c	41c	36d	--
4	N	24	--	23	--	--	--	--
Median % Reduction	1	--	41e	--	--	--	--
% Responders	8	--	35d	--	--	--	--
5	N	30	--	--	30	--	--	--
Median % Reduction	-12	--	--	46f	--	--	--
% Responders	10	--	--	47c	--	--	--
6	N	28	--	--	--	28	--	--
Median % Reduction	-21	--	--	--	24c	--	--
% Responders	0	--	--	--	43c	--	--
7	N	91	168	--	--	--	--	--
Median % Reduction	20	44c	--	--	--	--	--
% Responders	24	45c	--	--	--	--	--
Partial-Onset Seizures Studies in Pediatric Patients
8	N	45	--	--	--	--	--	41
Median % Reduction	11	--	--	--	--	--	33d
% Responders	20	--	--	--	--	--	39
Primary Generalized Tonic-Clonich,
9	N	40	--	--	--	--	--	39
Median % Reduction	9	--	--	--	--	--	57d
% Responders	20	--	--	--	--	--	56c
Lennox-Gastaut Syndromei,
10	N	49	--	--	--	--	--	46
Median % Reduction	-5	--	--	--	--	--	15d
% Responders	14	--	--	--	--	--	28g
Improvement in Seizure Severityj	28	--	--	--	--	--	52d
Comparisons with placebo: a p=0.080; b p≤0.01; c p≤0.001; d p≤0.050; e p=0.065; f p≤0.005; g p=0.071; h Median % reduction and % responders are reported for PGTC seizures; i Median % reduction and % responders for drop attacks, i.e., tonic or atonic seizures; j Percentage of subjects who were minimally, much, or very much improved from baseline For Studies 8 and 9, specified target dosages (<9.3 mg/kg/day) were assigned based on subject's weight to approximate a dosage of 6 mg/kg per day, these dosages corresponded to mg/day dosages of 125, 175, 225, and 400 mg/day.

Subset analyses of the antiepileptic efficacy of topiramate tablets in these studies showed no differences as a function of gender, race, age, baseline seizure rate, or concomitant AED.

In clinical trials for epilepsy, daily dosages were decreased in weekly intervals by 50 to 100 mg/day in adults and over a 2- to 8-week period in pediatric patients; transition was permitted to a new antiepileptic regimen when clinically indicated.

14.3 Preventive Treatment of Migraine

Adult Patients

The results of 2 multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trials established the effectiveness of topiramate in the preventive treatment of migraine. The design of both trials (Study 11 was conducted in the U.S. and Study 12 was conducted in the U.S. and Canada) was identical, enrolling patients with a history of migraine, with or without aura, for at least 6 months, according to the International Headache Society (IHS) diagnostic criteria. Patients with a history of cluster headaches or basilar, ophthalmoplegic, hemiplegic, or transformed migraine headaches were excluded from the trials. Patients were required to have completed up to a 2-week washout of any prior migraine preventive medications before starting the baseline phase.

Patients who experienced 3 to 12 migraine headaches over the 4 weeks in the baseline phase were randomized to either topiramate 50 mg/day, 100 mg/day, 200 mg/day, or placebo and treated for a total of 26 weeks (8-week titration period and 18-week maintenance period). Treatment was initiated at 25 mg/day for one week, and then the daily dosage was increased by 25 mg increments each week until reaching the assigned target dose or maximum tolerated dose (administered twice daily).

Effectiveness of treatment was assessed by the reduction in migraine headache frequency, as measured by the change in 4-week migraine rate (according to migraines classified by IHS criteria) from the baseline phase to double-blind treatment period in each topiramate treatment group compared to placebo in the Intent-To-Treat (ITT) population.

In Study 11, a total of 469 patients (416 females, 53 males), ranging in age from 13 to 70 years, were randomized and provided efficacy data. Two hundred sixty-five patients completed the entire 26-week double-blind phase. The median average daily dosages were 48 mg/day, 88 mg/day, and 132 mg/day in the target dose groups of topiramate 50, 100, and 200 mg/day, respectively.

The mean migraine headache frequency rate at baseline was approximately 5.5 migraine headaches/28 days and was similar across treatment groups. The change in the mean 4-week migraine headache frequency from baseline to the double- blind phase was -1.3, -2.1, and -2.2 in the topiramate 50, 100, and 200 mg/day groups, respectively, versus -0.8 in the placebo group (see Figure 2). The treatment differences between the topiramate 100 and 200 mg/day groups versus placebo were similar and statistically significant (p<0.001 for both comparisons).

In Study 12, a total of 468 patients (406 females, 62 males), ranging in age from 12 to 65 years, were randomized and provided efficacy data. Two hundred fifty-five patients completed the entire 26-week double-blind phase. The median average daily dosages were 47 mg/day, 86 mg/day, and 150 mg/day in the target dose groups of topiramate 50, 100, and 200 mg/day, respectively.

