The dangerous drug attorneys at the Law Offices of Gregory Krasovsky provide legal support and representation to plaintiffs seeking to pursue a Topamax lawsuit.

In order to secure a maximum Topamax settlement, it is crucial to have a competent and experienced Topamax lawyer to guide you through all of the legal hurdles.

Contact a Topamax attorney today to schedule a free consultation and take your first step to recovering damages.

Topamax is an anticonvulsant drug, prescribed for patients with epilepsy; however, it is also approved by the FDA for migraine prevention treatment.

It has also been used to treat bipolar disorder and to counteract the effects of antidepressant medications. Unfortunately, there might be some harmful Topamax side effects, such as the following:

• Memory Loss
• Nausea
• Anorexia
• Upper Respitory Tract Infection
• Suicidal ideation, tendencies, attempts

Ortho-McNeil, the former producer of Topamax, has been fined $6.14 million for promoting Topamax for use as treatment for non-FDA approved psychiatric disorders.

While doctors are technically allowed to prescribe Topamax for any ailment, producers of drugs are not allowed to market the drug in such a way. In any case, there is no conclusive evidence that Topamax is a useful or effective treatment for most psychiatric disorders.

If you or your loved ones have experienced any serious complications as a result of Topamax (see below), or if you believe that a ill-informed prescription has been made, contact our attorneys today for a free consultation to discuss your legal options.

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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use TOPAMAX safely and effectively. See full prescribing information for TOPAMAX
TOPAMAX (topiramate) TABLETS, for oral use
TOPAMAX (topiramate capsules) SPRINKLE CAPSULES, for oral use Initial U.S. Approval: 1996

WARNINGS AND PRECAUTIONS

    Acute myopia and secondary angle closure glaucoma: can lead to permanent visual loss; discontinue TOPAMAX as soon as possible (5.1)
    Visual field defects: consider discontinuation of TOPAMAX (5.2)
    Oligohidrosis 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 TOPAMAX if clinically appropriate (5.4)
    Suicidal behavior and ideation: antiepileptic drugs increase the risk of suicidal behavior or ideation (5.5)
    Cognitive/neuropsychiatric adverse reactions: use caution when operating machinery including cars; depression and mood problems may occur (5.6)
    Fetal Toxicity: use during pregnancy can cause cleft lip and/or palate and being small for gestational age (5.7)
    Withdrawal of AEDs: withdraw TOPAMAX gradually (5.8)
    Hyperammonemia/encephalopathy: measure ammonia if encephalopathic symptoms occur (5.9)
    Kidney stones: avoid use with other carbonic anhydrase inhibitors, drugs causing metabolic acidosis, or in patients on a ketogenic diet (5.10)
    Hypothermia has been reported with and without hyperammonemia during topiramate treatment with concomitant valproic acid use (5.11)

ADVERSE REACTIONS

Epilepsy: Most common (≥10% more frequent than placebo or low-dose TOPAMAX) adverse reactions in adult and pediatric patients were: paresthesia, anorexia, weight loss, speech disorders/related speech problems, fatigue, dizziness, somnolence, nervousness, psychomotor slowing, abnormal vision and fever (6.1)  

Migraine: Most common (≥5% more frequent than placebo) adverse reactions in adult and pediatric patients were: paresthesia, anorexia, weight loss, difficulty with memory, taste perversion, diarrhea, hypoesthesia, nausea, abdominal pain and upper respiratory tract infection (6.1) 

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

    Acute Myopia and Secondary Angle Closure Glaucoma [see Warnings and Precautions (5.1)]
    Visual Field Defects [see Warnings and Precautions (5.2)]
    Oligohidrosis and Hyperthermia [see Warnings and Precautions (5.3)]
    Metabolic Acidosis [see Warnings and Precautions (5.4)]
    Suicidal Behavior and Ideation [see Warnings and Precautions (5.5)]
    Cognitive/Neuropsychiatric Adverse Reactions [see Warnings and Precautions (5.6)]
    Hyperammonemia and Encephalopathy (Without and With Concomitant Valproic Acid [VPA] Use) [see Warnings and Precautions (5.9)]
    Kidney Stones [see Warnings and Precautions (5.10)]
    Hypothermia with Concomitant Valproic Acid (VPA) Use [see Warnings and Precautions (5.11)]

https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020505s057_020844s048lbl.pdf

