"The U.S. Food and Drug Administration today approved Aptiom (eslicarbazepine acetate) as an add-on medication to treat seizures associated with epilepsy.
Epilepsy is a brain disorder caused by abnormal or excessive activity in the brain"...
Acute Myopia And Secondary Angle Closure Glaucoma
A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients receiving topiramate. Symptoms include acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings can include myopia, anterior chamber shallowing, ocular hyperemia (redness) and increased intraocular pressure. Mydriasis may or may not be present. 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 topiramate 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 TROKENDI XR® as rapidly as possible, according to the judgment of the treating physician. Other measures, in conjunction with discontinuation of TROKENDI XR®, may be helpful.
Oligohydrosis And Hyperthermia
Oligohydrosis (decreased sweating), resulting in hospitalization in some cases, has been reported in association with topiramate use. Decreased sweating and an elevation in body temperature above normal characterized these cases. Some of the cases were reported after exposure to elevated environmental temperatures.
The majority of the reports have been in pediatric patients. Patients, especially pediatric patients, treated with TROKENDI XR® should be monitored closely for evidence of decreased sweating and increased body temperature, especially in hot weather. Caution should be used when TROKENDI XR® is prescribed with other drugs that predispose patients to heat-related disorders; these drugs include, but are not limited to, other carbonic anhydrase inhibitors and drugs with anticholinergic activity.
Hyperchloremic, non-anion gap, metabolic acidosis (i.e., decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis) is associated with topiramate, and can be expected with treatment with TROKENDI XR®. This metabolic acidosis is caused by renal bicarbonate loss due to the inhibitory effect of topiramate on carbonic anhydrase. Such electrolyte imbalance has been observed with the use of topiramate in placebo-controlled clinical trials and in the post-marketing period. Generally, topiramate-induced metabolic acidosis occurs early in treatment although cases can occur at any time during treatment. Bicarbonate decrements are usually mild to moderate (average decrease of 4 mEq/L at daily doses of 400 mg in adults and at approximately 6 mg/kg/day in pediatric patients); rarely, patients can experience severe decrements to values below 10 mEq/L. Conditions or therapies that predispose patients to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhea, ketogenic diet or specific drugs) may be additive to the bicarbonate lowering effects of topiramate.
Manifestations Of Metabolic Acidosis
Some manifestations of acute or chronic metabolic acidosis may include hyperventilation, nonspecific symptoms such as fatigue and anorexia, or more severe sequelae including cardiac arrhythmias or stupor. Chronic, untreated metabolic acidosis may increase the risk for nephrolithiasis or nephrocalcinosis, and may also result in osteomalacia (referred to as rickets in pediatric patients) and/or osteoporosis with an increased risk for fractures. Chronic metabolic acidosis in pediatric patients may also reduce growth rates. A reduction in growth rate may eventually decrease the maximal height achieved. The effect of topiramate on growth and bone-related sequelae has not been systematically investigated in long-term, placebo-controlled trials. Longterm, open-label treatment of infants/toddlers, with intractable partial epilepsy, for up to 1 year, showed reductions from baseline in Z SCORES for length, weight, and head circumference compared to age and sexmatched normative data, although these patients with epilepsy are likely to have different growth rates than normal infants. Reductions in Z SCORES for length and weight were correlated to the degree of acidosis [see Pediatric Use]. Topiramate treatment that causes metabolic acidosis during pregnancy can possibly produce adverse effects on the fetus and might also cause metabolic acidosis in the neonate from possible transfer of topiramate to the fetus [see Fetal Toxicity and Use in Specific Populations].
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, and 1% for placebo. Metabolic acidosis has been observed at doses as low as 50 mg per day. The incidence of persistent decreases in serum bicarbonate in adult patients ( ≥ 16 years of age) in the epilepsy controlled clinical trial for monotherapy was 14% for 50 mg per day and 25% for 400 mg per day. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value less than 17 mEq/L and greater than 5 mEq/L decrease from pretreatment) in the adjunctive therapy trials was 3% for 400 mg per day, and 0% for placebo, and in the monotherapy trial was 1% for 50 mg per day and 6% for 400 mg per day. Serum bicarbonate levels have not been systematically evaluated at daily doses greater than 400 mg per day.
