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Topiramate

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Overview

What is Topiramate?

Topiramate is a sulfamate-substituted monosaccharide. Topiramate tablets are available as 25 mg, 50 mg, 100 mg, and 200 mg capsule-shaped tablets for oral administration.

Topiramate is a white crystalline powder with a bitter taste. Topiramate is most soluble in alkaline solutions containing sodium hydroxide or sodium phosphate and having a pH of 9 to 10. It is freely soluble in acetone, chloroform, dimethylsulfoxide, and ethanol. The solubility in water is 9.8 mg/mL. Its saturated solution has a pH of 6.3. Topiramate is designated chemically as 2,3:4,5-Di--isopropylidene-β-D-fructopyranose sulfamate and has the following structural formula:

CHNOS M.W. 339.37

Topiramate tablets contain the following inactive ingredients: colloidal silicon dioxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, pregelatinized starch, sodium starch glycolate, and titanium dioxide. In addition: the 50 mg tablets also contain iron oxide yellow, polyvinyl alcohol-part. hydrolyzed, and talc; the 25 mg, 100 mg, and 200 mg tablets also contain hypromellose and polydextrose; the 100 mg tablets also contain iron oxide yellow and iron oxide black; the 200 mg tablets also contain iron oxide red, FD&C red #40, and FD&C blue #2.



What does Topiramate look like?



What are the available doses of Topiramate?

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What should I talk to my health care provider before I take Topiramate?

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How should I use Topiramate?

Topiramate tablets are indicated as initial monotherapy in patients 10 years of age and older with partial onset or primary generalized tonic-clonic seizures.

Effectiveness was demonstrated in a controlled trial in patients with epilepsy who had no more than 2 seizures in the 3 months prior to enrollment. Safety and effectiveness in patients who were converted to monotherapy from a previous regimen of other anticonvulsant drugs have not been established in controlled trials.

In the controlled add-on trials, no correlation has been demonstrated between trough plasma concentrations of topiramate and clinical efficacy. No evidence of tolerance has been demonstrated in humans. Doses above 400 mg/day (600, 800, or 1000 mg/day) have not been shown to improve responses in dose-response studies in adults with partial onset seizures.

It is not necessary to monitor topiramate plasma concentrations to optimize topiramate therapy. On occasion, the addition of topiramate to phenytoin may require an adjustment of the dose of phenytoin to achieve optimal clinical outcome. Addition or withdrawal of phenytoin and/or carbamazepine during adjunctive therapy with topiramate tablets may require adjustment of the dose of topiramate. Because of the bitter taste, tablets should not be broken.

Topiramate tablets can be taken without regard to meals.


What interacts with Topiramate?

Topiramate tablets are contraindicated in patients with a history of hypersensitivity to any component of this product.



What are the warnings of Topiramate?

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 topiramate 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 postmarketing 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 to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhea, surgery, ketogenic diet, or 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 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 ( 5 mEq/L decrease from pretreatment) in these trials was 11% for topiramate and 0% for placebo. Cases of moderately severe metabolic acidosis have been reported in patients as young as 5 months old, especially at daily doses above 5 mg/kg/day.

In pediatric patients (10 years up to 16 years of age), the incidence of persistent treatment-emergent decreases in serum bicarbonate in the epilepsy controlled clinical trial for monotherapy was 7% for 50 mg/day and 20% for 400 mg/day. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value 5 mEq/L decrease from pretreatment) in this trial was 4% for 50 mg/day and 4% for 400 mg/day.

The incidence of persistent treatment-emergent decreases in serum bicarbonate in placebo-controlled trials for adults 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 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
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.

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.

Acute Myopia and Secondary Angle Closure Glaucoma

A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients receiving topiramate. Symptoms include acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings can include myopia, anterior chamber shallowing, ocular hyperemia (redness) and increased intraocular pressure. Mydriasis may or may not be present. This syndrome may be associated with supraciliary effusion resulting in anterior displacement of the lens and iris, with secondary angle closure glaucoma. Symptoms typically occur within 1 month of initiating topiramate therapy. In contrast to primary narrow angle glaucoma, which is rare under 40 years of age, secondary angle closure glaucoma associated with topiramate has been reported in pediatric patients as well as adults. The primary treatment to reverse symptoms is discontinuation of topiramate as rapidly as possible, according to the judgement of the treating physician. Other measures, in conjunction with discontinuation of topiramate, may be helpful.

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

Oligohidrosis and Hyperthermia

Oligohidrosis (decreased sweating), infrequently resulting in hospitalization, 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 children. Patients, especially pediatric patients, treated with topiramate should be monitored closely for evidence of decreased sweating and increased body temperature, especially in hot weather. Caution should be used when topiramate 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.

Withdrawal of AEDs

Antiepileptic drugs, including topiramate tablets, should be withdrawn gradually to minimize the potential of increased seizure frequency.

Cognitive/Neuropsychiatric Adverse Events

Adults

Adverse events most often associated with the use of topiramate were related to the central nervous system and were observed in the epilepsy 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.

Cognitive-related dysfunction

The majority of cognitive-related adverse events 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 events. Many of these events contributed to withdrawal from treatment [see , and ].

In the original add-on epilepsy controlled trials (using rapid titration such as 100 to 200 mg/day weekly increments), the proportion of patients who experienced one or more cognitive-related adverse events was 42% for 200 mg/day, 41% for 400 mg/day, 52% for 600 mg/day, 56% for 800 and 1000 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 events in the titration phase had a dose-related recurrence of these events in the maintenance phase.

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

Psychiatric/behavioral disturbances

Psychiatric/behavioral disturbances (depression or mood problems) were dose-related for the epilepsy population.

Somnolence/fatigue

Somnolence and fatigue were the adverse events most frequently reported during clinical trials of topiramate for adjunctive epilepsy. For the adjunctive epilepsy population, the incidence of somnolence did not differ substantially between 200 mg/day and 1000 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).

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

Pediatric Patients

In double-blind adjunctive therapy and monotherapy epilepsy clinical studies, the incidences of cognitive/neuropsychiatric adverse events in pediatric patients were generally lower than observed in adults. These events included psychomotor slowing, difficulty with concentration/attention, speech disorders/related speech problems and language problems. The most frequently reported neuropsychiatric events in pediatric patients during adjunctive therapy double-blind studies were somnolence and fatigue. The most frequently reported neuropsychiatric events 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 events 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 events. The most common adverse event associated with discontinuation of therapy was difficulty with concentration/attention; all occurred in the 400 mg/day group.

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 (2,796 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 topiramate (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 topiramate program, to 0.005 for patients with refractory epilepsy).