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TOPAMAX- topiramate tablet, coated

• 5 WARNINGS AND PRECAUTIONS

   

   

  5.1 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 TOPAMAX® (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 TOPAMAX® therapy. In contrast to primary narrow angle glaucoma, which is rare under 40 years of age, secondary angle closure glaucoma associated with topiramate has been reported in pediatric patients as well as adults. The primary treatment to reverse symptoms is discontinuation of TOPAMAX® as rapidly as possible, according to the judgment of the treating physician. Other measures, in conjunction with discontinuation of TOPAMAX®, may be helpful.

  Elevated intraocular pressure of any etiology, if left untreated, can lead to serious sequelae including permanent vision loss.

   

  5.2 Oligohidrosis and Hyperthermia

  Oligohidrosis (decreased sweating), infrequently resulting in hospitalization, has been reported in association with TOPAMAX® 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 TOPAMAX® should be monitored closely for evidence of decreased sweating and increased body temperature, especially in hot weather. Caution should be used when TOPAMAX® 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.

   

  5.3 Metabolic Acidosis

  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 TOPAMAX® treatment. 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-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.

  In adults, the incidence of persistent treatment-emergent decreases in serum bicarbonate (levels of <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/day, and 1% for placebo. Metabolic acidosis has been observed at doses as low as 50 mg/day. The incidence of persistent treatment-emergent decreases in serum bicarbonate in adults in the epilepsy controlled clinical trial for monotherapy was 15% for 50 mg/day and 25% for 400 mg/day. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value <17 mEq/L and >5 mEq/L decrease from pretreatment) in the adjunctive therapy trials was 3% for 400 mg/day, and 0% for placebo and in the monotherapy trial was 1% for 50 mg/day and 7% for 400 mg/day. Serum bicarbonate levels have not been systematically evaluated at daily doses greater than 400 mg/day.

  In pediatric patients (2 to 16 years of age), the incidence of persistent treatment-emergent decreases in serum bicarbonate in placebo-controlled trials for adjunctive treatment of Lennox-Gastaut syndrome or refractory partial onset seizures was 67% for TOPAMAX® (at approximately 6 mg/kg/day), and 10% for placebo. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value <17 mEq/L and >5 mEq/L decrease from pretreatment) in these trials was 11% for TOPAMAX® 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.

  Although not approved for use in patients under 2 years of age with partial onset seizures, a controlled trial that examined this population 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 <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., <17 mEq/L and >5 mEq/L decrease from baseline of ≥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 Special Populations (8.4)].

  In pediatric patients (6 to 15 years of age), the incidence of persistent treatment-emergent decreases in serum bicarbonate in the epilepsy controlled clinical trial for monotherapy was 9% for 50 mg/day and 25% for 400 mg/day. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value <17 mEq/L and >5 mEq/L decrease from pretreatment) in this trial was 1% for 50 mg/day and 6% for 400 mg/day. In adult patients (≥16 years of age), the incidence of persistent treatment-emergent decreases in serum bicarbonate in the epilepsy controlled clinical trial for monotherapy was 14% for 50 mg/day and 25% for 400 mg/day. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value <17 mEq/L and >5 mEq/L decrease from pretreatment) in this trial for adults was 1% for 50 mg/day and 6% for 400 mg/day.

  The incidence of persistent treatment-emergent decreases in serum bicarbonate in placebo-controlled trials for adults for prophylaxis of migraine was 44% for 200 mg/day, 39% for 100 mg/day, 23% for 50 mg/day, and 7% for placebo. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value <17 mEq/L and >5 mEq/L decrease from pretreatment) in these trials was 11% for 200 mg/day, 9% for 100 mg/day, 2% for 50 mg/day, and <1% for placebo.