Pediatric Patients (2 Years to 16 Years of Age)
Although TROKENDI XR® is not approved for use in patients below the age of 6, the incidence of persistent decreases in serum bicarbonate in placebo-controlled trials for adjunctive treatment of Lennox-Gastaut syndrome or refractory partial onset seizures in patients age 2 years to 16 years was 67% for topiramate (at approximately 6 mg/kg/day), and 10% for placebo. The incidence of markedly abnormally low serum bicarbonate (i.e., absolute value less than 17 mEq/L and greater than 5 mEq/L decrease from pretreatment) in these trials was 11% for topiramate and 0% for placebo. Cases of moderately severe metabolic acidosis have been reported in patients as young as 5 months old, especially at daily doses above 5 mg/kg/day.
In pediatric patients (6 years to 15 years of age), the incidence of persistent decreases in serum bicarbonate in the epilepsy controlled clinical trial for monotherapy performed with topiramate was 9% for 50 mg per day and 25% for 400 mg per day. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value less than 17 mEq/L and greater than 5 mEq/L decrease from pretreatment) in this trial was 1% for 50 mg per day and 6% for 400 mg per day.
Pediatric Patients (Under 2 Years of Age)
Although TROKENDI XR® is not approved for use in patients less than 6 years of age, a study of topiramate as adjunctive use in patients under 2 years of age with partial onset seizures revealed that topiramate produced a metabolic acidosis that is notably greater in magnitude than that observed in controlled trials in older children and adults. The mean treatment difference (25 mg/kg/day topiramate-placebo) was -5.9 mEq/L for bicarbonate. The incidence of metabolic acidosis (defined by a serum bicarbonate less than 20 mEq/L) was 0% for placebo, 30% for 5 mg/kg/day, 50% for 15 mg/kg/day, and 45% for 25 mg/kg/day. The incidence of markedly abnormal changes (i.e., less than 17 mEq/L and greater than 5 mEq/L decrease from baseline of greater than or equal to 20 mEq/L) was 0% for placebo, 4% for 5 mg/kg/day, 5% for 15 mg/kg/day, and 5% for 25 mg/kg/day [see Use in Specific Populations].
Risk Mitigation Strategies
Measurement of baseline and periodic serum bicarbonate during topiramate treatment is recommended. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing topiramate (using dose tapering). If the decision is made to continue patients on topiramate in the face of persistent acidosis, alkali treatment should be considered.
Interaction With Alcohol
In vitro data show that, in the presence of alcohol, the pattern of topiramate release from TROKENDI XR® capsules is significantly altered. As a result, plasma levels of topiramate with TROKENDI XR® may be markedly higher soon after dosing and subtherapeutic later in the day. Therefore, alcohol use should be completely avoided within 6 hours prior to and 6 hours after TROKENDI XR® administration.
Suicidal Behavior And Ideation
Antiepileptic drugs (AEDs) increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED, including TROKENDI XR® for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed.
Table 2 shows absolute and relative risk by indication for all evaluated AEDs.
Table 2: Risk by Indication for Antiepileptic Drugs in
the Pooled Analysis
|Indication||Placebo Patients with Events per 1,000 Patients||Drug Patients with Events per 1,000 Patients||Relative Risk: Incidence of Events in Drug Patients/ Incidence in Placebo Patients||Risk Difference: Additional Drug Patients with Events per 1,000 Patients|
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
Anyone considering prescribing TROKENDI XR® or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior or the emergence of suicidal thoughts, behavior or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
Cognitive/Neuropsychiatric Adverse Reactions
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 the epilepsy population. In adults, the most frequent of these can be classified into three general categories: 1) Cognitiverelated 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.
Cognitive Related Dysfunction
The majority of cognitive-related adverse reactions were mild to moderate in severity, and they frequently occurred in isolation. Rapid titration rate and higher initial dose were associated with higher incidences of these reactions. Many of these reactions contributed to withdrawal from treatment [see ADVERSE REACTIONS].
In the adjunctive epilepsy controlled trials conducted with topiramate (using rapid titration such as 100 mg per day to 200 mg per day weekly increments), the proportion of patients who experienced one or more cognitiverelated adverse reactions was 42% for 200 mg per day, 41% for 400 mg per day, 52% for 600 mg per day, 56% for 800 and 1,000 mg per day, and 14% for placebo. These dose-related adverse reactions began with a similar frequency in the titration or in the maintenance phase, although in some patients the events began during titration and persisted into the maintenance phase. Some patients who experienced one or more cognitiverelated adverse reactions in the titration phase had a dose-related recurrence of these reactions in the maintenance phase.
In the monotherapy epilepsy controlled trial conducted with topiramate, the proportion of patients who experienced one or more cognitive-related adverse reactions was 19% for topiramate 50 mg per day and 26% for 400 mg per day.
Psychiatric/behavioral disturbances (depression or mood) were dose-related for the epilepsy population treated with topiramate.
