Drug Safety-related Labeling Changes (SrLC)

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TOPAMAX (NDA-020505)

(TOPIRAMATE)

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

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05/03/2023 (SUPPL-65)

Approved Drug Label (PDF)

7 Drug Interactions

7.4 Contraceptives

Subsection title revised
Additions and/or revisions underlined:

The possibility of decreased contraceptive efficacy and increased breakthrough bleeding may occur in patients taking contraceptive products with TOPAMAX®. 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)].

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

MEDICATION GUIDE

Additions and/or revisions underlined:

…

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

…

Tell your healthcare provider about all the medicines you take, including prescription and over-the- counter medicines, vitamins, and herbal supplements. TOPAMAX 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 that contains hormones (such as pills, implants, patches or injections). TOPAMAX may make your birth control less effective. Tell your healthcare provider if your menstrual bleeding changes while you are using birth control and TOPAMAX.

…

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:
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Fetal Toxicity

Inform pregnant women and women of childbearing potential that use of TOPAMAX during pregnancy can cause fetal harm. TOPAMAX® increases 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. 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 TOPAMAX 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 TOPAMAX, 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)].

10/20/2022 (SUPPL-64)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.7 Fetal Toxicity

Additions and/or revisions underlined:

TOPAMAX 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 malformations, 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 received topiramate at clinically relevant doses, structural malformations, including craniofacial defects, and reduced fetal weights occurred in offspring [see Use in Specific Populations (8.1)].

…

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

…

TOPAMAX 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 malformations, including but not limited to cleft lip and/or cleft palate (oral clefts), and of being small for gestational age (SGA) [see Human Data]. SGA has been observed at all doses and appears to be dose-dependent. The prevalence of SGA is greater in infants of women who received higher doses of topiramate during pregnancy. In addition, the prevalence of SGA in infants of women who continued topiramate use until later in pregnancy is higher compared to the prevalence in infants of women who stopped topiramate use before the third trimester.

In multiple animal species, topiramate produced developmental toxicity, including increased incidences of fetal malformations, in the absence of maternal toxicity at clinically relevant doses [see Animal Data].

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 2-4% and 15-20%, respectively.

…

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 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]5.9–26.37) 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

Additions and/or revisions underlined:

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 Topamax 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 [see Adverse Reactions (6.1) and Clinical Studies (14.2)].

Pediatric Patients Below the Age of 2 Years

…

Monotherapy Treatment for Epilepsy

Pediatric Patients 2 Years of Age and Older

The safety and effectiveness of TOPAMAX 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)].

…

Pediatric Patients Below the Age of 2 Years

…

In the pediatric trials (12 to 17 years of age) in which patients were randomized to placebo or a fixed daily dose of TOPAMAX®, the most common adverse reactions with TOPAMAX® 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 [see Adverse Reactions (6)].

…

Pediatric Patients Below the Age of 12 Years

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MEDICATION GUIDE

Additions and/or revisions underlined:

…

TOPAMAX can harm your unborn baby.

• If you take TOPAMAX during pregnancy, your baby has a higher risk for birth defects including cleft lip and cleft palate. These defects can begin early in pregnancy, even before you know you are pregnant.

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

…

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

Inform pregnant women and women of childbearing potential that use of TOPAMAX? during pregnancy can cause fetal harm. Topamax increases 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. 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 TOPAMAX 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.

01/13/2022 (SUPPL-62)

Approved Drug Label (PDF)

5 Warnings and Precautions

Additions and/or revisions underlined:

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 TOPAMAX® demonstrated that TOPAMAX® 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 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 pediatrics.

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 TOPAMAX® 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 TOPAMAX®-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 9 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 TOPAMAX 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 TOPAMAX®-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 TOPAMAX® 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 TOPAMAX® 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 TOPAMAX® group compared to the control group. Negative effects on weight and height were seen across all TOPAMAX® age subgroups. Growth (height and weight) of children receiving prolonged TOPAMAX® 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 TOPAMAX-treated pediatric patients in a 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 the bulleted line listing:

• Decrease of 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

8.4 Pediatric Use

Newly added information:

Monotherapy Treatment in Patients 2 Years of Age and Older

The safety and effectiveness for partial-onset 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 TOPAMAX® (N=28, 6-15 years of age) versus levetiracetam (N=35, 4-15 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 10 summarizes effects of TOPAMAX® at 12 months for key safety outcomes including BMD, height, height velocity, and weight. All Least Square Mean values for TOPAMAX® and the comparator were positive. Therefore, the Least Square Mean treatment differences shown reflect a TOPAMAX®-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 10 Summary of TOPAMAX® 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 TOPAMAX®-treated patients at some time in the study [see Warnings and Precautions (5.4)]. Over the whole study, 76% more TOPAMAX®-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 TOPAMAX®-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.