  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. Long-term, 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 sex-matched 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 Use in Specific Populations (8.4)]. 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 Warnings and Precautions (5.6) and Use in Specific Populations (8.1)].

  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.

   

  5.4 Suicidal Behavior and Ideation

  Antiepileptic drugs (AEDs), including TOPAMAX®, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED 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 4 shows absolute and relative risk by indication for all evaluated AEDs.

  Table 4: Risk by Indication for Antiepileptic Drugs in the Pooled Analysis

  Indication	Placebo Patients with Events per 1000 Patients	Drug Patients with Events per 1000 Patients	Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients	Risk Difference: Additional Drug Patients with Events per 1000 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 TOPAMAX® 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, or behavior or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

   

  5.5 Cognitive/Neuropsychiatric Adverse Reactions

  Adverse reactions most often associated with the use of TOPAMAX® were related to the central nervous system and were observed in both the epilepsy and migraine populations. In adults, the most frequent of these can be classified into three general categories: 1) Cognitive-related dysfunction (e.g., confusion, psychomotor slowing, difficulty with concentration/attention, difficulty with memory, speech or language problems, particularly word-finding difficulties); 2) Psychiatric/behavioral disturbances (e.g., depression or mood problems); and 3) Somnolence or fatigue.

   

  Adult Patients

   

  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 (6)].

  In the add-on epilepsy controlled trials (using rapid titration such as 100–200 mg/day weekly increments), the proportion of patients who experienced one or more cognitive-related adverse reactions was 42% for 200 mg/day, 41% for 400 mg/day, 52% for 600 mg/day, 56% for 800 and 1,000 mg/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 cognitive-related adverse reactions in the titration phase had a dose-related recurrence of these reactions in the maintenance phase.

  In the monotherapy epilepsy controlled trial, the proportion of patients who experienced one or more cognitive-related adverse reactions was 19% for TOPAMAX® 50 mg/day and 26% for 400 mg/day.

  In the 6-month migraine prophylaxis controlled trials using a slower titration regimen (25 mg/day weekly increments), the proportion of patients who experienced one or more cognitive-related adverse reactions was 19% for TOPAMAX® 50 mg/day, 22% for 100 mg/day (the recommended dose), 28% for 200 mg/day, and 10% for placebo. These dose-related adverse reactions typically began in the titration phase and often persisted into the maintenance phase, but infrequently began in the maintenance phase. Some patients experienced a recurrence of one or more of these cognitive adverse reactions and this recurrence was typically in the titration phase. A relatively small proportion of topiramate-treated patients experienced more than one concurrent cognitive adverse reaction. The most common cognitive adverse reactions occurring together included difficulty with memory along with difficulty with concentration/attention, difficulty with memory along with language problems, and difficulty with concentration/attention along with language problems. Rarely, topiramate-treated patients experienced three concurrent cognitive reactions.

   

  Psychiatric/Behavioral Disturbances

  Psychiatric/behavioral disturbances (depression or mood) were dose-related for both the epilepsy and migraine populations [see Warnings and Precautions (5.4)].

   

  Somnolence/Fatigue

  Somnolence and fatigue were the adverse reactions most frequently reported during clinical trials of TOPAMAX® for adjunctive epilepsy. For the adjunctive epilepsy population, the incidence of somnolence did not differ substantially between 200 mg/day and 1,000 mg/day, but the incidence of fatigue was dose-related and increased at dosages above 400 mg/day. For the monotherapy epilepsy population in the 50 mg/day and 400 mg/day groups, the incidence of somnolence was dose-related (9% for the 50 mg/day group and 15% for the 400 mg/day group) and the incidence of fatigue was comparable in both treatment groups (14% each). For the migraine population, fatigue and somnolence were dose-related and more common in the titration phase.

  Additional nonspecific CNS events commonly observed with topiramate in the add-on epilepsy population included dizziness or ataxia.

   

  Pediatric Patients

  In double-blind adjunctive therapy and monotherapy epilepsy clinical studies, 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/day and 400 mg/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, 1 pediatric patient (2%) in the 50 mg/day group and 7 pediatric patients (12%) in the 400 mg/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/day group.

