TOPIRAMATE Drug Interactions: What You Need to Know

INTERACTIONS Oral contraceptives: Decreased contraceptive efficacy and increased breakthrough bleeding, especially at doses greater than 200 mg per day ( 7.5 ) Monitor lithium levels if lithium is used with high-dose topiramate extended-release capsules ( 7.8 )

7.1 Alcohol Alcohol use is contraindicated within 6 hours prior to and 6 hours after topiramate extended-release capsules administration <span class="opacity-50 text-xs">[see Contraindications (4) and Warnings and Precautions ( 5.5 )]</span> .

7.2 Antiepileptic Drugs Concomitant administration of phenytoin or carbamazepine with topiramate resulted in a clinically significant decrease in plasma concentrations of topiramate when compared to topiramate given alone. A dosage adjustment may be needed <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.1 ), Clinical Pharmacology ( 12.3) ]</span> . Concomitant administration of valproic acid and topiramate has been associated with hypothermia and hyperammonemia with and without encephalopathy. Examine blood ammonia levels in patients in whom the onset of hypothermia has been reported <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.13 , 5.15 ) and Clinical Pharmacology ( 12.3 )]</span> .

7.3 Other Carbonic Anhydrase Inhibitors Concomitant use of topiramate, a carbonic anhydrase inhibitor, with any other carbonic anhydrase inhibitor (e.g., zonisamide or acetazolamide) may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation. Patients should be monitored for the appearance or worsening of metabolic acidosis when topiramate extended-release capsules is given concomitantly with another carbonic anhydrase inhibitor <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3) ]</span> .

7.4 CNS Depressants Concomitant administration of topiramate with other CNS depressant drugs or alcohol has not been evaluated in clinical studies. Because of the potential of topiramate to cause CNS depression, as well as other cognitive and/or neuropsychiatric adverse reactions, topiramate extended-release capsules should be used with extreme caution if used in combination with alcohol and other CNS depressants <span class="opacity-50 text-xs">[see Contraindications (4) and Warnings and Precautions ( 5.7) ]</span> .

7.5 Oral Contraceptives The possibility of decreased contraceptive efficacy and increased breakthrough bleeding may occur in patients taking combination oral contraceptive products with topiramate extended-release capsules. Patients taking estrogen-containing contraceptives should be asked to report any change in their bleeding patterns. Contraceptive efficacy can be decreased even in the absence of breakthrough bleeding <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .

7.6 Hydrochlorothiazide (HCTZ) Topiramate C max and AUC increased when HCTZ was added to immediate-release topiramate. The clinical significance of this change is unknown. The addition of HCTZ to topiramate extended-release capsules may require a decrease in the topiramate extended-release capsules dose <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> .

7.7 Pioglitazone A decrease in the exposure of pioglitazone and its active metabolites were noted with the concurrent use of pioglitazone and immediate-release topiramate in a clinical trial. The clinical relevance of these observations is unknown; however, when topiramate extended-release capsules is added to pioglitazone therapy or pioglitazone is added to topiramate extended-release capsules therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .

7.8 Lithium An increase in systemic exposure of lithium following topiramate doses of up to 600 mg/day can occur. Lithium levels should be monitored when co-administered with high-dose topiramate extended-release capsules <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .

7.9 Amitriptyline Some patients may experience a large increase in amitriptyline concentration in the presence of topiramate extended-release capsules and any adjustments in amitriptyline dose should be made according to the patients’ clinical response and not on the basis of plasma levels <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3) ]</span>.

7.1 Alcohol Alcohol use is contraindicated within 6 hours prior to and 6 hours after topiramate extended-release capsules administration <span class="opacity-50 text-xs">[see Contraindications (4) and Warnings and Precautions ( 5.5 )]</span> .

7.2 Antiepileptic Drugs Concomitant administration of phenytoin or carbamazepine with topiramate resulted in a clinically significant decrease in plasma concentrations of topiramate when compared to topiramate given alone. A dosage adjustment may be needed <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.1 ), Clinical Pharmacology ( 12.3) ]</span> . Concomitant administration of valproic acid and topiramate has been associated with hypothermia and hyperammonemia with and without encephalopathy. Examine blood ammonia levels in patients in whom the onset of hypothermia has been reported <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.13 , 5.15 ) and Clinical Pharmacology ( 12.3 )]</span> .

