Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

QUDEXY XR (NDA-205122)

(TOPIRAMATE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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03/28/2024 (SUPPL-16)

Approved Drug Label (PDF)

7 Drug Interactions

7.4 Contraceptives

Additions and/or revisions underlined:

The possibility of decreased contraceptive efficacy and increased breakthrough bleeding may occur in patients taking contraceptive products with QUDEXY XR. Patients taking estrogen- containing or progestin-only contraceptives should be asked to report any change in their bleeding patterns. Contraceptive efficacy can be decreased even in the absence of breakthrough bleeding [see Clinical Pharmacology (12.3)].

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

…

Monotherapy Treatment for Epilepsy

Pediatric Patients 2 Years of Age and Older

The safety and effectiveness of QUDEXY XR as monotherapy for the treatment of partial-onset seizures or primary generalized tonic-clonic seizures have been established in pediatric patients aged 2 years and older and is based on controlled trials with immediate-release topiramate [see Adverse Reactions (6.1), Clinical Studies (14.1)].

…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

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 QUDEXY XR, keeping in mind that there is a potential for decreased contraceptive efficacy when using estrogen-containing or progestin- only contraceptives with topiramate [see Drug Interactions (7.4)].

…

MEDICATION GUIDE

Additions and/or revisions underlined:

…

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

…

birth control that contains hormones (such as pills, implants, patches or injections). QUDEXY XR may make your birth control less effective. Tell your healthcare provider if your menstrual bleeding changes while you are using birth control and QUDEXY XR.

…

12/02/2022 (SUPPL-14)

Approved Drug Label (PDF)

5 Warnings and Precautions

Additions and/or revisions underlined:

5.2 Visual Field Defects

Visual field defects (independent of elevated intraocular pressure) have been reported in clinical trials and in postmarketing experience in patients receiving topiramate independent of elevated intraocular pressure. In clinical trials, most of …

5.3 Oligohydrosis and Hyperthermia

Oligohydrosis (decreased sweating), infrequently resulting in hospitalization in some cases, has been reported in association with topiramate use. Decreased sweating …

5.4 Metabolic Acidosis

… Chronic, untreated metabolic acidosis may increase the risk for nephrolithiasis or nephrocalcinosis and may also result in osteomalacia (referred to as rickets in pediatric patients) and/or osteoporosis with an increased risk for fractures [see Warnings and Precautions (5.9, 5.13)]. A one-year, active-controlled study of pediatric patients treated with immediate-release topiramate demonstrated that topiramate decreased lumbar spine bone mineral density and that this lumbar spine bone mineral density decrease was correlated (using change from baseline for lumbar spine Z score at final visit versus lowest post-treatment serum bicarbonate) with decreased serum bicarbonate, a reflection of metabolic acidosis [see Warnings and Precautions (5.9), Use in Specific Populations (8.4)]. Chronic metabolic acidosis in pediatric patients may also reduce growth rates, which may decrease the maximal height achieved. Long-term, open- label treatment of pediatric patients …

5.7 Fetal Toxicity

QUDEXY XR can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in utero have an increased risk of major congenital malformation, including but not limited to cleft lip and/or cleft palate (oral clefts), and of being small for gestational age (SGA). When multiple species of pregnant animals …

Newly added subsections:

5.9 Decrease in Bone Mineral Density

Results of a one-year active-controlled study in pediatric patients (N=63) demonstrated negative effects of immediate-release topiramate monotherapy on bone mineral acquisition via statistically significant decreases in bone mineral density (BMD) measured in lumbar spine and in total body less head [see Use in Specific Populations (8.4)]. Twenty-one percent of immediate-release topiramate-treated patients experienced clinically important reductions in BMD (Z score change from baseline of -0.5 or greater) compared to 0 patients in the control group. Although decreases in BMD occurred across all pediatric age subgroups, patients 6 to years of age were most commonly affected. The sample size and study duration were too small to determine if fracture risk is increased. Decreased BMD in the lumbar spine was correlated with decreased serum bicarbonate, which commonly occurs with topiramate treatment and reflects metabolic acidosis, a known cause of increased bone resorption [see Warnings and Precautions (5.4)]. Although small decreases in some markers of bone metabolism (e.g., serum alkaline phosphatase, calcium, phosphorus, and 1,25-dihydroxyvitamin D) occurred in immediate-release topiramate-treated patients, more significant decreases in serum parathyroid hormone and 25-hydroxyvitamin D, hormones involved in bone metabolism, were observed, along with an increased excretion of urinary calcium.

5.10 Negative Effects on Growth (Height and Weight)

Results of a one-year active-controlled study of pediatric patients (N=63) demonstrated negative effects of immediate-release topiramate monotherapy on growth (i.e., height and weight) [see Use in Specific Populations (8.4)]. Although continued growth was observed in both treatment groups, the immediate-release topiramate group showed statistically significant reductions in mean annual change from baseline in body weight compared to the control group. A similar trend of attenuation in height velocity and height change from baseline was also observed in the immediate-release topiramate group compared to the control group. Negative effects on weight and height were seen across all topiramate age subgroups. Growth (height and weight) of children receiving prolonged QUDEXY XR therapy should be carefully monitored.

Additions and/or revisions underlined:

5.13 Kidney Stones

… Increased fluid intake increases the urinary output, lowering the concentration of substances involved in stone formation. Hydration is recommended to reduce new stone formation.

An increase in urinary calcium and a marked decrease in urinary citrate was observed in immediate-release topiramate-treated pediatric patients in one-year active-controlled study [see Use in Specific Populations (8.4)]. This increased ratio of urinary calcium/citrate increases the risk of kidney stones and/or nephrocalcinosis.

6 Adverse Reactions

Newly added to bulleted line listing:

Decrease in Bone Mineral Density [see Warnings and Precautions (5.9)]
Negative Effects on Growth (Height and Weight) [see Warnings and Precautions (5.10)]

8 Use in Specific Populations

8.1 Pregnancy

Risk Summary

Additions and/or revisions underlined:

QUDEXY XR can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in utero have increased risk of major congenital malformations, including but not limited to cleft lip and/or cleft palate (oral clefts) …

All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2% to 4% and 15% to 20%, respectively …

… Data

Human Data

Data from pregnancy registries indicate an increased risk of major congenital malformations, including but not limited to oral clefts in infants exposed to topiramate during the first trimester of pregnancy. Other than oral clefts, no specific pattern of major congenital malformations or grouping of major congenital malformation types were observed. In the NAAED pregnancy registry, when topiramate-exposed infants with only oral clefts were excluded, the prevalence of major congenital malformations (4.1%) was higher than that in infants exposed to a reference AED (1.8%) or in infants with mothers without epilepsy and without exposure to AEDs (1.1%). The prevalence of oral clefts among topiramate-exposed infants (1.4%) was higher than the prevalence in infants exposed to a reference AED (0.3%) or the prevalence in infants with mothers without epilepsy and without exposure to AEDs (0.11%). It was also higher than the background prevalence in the United States (0.17%) as estimated by the Centers for Disease Control and Prevention (CDC). The relative risk of oral clefts in topiramate-exposed pregnancies in the NAAED Pregnancy Registry was 12.5 (95% Confidence Interval=[CI] 5.9 to 26.37) as compared to the risk in a background population of untreated women. The UK Epilepsy and Pregnancy Register reported a prevalence of oral clefts among infants exposed to topiramate monotherapy (3.2%) that was 16 times higher than the background rate in the UK (0.2%) …

8.3 Females and Males of Reproductive Potential

Contraception

Women of childbearing potential who are not planning a pregnancy should use effective contraception because of the risk of major congenital malformations, including oral clefts, and the risk of infants being SGA [see Drug Interactions (7.4) and Use in Specific Populations (8.1)].