   

  5.6 Fetal Toxicity

  TOPAMAX® can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in utero have an increased risk for cleft lip and/or cleft palate (oral clefts). When multiple species of pregnant animals received topiramate at clinically relevant doses, structural malformations, including craniofacial defects, and reduced fetal weights occurred in offspring [see Use in Specific Populations (8.1)].

  Consider the benefits and the risks of TOPAMAX® when administering this drug in women of childbearing potential, particularly when TOPAMAX® is considered for a condition not usually associated with permanent injury or death [see Use in Specific Populations (8.9) and Patient Counseling Information (17.8)]. TOPAMAX® 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 apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1) and (8.9)].

   

  5.7 Withdrawal of Antiepileptic Drugs (AEDs)

  In patients with or without a history of seizures or epilepsy, antiepileptic drugs, including TOPAMAX®, should be gradually withdrawn to minimize the potential for seizures or increased seizure frequency [see Clinical Studies (14)]. In situations where rapid withdrawal of TOPAMAX® is medically required, appropriate monitoring is recommended.

   

  5.8 Sudden Unexplained Death in Epilepsy (SUDEP)

  During the course of premarketing development of topiramate tablets, 10 sudden and unexplained deaths were recorded among a cohort of treated patients (2796 subject years of exposure). This represents an incidence of 0.0035 deaths per patient year. Although this rate exceeds that expected in a healthy population matched for age and sex, it is within the range of estimates for the incidence of sudden unexplained deaths in patients with epilepsy not receiving TOPAMAX® (ranging from 0.0005 for the general population of patients with epilepsy, to 0.003 for a clinical trial population similar to that in the TOPAMAX® program, to 0.005 for patients with refractory epilepsy).

   

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

   

  Hyperammonemia/Encephalopathy Without Concomitant Valproic Acid (VPA)

  Topiramate treatment has produced hyperammonemia (in some instances dose-related) in clinical investigational programs of adolescents (12–16 years) who were treated with topiramate monotherapy for migraine prophylaxis (incidence above the upper limit of normal, 22% for placebo, 26% for 50 mg/day, 41% for 100 mg/day) and in very young pediatric patients (1–24 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). TOPAMAX® is not approved as monotherapy for migraine prophylaxis in adolescent patients or as adjunctive treatment of partial onset seizures in pediatric patients less than 2 years old. In some patients, ammonia was markedly increased (≥50% above upper limit of normal). In adolescent patients, the incidence of markedly increased hyperammonemia was 6% for placebo, 6% for 50 mg, and 12% for 100 mg topiramate daily. The hyperammonemia associated with topiramate treatment occurred with and without encephalopathy in placebo-controlled trials and in an open-label, extension trial. 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 post-marketing 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 post-marketing 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 TOPAMAX® is not indicated for use in infants/toddlers (1–24 months), VPA clearly produced a dose-related increase in the incidence of treatment-emergent 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. Markedly increased, dose-related hyperammonemia (0% for placebo and 5 mg/kg/day, 7% for 15 mg/kg/day, 8% for 25 mg/kg/day) also occurred in these infants/toddlers. Dose-related hyperammonemia was similarly observed in a long-term extension trial in these very young, pediatric patients [see Use in Specific Populations (8.4)].

  Hyperammonemia with and without encephalopathy has also been observed in post-marketing reports in patients taking topiramate with VPA.

  The hyperammonemia associated with topiramate treatment appears to be more common when topiramate is 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 treatment or an interaction of concomitant topiramate 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.

   

  5.10 Kidney Stones

  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. During long-term (up to 1 year) topiramate treatment in an open-label extension study of 284 pediatric patients 1–24 months old with epilepsy, 7% developed kidney or bladder stones that were diagnosed clinically or by sonogram. TOPAMAX® is not approved for pediatric patients less than 2 years old [see Use in Specific Populations (8.4)].

  An explanation for the association of TOPAMAX® and kidney stones may lie 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 Warnings and Precautions (5.3)]. The concomitant use of TOPAMAX® 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.

