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.
TROKENDI XR (NDA-201635)
(TOPIRAMATE)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
01/04/2024 (SUPPL-32)
10/07/2022 (SUPPL-30)
02/03/2022 (SUPPL-29)
11/18/2020 (SUPPL-25)
02/21/2019 (SUPPL-20)
5 Warnings and Precautions
5.8 Fetal Toxicity(Additions and/or revisions are underlined)
TROKENDI 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.
6 Adverse Reactions
6.1 Clinical Trials Experience(Additions and/or revisions are underlined)
…
Pediatric Patients 6 Years to 15 Years of Age
The most common adverse reactions in the controlled trial (Study 1) that occurred in pediatric patients in the 400 mg/day topiramate group and at an incidence higher (greater than or equal to 10%) than in the 50 mg/day group were fever and weight loss (see Table 3).
Approximately 14% of the 77 pediatric patients in the 400 mg/day group who received topiramate as monotherapy in the controlled clinical trial discontinued therapy due to adverse reactions. The most common (? 2% more frequent than in the 50 mg/day group) adverse reactions resulting in discontinuation in this trial were difficulty with concentration/attention, fever, flushing, and confusion.
Table 3 represents the incidence of adverse reactions occurring in at least 3% of adult and pediatric patients treated with 400 mg/day immediate-release topiramate and occurring with greater incidence than 50 mg/day topiramate.
Table 3: Adverse Reactions in the High Dose Group As Compared to the Low Dose Group, in Monotherapy Epilepsy Trials in Adult and Pediatric Patients
(Tables has been revised; please refer to label)
…
6.2 Postmarketing Experience
(Additions and/or revisions are underlined)
…
Hematological Disorders: decrease of the International Normalized Ratio (INR) or prothrombin time when given concomitantly with vitamin K antagonist anticoagulant medications such as warfarin.
8 Use in Specific Populations
8.1 Pregnancy(Additions and/or revisions are underlined)
Pregnancy Exposure Registry
There is a pregnancy exposure registry that
monitors pregnancy outcomes in women
exposed to antiepileptic drugs (AEDs),
such as TROKENDI XR,
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
TROKENDI 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 for cleft lip and/or cleft palate (oral clefts) and for being small for gestational age (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 demonstrated developmental toxicity, including increased incidences of fetal malformations, in the absence of maternal toxicity at clinically relevant doses.
…
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 reference AEDs (0.36%) , or the prevalence in infants of 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 who were 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 orally 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 an increased incidence of 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 an increased incidence of fetal malformations (primarily rib and vertebral malformations) was 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/day) 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 is less than the MRHD for epilepsy or migraine on a mg/m2 basis.
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.
…
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION(Additions and/or revisions are underlined)
…
Fetal Toxicity
Counsel pregnant women and women of childbearing potential that use of TROKENDI XR during pregnancy can cause fetal harm, including an increased risk for cleft lip and/or cleft palate (oral clefts), which occur earlyin pregnancy 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 from chronic metabolic acidosis with use of TROKENDI XR during pregnancy. When appropriate, prescribers should counsel pregnant women and women of childbearing potential about alternative therapeutic options.
Advise women of childbearing potential who are not planning a pregnancy to use effective contraception while using topiramate, keeping in mind that there is a potential for decreased contraceptive efficacy when using estrogen-containing birth control with topiramate.
Encourage pregnant women using TROKENDI XR to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. The registry is collecting information about the safety of antiepileptic drugs during pregnancy.
MEDICATION GUIDE
Before taking Trokendi XR, tell your healthcare provider about all of your medical conditions, including if you:
have or have had depression, mood problems, or suicidal thoughts or behavior
have kidney problems, kidney stones, or are getting kidney dialysis
have a history of metabolic acidosis (too much acid in the blood)
have liver problems
have weak, brittle or soft bones (osteomalacia, osteoporosis, osteopenia, or decreased bone density)
have lung or breathing problems
have eye problems, especially glaucoma
have diarrhea
have a growth problem
are on a diet high in fat and low in carbohydrates, which is called a ketogenic diet
are having surgery
are pregnant or plan to become pregnant
are breastfeeding. Trokendi XR passes into your breast milk. Breastfed babies may be sleepy or have diarrhea. It is not known if the Trokendi XR 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 Trokendi XR.
…..
How should I store Trokendi XR?
Store Trokendi XR capsules at room temperature between 59?F to 86?F (15?C to 30?C).
Keep Trokendi XR in a tightly closed container.
Keep Trokendi XR dry and away from moisture and light.
Keep Trokendi XR and all medicines out of the reach of children.
….
What are the ingredients in Trokendi XR? Active ingredient: topiramate
Inactive ingredients: Sugar spheres, NF; hypromellose (Type 2910), USP; mannitol, USP; docusate sodium, USP;
benzoate, NF; ethylcellulose, NF; oleic acid, NF; medium chain triglycerides, NF; polyethylene glycol, NF; polyvinyl alcohol, USP; titanium dioxide, USP; talc, USP; lecithin, NF; xanthan gum, NF; glycerin, USP-NF. Capsule shells: Gelatin, USP; titanium dioxide, USP; colorants.
…
01/03/2018 (SUPPL-18)
04/05/2017 (SUPPL-11)
5 Warnings and Precautions
5.4 Metabolic Acidosis(additions underlined)
…
Epilepsy
Adult Patients
In adults, the incidence of persistent decreases in serum bicarbonate (levels of less than 20 mEq/L at two consecutive visits or at the final visit) in controlled clinical trials for adjunctive treatment of epilepsy was 32% for 400 mg per day.