8.4 Pediatric Use

Additions and/or revisions underlined:

Adjunctive Treatment for Epilepsy

Pediatric Patients 2 Years of Age and Older

The safety and effectiveness of QUDEXY XR as adjunctive therapy for the treatment of partial- onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox- Gastaut syndrome have been established in pediatric patients 2 years of age and older and is based on controlled trials with immediate-release topiramate [see Adverse Reactions (6.1) and Clinical Studies (14.3, 14.4)].

The adverse reactions (both common and serious) in pediatric patients are similar to those seen in adults [see Warnings and Precautions (5) and Adverse Reactions (6)] …

… Pediatric Patients Below the Age of 2 Years

… In general, the adverse reaction profile for immediate-release topiramate in this population was similar to that of older pediatric patients, although results from the above controlled study and an open-label, long-term extension study in these pediatric patients 1 to 24 months old suggested some adverse reactions/toxicities not previously observed in older pediatric patients and adults; i.e., growth/length retardation, certain clinical laboratory abnormalities, and other adverse reactions/toxicities that occurred with a greater frequency and/or greater severity than had been recognized previously from studies in older pediatric patients or adults for various indications …

… Treatment with immediate-release topiramate for up to 1 year was associated with reductions in Z SCORES for length, weight, and head circumference [see Warnings and Precautions (5.4), Adverse Reactions (6.1)] …

Monotherapy Treatment for Epilepsy Pediatric Patients less than or equal to 2 Years of Age and Older

The safety and effectiveness of QUDEXY XR as monotherapy for the treatment of partial-onset seizures or primary generalized tonic-clonic seizures have been established in pediatric patients aged 2 years and older [see Adverse Reactions (6.1), Clinical Studies (14.1)].

A one-year, active-controlled, open-label study with blinded assessments of bone mineral density (BMD) and growth in pediatric patients 4 to 15 years of age, including 63 patients with recent or new onset of epilepsy, was conducted to assess effects of immediate-release topiramate (N=28,

6 to 15 years of age) versus levetiracetam (N=35, 4 to 15 years of age) monotherapy on bone mineralization and on height and weight, which reflect growth. Effects on bone mineralization were evaluated via dual-energy X-ray absorptiometry and blood markers. Table 11 summarizes effects of immediate-release topiramate at 12 months for key safety outcomes including BMD, height, height velocity, and weight. All Least Square Mean values for immediate-release topiramate and the comparator were positive. Therefore, the Least Square Mean treatment differences shown reflect a topiramate induced attenuation of the key safety outcomes.

Statistically significant effects were observed for decreases in BMD (and bone mineral content) in lumbar spine and total body less head and in weight. Subgroup analyses according to age demonstrated similar negative effects for all key safety outcomes (i.e., BMD, height, weight).

Table 11: Summary of Immediate-Release Topiramate Treatment Difference Results at 12 Months for Key Safety Outcomes (Newly added table; please refer to label for complete information).

Metabolic acidosis (serum bicarbonate < 20 mEq/L) was observed in all immediate-release topiramate-treated patients at some time in the study [see Warnings and Precautions (5.4)]. Over the whole study, 76% more immediate-release topiramate-treated patients experienced persistent metabolic acidosis (i.e., 2 consecutive visits with or final serum bicarbonate < 20 mEq/L) compared to levetiracetam-treated patients. Over the whole study, 35% more immediate-release topiramate-treated patients experienced a markedly abnormally low serum bicarbonate (i.e., absolute value < 17 mEq/L and greater than or equal to 5 mEq/L decrease from pre-treatment), indicating the frequency of more severe metabolic acidosis, compared to levetiracetam-treated patients. The decrease in BMD at 12 months was correlated with decreased serum bicarbonate, suggesting that metabolic acidosis was at least a partial factor contributing to this adverse effect on BMD.

Immediate-release topiramate-treated patients exhibited an increased risk for developing an increased serum creatinine and an increased serum glucose above the normal reference range compared to control patients.

Pediatric Patients Below the Age of 2 Years

Safety and effectiveness in patients below the age of 2 years have not been established for the monotherapy treatment of epilepsy …

… Pediatric Patients Below the Age of 12 Years

Safety and effectiveness in pediatric patients below the age of 12 years have not been established for the preventive treatment of migraine …

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

What is the most important information I should know about QUDEXY XR?

QUDEXY XR can harm your unborn baby.

Birth defects may happen even in children born to women who are not taking any medicines and do not have other risk factors …

QUDEXY XR may decrease the density of bones when used over a long period.

QUDEXY XR may slow height increase and weight gain in children and adolescents when used over a long period.

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Fetal Toxicity

Inform pregnant women and women of childbearing potential that use of QUDEXY XR during pregnancy can cause fetal harm. QUDEXY XR increased the risk of major congenital malformations, including but not limited to cleft lip and/or cleft palate (oral clefts), which occur early in pregnancy before many women know they are pregnant …

… Decrease in Bone Mineral Density

Inform the patient or caregiver that long-term treatment with QUDEXY XR can decrease bone formation and increase bone resorption in children [see Warnings and Precautions (5.9)].

Negative Effects on Growth (Height and Weight)

Discuss with the patient or caregiver that long-term QUDEXY XR treatment may attenuate growth as reflected by slower height increase and weight gain in pediatric patients [see Warnings and Precautions (5.10)].

02/04/2022 (SUPPL-12)

Approved Drug Label (PDF)

5 Warnings and Precautions

Additions and/or revisions underlined:

5.1 Acute Myopia and Secondary Angle Closure Glaucoma Syndrome

A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients receiving topiramate. Symptoms include acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings can include some or all of the following: myopia, mydriasis, anterior chamber shallowing, ocular hyperemia (redness), choroidal detachments, retinal pigment epithelial detachments, macular striae, and increased intraocular pressure. This syndrome may be associated with supraciliary effusion resulting in anterior displacement of the lens and iris, with secondary angle closure glaucoma …

02/18/2021 (SUPPL-11)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.9 Serious Skin Reactions

New subsection added

Serious skin reactions (Stevens-Johnson Syndrome [SJS] and Toxic Epidermal Necrolysis [TEN]) have been reported in patients receiving topiramate. QUDEXY XR should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered. Inform patients about the signs of serious skin reactions.

6 Adverse Reactions

Addition of the following to the bulleted line listing:

Serious Skin Reactions [see Warnings and Precautions (5.9)]

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions underlined

What are the possible side effects of QUDEXY XR?

QUDEXY XR may cause serious side effects, including:

…

Serious skin reactions. QUDEXY XR may cause a severe rash with blisters and peeling skin, especially around the mouth, nose, eyes, and genitals (Stevens-Johnson syndrome). QUDEXY XR may also cause a rash with blisters and peeling skin over much of the body that may cause death (toxic epidermal necrolysis). Call your healthcare provider right away if you develop a skin rash or blisters.
…

PATIENT COUNSELING INFORMATION

Additions underlined

…

Serious Skin Reactions

Inform patients about the signs of serious skin reactions. Instruct patients to immediately inform their healthcare provider at the first appearance of skin rash [see Warnings and Precautions (5.9)].

…

02/14/2020 (SUPPL-10)

Approved Drug Label (PDF)

6 Adverse Reactions

6.3 Postmarketing Experience

Addition of ‘nephrocalcinosis’ to Urinary System Disorders

02/21/2019 (SUPPL-8)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.7 Fetal Toxicity

QUDEXY XR can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in utero have an increased risk for cleft lip and/or cleft palate (oral clefts) and for being small for gestational age. When multiple species of pregnant animals received topiramate at clinically relevant doses, structural malformations, including craniofacial defects, and reduced fetal weights occurred in offspring …

5.9 Hyperammonemia and Encephalopathy Without and With Concomitant Valproic Acid Use

Topiramate treatment can cause hyperammonemia with or without encephalopathy. The risk for hyperammonemia with topiramate appears dose-related.