7.3 Other Carbonic Anhydrase Inhibitors Concomitant use of topiramate, a carbonic anhydrase inhibitor, with any other carbonic anhydrase inhibitor (e.g., zonisamide or acetazolamide) may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation. Patients should be monitored for the appearance or worsening of metabolic acidosis when topiramate extended-release capsules is given concomitantly with another carbonic anhydrase inhibitor <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3) ]</span> .

7.4 CNS Depressants Concomitant administration of topiramate with other CNS depressant drugs or alcohol has not been evaluated in clinical studies. Because of the potential of topiramate to cause CNS depression, as well as other cognitive and/or neuropsychiatric adverse reactions, topiramate extended-release capsules should be used with extreme caution if used in combination with alcohol and other CNS depressants <span class="opacity-50 text-xs">[see Contraindications (4) and Warnings and Precautions ( 5.7) ]</span> .

7.5 Oral Contraceptives The possibility of decreased contraceptive efficacy and increased breakthrough bleeding may occur in patients taking combination oral contraceptive products with topiramate extended-release capsules. Patients taking estrogen-containing contraceptives should be asked to report any change in their bleeding patterns. Contraceptive efficacy can be decreased even in the absence of breakthrough bleeding <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .

7.6 Hydrochlorothiazide (HCTZ) Topiramate C max and AUC increased when HCTZ was added to immediate-release topiramate. The clinical significance of this change is unknown. The addition of HCTZ to topiramate extended-release capsules may require a decrease in the topiramate extended-release capsules dose <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> .

7.7 Pioglitazone A decrease in the exposure of pioglitazone and its active metabolites were noted with the concurrent use of pioglitazone and immediate-release topiramate in a clinical trial. The clinical relevance of these observations is unknown; however, when topiramate extended-release capsules is added to pioglitazone therapy or pioglitazone is added to topiramate extended-release capsules therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .

7.8 Lithium An increase in systemic exposure of lithium following topiramate doses of up to 600 mg/day can occur. Lithium levels should be monitored when co-administered with high-dose topiramate extended-release capsules <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .

7.9 Amitriptyline Some patients may experience a large increase in amitriptyline concentration in the presence of topiramate extended-release capsules and any adjustments in amitriptyline dose should be made according to the patients’ clinical response and not on the basis of plasma levels <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3) ]</span>.

Topiramate extended-release capsules are contraindicated in patients: With recent alcohol use (i.e., within 6 hours prior to and 6 hours after topiramate extended-release capsules use) [see Warnings and Precautions ( 5.5 )] With recent alcohol use, i.e., within 6 hours prior to and 6 hours after topiramate extended-release capsules use ( 4 , 5.5 )

AND PRECAUTIONS Acute myopia and secondary angle closure glaucoma: can lead to permanent visual loss; discontinue topiramate extended-release capsules as soon as possible ( 5.1 ) Visual field defects: consider discontinuation of topiramate extended-release capsules ( 5.2 ) Oligohydrosis and hyperthermia: monitor decreased sweating and increased body temperature, especially in pediatric patients ( 5.3 ) Metabolic acidosis: baseline and periodic measurement of serum bicarbonate is recommended; consider dose reduction or discontinuation of topiramate extended-release capsules if clinically appropriate ( 5.4 ) Suicidal behavior and ideation: antiepileptic drugs increase the risk of suicidal behavior or ideation ( 5.6 ) Cognitive/neuropsychiatric adverse reactions: use caution when operating machinery including cars; depression and mood problems may occur ( 5.7 ) Fetal toxicity: use during pregnancy can cause cleft lip and/or palate and being small for gestational age (5.8) Withdrawal of AEDs: withdraw topiramate extended-release capsules gradually (5.9) Decrease in Bone Mineral Density: has been shown to decrease bone mineral density and bone mineral content in pediatric patients ( 5.10) Negative effects on growth (height and weight): may slow height increase and weight gain; carefully monitor children receiving prolonged therapy (5.11) Serious skin reactions: If SJS or TEN is suspected, discontinue topiramate extended-release capsules ( 5.12 ) Hyperammonemia/encephalopathy: measure ammonia if encephalopathic symptoms occur (5.13 ) Kidney stones: avoid use with other carbonic anhydrase inhibitors, other drugs causing metabolic acidosis, or in patients on a ketogenic diet ( 5.14 ) Hypothermia has been reported with and without hyperammonemia during topiramate treatment with concomitant valproic acid use ( 5.15 )