Somnolence and fatigue were the adverse reactions most frequently reported during clinical trials of topiramate for adjunctive epilepsy. For the adjunctive epilepsy population, the incidence of somnolence did not differ substantially between 200 mg per day and 1,000 mg per day, but the incidence of fatigue was dose-related and increased at dosages above 400 mg per day. For the monotherapy epilepsy population in the 50 mg per day and 400 mg per day groups, the incidence of somnolence was dose-related (9% for the 50 mg per day group and 15% for the 400 mg per day group) and the incidence of fatigue was comparable in both treatment groups (14% each). For other uses not approved for TROKENDI XR®, somnolence and fatigue were dose-related and more common in the titration phase.
Additional nonspecific CNS events commonly observed with topiramate in the adjunctive epilepsy population include dizziness or ataxia.
In double-blind adjunctive therapy and monotherapy epilepsy clinical studies conducted with topiramate, the incidences of cognitive/neuropsychiatric adverse reactions in pediatric patients were generally lower than observed in adults. These reactions included psychomotor slowing, difficulty with concentration/attention, speech disorders/related speech problems and language problems. The most frequently reported neuropsychiatric reactions in pediatric patients during adjunctive therapy double-blind studies were somnolence and fatigue. The most frequently reported neuropsychiatric reactions in pediatric patients in the 50 mg per day and 400 mg per day groups during the monotherapy double-blind study were headache, dizziness, anorexia, and somnolence.
No patients discontinued treatment due to any adverse reactions in the adjunctive epilepsy double-blind trials. In the monotherapy epilepsy double-blind trial conducted with immediate-release topiramate product, 1 pediatric patient (2%) in the 50 mg per day group and 7 pediatric patients (12%) in the 400 mg per day group discontinued treatment due to any adverse reactions. The most common adverse reaction associated with discontinuation of therapy was difficulty with concentration/attention; all occurred in the 400 mg per day group.
Topiramate can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in utero have an increased risk for cleft lip and/or cleft palate (oral clefts) and for being small for gestational age. In multiple species, oral administration of topiramate to pregnant animals at clinically relevant doses resulted in structural malformations, including craniofacial defects, and reduced body weights in offspring [see Use in Specific Populations].
Consider the benefits and risks of TROKENDI XR® when administering the drug in women of childbearing potential, particularly when TROKENDI XR® is considered for a condition not usually associated with permanent injury or death [see Use in Specific Populations]. TROKENDI XR® should be used during pregnancy only if the potential benefit outweighs the potential risk. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be informed of the potential hazard to a fetus [see Use in Specific Populations].
Withdrawal Of Antiepileptic Drugs
In patients with or without a history of seizures or epilepsy, antiepileptic drugs including TROKENDI XR® should be gradually withdrawn to minimize the potential for seizures or increased seizure frequency [see Clinical Studies]. In situations where rapid withdrawal of TROKENDI XR® is medically required, appropriate monitoring is recommended.
Hyperammonemia And Encephalopathy
Hyperammonemia/Encephalopathy Without Concomitant Valproic Acid (VPA)
Topiramate treatment has produced hyperammonemia (in some instances dose-related) in clinical investigational programs in very young pediatric patients (1 month to 24 months) who were treated with adjunctive topiramate for partial onset epilepsy (8% for placebo, 10% for 5 mg/kg/day, 0% for 15 mg/kg/day, 9% for 25 mg/kg/day). TROKENDI XR® is not approved as adjunctive treatment of partial onset seizures in pediatric patients less than 6 years old. In some patients, ammonia was markedly increased (greater than or equal to 50% above upper limit of normal). The hyperammonemia associated with topiramate treatment occurred with and without encephalopathy in placebo-controlled trials, and in an open-label, extension trial of infants with refractory epilepsy. Dose-related hyperammonemia was also observed in the extension trial in pediatric patients up to 2 years old. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting.
Hyperammonemia with and without encephalopathy has also been observed in postmarketing reports in patients who were taking topiramate without concomitant valproic acid (VPA).
Hyperammonemia/Encephalopathy With Concomitant Valproic Acid (VPA)
Concomitant administration of topiramate and valproic acid (VPA) has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone based upon postmarketing reports. Although hyperammonemia may be asymptomatic, clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting. In most cases, symptoms and signs abated with discontinuation of either drug. This adverse reaction is not due to a pharmacokinetic interaction.