What are the precautions of Topiramate?

Hyperammonemia and Encephalopathy Associated With Concomitant Valproic Acid Use

Concomitant administration of topiramate and valproic acid has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone. 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 event is not due to a pharmacokinetic interaction.

It is not known if topiramate monotherapy is associated with 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, an interaction of topiramate and valproic acid may exacerbate existing defects or unmask deficiencies in susceptible persons.

In patients who develop unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured.

Kidney Stones

A total of 32/2,086 (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.

An explanation for the association of topiramate and kidney stones may lie in the fact that topiramate is a carbonic anhydrase inhibitor. Carbonic anhydrase inhibitors, e.g., acetazolamide or dichlorphenamide, promote stone formation by reducing urinary citrate excretion and by increasing urinary pH. The concomitant use of topiramate with other carbonic anhydrase inhibitors 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.

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 topiramate. Paresthesia was more frequently reported in the monotherapy epilepsy trials versus the adjunctive therapy epilepsy trials. In the majority of instances, paresthesia did not lead to treatment discontinuation.

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 ).

Decreased Hepatic Function

In hepatically impaired patients, topiramate should be administered with caution as the clearance of topiramate may be decreased.

Information for Patients

Patients taking topiramate tablets should be told to seek immediate medical attention if they experience blurred vision or periorbital pain.

Patients, especially pediatric patients, treated with topiramate tablets should be monitored closely for evidence of decreased sweating and increased body temperature, especially in hot weather.

Patients, particularly those with predisposing factors, should be instructed to maintain an adequate fluid intake in order to minimize the risk of renal stone formation [see ,, for support regarding hydration as a preventative measure].

Patients should be warned about the potential for somnolence, dizziness, confusion, and difficulty concentrating and advised not to drive or operate machinery until they have gained sufficient experience on topiramate to gauge whether it adversely affects their mental and/or motor performance.

Additional food intake may be considered if the patient is losing weight while on this medication.

Laboratory Tests

Measurement of baseline and periodic serum bicarbonate during topiramate treatment is recommended (see ).

Drug Interactions

In vitro

Antiepileptic Drugs

Potential interactions between topiramate and standard AEDs were assessed in controlled clinical pharmacokinetic studies in patients with epilepsy. The effects of these interactions on mean plasma AUCs are summarized in .

In , the second column (AED concentration) describes what happens to the concentration of the AED listed in the first column when topiramate is added.

The third column (topiramate concentration) describes how the coadministration of a drug listed in the first column modifies the concentration of topiramate in experimental settings when topiramate was given alone.

In addition to the pharmacokinetic interaction described in the above table, concomitant administration of valproic acid and topiramate has been associated with hyperammonemia with and without encephalopathy (see , ).

Table 3: Summary of AED Interactions With Topiramate Tablets
Array
a
b
NC = Less than 10% change in plasma concentration.AED = Antiepileptic drug.NE = Not Evaluated.TPM = Topiramate.
AED AED Topiramate
Coadministered Concentration Concentration
Phenytoin NC or 25% increase 48% decrease
Carbamazepine (CBZ) NC 40% decrease
CBZ epoxide NC NE
Valproic acid 11% decrease 14% decrease
Phenobarbital NC NE
Primidone NC NE
Lamotrigine NC at TPM doses up to 400 mg/day 15% increase


Other Drug Interactions

Digoxin

In a single-dose study, serum digoxin AUC was decreased by 12% with concomitant topiramate administration. The clinical relevance of this observation has not been established.

CNS depressants

Concomitant administration of topiramate tablets and alcohol or other CNS depressant drugs 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 events, topiramate should be used with extreme caution if used in combination with alcohol and other CNS depressants.

Oral contraceptives

In a pharmacokinetic interaction study in healthy volunteers with a concomitantly administered combination oral contraceptive product containing 1 mg norethindrone (NET) plus 35 mcg ethinyl estradiol (EE), topiramate given in the absence of other medications at doses of 50 to 200 mg/day was not associated with statistically significant changes in mean exposure (AUC) to either component of the oral contraceptive. In another study, exposure to EE was statistically significantly decreased at doses of 200, 400, and 800 mg/day (18%, 21%, and 30%, respectively) when given as adjunctive therapy in patients taking valproic acid. In both studies, topiramate (50 mg/day to 800 mg/day) did not significantly affect exposure to NET. Although there was a dose dependent decrease in EE exposure for doses between 200 to 800 mg/day, there was no significant dose dependent change in EE exposure for doses of 50 to 200 mg/day. The clinical significance of the changes observed is not known. The possibility of decreased contraceptive efficacy and increased breakthrough bleeding should be considered in patients taking combination oral contraceptive products with topiramate. 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.

Hydrochlorothiazide (HCTZ)

A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of hydrochlorothiazide (25 mg q24h) and topiramate (96 mg q12h) when administered alone and concomitantly. The results of this study indicate that topiramate C increased by 27% and AUC increased by 29% when hydrochlorothiazide was added to topiramate. The clinical significance of this change is unknown. The addition of hydrochlorothiazide to topiramate therapy may require an adjustment of the topiramate dose. The steady-state pharmacokinetics of hydrochlorothiazide were not significantly influenced by the concomitant administration of topiramate. Clinical laboratory results indicated decreases in serum potassium after topiramate or hydrochlorothiazide administration, which were greater when hydrochlorothiazide and topiramate were administered in combination.

Pioglitazone

A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of topiramate and pioglitazone when administered alone and concomitantly. A 15% decrease in the AUC of pioglitazone with no alteration in C was observed. This finding was not statistically significant. In addition, a 13% and 16% decrease in Cand AUC respectively, of the active hydroxy-metabolite was noted as well as a 60% decrease in Cand AUCof the active keto-metabolite. The clinical significance of these findings is not known. When topiramate is added to pioglitazone therapy or pioglitazone is added to topiramate therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state.

Lithium

Multiple dosing of topiramate 100 mg every 12 hrs decreased the AUC and C of lithium (300 mg every 8 hrs) by 20% (N = 12, 6 M; 6 F).

Haloperidol

The pharmacokinetics of a single dose of haloperidol (5 mg) were not affected following multiple dosing of topiramate (100 mg every 12 hr) in 13 healthy adults 6 M, 7 F).

Amitriptyline

There was a 12% increase in AUC and C for amitriptyline (25 mg per day) in 18 normal subjects (9 male; 9 female) receiving 200 mg/day of topiramate. Some subjects may experience a large increase in amitriptyline concentration in the presence of topiramate and any adjustments in amitriptyline dose should be made according to the patient’s clinical response and not on the basis of plasma levels.

