Drug Safety-related Labeling Changes (SrLC)

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EPRONTIA (NDA-214679)

(TOPIRAMATE)

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

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03/06/2026 (SUPPL-12)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined:

EPRONTIA is contraindicated in patients with a history of hypersensitivity reaction to topiramate, EPRONTIA, or any of the inactive ingredients of EPRONTIA. Anaphylaxis and angioedema have occurred with topiramate [see Warnings and Precautions (5.13)].

5 Warnings and Precautions

5.11 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Reactions

Newly added subsection

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multiorgan hypersensitivity, has been reported in patients taking topiramate. DRESS may be fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. EPRONTIA should be discontinued if an alternative etiology for the signs or symptoms cannot be established.

5.13 Anaphylaxis and Angioedema

Newly added subsection

Hypersensitivity reactions, including anaphylaxis and angioedema, have occurred in patients treated with topiramate in the postmarketing setting. If a hypersensitivity reaction occurs, discontinue EPRONTIA and initiate appropriate therapy [see Contraindications (4)].

6 Adverse Reactions

Additions and/or revisions underlined:

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

. . .

• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Reactions [see Warnings and Precautions (5.11)]
• Serious Skin Reactions [see Warnings and Precautions (5.12)]
• Anaphylaxis and Angioedema [see Warnings and Precautions (5.13)]

. . .

6.2 Postmarketing Experience

Additions and/or revisions underlined:

. . .

Body as a Whole-General Disorders: immediate hypersensitivity reactions (including anaphylaxis and angioedema [see Warnings and Precautions (5.13)]), delayed hypersensitivity reactions (including facial swelling, lip swelling, periorbital swelling, tongue swelling), oligohydrosis and hyperthermia [see Warnings and Precautions (5.3)], hyperammonemia, hyperammonemic encephalopathy [see Warnings and Precautions (5.14)], hypothermia with concomitant valproic acid [see Warnings and Precautions (5.16)].

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

Skin and Appendage Disorders: bullous skin reactions (including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis) [see Warnings and Precautions (5.11)], pemphigus, urticaria.

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

MEDICATION GUIDE

Additions and/or revisions underlined:

. . .

Who should not take EPRONTIA?

Do not take EPRONTIA if you are allergic to topiramate, EPRONTIA, or any of the ingredients in EPRONTIA. See the end of this Medication Guide for a complete list of ingredients in EPRONTIA.

. . .

What are the possible side effects of EPRONTIA? EPRONTIA may cause serious side effects including:

See "What is the most important information I should know about EPRONTIA?"

. . .

• Severe multiorgan reactions. Treatment with EPRONTIA may cause a serious allergic reaction that may affect your skin or other parts of your body such as your liver, kidneys, heart, or blood cells. This allergic reaction can be life-threatening and can cause death, particularly if it is not treated as early as possible. Contact your healthcare provider or get medical help right away if you have:
• blistering and peeling of your skin or skin rash
• fever or swollen glands that do not go away
• hives
• swelling of your face, eyes, lips, tongue, or throat
• sores in your mouth,
• trouble swallowing or breathing
• dark urine
• yellowing of the skin or whites of the eyes

. . .

• Allergic reactions. Serious allergic reactions can happen after you take EPRONTIA. Get emergency help right away if you have swelling of the face, lips, eyes, tongue, or throat, or trouble swallowing or breathing.

. . .

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

. . .

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Reactions

Instruct patients that a fever associated with other organ system involvement (rash, lymphadenopathy, etc.) may be drug-related. Advise patients to report such reactions to a healthcare provider immediately [see Warnings and Precautions (5.11)].

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 (5.12)].

Anaphylaxis and Angioedema

Inform patients about the signs and symptoms of hypersensitivity reactions such as anaphylaxis and angioedema, which can occur with EPRONTIA. Advise patients to seek immediate medical attention if they experience any symptoms of serious hypersensitivity reactions [see Warnings and Precautions (5.13)].

. . .

05/17/2024 (SUPPL-7)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.7 Fetal Toxicity

Additions and/or revisions underlined:

EPRONTIA 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)].

…

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 EPRONTIA. 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:

Adjunctive Treatment for Epilepsy

Pediatric Patients 2 Years of Age and Older

The safety and effectiveness of EPRONTIA 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 2 Years of Age and Older

The safety and effectiveness of EPRONTIA 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 Clinical Trials Experience (6.1), Clinical Studies (14.1)].

…

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.

…

8.1 Pregnancy

Additions and/or revisions underlined:

…

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 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].

…

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.

…

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 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)].

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

Fetal Toxicity

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

…

Administration Instructions

Counsel patients that EPRONTIA may be taken with or without food. Advise patients that the dosage of EPRONTIA should be measured using a calibrated measuring device and not a household teaspoon and they may ask their pharmacist for an oral dosing syringe if you do not have one. Instruct patients to discard any unused EPRONTIA after 90 days of first opening the bottle [see Dosage and Administration (2.4)].

…

 

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. EPRONTIA 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). EPRONTIA may make your birth control less effective. Tell your healthcare provider if your menstrual bleeding changes while you are using birth control and EPRONTIA.

  …

  How should I take EPRONTIA?

• Take EPRONTIA Oral Solution exactly as prescribed.

• Your healthcare provider may change your dose. Do not change your dose without talking to your healthcare provider.

• EPRONTIA can be taken before, during, or after a meal. Drink plenty of fluids during the day. This may help prevent kidney stones while taking EPRONTIA.

  …

   

  What are the possible side effects of EPRONTIA?

  EPRONTIA may cause serious side effects including:

  See “What is the most important information I should know about EPRONTIA?”

• High blood ammonia levels. High ammonia in the blood can affect your mental activities, slow your alertness, make you feel tired, or cause vomiting. This has happened when EPRONTIA is taken with a medicine called valproic acid (DEPAKENE and DEPAKOTE). Call your healthcare provider right away if you develop unexplained tiredness, vomiting, slowing of your thinking or reaction time, or changes in your mental activities.

  …

10/26/2022 (SUPPL-2)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Metabolic Acidosis

Additions and/or revisions underlined:

… 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 [see Warnings and Precautions (5.9, 5.13)]. A one-year, active-controlled study of pediatric patients treated with 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 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 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 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 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 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 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 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 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 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 EPRONTIA therapy should be carefully monitored.

5.13 Kidney Stones

Additions and/or revisions underlined:

… 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 topiramate- 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 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

Following the Monotherapy Treatment in Partial-Onset Epilepsy in Patients <2 Years of Old, newly information is added:

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 topiramate (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 topiramate at 12 months for key safety outcomes including BMD, height, height velocity, and weight. All Least Square Mean values for 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 10: Summary of 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 topiramate-treated patients at some time in the study [see Warnings and Precautions (5.4)]. Over the whole study, 76% more 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 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.

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.

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

MEDICATION GUIDE

What is the most important information I should know about EPRONTIA?

Additions and/or revisions underlined:

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

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

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

How should I store EPRONTIA?

• Store EPRONTIA at room temperature between 68°F to 77°F (20°C to 25°C).

• Throw away (discard) unused portion 60 days after first opening …

PATIENT COUNSELING INFORMATION

Newly added information:

Decrease in Bone Mineral Density

Inform the patient or caregiver that long-term treatment with EPRONTIA 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 EPRONTIA treatment may attenuate

growth as reflected by slower height increase and weight gain in pediatric patients [see Warnings

and Precautions (5.10)].