Although TROKENDI XR® is not indicated for use in infants/toddlers (1 month to 24 months), topiramate with concomitant VPA clearly produced a dose-related increase in the incidence of hyperammonemia (above the upper limit of normal, 0% for placebo, 12% for 5 mg/kg/day, 7% for 15 mg/kg/day, 17% for 25 mg/kg/day) in an investigational program using topiramate. Markedly increased, dose-related hyperammonemia (0% for placebo and 5 mg/kg/day, 7% for 15 mg/kg/day, and 8% for 25 mg/kg/day) also occurred in these infants/toddlers. Dose-related hyperammonemia was similarly observed in a long-term, extension trial utilizing topiramate in these very young, pediatric patients [see Use in Specific Populations].
Hyperammonemia with and without encephalopathy has also been observed in postmarketing reports in patients taking topiramate with valproic acid (VPA).
The hyperammonemia associated with topiramate treatment appears to be more common when used concomitantly with VPA.
Monitoring For Hyperammonemia
Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy. Although not studied, topiramate or TROKENDI XR® treatment or an interaction of concomitant topiramate-based product and valproic acid treatment may exacerbate existing defects or unmask deficiencies in susceptible persons.
In patients who develop unexplained lethargy, vomiting, or changes in mental status associated with any topiramate treatment, hyperammonemic encephalopathy should be considered and an ammonia level should be measured.
A total of 32/2086 (1.5%) of adults exposed to topiramate during its adjunctive epilepsy therapy development reported the occurrence of kidney stones, an incidence about 2 to 4 times greater than expected in a similar, untreated population. In the double-blind monotherapy epilepsy study, a total of 4/319 (1.3%) of adults exposed to topiramate reported the occurrence of kidney stones. As in the general population, the incidence of stone formation among topiramate treated patients was higher in men. Kidney stones have also been reported in pediatric patients taking topiramate for epilepsy. During long-term (up to 1 year) topiramate treatment in an open-label extension study of 284 pediatric patients 1 month to 24 months old with epilepsy, 7% developed kidney or bladder stones that were diagnosed clinically or by sonogram. TROKENDI XR® is not approved for pediatric patients less than 6 years old [see Use in Specific Populations].
TROKENDI XR® would be expected to have the same effect as topiramate on the formation of kidney stones. An explanation for the association of topiramate and kidney stones may lay in the fact that topiramate is a carbonic anhydrase inhibitor. Carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) can promote stone formation by reducing urinary citrate excretion and by increasing urinary pH [see Metabolic Acidosis]. The concomitant use of TROKENDI XR® with any other drug producing metabolic acidosis, or potentially in patients on a ketogenic diet may create a physiological environment that increases the risk of kidney stone formation, and should therefore be avoided.
Increased fluid intake increases the urinary output, lowering the concentration of substances involved in stone formation. Hydration is recommended to reduce new stone formation.
Hypothermia With Concomitant Valproic Acid Use
Hypothermia, defined as an unintentional drop in body core temperature to less than 35°C (95°F) has been reported in association with topiramate use with concomitant valproic acid (VPA) both in the presence and in the absence of hyperammonemia. This adverse reaction in patients using concomitant topiramate and valproate can occur after starting topiramate treatment or after increasing the daily dose of topiramate [see DRUG INTERACTIONS]. Consideration should be given to stopping topiramate or valproate in patients who develop hypothermia, which may be manifested by a variety of clinical abnormalities including lethargy, confusion, coma, and significant alterations in other major organ systems such as the cardiovascular and respiratory systems. Clinical management and assessment should include examination of blood ammonia levels.
Paresthesia (usually tingling of the extremities), an effect associated with the use of other carbonic anhydrase inhibitors, appears to be a common effect of topiramate. Paresthesia was more frequently reported in the monotherapy epilepsy trials conducted with topiramate than in the adjunctive therapy epilepsy trials conducted with the same product. In the majority of instances, paresthesia did not lead to treatment discontinuation.
Interaction With Other CNS Depressants
Topiramate is a CNS depressant. Concomitant administration of topiramate with other CNS depressant drugs can result in significant CNS depression. Patients should be watched carefully when TROKENDI XR® is coadministered with other CNS depressant drugs.
Visual Field Defects
Visual field defects (independent of elevated intraocular pressure) have been reported in clinical trials and in postmarketing experience in patients receiving topiramate. In clinical trials, most of these events were reversible after topiramate discontinuation. If visual problems occur at any time during topiramate treatment, consideration should be given to discontinuing the drug.
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Counsel patients to swallow TROKENDI XR® capsules whole and intact. TROKENDI XR® should not be sprinkled on food, chewed or crushed [See DOSAGE AND ADMINISTRATION].