5.1 Acute Myopia and Secondary Angle Closure Glaucoma Syndrome A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients receiving topiramate. Symptoms include acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings can include some or all of the following: myopia, mydriasis, anterior chamber shallowing, ocular hyperemia (redness), choroidal detachments, retinal pigment epithelial detachments, macular striae, and increased intraocular pressure. This syndrome may be associated with supraciliary effusion resulting in anterior displacement of the lens and iris, with secondary angle closure glaucoma. 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 topiramate extended-release capsules as rapidly as possible, according to the judgment of the treating physician. Other measures, in conjunction with discontinuation of topiramate extended-release capsules, may be helpful. Elevated intraocular pressure of any etiology, if left untreated, can lead to serious sequelae including permanent vision loss.

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

5.3 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 topiramate extended-release capsules should be monitored closely for evidence of decreased sweating and increased body temperature, especially in hot weather. Caution should be used when topiramate extended-release capsules is given 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.

5.4 Metabolic Acidosis Topiramate extended-release capsules can cause hyperchloremic, non-anion gap, metabolic acidosis (i.e., decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis). This metabolic acidosis is caused by renal bicarbonate loss due carbonic anhydrase inhibition by topiramate extended-release capsules. Topiramate extended-release capsules-induced metabolic acidosis can occur at any time during treatment. Bicarbonate decrements are usually mild to moderate (average decrease of 4 mEq/L at daily doses of 400 mg in adults and at approximately 6 mg/kg/day in pediatric patients); rarely, patients can experience severe decrements to values below 10 mEq/L. Conditions or therapies that predispose patients to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhea, ketogenic diet, or specific drugs) may be additive to the bicarbonate lowering effects of topiramate extended-release capsules. Metabolic acidosis was commonly observed in adult and pediatric patients treated with immediate-release topiramate in clinical trials. The incidence of decreased serum bicarbonate in pediatric trials for adjunctive treatment of Lennox-Gastaut syndrome or refractory partial onset seizures was as high as 67% for immediate-release topiramate (at approximately 6 mg/kg/day), and 10% for placebo. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value &lt;17 mEq/L and ≥5mEq/L decrease from pretreatment) in these trials was up to 11%, compared to ≤2% for placebo. Manifestations of acute or chronic metabolic acidosis may include hyperventilation, nonspecific symptoms such as fatigue and anorexia, or more severe sequelae including cardiac arrhythmias or stupor. Chronic, untreated metabolic acidosis may increase the risk for nephrolithiasis or nephrocalcinosis and may also result in osteomalacia (referred to as rickets in pediatric patients) and/or osteoporosis with an increased risk for fractures <span class="opacity-50 text-xs">[see Warnings and Precautions (5.10 , 5.14 )]</span> . A one-year, active-controlled study of pediatric patients treated with immediate-release topiramate demonstrated that immediate-release 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.10) , Use in Specific Populations ( 8.4 )]</span>. 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. Reductions in length and weight were correlated to the degree of acidosis <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.4 )]</span> . Topiramate extended-release capsules 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.8 ) and Use in Specific Populations ( 8.1 )]</span> . Measurement of Serum Bicarbonate in Epilepsy and Migraine Patients 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 extended-release capsules (using dose tapering). If the decision is made to continue patients on topiramate extended-release capsules in the face of persistent acidosis, alkali treatment should be considered.

5.5 Interaction With Alcohol In vitro data show that, in the presence of alcohol, the pattern of topiramate release from topiramate extended-release capsules is significantly altered. As a result, plasma levels of topiramate with topiramate extended-release capsules 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 topiramate extended-release capsules administration.

5.6 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 topiramate extended-release capsules 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 Epilepsy 1.0 3.4 3.5

2.4 Psychiatric 5.7 8.5 1.5

2.9 Other 1.0 1.8 1.9

0.9 Total 2.4 4.3 1.8

1.9 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 topiramate extended-release capsules 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.