Hyperammonemia has been reported more frequently when topiramate is used concomitantly with valproic acid. Postmarketing cases of hyperammonemia with or without encephalopathy have been reported with topiramate and valproic acid in patients who previously tolerated either drug alone.

Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy and/or vomiting. In most cases, hyperammonemic encephalopathy abated with discontinuation of treatment.

The incidence of hyperammonemia in pediatric patients 12 to 17 years of age in migraine prophylaxis trials was 26% in patients taking topiramate monotherapy at 100 mg/day, and 14% in patients taking topiramate at 50 mg/day, compared to 9% in patients taking placebo. There was also an increased incidence of markedly increased hyperammonemia at the 100 mg dose.

Dose-related hyperammonemia was also seen in pediatric patients 1 to 24 months of age treated with topiramate and concomitant valproic acid for partial onset epilepsy and this was not due to a pharmacokinetic interaction.

In some patients, hyperammonemia can be asymptomatic. Monitoring for Hyperammonemia

Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy. Although not studied, topiramate treatment or an interaction of concomitant topiramate and valproic acid treatment may exacerbate existing defects or unmask deficiencies in susceptible persons …

5.10 Kidney Stones

Topiramate increases the risk of kidney stones. During adjunctive epilepsy trials, the risk for kidney stones in immediate-release topiramate-treated adults was 1.5%, an incidence about 2 to 4 times greater than expected in a similar, untreated population. As in the general population, the incidence of stone formation among topiramate-treated patients was higher in men. Kidney stones have also been reported in pediatric patients taking topiramate for epilepsy or migraine.

During long-term (up to 1 year) topiramate treatment in an open-label extension study of 284 pediatric patients 1 to 24 months old with epilepsy, 7% developed kidney or bladder stones. QUDEXY XR is not approved for treatment of epilepsy in pediatric patients less than 2 years old.

QUDEXY XR Topiramate is a carbonic anhydrase inhibitor. Carbonic anhydrase inhibitors can promote stone formation by reducing urinary citrate excretion and by increasing urinary pH. The concomitant use of QUDEXY XR with any other drug producing metabolic acidosis, or potentially in patients on a ketogenic diet, may create a physiological environment that increases the risk of kidney stone formation, and should therefore be avoided.

Increased fluid intake increases the urinary output, lowering the concentration of substances involved in stone formation. Hydration is recommended to reduce new stone formation.

5.11 Hypothermia With Concomitant Valproic Acid Use

Hypothermia, defined as a drop in body core temperature to <35ºC (95ºF), has been reported in association with topiramate use with concomitant valproic acid both in conjunction with hyperammonemia and in the absence of hyperammonemia. This adverse reaction in patients using concomitant topiramate and valproate can occur after starting topiramate treatment or after increasing the daily dose of topiramate. Consideration should be given to stopping QUDEXY XR or valproate in patients who develop hypothermia, which may be manifested by a variety of clinical abnormalities including lethargy, confusion, coma, and significant alterations in other major organ systems such as the cardiovascular and respiratory systems. Clinical management and assessment should include examination of blood ammonia levels.

5.2 Visual Field Defects

(Additions and/or revisions are underlined)

Visual field defects (independent of elevated intraocular pressure) have been reported in patients receiving topiramate independent of elevated intraocular pressure. In clinical trials, most of these events were reversible after topiramate discontinuation. If visual problems occur at any time during treatment with topiramate, consideration should be given to discontinuing the drug.

5.4 Metabolic Acidosis

Additions and/or revisions underlined:

QUDEXY XR can cause hyperchloremic, non-anion gap, metabolic acidosis (i.e., decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis). This metabolic acidosis is caused by renal bicarbonate loss due to carbonic anhydrase inhibition by QUDEXY XR. QUDEXY XR-induced metabolic acidosis can occur at any time during treatment. Bicarbonate decrements are usually mild to moderate (average decrease of 4 mEq/L at daily doses of 400 mg in adults and at approximately 6 mg/kg/day in pediatric patients); rarely, patients can experience severe decrements to values below 10 mEq/L. Conditions or therapies that predispose patients to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhea, ketogenic diet or specific drugs) may be additive to the bicarbonate lowering effects of QUDEXY XR.

Metabolic acidosis was commonly observed in adult and pediatric patients treated with immediate-release topiramate in clinical trials. The incidence of decreased serum bicarbonate in pediatric trials, for adjunctive treatment of Lennox-Gastaut syndrome or refractory partial onset seizures was as high as 67% for immediate-release topiramate (at approximately 6 mg/kg/day), and 10% for placebo. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value < 17 mEq/L and >5 mEq/L decrease from pretreatment) in these trials was up to 11%, compared to less than or equal to 2% for placebo.

Manifestations of acute or chronic metabolic acidosis may include hyperventilation, nonspecific symptoms such as fatigue and anorexia, or more severe sequelae including cardiac arrhythmias or stupor. Chronic, untreated metabolic acidosis may increase the risk for nephrolithiasis or nephrocalcinosis and may also result in osteomalacia (referred to as rickets in pediatric patients) and/or osteoporosis with an increased risk for fractures. Chronic metabolic acidosis in pediatric patients may also reduce growth rates, which may decrease the maximal height achieved. The effect of topiramate on growth and bone-related sequelae has not been systematically investigated in long-term, placebo-controlled trials. Long-term, open-label treatment of pediatric patients 1 to 24 months old, with intractable partial epilepsy, for up to 1 year, showed reductions from baseline in length, weight, and head circumference compared to age and sex-matched normative data, although these patients with epilepsy are likely to have different growth rates than normal 1 to 24 month old patients. Reductions in length and weight were correlated to the degree of acidosis. QUDEXY XR treatment that causes metabolic acidosis during pregnancy can possibly produce adverse effects on the fetus and might also cause metabolic acidosis in the neonate from possible transfer of topiramate to the fetus

Measurement of Serum Bicarbonate in Epilepsy and Migraine Patients

Measurement of baseline and periodic serum bicarbonate during QUDEXY XR treatment is recommended. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing QUDEXY XR (using dose tapering). If the decision is made to continue patients on QUDEXY XR in the face of persistent acidosis, alkali treatment should be considered.

5.6 Cognitive/Neuropsychiatric Adverse Reactions

Additions and/or revisions underlined:

Immediate-release topiramate can cause, and therefore expected to be caused by QUDEXY XR, cognitive/neuropsychiatric adverse reactions. The most frequent of these can be classified into three general categories: 1) Cognitive-related dysfunction (e.g., confusion, psychomotor slowing, difficulty with concentration/attention, difficulty with memory, speech or language problems, particularly word-finding difficulties); 2) Psychiatric/behavioral disturbances (e.g., depression or mood problems); and 3) Somnolence or fatigue.

Adult Patients

Cognitive Related Dysfunction

Rapid titration rate and higher initial dose were associated with higher incidences of cognitive-related dysfunction.

In adult epilepsy add-on controlled trials, which used rapid titration (100 to 200 mg/day weekly increments) and target immediate-release topiramate doses of 200 mg to 1000 mg/day, 56% of patients in the 800 mg/day and 1000 mg/day dose groups experienced cognitive-related dysfunction compared to approximately 42% of patients in the 200 to 400 mg/day groups and 14% for placebo. In this rapid titration regimen, these dose-related adverse reactions began in the titration or in the maintenance phase, and in some patients these events began during titration and persisted into the maintenance phase.

In the monotherapy epilepsy controlled trial conducted with immediate-release topiramate, the proportion of patients who experienced one or more cognitive-related adverse reactions was 19% for topiramate 50 mg per day and 26% for 400 mg per day.