Consumption Of Alcohol
Advise patients to completely avoid consumption of alcohol at least 6 hours prior to and 6 hours after taking TROKENDI XR®[see WARNINGS AND PRECAUTIONS].
Acute Myopia And Secondary Angle Closure Glaucoma
Advise patients taking TROKENDI XR® to seek immediate medical attention if they experience blurred vision, visual disturbances or periorbital pain [see WARNINGS AND PRECAUTIONS].
Oligohydrosis And Hyperthermia
Counsel patients that TROKENDI XR®, especially pediatric patients, can cause decreased sweating and increased body temperature, especially in hot weather, and they should seek medical attention if this is noticed [see WARNINGS AND PRECAUTIONS].
Inform patients about the potentially significant risk for metabolic acidosis that may be asymptomatic and may be associated with adverse effects on kidneys (e.g., kidney stones, nephrocalcinosis), bones (e.g., osteoporosis, osteomalacia, and/or rickets in children), and growth (e.g., growth delay/retardation) in pediatric patients, and on the fetus [see WARNINGS AND PRECAUTIONS].
Suicidal Behavior And Ideation
Counsel patients, their caregivers, and families that AEDs, including TROKENDI XR®, may increase the risk of suicidal thoughts and behavior and they should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior or the emergence of suicidal thoughts, behavior or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers [see WARNINGS AND PRECAUTIONS].
Interference With Cognitive And Motor Performance
Warn patients about the potential for somnolence, dizziness, confusion, difficulty concentrating, visual effects and advise them not to drive or operate machinery until they have gained sufficient experience on TROKENDI XR® to gauge whether it adversely affects their mental performance, motor performance, and/or vision [see WARNINGS AND PRECAUTIONS].
Advise patients that even when taking TROKENDI XR® or other anticonvulsants, some patients with epilepsy will continue to have unpredictable seizures. Therefore, counsel all patients taking TROKENDI XR® for epilepsy to exercise appropriate caution when engaging in any activities where loss of consciousness could result in serious danger to themselves or those around them (including swimming, driving a car, climbing in high places, etc.). Some patients with refractory epilepsy will need to avoid such activities altogether. Physicians should discuss the appropriate level of caution with their patients, before patients with epilepsy engage in such activities.
Counsel pregnant women and women of childbearing potential that use of topiramate during pregnancy can cause fetal harm, including an increased risk for cleft lip and/or cleft palate (oral clefts), which occur early in pregnancy before many women know they are pregnant. Also inform patients that infants exposed to topiramate monotherapy in utero may be small for their gestational age [see Use in Specific Populations]. 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 [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].
Encourage pregnant women using topiramate to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. The registry is collecting information about the safety of antiepileptic drugs during pregnancy. 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/ [see Use in Specific Populations].
Hyperammonemia And Encephalopathy
Warn patients about the possible development of hyperammonemia with or without encephalopathy. Although hyperammonemia may be asymptomatic, clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting. This hyperammonemia and encephalopathy can develop with topiramate treatment alone or with topiramate treatment with concomitant valproic acid (VPA). Patients should be instructed to contact their physician if they develop unexplained lethargy, vomiting, or changes in mental status [see WARNINGS AND PRECAUTIONS].
Instruct patients, particularly those with predisposing factors, to maintain an adequate fluid intake in order to minimize the risk of kidney stone formation [see WARNINGS AND PRECAUTIONS].
Counsel patients that TROKENDI XR® can cause a reduction in body temperature, which can lead to alterations in mental status. If they note such changes, they should call their health care professional and measure their body temperature. Patients taking concomitant valproic acid should be specifically counseled on this potential adverse reaction [see WARNINGS AND PRECAUTIONS].
Counsel patients that they may experience tingling in the arms and legs. If this symptom occurs, they should consult with their physician [see WARNINGS AND PRECAUTIONS].
Carcinogenesis, Mutagenesis, And Impairment Of Fertility
An increase in urinary bladder tumors was observed in mice given topiramate (20, 75, and 300 mg/kg/day) in the diet for 21 months. An increase in the incidence of bladder tumors in males and females receiving 300 mg/kg was primarily due to the increased occurrence of a smooth muscle tumor considered histomorphologically unique to mice. The higher of the doses not associated with an increase in tumors (75 mg/kg/day) is equivalent to the maximum recommended human dose (MRHD) on a mg/m² basis. The relevance of this finding to human carcinogenic risk is uncertain.
No evidence of carcinogenicity was seen in rats following oral administration of topiramate for 2 years at doses up to 120 mg/kg/day (approximately 3 times the MRHD on a mg/m² basis).