   

  5.11 Hypothermia with Concomitant Valproic Acid (VPA) Use

  Hypothermia, defined as an unintentional drop in body core temperature to <35°C (95°F), has been reported in association with topiramate use with concomitant valproic acid (VPA) both in conjunction with hyperammonemia 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 (7.1)]. 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.

   

  5.12 Paresthesia

  Paresthesia (usually tingling of the extremities), an effect associated with the use of other carbonic anhydrase inhibitors, appears to be a common effect of TOPAMAX®. Paresthesia was more frequently reported in the monotherapy epilepsy trials and migraine prophylaxis trials than in the adjunctive therapy epilepsy trials. In the majority of instances, paresthesia did not lead to treatment discontinuation.

   

  5.13 Adjustment of Dose in Renal Failure

  The major route of elimination of unchanged topiramate and its metabolites is via the kidney. Dosage adjustment may be required in patients with reduced renal function [see Dosage and Administration (2.4)].

   

  5.14 Decreased Hepatic Function

  In hepatically impaired patients, TOPAMAX® should be administered with caution as the clearance of topiramate may be decreased [see Dosage and Administration (2.7)].

   

  5.15 Monitoring: Laboratory Tests

  Topiramate treatment was associated with changes in several clinical laboratory analytes in randomized, double-blind, placebo-controlled studies.

  Topiramate treatment causes non-anion gap, hyperchloremic metabolic acidosis manifested by a decrease in serum bicarbonate and an increase in serum chloride. Measurement of baseline and periodic serum bicarbonate during TOPAMAX® treatment is recommended [see Warnings and Precautions (5.3)].

  Controlled trials of adjunctive topiramate treatment of adults for partial onset seizures showed an increased incidence of markedly decreased serum phosphorus (6% topiramate, 2% placebo), markedly increased serum alkaline phosphatase (3% topiramate, 1% placebo), and decreased serum potassium (0.4 % topiramate, 0.1 % placebo). The clinical significance of these abnormalities has not been clearly established.

  Changes in several clinical laboratory values (i.e., increased creatinine, BUN, alkaline phosphatase, total protein, total eosinophil count, and decreased potassium) have been observed in a clinical investigational program in very young (<2 years) pediatric patients who were treated with adjunctive topiramate for partial onset seizures [see Use in Specific Populations (8.4)].

  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 12–16 years) who were treated for migraine prophylaxis in a double-blind, placebo-controlled study.

  TOPAMAX® treatment with or without concomitant valproic acid (VPA) can cause hyperammonemia with or without encephalopathy [see Warnings and Precautions (5.9)].

  Close
• 6 ADVERSE REACTIONS

   

  Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

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

  • Acute Myopia and Secondary Angle Closure [see Warnings and Precautions (5.1)]
  • Oligohidrosis and Hyperthermia [see Warnings and Precautions (5.2)]
  • Metabolic Acidosis [see Warnings and Precautions (5.3)]
  • Suicidal Behavior and Ideation [see Warnings and Precautions (5.4)]
  • Cognitive/Neuropsychiatric Adverse Reactions [see Warnings and Precautions (5.5)]
  • Fetal Toxicity [see Warnings and Precautions (5.6) and Use in Specific Populations (8.1)]
  • Withdrawal of Antiepileptic Drugs (AEDs) [see Warnings and Precautions (5.7)]
  • Sudden Unexplained Death in Epilepsy (SUDEP) [see Warnings and Precautions (5.8)]
  • Hyperammonemia and Encephalopathy (Without and With Concomitant Valproic Acid [VPA] Use [see Warnings and Precautions (5.9)]
  • Kidney Stones [see Warnings and Precautions (5.10)]
  • Hypothermia with Concomitant Valproic Acid (VPA) Use [see Warnings and Precautions (5.11)]
  • Paresthesia [see Warnings and Precautions (5.12)]

  The data described in the following sections were obtained using TOPAMAX® (topiramate) Tablets.

 https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=88c9d1ca-f3a8-4078-8de7-21fd9040dd20

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