Sumatriptan

Multiple dosing of topiramate (100 mg every 12 hr) in 24 healthy volunteers (14 M, 10 F) did not affect the pharmacokinetics of a single dose sumatriptan either orally (100 mg) or subcutaneously (6 mg).

Risperidone

There was a 25% decrease in exposure to risperidone (2 mg single dose) in 12 healthy volunteers (6 M, 6 F) receiving 200 mg/day of topiramate. Therefore, patients receiving risperidone in combination with topiramate should be closely monitored for clinical response.

Propranolol

Multiple dosing of topiramate (200 mg/day) in 34 healthy volunteers (17 M, 17 F) did not affect the pharmacokinetics of propranolol following daily 160 mg doses. Propranolol doses of 160 mg/day in 39 volunteers (27 M, 12 F) had no effect on the exposure to topiramate at a dose of 200 mg/day of topiramate.

Dihydroergotamine

Multiple dosing of topiramate (200 mg/day) in 24 healthy volunteers (12 M, 12 F) did not affect the pharmacokinetics of a 1 mg subcutaneous dose of dihydroergotamine. Similarly, a 1 mg subcutaneous dose of dihydroergotamine did not affect the pharmacokinetics of a 200 mg/day dose of topiramate in the same study.

Others

Concomitant use of topiramate, a carbonic anhydrase inhibitor, with other carbonic anhydrase inhibitors, e.g., acetazolamide or dichlorphenamide, may create a physiological environment that increases the risk of renal stone formation, and should therefore be avoided.

Drug/Laboratory Test Interactions

There are no known interactions of topiramate with commonly used laboratory tests.

Carcinogenesis, Mutagenesis, Impairment of Fertility

An increase in urinary bladder tumors was observed in mice given topiramate (20, 75, and 300 mg/kg) in the diet for 21 months. The elevated bladder tumor incidence, which was statistically significant in males and females receiving 300 mg/kg, was primarily due to the increased occurrence of a smooth muscle tumor considered histomorphologically unique to mice. Plasma exposures in mice receiving 300 mg/kg were approximately 0.5 to 1 times steady-state exposures measured in patients receiving topiramate monotherapy at the recommended human dose (RHD) of 400 mg, and 1.5 to 2 times steady-state topiramate exposures in patients receiving 400 mg of topiramate plus phenytoin. The relevance of this finding to human carcinogenic risk is uncertain. No evidence of carcinogenicity was seen in rats following oral administration of topiramate for 2 years at doses up to 120 mg/kg (approximately 3 times the RHD on a mg/m basis).

Topiramate did not demonstrate genotoxic potential when tested in a battery of and assays. Topiramate was not mutagenic in the Ames test or the mouse lymphoma assay; it did not increase unscheduled DNA synthesis in rat hepatocytes ; and it did not increase chromosomal aberrations in human lymphocytes or in rat bone marrow .

No adverse effects on male or female fertility were observed in rats at doses up to 100 mg/kg (2.5 times the RHD on a mg/m basis).

Pregnancy

Teratogenic Effects

Pregnancy category C

Topiramate has demonstrated selective developmental toxicity, including teratogenicity, in experimental animal studies. When oral doses of 20, 100, or 500 mg/kg were administered to pregnant mice during the period of organogenesis, the incidence of fetal malformations (primarily craniofacial defects) was increased at all doses. The low dose is approximately 0.2 times the recommended human dose (RHD = 400 mg/day) on a mg/m basis. Fetal body weights and skeletal ossification were reduced at 500 mg/kg in conjunction with decreased maternal body weight gain.

In rat studies (oral doses of 20, 100, and 500 mg/kg or 0.2, 2.5, 30, and 400 mg/kg), the frequency of limb malformations (ectrodactyly, micromelia, and amelia) was increased among the offspring of dams treated with 400 mg/kg (10 times the RHD on a mg/m basis) or greater during the organogenesis period of pregnancy. Embryotoxicity (reduced fetal body weights, increased incidence of structural variations) was observed at doses as low as 20 mg/kg (0.5 times the RHD on a mg/mbasis). Clinical signs of maternal toxicity were seen at 400 mg/kg and above, and maternal body weight gain was reduced during treatment with 100 mg/kg or greater.

In rabbit studies (20, 60, and 180 mg/kg or 10, 35, and 120 mg/kg orally during organogenesis), embryo/fetal mortality was increased at 35 mg/kg (2 times the RHD on a mg/m basis) or greater, and teratogenic effects (primarily rib and vertebral malformations) were observed at 120 mg/kg (6 times the RHD on a mg/m basis). Evidence of maternal toxicity (decreased body weight gain, clinical signs, and/or mortality) was seen at 35 mg/kg and above.

When female rats were treated during the latter part of gestation and throughout lactation (0.2, 4, 20, and 100 mg/kg or 2, 20, and 200 mg/kg), offspring exhibited decreased viability and delayed physical development at 200 mg/kg (5 times the RHD on a mg/m basis) and reductions in pre- and/or postweaning body weight gain at 2 mg/kg (0.05 times the RHD on a mg/m basis) and above. Maternal toxicity (decreased body weight gain, clinical signs) was evident at 100 mg/kg or greater.

In a rat embryo/fetal development study with a postnatal component (0.2, 2.5, 30, or 400 mg/kg during organogenesis; noted above), pups exhibited delayed physical development at 400 mg/kg (10 times the RHD on a mg/m basis) and persistent reductions in body weight gain at 30 mg/kg (1 times the RHD on a mg/m basis) and higher.

There are no studies using topiramate in pregnant women. Topiramate should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.

In postmarketing experience, cases of hypospadias have been reported in male infants exposed to topiramate, with or without other anticonvulsants; however, a causal relationship with topiramate has not been established.

Labor and Delivery

In studies of rats where dams were allowed to deliver pups naturally, no drug-related effects on gestation length or parturition were observed at dosage levels up to 200 mg/kg/day.

The effect of topiramate on labor and delivery in humans is unknown.

Nursing Mothers

Topiramate is excreted in the milk of lactating rats. The excretion of topiramate in human milk has not been evaluated in controlled studies. Limited observations in patients suggest an extensive secretion of topiramate into breast milk. Since many drugs are excreted in human milk, and because the potential for serious adverse reactions in nursing infants to topiramate is unknown, the potential benefit to the mother should be weighed against the potential risk to the infant when considering recommendations regarding nursing.