Topiramate did not demonstrate genotoxic potential when tested in a battery of in vitro and in vivo assays. Topiramate was not mutagenic in the Ames test or the in vitro mouse lymphoma assay; it did not increase unscheduled DNA synthesis in rat hepatocytes in vitro; and it did not increase chromosomal aberrations in human lymphocytes in vitro or in rat bone marrow in vivo.
Impairment Of Fertility
No adverse effects on male or female fertility were observed in rats administered oral doses of up to 100 mg/kg/day (2.5 times the MRHD on a mg/m² basis) prior to and during mating and early pregnancy.
Use In Specific Populations
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to topiramate during pregnancy. Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll-free number 1-888-233-2334. Information about the North American Drug Pregnancy Registry can be found at http://www.aedpregnancyregistry.org/.
Topiramate can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in utero have increased risk for cleft lip and/or cleft palate (oral clefts) and for being small for gestational age [see Human Data].
In multiple animal species, topiramate demonstrated developmental toxicity, including teratogenicity, in the absence of maternal toxicity at clinically relevant doses [see Animal Data].
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Fetal/Neonatal Adverse reactions
Consider the benefits and risks of topiramate when prescribing this drug to women of childbearing potential, particularly when topiramate is considered for a condition not usually associated with permanent injury or death. Because of the risk of oral clefts to the fetus, which occur in the first trimester of pregnancy before many women know they are pregnant, all women of childbearing potential should be informed of the potential risk to the fetus from exposure to topiramate. Women who are planning a pregnancy should be counseled regarding the relative risks and benefits of topiramate use during pregnancy, and alternative therapeutic options should be considered for these patients.
Labor Or Delivery
Although the effect of topiramate on labor and delivery in humans has not been established, the development of topiramate-induced metabolic acidosis in the mother and/or in the fetus might affect the fetus' ability to tolerate labor [see Use in Specific Populations].
Topiramate treatment can cause metabolic acidosis [see WARNINGS AND PRECAUTIONS]. 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 [see WARNINGS AND PRECAUTIONS]. Newborns of mothers treated with topiramate should be monitored for metabolic acidosis because of transfer of topiramate to the fetus and possible occurrence of transient metabolic acidosis following birth.
Data from the NAAED Pregnancy Registry indicate an increased risk of oral clefts in infants exposed to topiramate monotherapy during the first trimester of pregnancy. The prevalence of oral clefts was 1.2% compared to a prevalence of 0.39% - 0.46% in infants exposed to other AEDs, and a prevalence of 0.12% in infants of mothers without epilepsy or treatment with other AEDs. For comparison, the Centers for Disease Control and Prevention (CDC) reviewed available data on oral clefts in the United States and found a similar background rate of 0.17%. The relative risk of oral clefts in topiramate-exposed pregnancies in the NAAED Pregnancy Registry was 9.6 (95% Confidence Interval=[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 similarly increased prevalence of oral clefts of 3.2% among infants exposed to topiramate monotherapy. The observed rate of oral clefts was 16 times higher than the background rate in the UK, which is approximately 0.2%.
Data from the NAAED pregnancy registry and a population-based birth registry cohort indicate that exposure to topiramate in utero is associated with an increased risk of small for gestational age (SGA) newborns (birth weight < 10th percentile). In the NAAED pregnancy registry, 18% of topiramate-exposed newborns were SGA compared to 7% of newborns exposed to a reference AED, and 5% of newborns of mothers without epilepsy and without AED exposure. In the Medical Birth Registry of Norway (MBRN), a population-based pregnancy registry, 25% of newborns in the topiramate monotherapy exposure group were SGA compared to 9 % in the comparison group who were unexposed to AEDs. The long-term consequences of the SGA findings are not known.
When topiramate (20, 100, and 500 mg/kg/day) was administered orally to pregnant mice during the period of organogenesis, the incidence of fetal malformations (primarily craniofacial defects) was increased at all doses. Fetal body weights and skeletal ossification were reduced at the highest dose tested in conjunction with decreased maternal body weight gain. A no-effect dose for embryofetal developmental toxicity in mice was not identified. The lowest dose tested, which was associated with teratogenic effects, is less than the maximum recommended human dose (MRHD) of 400 mg/day on a body surface area (mg/m²) basis.
In pregnant rats administered topiramate (20, 100, and 500 mg/kg/day or 0.2, 2.5, 30, and 400 mg/kg/day) orally during the period of organogenesis, the frequency of limb malformations (ectrodactyly, micromelia, and amelia) was increased in fetuses at 400 or 500 mg/kg/day. Embryotoxicity (reduced fetal body weights, increased incidences of structural variations) was observed at doses as low as 20 mg/kg/day. Clinical signs of maternal toxicity were seen at 400 mg/kg/day and above, and maternal body weight gain was reduced at doses of 100 mg/kg/day or greater. The no-effect dose for embryofetal developmental toxicity in rats is less than the MRHD on a mg/m² basis.