In the 6-month migraine prophylaxis controlled trials of immediate-release topiramate using a slower titration regimen (25 mg/day weekly increments), the proportion of patients who experienced one or more cognitive-related adverse reactions was 19% for topiramate 50 mg/day, 22% for 100 mg/day (the recommended dose), 28% for 200 mg/day, and 10% for placebo.

Cognitive adverse reactions most commonly developed during titration and sometimes persisted after completion of titration.

Psychiatric/Behavioral Disturbances

Psychiatric/behavioral disturbances (e.g., depression or mood) were dose-related for both the adjunctive epilepsy and migraine populations treated with topiramate [see Warnings and Precautions (5.5)].

Somnolence/Fatigue

Somnolence and fatigue were the adverse reactions most frequently reported during clinical trials of topiramate for adjunctive epilepsy. For the adjunctive epilepsy population, the incidence of fatigue appeared dose-related. For the monotherapy epilepsy population, the incidence of somnolence was dose-related. For the migraine population, the incidences of both somnolence and fatigue were dose-related and more common in the titration phase.

Pediatric Patients

In pediatric epilepsy trials (adjunctive Inand monotherapy), the incidence of cognitive/neuropsychiatric adverse reactions was generally lower than that observed in adults. These reactions included psychomotor slowing, difficulty with concentration/attention, speech disorders/related speech problems, and language problems. The most frequently reported cognitive/neuropsychiatric reactions in pediatric epilepsy patients during adjunctive therapy double-blind studies were somnolence and fatigue. The most frequently reported cognitive/neuropsychiatric reactions in pediatric epilepsy patients in the 50 mg/day and 400 mg/day groups during the monotherapy double-blind study were headache, dizziness, anorexia, and somnolence.

In pediatric migraine patients, the incidence of cognitive/neuropsychiatric adverse reactions was increased in topiramate-treated patients compared to placebo.

The risk for cognitive/neuropsychiatric adverse reactions was dose-dependent, and was greatest at the highest dose (200 mg). This risk for cognitive/neuropsychiatric adverse reactions was also greater in younger patients (6 to 11 years of age) than in older patients (12 to 17 years of age).

The most common cognitive/neuropsychiatric adverse reaction in these trials was difficulty with concentration/attention. Cognitive adverse reactions most commonly developed during the titration period and sometimes persisted for various durations after completion of titration.

The Cambridge Neuropsychological Test Automated Battery (CANTAB) was administered to adolescents (12 to 17 years of age) to assess the effects of topiramate on cognitive function at baseline and at the end of the Study 13. Mean change from baseline in certain CANTAB tests suggests that topiramate treatment may result in psychomotor slowing and decreased verbal fluency.

6 Adverse Reactions

Additions and/or revisions underlined:

Hyperammonemia and Encephalopathy (Without and With Concomitant Valproic Acid Use)

The data described in section 6.1 were obtained using immediate-release topiramate tablets.

6.1 Clinical Trials Experience with Immediate-Release Topiramate

(Extensive changes to this subsection, please refer to the label)

6.3 Post-marketing Experience

The following adverse reactions have been identified during post-approval use of immediate-release topiramate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hematological Disorders: decrease of the International Normalized Ratio (INR) or prothrombin time when given concomitantly with Vitamin K antagonist anticoagulant medications such as warfarin.

7 Drug Interactions

7.1 Antiepileptic Drugs

(Additions and/or revisions are underlined)

Concomitant administration of phenytoin or carbamazepine with topiramate resulted in a clinically significant decrease in plasma concentrations of topiramate when compared to topiramate given alone. A dosage adjustment may be needed.

Concomitant administration of valproic acid and topiramate has been associated with hypothermia and hyperammonemia with and without encephalopathy. Examine blood ammonia levels in patients in whom the onset of hypothermia has been reported.

7.3 CNS Depressants

(Additions and/or revisions are underlined)

Concomitant administration of topiramate and alcohol or other CNS depressant drugs has not been evaluated in clinical studies. Because of the potential of topiramate to cause

CNS depression, as well as other cognitive and/or neuropsychiatric adverse reactions, QUDEXY XR should be used with extreme caution if used in combination with alcohol and other

CNS depressants

7.4 Oral Contraceptives

(Additions and/or revisions are underlined)

The possibility of decreased contraceptive efficacy and increased breakthrough bleeding may occur in patients taking combination oral contraceptive products with QUDEXY XR. Patients taking estrogen-containing contraceptives should be asked to report any change in their bleeding patterns. Contraceptive efficacy can be decreased even in the absence of breakthrough bleeding.

(Newly added subsection)

7.5 Hydrochlorothiazide (HCTZ)

Topiramate Cmax and AUC increased when HCTZ was added to immediate-release topiramate. The clinical significance of this change is unknown. The addition of HCTZ to QUDEXY XR may require a decrease in the QUDEXY XR dose.

(Newly added subsection)

7.6 Pioglitazone

A decrease in the exposure of pioglitazone and its active metabolites were noted with the concurrent use of pioglitazone and immediate-release topiramate in a clinical trial. The clinical relevance of these observations is unknown; however, when QUDEXY XR is added to pioglitazone therapy or pioglitazone is added to QUDEXY XR therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state.

7.7 Lithium

(Additions and/or revisions are underlined)

An increase in systemic exposure of lithium following topiramate doses of up to 600 mg per /day can occur. Lithium levels should be monitored when co-administered with high-dose QUDEXY XR.

7.8 Amitriptyline

(Newly added subsection)

Some patients may experience a large increase in amitriptyline concentration in the presence of QUDEXY XR and any adjustments in amitriptyline dose should be made according to the patient’s clinical response and not on the basis of plasma levels.

8 Use in Specific Populations

8.1 Pregnancy

(Extensive changes, please refer to the label)

8.2 Lactation

(Additions and/or revisions are underlined)

Risk Summary

Topiramate is excreted in human milk [see Data]. The effects of topiramate on milk production are unknown. Diarrhea and somnolence have been reported in breastfed infants whose mothers receive topiramate treatment.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for QUDEXY XR and any potential adverse effects on the breastfed infant from QUDEXY XR or from the underlying maternal condition.

Data

Human Data

Limited data from 5 women with epilepsy treated with topiramate during lactation showed drug levels in milk similar to those in maternal plasma.

8.4 Pediatric Use

(Additions and/or revisions are underlined)

Adjunctive Treatment for Partial-Onset Epilepsy in Pediatric Patients 1 to 24 months

The following pediatric use information is based on studies conducted with immediate-release topiramate.

Safety and effectiveness in patients below the age of 2 years have not been established for the adjunctive therapy treatment of partial onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome. In a single randomized, double-blind, Mplacebo-controlled investigational trial, the efficacy, safety, and tolerability of immediate-release topiramate oral liquid and sprinkle formulations as an adjunct to concurrent antiepileptic drug therapy in pediatric patients 1 to 24 months of age with refractory partial-onset seizures were assessed …

In general, the adverse reaction profile for immediate-release topiramate in this population was similar to that of older pediatric patients, although results from the above controlled study, and an open-label, long-term extension study in these pediatric patients 1 to 24 months old suggested some adverse reactions/toxicities not previously observed in older pediatric patients and adults; i.e., growth/length retardation, certain clinical laboratory abnormalities, and other adverse reactions that occurred …

These very young pediatric patients appeared to experience an increased risk for infections (any topiramate dose 12%, placebo 0%) and of respiratory disorders (any topiramate dose 40%, placebo 16%). The following adverse reactions were observed in at least 3% of patients on immediate-release topiramate and were 3% to 7% more frequent than in patients on placebo: viral infection, bronchitis, pharyngitis, rhinitis, otitis media, upper respiratory infection, cough, and bronchospasm. A generally similar profile was observed in older pediatric patients.