Pediatric Use

Safety and effectiveness in patients below the age of 2 years have not been established for the adjunctive therapy treatment of partial onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome. Safety and effectiveness in patients below the age of 10 years have not been established for the monotherapy treatment of epilepsy. Topiramate is associated with metabolic acidosis. Chronic untreated metabolic acidosis in pediatric patients may cause osteomalacia/rickets and may 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 (see ).

Geriatric Use

In clinical trials, 3% of patients were over 60. No age related difference in effectiveness or adverse effects were evident. However, clinical studies of topiramate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Dosage adjustment may be necessary for elderly with impaired renal function (creatinine clearance rate ≤ 70 mL/min/1.73 m) due to reduced clearance of topiramate (see and ).

Race and Gender Effects

Evaluation of effectiveness and safety in clinical trials has shown no race or gender related effects.


What are the side effects of Topiramate?

The data described in the following section were obtained using topiramate tablets.

Monotherapy Epilepsy

The adverse events in the controlled trial that occurred most commonly in adults in the 400 mg/day group and at a rate higher than the 50 mg/day group were: paresthesia, weight decrease, somnolence, anorexia, dizziness, and difficulty with memory NOS [see ].

The adverse events in the controlled trial that occurred most commonly in children (10 years up to 16 years of age) in the 400 mg/day group and at a rate higher than the 50 mg/day group were: weight decrease, upper respiratory tract infection, paresthesia, anorexia, diarrhea, and mood problems [see ].

Approximately 21% of the 159 adult patients in the 400 mg/day group who received topiramate as monotherapy in the controlled clinical trial discontinued therapy due to adverse events. Adverse events associated with discontinuing therapy (≥2%) included depression, insomnia, difficulty with memory (NOS), somnolence, paresthesia, psychomotor slowing, dizziness, and nausea.

Approximately 12% of the 57 pediatric patients in the 400 mg/day group who received topiramate as monotherapy in the controlled clinical trial discontinued therapy due to adverse events. Adverse events associated with discontinuing therapy (≥5%) included difficulty with concentration/attention.

The prescriber should be aware that these data cannot be used to predict the frequency of adverse events in the course of usual medical practice where patient characteristics and other factors may differ from those prevailing during the clinical study. Similarly, the cited frequencies cannot be directly compared with data obtained from other clinical investigations involving different treatments, uses, or investigators. Inspection of these frequencies, however, does provide the prescribing physician with a basis to estimate the relative contribution of drug and non-drug factors to the adverse event incidences in the population studied.

Table 5: Incidence of Treatment-Emergent Adverse Events in the Monotherapy Epilepsy Trial in Adults Where Rate Was at Least 2% in the 400 mg/day Topiramate Group and Greater Than the Rate in the 50 mg/day Topiramate Group
Arraya
Topiramate Dosage (mg/day)
Body System50(N= 160)400(N=159)
Body as a Whole-General Disorders
   Asthenia46
   Leg Pain23
   Chest Pain12
Central & Peripheral Nervous System Disorders
   Paresthesia2140
   Dizziness1314
   Hypoaesthesia45
   Ataxia34
   Hypertonia03
Gastro-Intestinal System Disorders
   Diarrhea56
   Constipation14
   Gastritis03
   Dry Mouth13
   Gastroesophageal Reflux12
Liver and Biliary System Disorders
   Gamma-GT Increased13
Metabolic and Nutritional Disorders
   Weight Decrease616
Psychiatric Disorders
   Somnolence915
   Anorexia414
   Difficulty with Memory NOS510
   Insomnia89
   Depression79
   Difficulty with Concentration/Attention78
   Anxiety46
   Psychomotor Slowing35
   Mood Problems25
   Confusion34
   Cognitive Problem NOS14
   Libido Decreased03
Reproductive Disorders, Female
   Vaginal Hemorrhage03
Red Blood Cell Disorders
   Anemia12
Resistance Mechanism Disorders
   Infection Viral68
   Infection23
Respiratory System Disorders
   Bronchitis34
   Rhinitis24
   Dyspnea12
Skin and Appendages Disorders
   Rash14
   Pruritus14
   Acne23
Special Senses Other, Disorders
   Taste Perversion35
Urinary System Disorders
   Cystitis13
   Renal Calculus03
   Urinary Tract Infection12
   Dysuria02
   Micturition Frequency02
Table 6: Incidence of Treatment-Emergent Adverse Events in the Monotherapy Epilepsy Trial in Children Ages 10 up to 16 Years Where Rate Was at Least 5% in the 400 mg/day Topiramate Group and Greater Than the Rate in the 50 mg/day Topiramate Group
Arraya
Topiramate Dosage (mg/day)
Body System50(N=57)400(N=57)
Body as a Whole-General Disorders
   Fever09
Central & Peripheral Nervous System Disorders
   Paresthesia216
Gastro-Intestinal System Disorders
   Diarrhea511
Metabolic and Nutritional Disorders
   Weight Decrease721
Psychiatric Disorders
   Anorexia1114
   Mood Problems211
   Difficulty with Concentration/Attention49
   Cognitive Problems NOS07
   Nervousness45
Resistance Mechanism Disorders
   Infection Viral49
   Infection27
Respiratory System Disorders
   Upper Respiratory Tract Infection1618
   Rhinitis27
   Bronchitis27
   Sinusitis25
Skin and Appendages Disorders
   Alopecia25


Adjunctive Therapy Epilepsy

The most commonly observed adverse events associated with the use of topiramate at dosages of 200 to 400 mg/day in controlled trials in adults with partial onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome, that were seen at greater frequency in topiramate-treated patients and did not appear to be dose-related were: somnolence, dizziness, ataxia, speech disorders and related speech problems, psychomotor slowing, abnormal vision, difficulty with memory, paresthesia and diplopia [see ]. The most common dose-related adverse events at dosages of 200 to 1,000 mg/day were: fatigue, nervousness, difficulty with concentration or attention, confusion, depression, anorexia, language problems, anxiety, mood problems, and weight decrease [see ].

Adverse events associated with the use of topiramate at dosages of 5 to 9 mg/kg/day in controlled trials in pediatric patients with partial onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome, that were seen at greater frequency in topiramate-treated patients were: fatigue, somnolence, anorexia, nervousness, difficulty with concentration/attention, difficulty with memory, aggressive reaction, and weight decrease [see ].

In controlled clinical trials in adults, 11% of patients receiving topiramate 200 to 400 mg/day as adjunctive therapy discontinued due to adverse events. This rate appeared to increase at dosages above 400 mg/day. Adverse events associated with discontinuing therapy included somnolence, dizziness, anxiety, difficulty with concentration or attention, fatigue, and paresthesia and increased at dosages above 400 mg/day. None of the pediatric patients who received topiramate adjunctive therapy at 5 to 9 mg/kg/day in controlled clinical trials discontinued due to adverse events.