In pregnant rabbits administered topiramate (20, 60, and 180 mg/kg/day or 10, 35, and 120 mg/kg/day) orally during organogenesis, embryofetal mortality was increased at 35 mg/kg/day and teratogenic effects (primarily rib and vertebral malformations) were observed at 120 mg/kg/day. Evidence of maternal toxicity (decreased body weight gain, clinical signs, and/or mortality) was seen at 35 mg/kg/day and above. The no-effect dose (20 mg/kg/day) for embryofetal developmental toxicity in rabbits is equivalent to the MRHD on a mg/m² basis.
When topiramate (0.2, 4, 20, and 100 mg/kg/day or 2, 20, and 200 mg/kg/day) was administered orally to female rats during the latter part of gestation and throughout lactation, offspring exhibited decreased viability and delayed physical development at 200 mg/kg/day and reductions in pre-and/or postweaning body weight gain at 2 mg/kg/day and above. Maternal toxicity (decreased body weight gain, clinical signs) was evident at 100 mg/kg or greater. In a rat embryofetal development study which included postnatal assessment of offspring, oral administration of topiramate (0.2, 2.5, 30, and 400 mg/kg/day) to pregnant animals during the period of organogenesis resulted in delayed physical development at 400 mg/kg/day and persistent reductions in body weight gain at 30 mg/kg/day and higher in the offspring. The no-effect dose (0.2 mg/kg/day) for pre- and postnatal developmental toxicity is less than the MRHD on a mg/m² basis.
Topiramate is excreted in human milk [see Data]. The effects of topiramate exposure in breastfed infants are unknown.
The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for TROKENDI XR® and any potential adverse effects on the breastfed infant from TROKENDI XR® or from the underlying maternal condition.
Limited data from 5 women with epilepsy treated with topiramate during lactation showed drug levels in milk similar to those in maternal plasma.
Females And Males Of Reproductive Potential
Women of childbearing potential who are not planning a pregnancy should use effective contraception because of the risks to the fetus of oral clefts and of being small for gestational age [see DRUG INTERACTIONS and Use in Specific Populations].
Seizures In Pediatric Patients 6 Years Of Age And Older
The safety and effectiveness of TROKENDI XR® for treatment of partial onset seizures, primary generalized tonic-clonic seizures, or Lennox Gastaut syndromes in pediatric patients at least 6 years of age is based on controlled trials with immediate-release topiramate [see Clinical Studies].
The adverse reactions in pediatric patients treated for partial onset seizure, primary generalized tonic-clonic seizures, or Lennox Gastaut syndrome are similar to those seen in adults [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS].
These include, but are not limited to:
- oligohydrosis and hyperthermia [see WARNINGS AND PRECAUTIONS].
- dose-related increased incidence of metabolic acidosis [see WARNINGS AND PRECAUTIONS].
- dose-related increased incidence of hyperammonemia [see WARNINGS AND PRECAUTIONS].
Not Recommended For Pediatric Patients Younger Than 6 Years Of Age
The safety and effectiveness of TROKENDI XR® for treatment of partial onset seizures, primary generalized tonic-clonic seizures, or Lennox Gastaut syndromes in pediatric patients younger than 6 years of age has not been established.
Because the capsule must be swallowed whole, and may not be sprinkled on food, crushed or chewed, TROKENDI XR® is recommended only for children age 6 or older.
The following pediatric use information for adjunctive treatment for partial onset epilepsy in infants and toddlers (1 to 24 months) is based on studies conducted with immediate-release topiramate, which failed to demonstrate efficacy.
Safety and effectiveness of immediate-release topiramate in patients below the age of 2 years have not been established for the adjunctive therapy treatment of partial onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome. In a single randomized, double-blind, placebocontrolled investigational trial, the efficacy, safety, and tolerability of immediate-release topiramate oral liquid and sprinkle formulations as an adjunct to concurrent antiepileptic drug therapy in infants 1 to 24 months of age with refractory partial onset seizures, was assessed. After 20 days of double-blind treatment, immediate-release topiramate (at fixed doses of 5 mg/kg, 15 mg/kg, and 25 mg/kg per day) did not demonstrate efficacy compared with placebo in controlling seizures.