In this open-label, uncontrolled study, the mortality was 37 deaths/1000 patient years. It is not possible to know whether this mortality rate is related to immediate-release topiramate treatment, because the background mortality rate for a similar, significantly refractory, young pediatric population (1-24 months) with partial epilepsy is not known.

Monotherapy Treatment in Partial-Onset Epilepsy in Patients <2 Years Old

Safety and effectiveness in patients below the age of 2 years have not been established for the monotherapy treatment of epilepsy.

Migraine Prophylaxis in Pediatric Patients 12 to 17 Years of Age

Safety and effectiveness of topiramate in the prophylaxis of migraine was studied in 5 double- blind, randomized, placebo-controlled, parallel-group trials in a total of 219 pediatric patients, at doses of 50 to 200 mg/day, or 2 to 3 mg/kg/day. These comprised a fixed dose study in 103 pediatric patients 12 to 17 years of age, a flexible dose (2 to 3 mg/kg/day), placebo-controlled study in 157 pediatric patients 6 to 16 years of age (including 67 pediatric patients 12 to 16 years of age), and a total of 49 pediatric patients 12 to 17 years of age in 3 studies of migraine prophylaxis primarily in adults. Open-label extension phases of 3 studies enabled evaluation of long-term safety for up to 6 months after the end of the double-blind phase.

Efficacy of topiramate for migraine prophylaxis in pediatric patients 12 to 17 years of age is demonstrated for a 100 mg daily dose in Study 3. Efficacy of topiramate (2 to 3 mg/kg/day) for migraine prophylaxis was not demonstrated in a placebo- controlled trial of 157 pediatric patients (6 to 16 years of age) that included treatment of 67 pediatric patients 12 to 16 years of age for 20 weeks.

In the pediatric trials (12 to 17 years of age) in which patients were randomized to placebo or a fixed daily dose of immediate-release topiramate, the most common adverse reactions with immediate-release topiramate that were seen at an incidence higher (greater than or equal to 5%) than in the placebo group were: paresthesia, upper respiratory tract infection, anorexia, and abdominal pain).

The most common cognitive adverse reaction in pooled double-blind studies in pediatric patients 12 to 17 years of age was difficulty with concentration/attention.

Markedly abnormally low serum bicarbonate values indicative of metabolic acidosis were reported in topiramate-treated pediatric migraine patients.

In topiramate-treated pediatric patients (12 to 17 years of age) compared to placebo-treated patients, abnormally increased results were more frequent for creatinine, BUN, uric acid, chloride, ammonia, total protein, and platelets. Abnormally decreased results were observed with topiramate vs placebo treatment for phosphorus and bicarbonate [see Warnings and Precautions].

Notable changes (increases and decreases) from baseline in systolic blood pressure, diastolic blood pressure, and pulse that were observed occurred more commonly in pediatric patients treated with topiramate compared to pediatric patients treated with placebo.

Migraine Prophylaxis in Pediatric Patients 6 to 11 Years of Age

Safety and effectiveness in pediatric patients below the age of 12 years have not been established for the prophylaxis treatment of migraine headache.

In a double-blind study in 90 pediatric patients 6 to 11 years of age (including 59 topiramate treated and 31 placebo patients), the adverse reaction profile was generally similar to that seen in pooled double-blind studies of pediatric patients 12 to 17 years of age. The most common adverse reactions that occurred in immediate-release topiramate-treated pediatric patients 6 to 11 years of age, and at least twice as frequently than placebo, were gastroenteritis (12% topiramate, 6% placebo), sinusitis (10% topiramate, 3% placebo), weight loss (8% topiramate, 3% placebo) and paresthesia (7% topiramate, 0% placebo). Difficulty with concentration/attention occurred in 3 topiramate-treated patients (5%) and 0 placebo-treated patients.

The risk for cognitive adverse reaction was greater in younger patients (6 to 11 years of age) than in older patients (12 to 17 years of age) …

8.6 Renal Impairment

(Additions and/or revisions are underlined)

The clearance of topiramate is reduced in patients with moderate (creatinine clearance 30 to 69 mL/min/1.73m2) and severe (creatinine clearance less than 30 mL/min/1.73m2) renal impairment. A dosage adjustment is recommended in patients with moderate or severe renal impairment.

8.7 Patients Undergoing Hemodialysis

(Additions and/or revisions are underlined)

Topiramate is cleared by hemodialysis at a rate that is 4 to 6 times greater than in a normal individual. A dosage adjustment may be required.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Extensive changes; please refer to label for complete information.

Other

Update reflects labeling change from February 2019.

03/29/2017 (SUPPL-3)

Approved Drug Label (PDF)

5 Warnings and Precautions

Additions and/or revisions underlined, unless otherwise noted:

5.4 Metabolic Acidosis

… may be additive to the bicarbonate lowering effects of topiramate.

Addition of the following:

Epilepsy

Pediatric Patients (under 2 years of age)

… 50% for 15 mg/kg/day, and 45% for 25 mg/kg/day. Addition of the following: The incidence of markedly abnormal changes (i.e., less than 17 mEq/L and greater than 5 mEq/L decrease from baseline of greater than or equal to 20 mEq/L) was 0% for placebo, 4% for 5 mg/kg/day, 5% for 15 mg/kg/day and 5% for 25 mg/kg/day.

Migraine

Additions and/or revisions underlined:

Adult Patients

The incidence of persistent decreases in serum bicarbonate in placebo-controlled trials in adults for the prophylaxis of migraine was 44% for 200 mg/day, 39% for 100 mg/day, 23% for 50 mg/day, and 7% for placebo. The incidence of markedly abnormally low serum bicarbonate (i.e., absolute value less than 17 mEq/L and greater than 5 mEq/L decrease from pretreatment) in these trials was 11% for 200 mg/day, 9% for 100 mg/day, 2% for 50 mg/day, and less than1% for placebo.

Adolescent Patients

In pooled, double-blind migraine prophylaxis studies in adolescent patients (12 to 17 years of age), the incidence of persistent decreases in serum bicarbonate was 77% for 200 mg/day, 27% for 100 mg/day, 30% for 50 mg/day, and 9% for placebo. The incidence of markedly low serum bicarbonate (i.e., absolute value less than17 mEq/L and greater then5 mEq/L decrease from pretreatment) was 6% for 100 mg/day, 2% for 50 mg/day, and 2% for placebo. This bicarbonate criterion was not met by any patients in the 200 mg/day group, which had a low number of subjects (n equals 13).

Measurement of Serum Bicarbonate in Epilepsy and Migraine Patients

5.5 Suicidal Behavior and Ideation

Table 4: Risk by Indication for Antiepileptic Drugs in the Pooled Analysis table number change

5.6 Cognitive/Neuropsychiatric Adverse Reactions

Adverse reactions most often associated with the use of topiramate, and therefore expected to be associated with the use of QUDEXY XR, were related to the central nervous system and were observed in both the epilepsy and migraine populations.

Addition of the following:

In the 6-month migraine prophylaxis controlled trials using a slower titration regimen (25 mg/day weekly increments), the proportion of patients who experienced one or more cognitive- related adverse reactions was 19% for topiramate 50 mg/day, 22% for 100 mg/day (the recommended dose), 28% for 200 mg/day, and 10% for placebo. These dose-related adverse reactions typically began in the titration phase and often persisted into the maintenance phase, but infrequently began in the maintenance phase. Some patients experienced a recurrence of one or more of these cognitive adverse reactions and this recurrence was typically in the titration phase. A relatively small proportion of topiramate-treated patients experienced more than one concurrent cognitive adverse reaction. The most common cognitive adverse reactions occurring together included difficulty with memory along with difficulty with concentration/attention, difficulty with memory along with language problems, and difficulty with concentration/attention along with language problems. Rarely, topiramate-treated patients experienced three concurrent cognitive reactions.