TOPAMAX®-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.

Additions and/or revisions underlined:

… 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 Adverse Reactions (6.1)] …

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

MEDICATION GUIDE

TOPAMAX can harm your unborn baby.

Additions and/or revisions underlined:

• Pregnancy Registry: If you become pregnant while taking TOPAMAX, 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 TOPAMAX and other antiepileptic drugs during pregnancy.

• TOPAMAX may decrease the density of bones when used over a long period.

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

PATIENT COUNSELING INFORMATION

Newly added information:

Decrease in Bone Mineral Density

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

06/30/2021 (SUPPL-63)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Acute Myopia and Secondary Angle Closure Glaucoma Syndrome

(Additions and/or revisions are underlined)

A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients receiving TOPAMAXÒ. 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. Symptoms typically occur within 1 month of initiating TOPAMAXÒ therapy. In contrast to primary narrow angle glaucoma, which is rare under 40 years of age, secondary angle closure glaucoma associated with topiramate has been reported in pediatric patients as well as adults. The primary treatment to reverse symptoms is discontinuation of TOPAMAX® as rapidly as possible, according to the judgment of the treating physician. Other measures, in conjunction with discontinuation of TOPAMAXÒ, may be helpful.

06/08/2020 (SUPPL-61)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.9 Serious Skin Reactions

(Newly added subsection)

Serious skin reactions (Stevens-Johnson Syndrome [SJS] and Toxic Epidermal Necrolysis [TEN]) have been reported in patients receiving topiramate. TOPAMAX 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

(Additions and/or revisions underlined)

The following serious adverse reactions are discussed in more detail in other sections of the labeling:

 

Acute Myopia and Secondary Angle Closure Glaucoma

Visual Field Defects

Oligohidrosis and Hyperthermia

Metabolic Acidosis

Suicidal Behavior and Ideation

Cognitive/Neuropsychiatric Adverse Reactions

Serious Skin Reactions

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions 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.

05/02/2019 (SUPPL-60)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

(addition underlined)

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Urinary System Disorders: kidney stones, nephrocalcinosis

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12/27/2018 (SUPPL-59)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; additions and/or revisions are underlined)

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to TOPAMAXÒ 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

TOPAMAXÒ 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 SGA. SGA has been observed at all doses and appears to be dose-dependent. The prevalence of SGA is greater in infants of women who received higher doses of topiramate during pregnancy. In addition, the prevalence of SGA in infants of women who continued topiramate use until later in pregnancy is higher compared to the prevalence in infants of women who stopped topiramate use before the third trimester.

In multiple animal species, topiramate produced developmental toxicity, including increased incidences of fetal malformations, in the absence of maternal toxicity at clinically relevant doses.

In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, 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, 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 TOPAMAXÒ 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.

TOPAMAX® 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 TOPAMAX® should be monitored for metabolic acidosis because of transfer of topiramate to the fetus and possible occurrence of transient metabolic acidosis following birth.

 

Based on limited information, topiramate has also been associated with pre-term labor and premature delivery.

Data

Human Data

Data from pregnancy registries indicate an increased risk of oral clefts in infants exposed to topiramate during the first trimester of pregnancy. In the NAAED pregnancy registry, the prevalence of oral clefts among topiramate-exposed infants (1.1%) was higher than the prevalence of infants exposed to a reference AED (0.36%) or the prevalence of infants in mothers without epilepsy and without exposure to AEDs (0.12%). It was also higher than the background prevalence in 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 9.6 (95% Confidence Interval [CI] 4.0 – 23.0) 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%).

 

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 SGA newborns (birth weight <10th percentile). In the NAAED pregnancy registry, 19.7% of topiramate-exposed newborns were SGA compared to 7.9% of newborns exposed to a reference AED and 5.4% 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 unexposed to AEDs. The long-term consequences of the SGA findings are not known.