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

Adult Patients

Cognitive-Related Dysfunction Rapid titration rate and higher initial dose were associated with higher incidences of cognitive-related dysfunction. In adult adjunctive epilepsy controlled trials, which used rapid titration (100 mg/day to 200 mg/day weekly increments), and target immediate-release topiramate doses of 200 mg/day to 1,000 mg/day, 56% of patients in the 800 mg/day and 1,000 mg/day dose groups experienced cognitive-related dysfunction compared to approximately 42% of patients in the 200 mg/day to 400 mg/day groups and 14% for placebo. In this rapid titration regimen, these dose-related adverse reactions began in the titration or in the maintenance phase, and in some patients these events began during titration and persisted into the maintenance phase. In the monotherapy epilepsy controlled trial conducted with immediate-release topiramate, the proportion of patients who experienced one or more cognitive-related adverse reactions was 19% for topiramate 50 mg per day and 26% for 400 mg per day. In the 6-month controlled trials for the preventive treatment of migraine with immediate-release topiramate using a slower titration regimen (25 mg 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. Cognitive adverse reactions most commonly developed during titration and sometimes persisted after completion of titration.

Psychiatric/Behavioral

Disturbances Psychiatric/behavioral disturbances (e.g., depression, mood) were dose-related for both the adjunctive epilepsy and migraine populations treated with topiramate [see Warnings and Precautions ( 5.6) ] .

Somnolence/Fatigue

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

Pediatric

Patients In pediatric epilepsy trials (adjunctive and monotherapy) conducted with topiramate, the incidence of cognitive/neuropsychiatric adverse reactions in pediatric patients was generally lower than that observed in adults. These reactions included psychomotor slowing, difficulty with concentration/attention, speech disorders/related speech problems and language problems. The most frequently reported neuropsychiatric reactions in pediatric epilepsy patients during adjunctive therapy double-blind studies were somnolence and fatigue. The most frequently reported cognitive/neuropsychiatric reactions in pediatric epilepsy patients in the 50 mg/day and 400 mg/day groups during the monotherapy double-blind study were headache, dizziness, anorexia, and somnolence. In pediatric migraine patients, the incidence of cognitive/neuropsychiatric adverse reactions was increased in immediate-release topiramate-treated patients compared to placebo. The risk for cognitive/neuropsychiatric adverse reactions was dose-dependent, and was greatest at the highest dose (200 mg). This risk for cognitive/neuropsychiatric adverse reactions was also greater in younger patients (6 to 11 years of age) than in older patients (12 to 17 years of age). The most common cognitive/neuropsychiatric adverse reaction in these trials was difficulty with concentration/attention. Cognitive adverse reactions most commonly developed during titration and sometimes persisted for various durations after completion of titration.

The Cambridge Neuropsychological Test Automated

Battery (CANTAB) was administered to adolescents (12 to 17 years of age) to assess the effects of topiramate on cognitive function at baseline at the end of the Study 3 [see Clinical Studies ( 14.4 )] . Mean change from baseline in certain CANTAB tests suggests that topiramate treatment may result in psychomotor slowing and decreased verbal fluency.

5.8 Fetal Toxicity Topiramate extended-release capsules 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 <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 )]</span> . Consider the benefits and risks of topiramate extended-release capsules when administering the drug in women of childbearing potential, particularly when topiramate extended-release capsules is considered for a condition not usually associated with permanent injury or death <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 )]</span> . Topiramate extended-release capsules 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 <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1 )]</span> .

5.9 Withdrawal of Antiepileptic Drugs In patients with or without a history of seizures or epilepsy, antiepileptic drugs, including topiramate extended-release capsules, should be gradually withdrawn to minimize the potential for seizures or increased seizure frequency <span class="opacity-50 text-xs">[see Clinical Studies ( 14) ]</span> . In situations where rapid withdrawal of topiramate extended-release capsules is medically required, appropriate monitoring is recommended.

5.10 Decrease in Bone Mineral Density Results of a one-year active-controlled study in pediatric patients (N=63) demonstrated negative effects of immediate-release topiramate monotherapy on bone mineral acquisition via statistically significant decreases in bone mineral density (BMD) measured in lumbar spine and in total body less head <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.4 )]</span>. Twenty-one percent of immediate-release topiramate-treated patients experienced clinically important reductions in BMD (Z score change from baseline of -0.5 or greater) compared to 0 patients in the control group. Although decreases in BMD occurred across all pediatric age subgroups, patients 6 to 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.4) ]</span>. Although small decreases in some markers of bone metabolism (e.g., serum alkaline phosphatase, calcium, phosphorus, and 1,25-dihydroxyvitamin D) occurred in immediate-release topiramate-treated patients, more significant decreases in serum parathyroid hormone and 25-hydroxyvitamin D, hormones involved in bone metabolism, were observed, along with an increased excretion of urinary calcium.