Approximately 28% of the 1,757 adults with epilepsy who received topiramate at dosages of 200 to 1,600 mg/day in clinical studies discontinued treatment because of adverse events; an individual patient could have reported more than one adverse event. These adverse events were: psychomotor slowing (4%), difficulty with memory (3.2%), fatigue (3.2%), confusion (3.1%), somnolence (3.2%), difficulty with concentration/attention (2.9%), anorexia (2.7%), depression (2.6%), dizziness (2.5%), weight decrease (2.5%), nervousness (2.3%), ataxia (2.1%), and paresthesia (2%). Approximately 11% of the 310 pediatric patients who received topiramate at dosages up to 30 mg/kg/day discontinued due to adverse events. Adverse events associated with discontinuing therapy included aggravated convulsions (2.3%), difficulty with concentration/attention (1.6%), language problems (1.3%), personality disorder (1.3%), and somnolence (1.3%).

Incidence in Epilepsy Controlled Clinical Trials - Adjunctive Therapy – Partial Onset Seizures, Primary Generalized Tonic-Clonic Seizures, and Lennox-Gastaut Syndrome

The prescriber should be aware that these data were obtained when topiramate was added to concurrent antiepileptic drug therapy and cannot be used to predict the frequency of adverse events in the course of usual medical practice where patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with data obtained from other clinical investigations involving different treatments, uses, or investigators. Inspection of these frequencies, however, does provide the prescribing physician with a basis to estimate the relative contribution of drug and non-drug factors to the adverse event incidences in the population studied.

Other Adverse Events Observed During Double-Blind Epilepsy Adjunctive Therapy Trials

Other events that occurred in more than 1% of adults treated with 200 to 400 mg of topiramate in placebo-controlled epilepsy trials but with equal or greater frequency in the placebo group were: headache, injury, anxiety, rash, pain, convulsions aggravated, coughing, fever, diarrhea, vomiting, muscle weakness, insomnia, personality disorder, dysmenorrhea, upper respiratory tract infection, and eye pain.

Table 7: Incidence of Treatment-Emergent Adverse Events in Placebo-Controlled, Add-On Epilepsy Trials in Adults Where Rate Was > 1% in Any Topiramate Group and Greater Than the Rate in Placebo-Treated Patients
a
b
c
Topiramate Dosage (mg/day)
Body SystemcPlacebo(N=291)200 to 400(N=183)600 to 1,000(N=414)
Body as a Whole-General Disorders
   Fatigue131530
   Asthenia163
   Back Pain453
   Chest Pain342
   Influenza-Like Symptoms234
   Leg Pain224
   Hot Flushes121
   Allergy123
   Edema121
   Body Odor010
   Rigors01
Central & Peripheral Nervous System Disorders
   Dizziness152532
   Ataxia71614
   Speech Disorders/Related Speech Problems21311
   Paresthesia41119
   Nystagmus71011
   Tremor699
   Language Problems1610
   Coordination Abnormal244
   Hypoaesthesia121
   Gait Abnormal132
   Muscle Contractions Involuntary122
   Stupor021
   Vertigo112
Gastro-Intestinal System Disorders
   Nausea81012
   Dyspepsia676
   Abdominal Pain467
   Constipation243
   Gastroenteritis121
   Dry Mouth124
   Gingivitis11
   GI Disorder10
Hearing and Vestibular Disorders
   Hearing Decreased121
Metabolic and Nutritional Disorders
   Weight Decrease3913
Muscle-Skeletal System Disorders
   Myalgia122
   Skeletal Pain010
Platelet, Bleeding, & Clotting Disorders
   Epistaxis121
Psychiatric Disorders
   Somnolence122928
   Nervousness61619
   Psychomotor Slowing21321
   Difficulty with Memory31214
   Anorexia41012
   Confusion51114
   Depression5513
   Difficulty with Concentration/Attention2614
   Mood Problems249
   Agitation233
   Aggressive Reaction233
   Emotional Lability133
   Cognitive Problems133
   Libido Decreased12
   Apathy113
   Depersonalization112
Reproductive Disorders, Female
   Breast Pain240
   Amenorrhea122
   Menorrhagia021
   Menstrual Disorder121
Reproductive Disorders, Male
   Prostatic Disorder20
Resistance Mechanism Disorders
   Infection121
   Infection Viral12
   Moniliasis10
Respiratory System Disorders
   Pharyngitis263
   Rhinitis676
   Sinusitis456
   Dyspnea112
Skin and Appendages Disorders
   Skin Disorder21
   Sweating Increased1
   Rash Erythematous1
Special Sense Other, Disorders
   Taste Perversion024
Urinary System Disorders
   Hematuria12
   Urinary Tract Infection123
   Micturition Frequency112
   Urinary Incontinence21
   Urine Abnormal01
Vision Disorders
   Vision Abnormal21310
   Diplopia51010
White Cell and RES Disorders
   Leukopenia121


Incidence in Study 119 – Add-On Therapy– Adults with Partial Onset Seizures

Study 119 was a randomized, double-blind, placebo-controlled, parallel group study with 3 treatment arms: 1) placebo; 2) topiramate 200 mg/day with a 25 mg/day starting dose, increased by 25 mg/day each week for 8 weeks until the 200 mg/day maintenance dose was reached; and 3) topiramate 200 mg/day with a 50 mg/day starting dose, increased by 50 mg/day each week for 4 weeks until the 200 mg/day maintenance dose was reached. All patients were maintained on concomitant carbamazepine with or without another concomitant antiepileptic drug.

The incidence of adverse events () did not differ significantly between the 2 topiramate regimens. Because the frequencies of adverse events reported in this study were markedly lower than those reported in the previous epilepsy studies, they cannot be directly compared with data obtained in other studies.