 

Animal Data

When topiramate (0, 20, 100, or 500 mg/kg/day) was administered to pregnant mice during the period of organogenesis, incidences of fetal malformations (primarily craniofacial defects) were 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 increased malformations, is less than the maximum recommended human dose (MRHD) for epilepsy (400 mg/day) or migraine (100 mg/day) on a body surface area (mg/m2) basis.

 

In pregnant rats administered topiramate (0, 20, 100, and 500 mg/kg/day or 0, 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 and 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 (2.5 mg/kg/day) for embryofetal developmental toxicity in rats is less than the MRHD for epilepsy or migraine on a mg/m2 basis.

In pregnant rabbits administered topiramate (0, 20, 60, and 180 mg/kg/day or 0, 10, 35, and 120 mg/kg/day)  orally  during   organogenesis,   embryofetal   mortality   was   increased  at 35 mg/kg/day, and increased incidences of fetal malformations (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 for epilepsy and approximately 4 times the MRHD for migraine on a mg/m2 basis.

When topiramate (0, 0.2, 4, 20, and 100 mg/kg/day or 0, 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/day or greater.

 

In a rat embryofetal development study which included postnatal assessment of offspring, oral administration of topiramate (0, 0.2, 2.5, 30, and 400 mg/kg) to pregnant animals during the period of organogenesis resulted in delayed physical development in offspring at 400 mg/kg/day and persistent reductions in body weight gain in offspring at 30 mg/kg/day and higher. The no-effect dose (0.2 mg/kg/day) for pre- and postnatal developmental toxicity in rats is less than the MRHD for epilepsy or migraine on a mg/m2 basis.

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; additions and/or revisions are underlined)

Risk Summary

Topiramate is excreted in human milk. 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 TOPAMAXÒ and any potential adverse effects on the breastfed infant from TOPAMAXÒ 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.

 

8.3 Females and Males of Reproductive Potential

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; additions and/or revisions are underlined)

 

Contraception

Women of childbearing potential who are not planning a pregnancy should use effective contraception because of the risks of oral clefts and SGA.

8.4 Pediatric Use

(Additions and/or revisions are underlined)

 

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Juvenile Animal Studies

When topiramate (0, 30, 90, and 300 mg/kg/day) was administered orally to rats during the juvenile period of development (postnatal days 12 to 50), bone growth plate thickness was reduced in males at the highest dose. The no-effect dose (90 mg/kg/day) for adverse developmental effects is approximately 2 times the maximum recommended pediatric dose (9 mg/kg/day) on a body surface area (mg/m2) basis.

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

Medication Guide

(Additions and/or revisions are underlined)

  

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

…

• are breastfeeding or plan to breastfeed. TOPAMAX passes into breast milk. Breastfed babies may be sleepy or have diarrhea. It is not known if the TOPAMAX 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 TOPAMAX.Tell your healthcare provider about all the medicines you take, including prescription and over-the- counter medicines, vitamins, and herbal supplements. …

 

06/19/2018 (SUPPL-58)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Addition of the following:

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

05/12/2017 (SUPPL-57)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.10 Kidney Stones

(Additions and/or revisions are underlined)

TOPAMAX increases the risk of kidney stones. During adjunctive epilepsy trials, the risk for kidney stones in TOPAMAX-treated adults was 1.5%, an incidence about 2 to 4 times greater than expected in a similar, untreated population.

5.4 Metabolic Acidosis

(Additions and/or revisions are underlined)

TOPAMAX   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).

Metabolic acidosis was commonly observed in adult and pediatric patients treated with TOPAMAX 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 TOPAMAX (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 < 2% for placebo.

…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 pediatrics…

5.6 Cognitive/Neuropsychiatric Adverse Reactions

(Additions and/or revisions are underlined)

TOPAMAX can cause cognitive/neuropsychiatric adverse reactions…

 

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 (100-200 mg/day weekly increments), and target TOPAMAX doses of 200 mg – 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 200-400 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.

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

 

Psychiatric/Behavioral Disturbances

Psychiatric/behavioral disturbances (e.g., depression, mood) were dose-related for both the adjunctive epilepsy and migraine populations

 

Somnolence/Fatigue

For the adjunctive epilepsy population, the incidence of fatigue, appeared dose related… For the migraine population, the incidences of both fatigue and somnolence were dose-related and more common in the titration phase.