5.11 Negative Effects on Growth (Height and Weight) Results of a one-year active-controlled study of pediatric patients (N=63) demonstrated negative effects of immediate-release topiramate monotherapy on growth (i.e., height and weight) <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.4) ]</span> . Although continued growth was observed in both treatment groups, the immediate-release topiramate group showed statistically significant reductions in mean annual change from baseline in body weight compared to the control group. A similar trend of attenuation in height velocity and height change from baseline was also observed in the immediate-release topiramate group compared to the control group. Negative effects on weight and height were seen across all immediate-release topiramate age subgroups. Growth (height and weight) of children receiving prolonged topiramate extended-release capsules therapy should be carefully monitored.

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

5.13 Hyperammonemia and Encephalopathy (Without and With Concomitant Valproic Acid Use) Topiramate treatment can cause hyperammonemia with or without encephalopathy <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2)]</span> . The risk for hyperammonemia with topiramate appears dose-related. Hyperammonemia has been reported more frequently when topiramate is used concomitantly with valproic acid. Postmarketing cases of hyperammonemia with or without encephalopathy have been reported with topiramate and valproic acid in patients who previously tolerated either drug alone <span class="opacity-50 text-xs">[see Drug Interactions (7.2) ]</span> . Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy and/or vomiting. In most cases, hyperammonemic encephalopathy abated with discontinuation of treatment. The incidence of hyperammonemia in pediatric patients 12 to 17 years of age in the preventive treatment of migraine trials was 26% in patients taking topiramate monotherapy at 100 mg/day, and 14% in patients taking topiramate at 50 mg/day, compared to 9% in patients taking placebo. There was also an increased incidence of markedly increased hyperammonemia at the 100 mg dose. Dose-related hyperammonemia was also seen in pediatric patients 1 to 24 months of age treated with topiramate and concomitant valproic acid for partial onset epilepsy, and this was not due to a pharmacokinetic interaction. In some patients, hyperammonemia can be asymptomatic. Monitoring for Hyperammonemia Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy. Although not studied, topiramate or topiramate extended-release capsules 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.

5.14 Kidney Stones Topiramate increases the risk of kidney stones. During adjunctive epilepsy trials, the risk for kidney stones in immediate-release topiramate-treated adults was 1.5%, an incidence about 2 to 4 times greater than expected in a similar, untreated population. As in the general population, the incidence of stone formation among topiramate-treated patients was higher in men. Kidney stones have also been reported in pediatric patients taking topiramate for epilepsy or migraine. During long-term (up to 1 year) topiramate treatment in an open-label extension study of 284 pediatric patients 1 to 24 months old with epilepsy, 7% developed kidney or bladder stones. Topiramate extended-release capsules would be expected to have the same effect as immediate-release topiramate on the formation of kidney stones. Topiramate extended-release capsules are not approved for treatment of epilepsy in pediatric patients less than 6 years old <span class="opacity-50 text-xs">[see Use in Specific Populations (8.4) ]</span> . Topiramate is a carbonic anhydrase inhibitor. Carbonic anhydrase inhibitors can promote stone formation by reducing urinary citrate excretion and by increasing urinary pH <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.4 )]</span> . The concomitant use of topiramate extended-release capsules 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. An increase in urinary calcium and a marked decrease in urinary citrate was observed in immediate-release topiramate-treated pediatric patients in a one-year active-controlled study <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.4 )]</span>. This increased ratio of urinary calcium/citrate increases the risk of kidney stones and/or nephrocalcinosis.

5.15 Hypothermia With Concomitant Valproic Acid Use Hypothermia, defined as a drop in body core temperature to &lt; 35ºC (95ºF), has been reported in association with topiramate use with concomitant valproic acid (VPA) both in conjunction with 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 <span class="opacity-50 text-xs">[see Drug Interactions ( 7.2) ]</span> . Consideration should be given to stopping topiramate extended-release capsules or valproate in patients who develop hypothermia, which may be manifested by a variety of clinical abnormalities including lethargy, confusion, coma, and significant alterations in other major organ systems such as the cardiovascular and respiratory systems. Clinical management and assessment should include examination of blood ammonia levels.