The mean migraine headache frequency rate at baseline was approximately 5.5 migraine headaches/28 days and was similar across treatment groups. The change in the mean 4-week migraine headache period frequency from baseline to the double-blind phase was -1.4, -2.1, and -2.4 in the topiramate 50, 100, and 200 mg/day groups, respectively, versus -1.1 in the placebo group (see Figure 2). The differences between the topiramate 100 and 200 mg/day groups versus placebo were similar and statistically significant (p=0.008 and p <0.001, respectively).

In both studies, there were no apparent differences in treatment effect within age or gender subgroups. Because most patients were Caucasian, there were insufficient numbers of patients from different races to make a meaningful comparison of race.

For patients withdrawing from topiramate, daily dosages were decreased in weekly intervals by 25 to 50 mg/day.

Figure 2: Reduction in 4-Week Migraine Headache Frequency

(Studies 11 and 12 for Adults and Adolescents)


Pediatric Patients 12 to 17 Years of Age

The effectiveness of topiramate for the preventive treatment of migraine in pediatric patients 12 to 17 years of age was established in a multicenter, randomized, double-blind, parallel-group trial (Study 13). The study enrolled 103 patients (40 male, 63 female) 12 to 17 years of age with episodic migraine headaches with or without aura. Patient selection was based on IHS criteria for migraines (using proposed revisions to the 1988 IHS pediatric migraine criteria [IHS-R criteria]).

Patients who experienced 3 to 12 migraine attacks (according to migraines classified by patient reported diaries) and ≤14 headache days (migraine and non-migraine) during the 4-week prospective baseline period were randomized to either topiramate 50 mg/day, 100 mg/day, or placebo and treated for a total of 16 weeks (4-week titration period followed by a 12-week maintenance period). Treatment was initiated at 25 mg/day for one week, and then the daily dosage was increased by 25 mg increments each week until reaching the assigned target dose or maximum tolerated dose (administered twice daily). Approximately 80% or more patients in each treatment group completed the study. The median average daily dosages were 45 and 79 mg/day in the target dose groups of topiramate 50 and 100 mg/day, respectively.

Effectiveness of treatment was assessed by comparing each topiramate treatment group to placebo (ITT population) for the percent reduction from baseline to the last 12 weeks of the double-blind phase in the monthly migraine attack rate (primary endpoint). The percent reduction from baseline to the last 12 weeks of the double-blind phase in average monthly migraine attack rate is shown in Table 13. The 100 mg topiramate dose produced a statistically significant treatment difference relative to placebo of 28% reduction from baseline in the monthly migraine attack rate.

The mean reduction from baseline to the last 12 weeks of the double-blind phase in average monthly attack rate, a key secondary efficacy endpoint in Study 13 (and the primary efficacy endpoint in Studies 11 and 12, of adults) was 3 for 100 mg topiramate dose and 1.7 for placebo. This 1.3 treatment difference in mean reduction from baseline of monthly migraine rate was statistically significant (p = 0.0087).

Table 13: Percent Reduction from Baseline to the Last 12 Weeks of Double-Blind Phase in Average Monthly Attack Rate: Study 13 (Intent-to-Treat Analysis Set)

Category	Placebo (N=33)	Topiramate 50 mg/day (N=35)	Topiramate ****100 mg/day ****(N=35)
Baseline
Median	3.6	4
Last 12 Weeks of Double-Blind Phase
Median	2.3	2.3	1
Percent Reduction (%)
Median	44.4	44.6	72.2
P-value versus Placebo a,b		0.7975	0.0164 c
a P-values (two-sided) for comparisons relative to placebo are generated by applying an ANCOVA model on ranks that includes subject's stratified age at baseline, treatment group, and analysis center as factors and monthly migraine attack rate during baseline period as a covariate. b P-values for the dose groups are the adjusted p-value according to the Hochberg multiple comparison procedure. c Indicates p-value is <0.05 (two-sided).

11 DESCRIPTION

Topiramate, USP is a sulfamate-substituted monosaccharide. Topiramate tablets, USP are available as 25 mg, 50 mg, 100 mg, and 200 mg round tablets for oral administration.

Topiramate, USP is a white to off white powder. It is freely soluble in dichloromethane.

Topiramate, USP has the molecular formula C12H21NO8S and a molecular weight of 339.36 g/mol. Topiramate, USP is designated chemically as 2,3:4,5-Di-O- isopropylidene-β-D-fructopyranose sulfamate and has the following structural formula:


Topiramate tablets, USP contain the following inactive ingredients: hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch, polyethylene glycol, polysorbate 80, sodium starch glycolate, and titanium dioxide. The 50 mg tablets also contain FD&C yellow# 6 and iron oxide yellow for color. The 100 mg and 200 mg tablets also contain iron oxide red and iron oxide yellow for color.