In general, the adverse reaction profile in this population was similar to that of older pediatric patients, although results from the above controlled study, and an open-label, long-term extension study in these infants/toddlers (1 to 24 months old) suggested some adverse reactions not previously observed in older pediatric patients and adults; i.e., growth/length retardation, certain clinical laboratory abnormalities, and other adverse reactions that occurred with a greater frequency and/or greater severity than had been recognized previously from studies in older pediatric patients or adults for various indications.
These very young pediatric patients appeared to experience an increased risk for infections (any topiramate dose 12%, placebo 0%) and of respiratory disorders (any topiramate dose 40%, placebo 16%). The following adverse reactions were observed in at least 3% of patients on immediate-release topiramate and were 3% to 7% more frequent than in patients on placebo: viral infection, bronchitis, pharyngitis, rhinitis, otitis media, upper respiratory infection, cough, and bronchospasm. A generally similar profile was observed in older children [see ADVERSE REACTIONS].
Immediate-release topiramate resulted in an increased incidence of patients with increased creatinine (any topiramate dose 5%, placebo 0%), BUN (any topiramate dose 3%, placebo 0%), and protein (any topiramate dose 34%, placebo 6%), and an increased incidence of decreased potassium (any topiramate dose 7%, placebo 0%). This increased frequency of abnormal values was not dose related. Creatinine was the only analyte showing a noteworthy increased incidence (topiramate 25 mg/kg/day 5%, placebo 0%) of a markedly abnormal increase [see ADVERSE REACTIONS]. The significance of these findings is uncertain.
Immediate-release topiramate treatment also produced a dose-related increase in the percentage of patients who had a shift from normal at baseline to high/increased (above the normal reference range) in total eosinophil count at the end of treatment. The incidence of these abnormal shifts was 6 % for placebo, 10% for 5 mg/kg/day, 9% for 15 mg/kg/day, 14% for 25 mg/kg/day, and 11% for any topiramate dose [see ADVERSE REACTIONS]. There was a mean dose-related increase in alkaline phosphatase. The significance of these findings is uncertain.
Treatment with immediate-release topiramate for up to 1 year was associated with reductions in Z SCORES for length, weight, and head circumference [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS].
In open-label, uncontrolled experience, increasing impairment of adaptive behavior was documented in behavioral testing over time in this population. There was a suggestion that this effect was dose-related. However, because of the absence of an appropriate control group, it is not known if this decrement in function was treatment related or reflects the patient's underlying disease (e.g., patients who received higher doses may have more severe underlying disease) [see WARNINGS AND PRECAUTIONS].
In this open-label, uncontrolled study, the mortality was 37 deaths/1000 patient years. It is not possible to know whether this mortality rate is related to immediate-release topiramate treatment, because the background mortality rate for a similar, significantly refractory, young pediatric population (1 month to 24 months) with partial epilepsy is not known.
Other Pediatric Studies
Topiramate treatment produced a dose-related increased shift in serum creatinine from normal at baseline to an increased value at the end of 4 months treatment in adolescent patients (ages 12 years to 16 years) in a doubleblind, placebo-controlled study [see ADVERSE REACTIONS].
Juvenile Animal Studies
When topiramate (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 tested. The higher of the doses not associated with effects on bone (90 mg/kg/day) is approximately 2 times the maximum recommended pediatric dose for epilepsy (9 mg/kg/day) on a body surface area (mg/m²) basis.
Clinical studies of immediate-release topiramate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Dosage adjustment is necessary for elderly with creatinine clearance less than 70 mL/min/1.73 m². Estimate GFR should be measured prior to dosing [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].
Race And Gender Effects
Evaluation of effectiveness and safety of topiramate in clinical trials has shown no race- or gender-related effects.
The clearance of topiramate was reduced by 42% in moderately renally impaired (creatinine clearance 30 to 69mL/min/1.73m²) and by 54% in severely renally impaired subjects (creatinine clearance less than 30 mL/min/1.73m²) compared to normal renal function subjects (creatinine clearance greater than 70 mL/min/1.73m²). One-half the usual starting and maintenance dose is recommended in patients with moderate or severe renal impairment [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].
Patients Undergoing Hemodialysis
Topiramate is cleared by hemodialysis at a rate that is 4 to 6 times greater than a normal individual. Accordingly, a prolonged period of dialysis may cause topiramate concentration to fall below that required to maintain an anti-seizure effect. To avoid rapid drops in topiramate plasma concentration during hemodialysis, a supplemental dose of topiramate may be required. The actual adjustment should take into account the duration of dialysis period, the clearance rate of the dialysis system being used, and the effective renal clearance of topiramate in the patient being dialyzed [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 12/30/2016
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