Table 8: Incidence of Treatment-Emergent Adverse Events in Study 119 Where Rate Was ≥ 2% in the Topiramate Group and Greater Than the Rate in Placebo-Treated Patients
a
b
c
Topiramate Dosage (mg/day)
Body System/cPlacebo(N=92)200(N=171)
Body as a Whole-General Disorders
   Fatigue49
   Chest Pain12
Cardiovascular Disorders, General
   Hypertension02
Central & Peripheral Nervous System Disorders
   Paresthesia29
   Dizziness47
   Tremor23
   Hypoasthesia02
   Leg Cramps02
   Language Problems02
Gastro-Intestinal System Disorders
   Abdominal Pain35
   Constipation04
   Diarrhea12
   Dyspepsia02
   Dry Mouth02
Hearing and Vestibular Disorders
   Tinnitus02
Metabolic and Nutritional Disorders
   Weight Decrease48
Psychiatric Disorders
   Somnolence915
   Anorexia79
   Nervousness29
   Difficulty with Concentration/Attention05
   Insomnia34
   Difficulty with Memory12
   Aggressive Reaction02
Respiratory System Disorders
   Rhinitis04
Urinary System Disorders
   Cystitis02
Vision Disorders
   Diplopia02
   Vision Abnormal02
Table 9: Incidence (%) of Dose-Related Adverse Events From Placebo-Controlled, Add-On Trials in Adults with Partial Onset Seizures
Arraya
Topiramate Dosage (mg/day)
Placebo(N = 216)200(N = 45)400(N = 68)600 to 1,000(N = 414)
Fatigue13111230
Nervousness7131819
Difficulty with Concentration/Attention17914
Confusion491014
Depression69713
Anorexia44612
Language problems2910
Anxiety62310
Mood problems2069
Weight decrease34913
Table 10: Incidence (%) of Treatment-Emergent Adverse Events in Placebo-Controlled, Add-On Epilepsy Trials in Pediatric Patients Ages 2 to 16 Years (Events that Occurred in at Least 1% of Topiramate-Treated Patients and Occurred More Frequently in Topiramate-Treated Than Placebo-Treated Patients)
a
b
Body System/Placebo(N=101)Topiramate(N=98)
Body as a Whole - General Disorders
    Fatigue516
    Injury1314
    Allergic Reaction12
    Back Pain01
    Pallor01
Cardiovascular Disorders, General
    Hypertension01
Central & Peripheral Nervous System Disorders
    Gait Abnormal58
    Ataxia26
    Hyperkinesia45
    Dizziness24
    Speech Disorders/Related Speech Problems24
    Hyporeflexia02
    Convulsions Grand Mal01
    Fecal Incontinence01
    Paresthesia01
Gastro-Intestinal System Disorders
    Nausea56
    Saliva Increased46
    Constipation45
    Gastroenteritis23
    Dysphagia01
    Flatulence01
    Gastroesophageal Reflux01
    Glossitis01
    Gum Hyperplasia01
Heart Rate and Rhythm Disorders
    Bradycardia01
Metabolic and Nutritional Disorders
    Weight Decrease19
    Thirst12
    Hypoglycemia01
    Weight Increase01
Platelet, Bleeding, & Clotting Disorders
    Purpura48
    Epistaxis14
    Hematoma01
    Prothrombin Increased01
    Thrombocytopenia01
Psychiatric Disorders
    Somnolence1626
    Anorexia1524
    Nervousness714
    Personality Disorder (Behavior Problems)911
    Difficulty with Concentration/Attention210
    Aggressive Reaction49
    Insomnia78
    Difficulty with Memory NOS05
    Confusion34
    Psychomotor Slowing23
    Appetite Increased01
    Neurosis01
Reproductive Disorders, Female
    Leukorrhoea02
Resistance Mechanism Disorders
    Infection Viral37
Respiratory System Disorders
    Pneumonia15
    Respiratory Disorder01
Skin and Appendages Disorders
    Skin Disorder23
    Alopecia12
    Dermatitis02
    Hypertrichosis12
    Rash Erythematous02
    Eczema01
    Seborrhoea01
    Skin Discoloration01
Urinary System Disorders
    Urinary Incontinence24
    Nocturia01
Vision Disorders
    Eye Abnormality12
    Vision Abnormal12
    Diplopia01
    Lacrimation Abnormal01
    Myopia01
White Cell and RES Disorders
    Leukopenia02


Other Adverse Events Observed During All Epilepsy Clinical Trials

Topiramate has been administered to 2,246 adults and 427 pediatric patients with epilepsy during all clinical studies, only some of which were placebo controlled. During these studies, all adverse events were recorded by the clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having adverse events, similar types of events were grouped into a smaller number of standardized categories using modified WHOART dictionary terminology. The frequencies presented represent the proportion of patients who experienced an event of the type cited on at least one occasion while receiving topiramate. Reported events are included except those already listed in the previous tables or text, those too general to be informative, and those not reasonably associated with the use of the drug.

Events are classified within body system categories and enumerated in order of decreasing frequency using the following definitions: occurring in at least 1/100 patients; occurring in 1/100 to 1/1000 patients; occurring in fewer than 1/1000 patients.

Autonomic Nervous System Disorders

Infrequent:

Body as a Whole:

Frequent:

Infrequent

Rare:

Cardiovascular Disorders, General:

Infrequent:

Central & Peripheral Nervous System Disorders:

Infrequent

Rare:

Gastrointestinal System Disorders:

Infrequent:

Rare:

Heart Rate and Rhythm Disorders:

Infrequent:

Liver and Biliary System Disorders:

Infrequent:

Metabolic and Nutritional Disorders:

Infrequent:

Rare:

Musculoskeletal System Disorders:

Frequent:

Infrequent:

Neoplasms:

Infrequent:

Rare:

Platelet, Bleeding, and Clotting Disorders:

Infrequent:

Psychiatric Disorders:

Frequent:

Infrequent:

Rare:

Red Blood Cell Disorders:

Frequent:

Rare:

Reproductive Disorders, Male:

Infrequent:

Skin and Appendages Disorders:

Infrequent:

Rare:

Special Senses Other, Disorders:

Infrequent:

Urinary System Disorders:

Infrequent:

Vascular (Extracardiac) Disorders:

Infrequent:

Rare:

Vision Disorders:

Frequent:

Infrequent:

Rare:

White Cell and Reticuloendothelial System Disorders:

Infrequent:

Rare:

Postmarketing and Other Experience

In addition to the adverse experiences reported during clinical testing of topiramate, the following adverse experiences have been reported worldwide in patients receiving topiramate post-approval.

These adverse experiences have not been listed above and data are insufficient to support an estimate of their incidence or to establish causation. The listing is alphabetized: bullous skin reactions (including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), hepatic failure (including fatalities), hepatitis, maculopathy, pancreatitis, pemphigus, and renal tubular acidosis.


What should I look out for while using Topiramate?

Topiramate tablets are contraindicated in patients with a history of hypersensitivity to any component of this product.


What might happen if I take too much Topiramate?

Overdoses of topiramate have been reported. Signs and symptoms included convulsions, drowsiness, speech disturbance, blurred vision, diplopia, mentation impaired, lethargy, abnormal coordination, stupor, hypotension, abdominal pain, agitation, dizziness and depression. The clinical consequences were not severe in most cases, but deaths have been reported after poly-drug overdoses involving topiramate.