 

Pediatric Patients

…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 TOPAMAX-treated patients compared to placebo.

The risk for cognitive/neuropsychiatric adverse reactions was dose-dependent, and was greatest at the200 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 titration and sometimes persisted for various durations after completion of titration.

5.7 Fetal Toxicity

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…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…

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

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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 TOPAMAX monotherapy at 100 mg/day, and14% in patients taking TOPAMAX 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 TOPAMAX and concomitant valproic acid for partial onset epilepsy and this was not due to a pharmacokinetic interaction.

In some patients, hyperammonemia can be  asymptomatic.

6 Adverse Reactions

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The following serious adverse reactions are discussed in more detail in other sections of the labeling:

• Acute Myopia and Secondary Angle Closure Glaucoma

6.1 Clinical Trials Experience

(Extensive revisions, please refer to label)

6.2 Postmarketing Experience

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The following adverse reactions have been identified during post approval use of TOPAMAX®. 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.

Body as a Whole-General Disorders: oligohydrosis and hyperthermia, hyperammonemia, hyperammonemic encephalopathy, hypothermia with concomitant valproic acid

Gastrointestinal System Disorders: hepatic failure (including fatalities), hepatitis, pancreatitis

Urinary System Disorders: kidney stones

Vision Disorders:  acute myopia, secondary angle closure glaucoma, maculopathy

7 Drug Interactions

7.1 Antiepileptic Drugs

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

7.3 Oral Contraceptives

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The possibility of decreased contraceptive efficacy and increased breakthrough bleeding may occur in patients taking combination oral contraceptive products with TOPAMAX.

7.4 Lithium

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An increase in systemic exposure of lithium following TOPAMAX doses of up to 600 mg/day can occur.

7.5 Other Carbonic Anhydrase Inhibitors

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…Therefore, patients given TOPAMAX concomitantly with another carbonic anhydrase inhibitor should be monitored particularly closely for the appearance or worsening of metabolic acidosis.

7.6 Hydrochlorothiazide (HCTZ)

(Newly added subsection)

Topiramate Cmax and AUC increased when HCTZ was added to TOPAMAX. The clinical significance of this change is unknown. The addition of HCTZ to TOPAMAX may require a decrease in the TOPAMAX dose.

7.7 Pioglitazone

(Newly added subsection)

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

7.8 Amitriptyline

(Newly added subsection)

Some patients may experience a large increase in amitriptyline concentration in the presence of TOPAMAX   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

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…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…

 

Pregnancy Registry

…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/.

 

Human Data

Data from pregnancy registries indicate an increased risk of oral clefts in infants exposed to topiramate during the first trimester of pregnancy. In the NAAED pregnancy registry, the prevalence of oral clefts among topiramate-exposed infants (1.1%) was higher than the prevalence of infants exposed to a reference AED (0.36%) or the prevalence of infants in mothers without epilepsy and without exposure to AEDs (0.12%). It was also higher than the background prevalence in United States (0.17%) as estimated by the Centers for Disease Control and Prevention (CDC)…

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, 19.7% of topiramate-exposed newborns were SGA compared to 7.9% of newborns exposed to a reference AED and 5.4% 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 unexposed to AEDs. The long term consequences of the SGA findings are not known.

8.4 Pediatric Use

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Migraine Prophylaxis in Pediatric Patients 12 to 17 Years of Age

…

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 12.

8.5 Geriatric Use

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…Dosage adjustment may be necessary for elderly with age-related renal impairment (creatinine clearance rate <70 mL/min/1.73 m2) resulting in reduced clearance.

8.6 Renal Impairment

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… A dosage adjustment is recommended in patients with moderate or severe renal impairment.

8.7 Patients Undergoing Hemodialysis

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… A dosage adjustment may be required.

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

17 PATIENT COUNSELING INFORMATION

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Fetal Toxicity

… Also inform patients that infants exposed to topiramate monotherapy in utero may be small for their gestational age…

MEDICATION GUIDE

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TOPAMAX can harm your unborn baby.

• If you take TOPAMAX during pregnancy, your baby may be smaller than expected at birth. Talk to your healthcare provider if you have questions about this risk during pregnancy.

What are the possible side effects of TOPAMAX?

The most common side effects of TOPAMAX include:

• infection
• decreased feeling or sensitivity, especially in the skin