Psychiatric/Behavioral Disturbances

Additions and/or revisions underlined:

Psychiatric/behavioral disturbances (depression or mood) were dose-related for both the epilepsy and migraine populations treated with topiramate.

Somnolence/Fatigue

… and 15% for the 400 mg per day group) and the incidence of fatigue was comparable in both treatment groups (14% each). For the migraine population, somnolence and fatigue were dose-related and more common in the titration phase.

Pediatric Patients

Epilepsy

Reactions replaces events throughout the second paragraph of this subsection.

Addition of the following:

Migraine

The incidence of cognitive adverse reactions was increased in topiramate-treated patients (7%) versus placebo (4%) in pooled, double-blind placebo-controlled studies in which adolescent patients (12 to 17 years) were randomized to placebo or one of several fixed daily doses of topiramate (50 mg, 100 mg, 200 mg).

The incidence of cognitive adverse reactions was also increased in a placebo-controlled study of pediatric patients (6 to 16 years) treated with 2 to 3 mg/kg/day of topiramate (10%) versus placebo treatment (2%). QUDEXY XR is not approved for prophylaxis of migraine in pediatric patients under 12 years of age.

The risk for cognitive adverse reactions was dose-dependent, and was particularly evident at the 200 mg dose. This risk for cognitive adverse reactions was also greater in younger patients (6 to 11 years) than in older patients (12 to 17 years). The most common cognitive adverse reaction in these trials was difficulty with concentration/attention. Cognitive adverse reactions most commonly developed in the titration period and sometimes persisted into the maintenance period. These adverse reactions typically occurred in isolation as single type of cognitive adverse reaction. Cognitive adverse reactions that led to study discontinuation occurred in one patient (difficulty with concentration/attention and language problems). The Cambridge Neuropsychological Test Automated Battery (CANTAB) was administered to adolescents (12 to 17 years) to assess the effects of topiramate on cognitive function at baseline and at the end of the Study 3. Mean change from baseline in certain CANTAB tests suggests that topiramate treatment may result in psychomotor slowing and decreased verbal fluency.

5.7 Fetal Toxicity

Additions and/or revisions underlined:

Topiramate can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in utero have an increased risk for cleft lip and/or cleft palate (oral clefts) and for being small for gestational age. In multiple species, oral administration of topiramate to pregnant animals at clinically relevant doses resulted in structural malformations, including craniofacial defects, and reduced body weights in offspring.

5.9 Hyperammonemia and Encephalopathy

Hyperammonemia/Encephalopathy Without Concomitant Valproic Acid (VPA)

Topiramate treatment has produced hyperammonemia (in some instances dose-related) in a clinical investigational program in adolescent patients (12 to 17 years) who were treated with topiramate for migraine prophylaxis. The incidence of hyperammonia (above the upper limit of normal reference) at any time in the trial was 9% for placebo, 14% for 50 mg, and 26% for 100 mg topiramate daily. In some patients, hyperammonemia was observed at the end of the trial at the final visit. The incidence of markedly increased hyperammonemia (at least 50% or higher above upper limit of normal) at any time in the trial in adolescent patients was also increased at 100 mg/day (9%) compared to 50 mg topiramate (0%) or placebo (3%). During this trial, markedly increased ammonia levels returned to normal in all but one patient (in whom the ammonia level fell to high instead of markedly abnormal).

Topiramate treatment has produced hyperammonemia in a clinical investigational program in very young pediatric patients… with and without encephalopathy in placebo- controlled trials, and in an open-label, extension trial of infants with refractory epilepsy. Dose- related hyperammonemia was also observed …

5.10 Kidney Stones

Additions and/or revisions underlined:

A total of 32/2086 (1.5%) of adults exposed … Kidney stones have also been reported in pediatric patients taking topiramate for epilepsy or migraine ... pediatric patients less than 2 years old.

Kidney stones have also been reported in pediatric patients taking topiramate for migraine prophylaxis. For the double-blind migraine prophylaxis studies, one adverse event (renal calculus) occurred in a topiramate-treated subject in the age 12 to 17 years group. The overall experience with open-label, long-term, topiramate treatment for migraine prophylaxis is limited in pediatric patients.

QUDEXY XR would be expected to have the same effect …

5.12 Paresthesia

Additions and/or revisions underlined:

… Paresthesia was more frequently reported in the monotherapy epilepsy trials and migraine prophylaxis trials conducted with immediate-release topiramate than …

6 Adverse Reactions

Additions and/or revisions underlined:

The following serious adverse reactions are discussed in more detail …

Adverse Reactions Observed in Monotherapy Epilepsy Trial

Adult Patients 16 Years of Age and Older

The adverse reactions in the monotherapy controlled trial (Study 1) …

Table number changes below; refer to label for superscript details:

Table 5: Adverse Reactions in the Immediate-Release Topiramate Monotherapy Trial with Incidence greater than or equal to 2% in Any Topiramate Group and Incidence in the 400 mg per Day Group Greater Than in the 50 mg per Day Group

Table 6: Incidence of Adverse Reactions in Placebo-Controlled, Adjunctive Epilepsy

Table 7: Incidence of Adverse Reactions in Study 7 a,b,c

Table 8: Incidence (%) of Dose-Related Adverse Reactions From Placebo-Controlled, Adjunctive

Trials in Adults With Partial Onset Seizures (Studies 2 through 7)a

Table 9: Incidence (%) of Adverse Reaction in Placebo-Controlled, Adjunctive Epilepsy

Trial in Pediatric Patients (Ages 2 Years to 16 Years) a,b,c (Study 8)

Addition of the following:

Migraine

Adults

In the four multicenter, randomized, double-blind, placebo-controlled, parallel group migraine prophylaxis clinical trials (which included 35 adolescent patients age 12 to 15 years), most of the adverse reactions with topiramate were mild or moderate in severity. Most adverse reactions occurred more frequently during the titration period than during the maintenance period.

The most common (greater than or equal to 5% more frequent than placebo) adverse reactions associated with the use of the 100 mg topiramate dose in controlled, migraine clinical trials of predominantly adults were paresthesia, anorexia, weight decrease, taste perversion, diarrhea, difficulty with memory, hypoesthesia, and nausea. Table 10 includes those adverse reactions reported for patients in the placebo-controlled trials where the incidence in any topiramate treatment group was at least 2% and was greater than that for placebo patients.

Table 10: Incidence (%) of Adverse Reactions in Placebo-Controlled, Migraine Trials Where Incidence Was greater than 2% in Any Topiramate Group and Greater Than the Rate in Placebo-Treated Patients a,b Newly added table to this section; please refer to label.

Of the 1135 patients exposed to topiramate in the adult placebo-controlled studies, 25% discontinued due to adverse reactions, compared to 10% of the 445 placebo patients. The adverse reactions associated with discontinuing therapy in the topiramate-treated patients included paresthesia (7%), fatigue (4%), nausea (4%), difficulty with concentration/attention (3%), insomnia (3%), anorexia (2%), and dizziness (2%).

Patients treated with topiramate experienced mean percent reductions in body weight that were dose-dependent. This change was not seen in the placebo group. Mean changes of 0%, -2%, -3%, and -4% were seen for the placebo group, topiramate 50 mg, 100 mg, and 200 mg groups, respectively.

Table 11 shows adverse reactions that were dose-dependent. Several central nervous system adverse reactions, including some that represented cognitive dysfunction, were dose-related. The most common dose-related adverse reactions (treatment differencegreater than or equal to 5% for the 100 mg dose) were paresthesia, nausea, anorexia, difficulty with memory, diarrhea, weight decrease, and hypoesthesia.