5.1 Acute Myopia and Secondary Angle Closure Glaucoma Syndrome A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients receiving topiramate. Symptoms include acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings can include some or all of the following: myopia, mydriasis, anterior chamber shallowing, ocular hyperemia (redness), choroidal detachments, retinal pigment epithelial detachments, macular striae, and increased intraocular pressure. This syndrome may be associated with supraciliary effusion resulting in anterior displacement of the lens and iris, with secondary angle closure glaucoma. 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 topiramate extended-release capsules as rapidly as possible, according to the judgment of the treating physician. Other measures, in conjunction with discontinuation of topiramate extended-release capsules, may be helpful. Elevated intraocular pressure of any etiology, if left untreated, can lead to serious sequelae including permanent vision loss.

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

5.3 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 topiramate extended-release capsules should be monitored closely for evidence of decreased sweating and increased body temperature, especially in hot weather. Caution should be used when topiramate extended-release capsules is given 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.

5.4 Metabolic Acidosis Topiramate extended-release capsules can cause hyperchloremic, non-anion gap, metabolic acidosis (i.e., decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis). This metabolic acidosis is caused by renal bicarbonate loss due carbonic anhydrase inhibition by topiramate extended-release capsules. Topiramate extended-release capsules-induced metabolic acidosis can occur at any time during treatment. Bicarbonate decrements are usually mild to moderate (average decrease of 4 mEq/L at daily doses of 400 mg in adults and at approximately 6 mg/kg/day in pediatric patients); rarely, patients can experience severe decrements to values below 10 mEq/L. Conditions or therapies that predispose patients to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhea, ketogenic diet, or specific drugs) may be additive to the bicarbonate lowering effects of topiramate extended-release capsules. Metabolic acidosis was commonly observed in adult and pediatric patients treated with immediate-release topiramate in clinical trials. The incidence of decreased serum bicarbonate in pediatric trials for adjunctive treatment of Lennox-Gastaut syndrome or refractory partial onset seizures was as high as 67% for immediate-release topiramate (at approximately 6 mg/kg/day), and 10% for placebo. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value &lt;17 mEq/L and ≥5mEq/L decrease from pretreatment) in these trials was up to 11%, compared to ≤2% for placebo. Manifestations of acute or chronic metabolic acidosis may include hyperventilation, nonspecific symptoms such as fatigue and anorexia, or more severe sequelae including cardiac arrhythmias or stupor. Chronic, untreated metabolic acidosis may increase the risk for nephrolithiasis or nephrocalcinosis and may also result in osteomalacia (referred to as rickets in pediatric patients) and/or osteoporosis with an increased risk for fractures <span class="opacity-50 text-xs">[see Warnings and Precautions (5.10 , 5.14 )]</span> . A one-year, active-controlled study of pediatric patients treated with immediate-release topiramate demonstrated that immediate-release 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.10) , Use in Specific Populations ( 8.4 )]</span>. 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. Reductions in length and weight were correlated to the degree of acidosis <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.4 )]</span> . Topiramate extended-release capsules 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.8 ) and Use in Specific Populations ( 8.1 )]</span> . Measurement of Serum Bicarbonate in Epilepsy and Migraine Patients 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 extended-release capsules (using dose tapering). If the decision is made to continue patients on topiramate extended-release capsules in the face of persistent acidosis, alkali treatment should be considered.

5.5 Interaction With Alcohol In vitro data show that, in the presence of alcohol, the pattern of topiramate release from topiramate extended-release capsules is significantly altered. As a result, plasma levels of topiramate with topiramate extended-release capsules 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 topiramate extended-release capsules administration.

5.6 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 topiramate extended-release capsules 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 Epilepsy 1.0 3.4 3.5

2.4 Psychiatric 5.7 8.5 1.5

2.9 Other 1.0 1.8 1.9

0.9 Total 2.4 4.3 1.8

1.9 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 topiramate extended-release capsules 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.