Migraine
Adult Patients
The incidence of persistent decreases in serum bicarbonate in placebo-controlled trials with immediate-release topiramate in adults for the prophylaxis of migraine was 44% for 200 mg per day, 39% for 100 mg per day, 23% for 50 mg per day, and 7% for placebo. The incidence of a markedly abnormally low serum bicarbonate (i.e. absolute value less than 17mEq/L, and greater than 5mEq/L decrease from pretreatment) in these trials was 11% for 200 mg per day, 9% for 100 mg per day, 2% for 50 mg per day, and less than 1% for placebo.
(additions underlined)
Adverse reactions most often associated with the use of topiramate, and
therefore expected to be associated with the use of TROKENDI XR®, were related
to the central nervous system and were observed in both the epilepsy and
migraine populations. In adults, 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
In the 6-month migraine prophylaxis controlled
trials of immediate release topiramate using a slower titration regimen (25mg
per day weekly increments), the proportion of patients who experienced one or
more cognitive- related adverse reactions was 19% for topiramate 50 mg per day,
22% for 100 mg per day (the recommended dose), 28% for 200 mg per 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
Psychiatric/behavioral disturbances (depression or mood) were
dose-related for both the epilepsy and migraine populations treated
with topiramate.
Somnolence/Fatigue
…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.
…
6 Adverse Reactions
6.1 Clinical Trials Experience(additions underlined)
Adverse Reactions Observed in Monotherapy Trial for Epilepsy
Adult Patients 16 Years of Age and Older
The adverse reactions in the controlled trial (Study 1) that occurred most commonly in adults in the 400 mg per day group and at an incidence higher (greater than or equal to 5%) than in the 50 mg per day group were paresthesia, weight decrease, somnolence, anorexia, and difficulty with memory.
…
Clinical Trial Experience in Migraine
Adult Patients
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) conducted with immediate-release topiramate, most of the adverse reactions 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 to5% 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 9 includes those adverse reactions reported for patients in the placebo-controlled trials where the incidence in any immediate-release topiramate group was at least 2% and was greater than that for placebo patients.
(please refer to table 9 in label)
Of the 1135 patients exposed to immediate-release topiramate in the 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 patients in these studies included paresthesia (7%), fatigue (4%), nausea (4%), difficulty with concentration/attention (3%), insomnia (3%), anorexia (2%) and dizziness (2%).
Patients treated in these studies 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, immediate-release topiramate 50 mg, 100 mg, and 200 mg groups, respectively.
Table 10 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 difference greater than or equal to 5% for the 100 mg dose) were: paresthesia, nausea, anorexia, difficulty with memory, diarrhea, weight decrease, and hypoesthesia.
(please refer to table 10 in label)
04/05/2017 (SUPPL-17)
5 Warnings and Precautions
5.10 Hyperammonemia and Encephalopathy(additions underlined)
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 hyperammonemia (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 (1 month to 24 months) who were treated with adjunctive topiramate for partial onset epilepsy…
…
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.
(additions underlined)
…
Migraine
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 <17 mEq/L and >5 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=13).
(additions underlined)
Adverse reactions most often associated with the use of topiramate, and
therefore expected to be associated with the use of TROKENDI XR®, were related
to the central nervous system and were observed in both the epilepsy and
migraine populations. In adults, 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.
…
In the 6-month migraine prophylaxis controlled
trials of immediate release topiramate using a slower titration regimen (25mg
per day weekly increments), the proportion of patients who experienced one or
more cognitive- related adverse reactions was 19% for topiramate 50 mg per day,
22% for 100 mg per day (the recommended dose), 28% for 200 mg per 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
Psychiatric/behavioral disturbances (depression or
mood) were dose-related for both the epilepsy and migraine populations treated
with topiramate
6 Adverse Reactions
6.1 Clinical Trials Experience(additions underlined)
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 immediate-release 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 immediate-release topiramate treated adolescent patients, the most commonly observed adverse reactions associated with the use of 100 mg of 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 (see Table 11). Table 11 shows adverse reactions from the adolescent pivotal trial (Study 3) demonstrating the efficacy of immediate-release topiramate in which there were 103 adolescent patients who were treated with placebo or 50 mg or 100 mg of immediate-release 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 immediate-release topiramate .Table 11 also shows adverse reactions in adolescents in the controlled migraine trials when the incidence in an immediate-release topiramate dose group was at least 5% or higher than the incidence of placebo. Many adverse reactions shown in Table 11 indicated a dose-dependent relationship.
(please refer to table 11 in label)
…
In the double-blind placebo-controlled studies, adverse reactions led to discontinuation of treatment in 8% of placebo patients compared with 6% of immediate-release topiramate-treated patients. Adverse reactions associated with discontinuing therapy that occurred in more than one immediate-release topiramate-treated patient were fatigue (1%), headache (1%), and somnolence (1%).
Laboratory Abnormalities
…
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.
8 Use in Specific Populations
8.4 Pediatric Use(additions underlined)
…
Topiramate produced a dose-related increased incidence of hyperammonemia.
…
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 mg/day 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 immediate-release topiramate, the most commonly observed adverse reactions associated with the use of 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 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 that were observed occurred more commonly in adolescents treated with topiramate compared to adolescents treated with placebo.
Migraine Prophylaxis in Children 6-11 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 immediate-release 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 reactions 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.