Table 11: Incidence (%) of Dose-Related Adverse Reactions From Placebo-Controlled, Migraine Trials a,b

Newly added table to this section; please refer to label.

Addition of the following:

Adolescents 12 to 17 Years of Age

In five, randomized, double-blind, placebo-controlled, parallel group migraine prophylaxis clinical trials, most of the adverse reactions with topiramate were mild or moderate in severity. Most adverse reactions occurred more frequently during the titration period than during the maintenance period. Among adverse reactions with onset during titration, approximately half persisted into the maintenance period.

In four, fixed-dose, double-blind migraine prophylaxis clinical trials in topiramate-treated adolescent patients, the most commonly observed adverse reactions associated with the use of 100 mg of topiramate that were seen at an incidence higher (? 5%) than in the placebo group were: paresthesia, upper respiratory tract infection, anorexia, and abdominal pain (see Table 12). Table 12 shows adverse reactions from the adolescent pivotal trial (Study 3 demonstrating the efficacy of topiramate) in which there were 103 adolescent patients who were treated with placebo or 50 mg or 100 mg of topiramate and three predominantly adult trials in which there were 49 adolescent patients (12 to 17 years) who were treated with placebo or 50 mg, 100 mg or 200 mg of topiramate [see Clinical Studies (14.7)]). Table 12 also shows adverse reactions in adolescents in the controlled migraine trials when the incidence in a topiramate dose group was at least 5% or higher than the incidence of placebo. Many adverse reactions shown in Table 12 indicated a dose-dependent relationship.

Table 12: Incidence (%) of Adverse Reactions in Pooled Placebo-Controlled, Migraine Trials in Adolescent Patients (12 to 17 Years of Age) Where Incidence Was greater than or equal to 5% or Greater Than the Placebo Incidence in Any Topiramate Group a,b Newly added table to this section; please refer to label..

In the double-blind placebo-controlled studies, adverse reactions led to discontinuation of treatment in 8% of placebo patients compared with 6% of topiramate-treated patients. Adverse reactions associated with discontinuing therapy that occurred in more than one topiramate- treated patient were fatigue (1%), headache (1%), and somnolence (1%) …

Epilepsy

Controlled trials of adjunctive topiramate …

Addition of the following:

Migraine

In pooled double-blind studies in pediatric patients (6 to 17 years), an increased risk for certain abnormalities (value outside normal reference range) in selected clinical laboratory analytes measured in blood has been observed during topiramate treatment of pediatric patients compared to placebo-treated patients. In some instances, abnormalities were also observed at the end of the trial at the final visit and the changes were considered markedly abnormal.

For patients 12 to 17 years, the following were noted to be abnormally increased more frequently with topiramate than with placebo: BUN, creatinine, uric acid, chloride, ammonia, total protein, and platelets . The following were abnormally decreased in some subjects: phosphorus and bicarbonate.

For patients 6 to 11 years, the following were noted to be abnormally increased more frequently with topiramate than with placebo: alkaline phosphatase, creatinine and eosinophils. Analytes abnormally decreased were: total white count and neutrophils. There was no testing for serum bicarbonate, chloride, ammonia, or phosphorus in these younger patients.

6.2 Clinical Trials Experience with QUDEXY XR

Table 13: Incidence (greater than or equal to 2%) of Adverse Reactions in Placebo-Controlled Adjunctive Therapy Clinical Trial in Patients With Partial Onset Seizures Newly added table to this section; please refer to label.

8 Use in Specific Populations

8.1 Pregnancy

PLLR conversion, as below:

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to topiramate during pregnancy. Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll-free number 1-888-233-2334. Information about the North American Drug Pregnancy Registry can be found at http://www.aedpregnancyregistry.org/.

Risk Summary

Topiramate can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in utero have increased risk for cleft lip and/or cleft palate (oral clefts) and for being small for gestational age.

In multiple animal species, topiramate demonstrated developmental toxicity, including teratogenicity, in the absence of maternal toxicity at clinically relevant doses.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse reactions

Consider the benefits and risks of topiramate when prescribing this drug to women of childbearing potential, particularly when topiramate is considered for a condition not usually associated with permanent injury or death. Because of the risk of oral clefts to the fetus, which occur in the first trimester of pregnancy before many women know they are pregnant, all women of childbearing potential should be informed of the potential risk to the fetus from exposure to topiramate. Women who are planning a pregnancy should be counseled regarding the relative risks and benefits of topiramate use during pregnancy, and alternative therapeutic options should be considered for these patients.

Labor or Delivery

Although the effect of topiramate on labor and delivery in humans has not been established, the development of topiramate-induced metabolic acidosis in the mother and/or in the fetus might affect the fetus’ ability to tolerate labor.

Topiramate treatment can cause metabolic acidosis. The effect of topiramate-induced metabolic acidosis has not been studied in pregnancy; however, metabolic acidosis in pregnancy (due to other causes) can cause decreased fetal growth, decreased fetal oxygenation, and fetal death, and may affect the fetus’ ability to tolerate labor. Pregnant patients should be monitored for metabolic acidosis and treated as in the nonpregnant state.. Newborns of mothers treated with topiramate should be monitored for metabolic acidosis because of transfer of topiramate to the fetus and possible occurrence of transient metabolic acidosis following birth.

Data

Human Data

Data from the NAAED Pregnancy Registry indicate an increased risk of oral clefts in infants exposed to topiramate monotherapy during the first trimester of pregnancy. The prevalence of oral clefts was 1.2% compared to a prevalence of 0.39% to 0.46% in infants exposed to other AEDs, and a prevalence of 0.12% in infants of mothers without epilepsy or treatment with other AEDs. For comparison, the Centers for Disease Control and Prevention (CDC) reviewed available data on oral clefts in the United States and found a similar background rate of 0.17%. The relative risk of oral clefts in topiramate-exposed pregnancies in the NAAED Pregnancy Registry was 9.6 (95% Confidence Interval equals [CI] 4.0 to 23.0) as compared to the risk in a background population of untreated women. The UK Epilepsy and Pregnancy Register reported a similarly increased prevalence of oral clefts of 3.2% among infants exposed to topiramate monotherapy. The observed rate of oral clefts was 16 times higher than the background rate in the UK, which is approximately 0.2%.

Data from the NAAED pregnancy registry and a population-based birth registry cohort indicate that exposure to topiramate in utero is associated with an increased risk of small for gestational age (SGA) newborns (birth weight <10th percentile). In the NAAED pregnancy registry, 18% of topiramate-exposed newborns were SGA compared to 7% of newborns exposed to a reference AED, and 5% of newborns of mothers without epilepsy and without AED exposure. In the Medical Birth Registry of Norway (MBRN), a population-based pregnancy registry, 25% of newborns in the topiramate monotherapy exposure group were SGA compared to 9% in the comparison group who were unexposed to AEDs. The long-term consequences of the SGA findings are not known.

Animal Data

When topiramate (20, 100, and 500 mg/kg/day) was administered orally to pregnant mice during the period of organogenesis, the incidence of fetal malformations (primarily craniofacial defects) was increased at all doses. Fetal body weights and skeletal ossification were reduced at the highest dose tested in conjunction with decreased maternal body weight gain. A no-effect dose for embryofetal developmental toxicity in mice was not identified. The lowest dose tested, which was associated with teratogenic effects, is less than the maximum recommended human dose I(MRHD) of 400 mg/day on a body surface area (mg/m2) basis.