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

Adult Patients

Cognitive-Related Dysfunction Rapid titration rate and higher initial dose were associated with higher incidences of cognitive-related dysfunction. In adult adjunctive epilepsy controlled trials, which used rapid titration (100 mg/day to 200 mg/day weekly increments), and target immediate-release topiramate doses of 200 mg/day to 1,000 mg/day, 56% of patients in the 800 mg/day and 1,000 mg/day dose groups experienced cognitive-related dysfunction compared to approximately 42% of patients in the 200 mg/day to 400 mg/day groups and 14% for placebo. In this rapid titration regimen, these dose-related adverse reactions began in the titration or in the maintenance phase, and in some patients these events began during titration and persisted into the maintenance phase. In the monotherapy epilepsy controlled trial conducted with immediate-release topiramate, the proportion of patients who experienced one or more cognitive-related adverse reactions was 19% for topiramate 50 mg per day and 26% for 400 mg per day. In the 6-month controlled trials for the preventive treatment of migraine with immediate-release topiramate using a slower titration regimen (25 mg 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. Cognitive adverse reactions most commonly developed during titration and sometimes persisted after completion of titration.

Psychiatric/Behavioral

Disturbances Psychiatric/behavioral disturbances (e.g., depression, mood) were dose-related for both the adjunctive epilepsy and migraine populations treated with topiramate [see Warnings and Precautions ( 5.6) ] .

Somnolence/Fatigue

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

Pediatric

Patients In pediatric epilepsy trials (adjunctive and monotherapy) conducted with topiramate, the incidence of cognitive/neuropsychiatric adverse reactions in pediatric patients was generally lower than that observed in adults. These reactions included psychomotor slowing, difficulty with concentration/attention, speech disorders/related speech problems and language problems. The most frequently reported neuropsychiatric reactions in pediatric epilepsy patients during adjunctive therapy double-blind studies were somnolence and fatigue. The most frequently reported cognitive/neuropsychiatric reactions in pediatric epilepsy patients in the 50 mg/day and 400 mg/day groups during the monotherapy double-blind study were headache, dizziness, anorexia, and somnolence. In pediatric migraine patients, the incidence of cognitive/neuropsychiatric adverse reactions was increased in immediate-release topiramate-treated patients compared to placebo. The risk for cognitive/neuropsychiatric adverse reactions was dose-dependent, and was greatest at the highest dose (200 mg). This risk for cognitive/neuropsychiatric adverse reactions was also greater in younger patients (6 to 11 years of age) than in older patients (12 to 17 years of age). The most common cognitive/neuropsychiatric adverse reaction in these trials was difficulty with concentration/attention. Cognitive adverse reactions most commonly developed during titration and sometimes persisted for various durations after completion of titration.

The Cambridge Neuropsychological Test Automated

Battery (CANTAB) was administered to adolescents (12 to 17 years of age) to assess the effects of topiramate on cognitive function at baseline at the end of the Study 3 [see Clinical Studies ( 14.4 )] . Mean change from baseline in certain CANTAB tests suggests that topiramate treatment may result in psychomotor slowing and decreased verbal fluency.

5.8 Fetal Toxicity Topiramate extended-release capsules 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 <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 )]</span> . Consider the benefits and risks of topiramate extended-release capsules when administering the drug in women of childbearing potential, particularly when topiramate extended-release capsules is considered for a condition not usually associated with permanent injury or death <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 )]</span> . Topiramate extended-release capsules 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 <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1 )]</span> .

5.9 Withdrawal of Antiepileptic Drugs In patients with or without a history of seizures or epilepsy, antiepileptic drugs, including topiramate extended-release capsules, should be gradually withdrawn to minimize the potential for seizures or increased seizure frequency <span class="opacity-50 text-xs">[see Clinical Studies ( 14) ]</span> . In situations where rapid withdrawal of topiramate extended-release capsules is medically required, appropriate monitoring is recommended.

5.10 Decrease in Bone Mineral Density Results of a one-year active-controlled study in pediatric patients (N=63) demonstrated negative effects of immediate-release topiramate monotherapy on bone mineral acquisition via statistically significant decreases in bone mineral density (BMD) measured in lumbar spine and in total body less head <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.4 )]</span>. Twenty-one percent of immediate-release topiramate-treated patients experienced clinically important reductions in BMD (Z score change from baseline of -0.5 or greater) compared to 0 patients in the control group. Although decreases in BMD occurred across all pediatric age subgroups, patients 6 to 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.4) ]</span>. Although small decreases in some markers of bone metabolism (e.g., serum alkaline phosphatase, calcium, phosphorus, and 1,25-dihydroxyvitamin D) occurred in immediate-release topiramate-treated patients, more significant decreases in serum parathyroid hormone and 25-hydroxyvitamin D, hormones involved in bone metabolism, were observed, along with an increased excretion of urinary calcium.