In pregnant rats administered topiramate (20, 100, and 500 mg/kg/day or 0.2, 2.5, 30, and 400 mg/kg/day) orally during the period of organogenesis, the frequency of limb malformations (ectrodactyly, micromelia, and amelia) was increased in fetuses at 400 or 500 mg/kg/day. Embryotoxicity (reduced fetal body weights, increased incidences of structural variations) was observed at doses as low as 20 mg/kg/day. Clinical signs of maternal toxicity were seen at 400 mg/kg/day and above, and maternal body weight gain was reduced at doses of 100 mg/kg/day or greater. The no-effect dose for embryofetal developmental toxicity in rats is less than the MRHD on a mg/m2 basis.

In pregnant rabbits administered topiramate (20, 60, and 180 mg/kg/day or 10, 35, and 120 mg/kg/day) orally during organogenesis, embryofetal mortality was increased at 35 mg/kg/day and teratogenic effects (primarily rib and vertebral malformations) were observed at 120 mg/kg/day. Evidence of maternal toxicity (decreased body weight gain, clinical signs, and/or mortality) was seen at 35 mg/kg/day and above. The no-effect dose (20 mg/kg/day) for embryofetal developmental toxicity in rabbits is equivalent to the MRHD on a mg/m2 basis.

When topiramate (0.2, 4, 20, and 100 mg/kg/day or 2, 20, and 200 mg/kg/day) was administered orally to female rats during the latter part of gestation and throughout lactation, offspring exhibited decreased viability and delayed physical development at 200 mg/kg/day and reductions in pre- and/or postweaning body weight gain at 2 mg/kg/day and above. Maternal toxicity (decreased body weight gain, clinical signs) was evident at 100 mg/kg or greater. In a rat embryofetal development study which included postnatal assessment of offspring, oral administration of topiramate (0.2, 2.5, 30, and 400 mg/kg/day) to pregnant animals during the period of organogenesis resulted in delayed physical development at 400 mg/kg/day and persistent reductions in body weight gain at 30 mg/kg/day and higher in the offspring. The no- effect dose (0.2 mg/kg/day) for pre- and postnatal developmental toxicity is less than the MRHD on a mg/m2 basis.

8.2 Lactation

PLLR conversion, as below:

Risk Summary

Topiramate is excreted in human milk. The effects of topiramate exposure in breastfed infants are unknown.

Data

Limited data from 5 women with epilepsy treated with topiramate during lactation showed drug levels in milk similar to those in maternal plasma.

8.3 Females and Males of Reproductive Potential

PLLR conversion, as below:

Contraception

Women of childbearing potential who are not planning a pregnancy should use effective contraception because of the risks to the fetus of oral clefts and of being small for gestational age.

8.4 Pediatric Use

Additions and/or revisions underlined:

Seizures in Pediatric Patients 2 Years of Age and Older

… The significance of these findings is uncertain.

Topiramate produced a dose-related increased incidence of hyperammonemia …

Treatment with immediate-release topiramate … young pediatric population (1 month to 24 months) with partial epilepsy is not known.

Monotherapy Treatment in Partial Onset Epilepsy in Patients less than 2 Years Old

Safety and effectiveness in patients below the age of 2 years have not been established for the monotherapy treatment of epilepsy.

Migraine Prophylaxis in Adolescents 12 to 17 Years

Safety and effectiveness of topiramate in the prophylaxis of migraine was studied in 5 double- blind, randomized, placebo-controlled, parallel-group trials in a total of 219 pediatric patients, at doses of 50 to 200 mg/day, or 2 to 3 mg/kg/day. These comprised a fixed dose study in 103 adolescents age 12 to 17 years, a flexible dose (2 to 3 mg/kg/day), placebo-controlled study in 157 pediatric patients age 6 to 16 years (including 67 adolescent patients age 12 to 16 years), and a total of 49 adolescents age 12 to 17 years in 3 studies of migraine prophylaxis primarily in adults. Open-label extension phases of 3 studies enabled evaluation of long-term safety for up to 6 months after the end of the double-blind phase.

Efficacy of topiramate for migraine prophylaxis in adolescents is demonstrated for a 100 mg daily dose in Study 3. Efficacy of topiramate (2 to 3 mg/kg/day) for migraine prophylaxis was not demonstrated in a placebo-controlled trial of 157 pediatric patients (6 to 16 years) that included treatment of 67 adolescents (12 to 16 years) for 20 weeks.

In the adolescent trials (12 to 17 years) in which patients were randomized to placebo or a fixed daily dose of topiramate, the most commonly observed adverse reactions associated with the use of topiramate that were seen at an incidence higher (greater than or equal to 5%) than in the placebo group were: paresthesia, upper respiratory tract infection, anorexia, and abdominal pain.

The most common cognitive adverse reaction in pooled double-blind studies in adolescent patients age 12 to 17 years was difficulty with concentration/attention.

Markedly abnormally low serum bicarbonate values indicative of metabolic acidosis were reported in topiramate-treated adolescent migraine patients.

In topiramate-treated adolescent patients (12 to 17 years) compared to placebo-treated patients, abnormally increased results were more frequent for creatinine, BUN, uric acid, chloride, ammonia, total protein, and platelets. Abnormally decreased results were observed with topiramate vs placebo treatment for phosphorus and bicarbonate.

Notable changes (increases and decreases) from baseline in systolic blood pressure, diastolic blood pressure, and pulse were observed occurred more commonly in adolescents treated with topiramate compared to adolescents treated with placebo.

Migraine Prophylaxis in Children 6 to 11 Years Old

Safety and effectiveness in pediatric patients below the age of 12 years have not been established for the prophylaxis treatment of migraine headache.

In a double-blind study in 90 children age 6 to 11 years (including 59 topiramate-treated and 31 placebo patients), the adverse reaction profile was generally similar to that in pooled double- blind studies of adolescents age 12 to 17 years. The adverse reactions that occurred most commonly in topiramate-treated children age 6 to 11 years, and at least twice as frequently than placebo, were gastroenteritis (12% topiramate, 6% placebo), sinusitis (10% topiramate, 3% placebo), weight decrease (8% topiramate, 3% placebo) and paresthesia (7% topiramate, 0% placebo). Difficulty with concentration/attention occurred in 3 topiramate-treated patients (5%) and 0 placebo patients.

The risk for cognitive adverse reaction was greater in younger patients (6 to 11 years) than in older patients (12 to 17 years).

For patients 6 to 11 years, the following were noted to be abnormally increased more frequently with topiramate than with placebo: alkaline phosphatase, creatinine, and eosinophils. Analytes abnormally decreased were: total white count and neutrophils.

Serum bicarbonate, chloride, phosphorus, and ammonia data were not collected for pediatric patients 6 to 11 years of age ….

Juvenile Animal Studies

When topiramate (30 mg/kg/day, 90 mg/kg/day or 300 mg/kg/day) …

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

How can I watch for early symptoms of suicidal thoughts and actions?

Cleft lip and cleft palate may happen …
Also, if you take QUDEXY XR during pregnancy, your baby may be smaller than expected at birth. The long- term effects of this are not known …
Tell your healthcare provider right away if you become pregnant …
If you take QUDEXY XR during pregnancy, your baby may be smaller than expected a birth. Talk to your healthcare provider if you have any questions about this risk during pregnancy ...

What is QUDEXY XR?

QUDEXY XR is a prescription medicine used:

to prevent migraine headaches in adults and adolescents 12 years of age and older.

The most common side effects of QUDEXY XR include: addition of the following:

Nausea
A change in the way foods taste
Upper respiratory tract infection
Diarrhea
Pain in the abdomen

PATIENT COUNSELING INFORMATION

Fetal Toxicity

Counsel pregnant women and women of childbearing potential … before many women know they are pregnant. Also inform patients that infants exposed to topiramate monotherapy in utero may be small for their gestational age. There may also be risks to the fetus …

Information about the North American Drug Pregnancy Registry can be found at http://www.aedpregnancyregistry.org/.

03/29/2017 (SUPPL-5)