5.11 Negative Effects on Growth (Height and Weight) Results of a one-year active-controlled study of pediatric patients (N=63) demonstrated negative effects of immediate-release topiramate monotherapy on growth (i.e., height and weight) <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.4) ]</span> . Although continued growth was observed in both treatment groups, the immediate-release topiramate group showed statistically significant reductions in mean annual change from baseline in body weight compared to the control group. A similar trend of attenuation in height velocity and height change from baseline was also observed in the immediate-release topiramate group compared to the control group. Negative effects on weight and height were seen across all immediate-release topiramate age subgroups. Growth (height and weight) of children receiving prolonged topiramate extended-release capsules therapy should be carefully monitored.

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

5.13 Hyperammonemia and Encephalopathy (Without and With Concomitant Valproic Acid Use) Topiramate treatment can cause hyperammonemia with or without encephalopathy <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2)]</span> . The risk for hyperammonemia with topiramate appears dose-related. Hyperammonemia has been reported more frequently when topiramate is used concomitantly with valproic acid. Postmarketing cases of hyperammonemia with or without encephalopathy have been reported with topiramate and valproic acid in patients who previously tolerated either drug alone <span class="opacity-50 text-xs">[see Drug Interactions (7.2) ]</span> . Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy and/or vomiting. In most cases, hyperammonemic encephalopathy abated with discontinuation of treatment. The incidence of hyperammonemia in pediatric patients 12 to 17 years of age in the preventive treatment of migraine trials was 26% in patients taking topiramate monotherapy at 100 mg/day, and 14% in patients taking topiramate at 50 mg/day, compared to 9% in patients taking placebo. There was also an increased incidence of markedly increased hyperammonemia at the 100 mg dose. Dose-related hyperammonemia was also seen in pediatric patients 1 to 24 months of age treated with topiramate and concomitant valproic acid for partial onset epilepsy, and this was not due to a pharmacokinetic interaction. In some patients, hyperammonemia can be asymptomatic. Monitoring for Hyperammonemia Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy. Although not studied, topiramate or topiramate extended-release capsules 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.

5.14 Kidney Stones Topiramate increases the risk of kidney stones. During adjunctive epilepsy trials, the risk for kidney stones in immediate-release topiramate-treated adults was 1.5%, an incidence about 2 to 4 times greater than expected in a similar, untreated population. As in the general population, the incidence of stone formation among topiramate-treated patients was higher in men. Kidney stones have also been reported in pediatric patients taking topiramate for epilepsy or migraine. During long-term (up to 1 year) topiramate treatment in an open-label extension study of 284 pediatric patients 1 to 24 months old with epilepsy, 7% developed kidney or bladder stones. Topiramate extended-release capsules would be expected to have the same effect as immediate-release topiramate on the formation of kidney stones. Topiramate extended-release capsules are not approved for treatment of epilepsy in pediatric patients less than 6 years old <span class="opacity-50 text-xs">[see Use in Specific Populations (8.4) ]</span> . Topiramate is a carbonic anhydrase inhibitor. Carbonic anhydrase inhibitors can promote stone formation by reducing urinary citrate excretion and by increasing urinary pH <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.4 )]</span> . The concomitant use of topiramate extended-release capsules 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. An increase in urinary calcium and a marked decrease in urinary citrate was observed in immediate-release topiramate-treated pediatric patients in a one-year active-controlled study <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.4 )]</span>. This increased ratio of urinary calcium/citrate increases the risk of kidney stones and/or nephrocalcinosis.

5.15 Hypothermia With Concomitant Valproic Acid Use Hypothermia, defined as a drop in body core temperature to &lt; 35ºC (95ºF), has been reported in association with topiramate use with concomitant valproic acid (VPA) both in conjunction with 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 <span class="opacity-50 text-xs">[see Drug Interactions ( 7.2) ]</span> . Consideration should be given to stopping topiramate extended-release capsules 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.