Topiramate overdose has resulted in severe metabolic acidosis (see ).

A patient who ingested a dose between 96 and 110 g topiramate was admitted to hospital with coma lasting 20 to 24 hours followed by full recovery after 3 to 4 days.

In acute topiramate overdose, if the ingestion is recent, the stomach should be emptied immediately by lavage or by induction of emesis. Activated charcoal has been shown to adsorb topiramate . Treatment should be appropriately supportive. Hemodialysis is an effective means of removing topiramate from the body.


How should I store and handle Topiramate?

Store below 30° C (86° F) [see USP].Dispense in a tight, light-resistant container as defined in USP/NF.BIBLIOGRAPHYAvailable on request.Manufactured by:Patheon Pharmaceuticals Inc.Cincinnati, OH 45215 USAFor: Corona, CA 92880This Product was Repackaged By:State of Florida DOH Central PharmacyStore below 30° C (86° F) [see USP].Dispense in a tight, light-resistant container as defined in USP/NF.BIBLIOGRAPHYAvailable on request.Manufactured by:Patheon Pharmaceuticals Inc.Cincinnati, OH 45215 USAFor: Corona, CA 92880This Product was Repackaged By:State of Florida DOH Central PharmacyStore below 30° C (86° F) [see USP].Dispense in a tight, light-resistant container as defined in USP/NF.BIBLIOGRAPHYAvailable on request.Manufactured by:Patheon Pharmaceuticals Inc.Cincinnati, OH 45215 USAFor: Corona, CA 92880This Product was Repackaged By:State of Florida DOH Central PharmacyStore below 30° C (86° F) [see USP].Dispense in a tight, light-resistant container as defined in USP/NF.BIBLIOGRAPHYAvailable on request.Manufactured by:Patheon Pharmaceuticals Inc.Cincinnati, OH 45215 USAFor: Corona, CA 92880This Product was Repackaged By:State of Florida DOH Central PharmacyStore below 30° C (86° F) [see USP].Dispense in a tight, light-resistant container as defined in USP/NF.BIBLIOGRAPHYAvailable on request.Manufactured by:Patheon Pharmaceuticals Inc.Cincinnati, OH 45215 USAFor: Corona, CA 92880This Product was Repackaged By:State of Florida DOH Central PharmacyStore below 30° C (86° F) [see USP].Dispense in a tight, light-resistant container as defined in USP/NF.BIBLIOGRAPHYAvailable on request.Manufactured by:Patheon Pharmaceuticals Inc.Cincinnati, OH 45215 USAFor: Corona, CA 92880This Product was Repackaged By:State of Florida DOH Central PharmacyStore below 30° C (86° F) [see USP].Dispense in a tight, light-resistant container as defined in USP/NF.BIBLIOGRAPHYAvailable on request.Manufactured by:Patheon Pharmaceuticals Inc.Cincinnati, OH 45215 USAFor: Corona, CA 92880This Product was Repackaged By:State of Florida DOH Central PharmacyStore below 30° C (86° F) [see USP].Dispense in a tight, light-resistant container as defined in USP/NF.BIBLIOGRAPHYAvailable on request.Manufactured by:Patheon Pharmaceuticals Inc.Cincinnati, OH 45215 USAFor: Corona, CA 92880This Product was Repackaged By:State of Florida DOH Central PharmacyTopiramate tablets are available as follows:25 mg – white to off-white, capsule-shaped tablets, debossed with “93” on one side and “155” on the other side. 50 mg – light-yellow, capsules-shaped tablets, debossed with “93” on one side and “7540” on the other side. 100 mg – yellow, capsule-shaped tablets, debossed with “93” on one side and “7219” on the other side. 200 mg – salmon, capsule-shaped tablets, debossed with “93” on one side and “7220” on the other side. They are supplied by as follows:Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].Protect from moisture.Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).Manufactured In Israel By:TEVA PHARMACEUTICAL IND. LTD.Jerusalem, 91010, IsraelManufactured For:TEVA PHARMACEUTICALS USASellersville, PA 18960This Product was Repackaged By:State of Florida DOH Central PharmacyTopiramate tablets are available as follows:25 mg – white to off-white, capsule-shaped tablets, debossed with “93” on one side and “155” on the other side. 50 mg – light-yellow, capsules-shaped tablets, debossed with “93” on one side and “7540” on the other side. 100 mg – yellow, capsule-shaped tablets, debossed with “93” on one side and “7219” on the other side. 200 mg – salmon, capsule-shaped tablets, debossed with “93” on one side and “7220” on the other side. They are supplied by as follows:Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].Protect from moisture.Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).Manufactured In Israel By:TEVA PHARMACEUTICAL IND. LTD.Jerusalem, 91010, IsraelManufactured For:TEVA PHARMACEUTICALS USASellersville, PA 18960This Product was Repackaged By:State of Florida DOH Central PharmacyTopiramate tablets are available as follows:25 mg – white to off-white, capsule-shaped tablets, debossed with “93” on one side and “155” on the other side. 50 mg – light-yellow, capsules-shaped tablets, debossed with “93” on one side and “7540” on the other side. 100 mg – yellow, capsule-shaped tablets, debossed with “93” on one side and “7219” on the other side. 200 mg – salmon, capsule-shaped tablets, debossed with “93” on one side and “7220” on the other side. They are supplied by as follows:Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].Protect from moisture.Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).Manufactured In Israel By:TEVA PHARMACEUTICAL IND. LTD.Jerusalem, 91010, IsraelManufactured For:TEVA PHARMACEUTICALS USASellersville, PA 18960This Product was Repackaged By:State of Florida DOH Central PharmacyTopiramate tablets are available as follows:25 mg – white to off-white, capsule-shaped tablets, debossed with “93” on one side and “155” on the other side. 50 mg – light-yellow, capsules-shaped tablets, debossed with “93” on one side and “7540” on the other side. 100 mg – yellow, capsule-shaped tablets, debossed with “93” on one side and “7219” on the other side. 200 mg – salmon, capsule-shaped tablets, debossed with “93” on one side and “7220” on the other side. They are supplied by as follows:Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].Protect from moisture.Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).Manufactured In Israel By:TEVA PHARMACEUTICAL IND. LTD.Jerusalem, 91010, IsraelManufactured For:TEVA PHARMACEUTICALS USASellersville, PA 18960This Product was Repackaged By:State of Florida DOH Central PharmacyTopiramate tablets are available as follows:25 mg – white to off-white, capsule-shaped tablets, debossed with “93” on one side and “155” on the other side. 50 mg – light-yellow, capsules-shaped tablets, debossed with “93” on one side and “7540” on the other side. 100 mg – yellow, capsule-shaped tablets, debossed with “93” on one side and “7219” on the other side. 200 mg – salmon, capsule-shaped tablets, debossed with “93” on one side and “7220” on the other side. They are supplied by as follows:Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].Protect from moisture.Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).Manufactured In Israel By:TEVA PHARMACEUTICAL IND. LTD.Jerusalem, 91010, IsraelManufactured For:TEVA PHARMACEUTICALS USASellersville, PA 18960This Product was Repackaged By:State of Florida DOH Central PharmacyTopiramate tablets are available as follows:25 mg – white to off-white, capsule-shaped tablets, debossed with “93” on one side and “155” on the other side. 50 mg – light-yellow, capsules-shaped tablets, debossed with “93” on one side and “7540” on the other side. 100 mg – yellow, capsule-shaped tablets, debossed with “93” on one side and “7219” on the other side. 200 mg – salmon, capsule-shaped tablets, debossed with “93” on one side and “7220” on the other side. They are supplied by as follows:Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].Protect from moisture.Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).Manufactured In Israel By:TEVA PHARMACEUTICAL IND. LTD.Jerusalem, 91010, IsraelManufactured For:TEVA PHARMACEUTICALS USASellersville, PA 18960This Product was Repackaged By:State of Florida DOH Central PharmacyTopiramate tablets are available as follows:25 mg – white to off-white, capsule-shaped tablets, debossed with “93” on one side and “155” on the other side. 50 mg – light-yellow, capsules-shaped tablets, debossed with “93” on one side and “7540” on the other side. 100 mg – yellow, capsule-shaped tablets, debossed with “93” on one side and “7219” on the other side. 200 mg – salmon, capsule-shaped tablets, debossed with “93” on one side and “7220” on the other side. They are supplied by as follows:Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].Protect from moisture.Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).Manufactured In Israel By:TEVA PHARMACEUTICAL IND. LTD.Jerusalem, 91010, IsraelManufactured For:TEVA PHARMACEUTICALS USASellersville, PA 18960This Product was Repackaged By:State of Florida DOH Central PharmacyTopiramate tablets are available as follows:25 mg – white to off-white, capsule-shaped tablets, debossed with “93” on one side and “155” on the other side. 50 mg – light-yellow, capsules-shaped tablets, debossed with “93” on one side and “7540” on the other side. 100 mg – yellow, capsule-shaped tablets, debossed with “93” on one side and “7219” on the other side. 200 mg – salmon, capsule-shaped tablets, debossed with “93” on one side and “7220” on the other side. They are supplied by as follows:Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].Protect from moisture.Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).Manufactured In Israel By:TEVA PHARMACEUTICAL IND. LTD.Jerusalem, 91010, IsraelManufactured For:TEVA PHARMACEUTICALS USASellersville, PA 18960This Product was Repackaged By:State of Florida DOH Central PharmacyTopiramate tablets are available as follows:25 mg – white to off-white, capsule-shaped tablets, debossed with “93” on one side and “155” on the other side. 50 mg – light-yellow, capsules-shaped tablets, debossed with “93” on one side and “7540” on the other side. 100 mg – yellow, capsule-shaped tablets, debossed with “93” on one side and “7219” on the other side. 200 mg – salmon, capsule-shaped tablets, debossed with “93” on one side and “7220” on the other side. They are supplied by as follows:Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].Protect from moisture.Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).Manufactured In Israel By:TEVA PHARMACEUTICAL IND. LTD.Jerusalem, 91010, IsraelManufactured For:TEVA PHARMACEUTICALS USASellersville, PA 18960This Product was Repackaged By:State of Florida DOH Central PharmacyTopiramate tablets are available as follows:25 mg – white to off-white, capsule-shaped tablets, debossed with “93” on one side and “155” on the other side. 50 mg – light-yellow, capsules-shaped tablets, debossed with “93” on one side and “7540” on the other side. 100 mg – yellow, capsule-shaped tablets, debossed with “93” on one side and “7219” on the other side. 200 mg – salmon, capsule-shaped tablets, debossed with “93” on one side and “7220” on the other side. They are supplied by as follows:Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].Protect from moisture.Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).Manufactured In Israel By:TEVA PHARMACEUTICAL IND. LTD.Jerusalem, 91010, IsraelManufactured For:TEVA PHARMACEUTICALS USASellersville, PA 18960This Product was Repackaged By:State of Florida DOH Central PharmacyTopiramate tablets are available as follows:25 mg – white to off-white, capsule-shaped tablets, debossed with “93” on one side and “155” on the other side. 50 mg – light-yellow, capsules-shaped tablets, debossed with “93” on one side and “7540” on the other side. 100 mg – yellow, capsule-shaped tablets, debossed with “93” on one side and “7219” on the other side. 200 mg – salmon, capsule-shaped tablets, debossed with “93” on one side and “7220” on the other side. They are supplied by as follows:Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].Protect from moisture.Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).Manufactured In Israel By:TEVA PHARMACEUTICAL IND. LTD.Jerusalem, 91010, IsraelManufactured For:TEVA PHARMACEUTICALS USASellersville, PA 18960This Product was Repackaged By:State of Florida DOH Central PharmacyTopiramate tablets are available as follows:25 mg – white to off-white, capsule-shaped tablets, debossed with “93” on one side and “155” on the other side. 50 mg – light-yellow, capsules-shaped tablets, debossed with “93” on one side and “7540” on the other side. 100 mg – yellow, capsule-shaped tablets, debossed with “93” on one side and “7219” on the other side. 200 mg – salmon, capsule-shaped tablets, debossed with “93” on one side and “7220” on the other side. They are supplied by as follows:Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].Protect from moisture.Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).Manufactured In Israel By:TEVA PHARMACEUTICAL IND. LTD.Jerusalem, 91010, IsraelManufactured For:TEVA PHARMACEUTICALS USASellersville, PA 18960This Product was Repackaged By:State of Florida DOH Central PharmacyTopiramate tablets are available as follows:25 mg – white to off-white, capsule-shaped tablets, debossed with “93” on one side and “155” on the other side. 50 mg – light-yellow, capsules-shaped tablets, debossed with “93” on one side and “7540” on the other side. 100 mg – yellow, capsule-shaped tablets, debossed with “93” on one side and “7219” on the other side. 200 mg – salmon, capsule-shaped tablets, debossed with “93” on one side and “7220” on the other side. They are supplied by as follows:Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].Protect from moisture.Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).Manufactured In Israel By:TEVA PHARMACEUTICAL IND. LTD.Jerusalem, 91010, IsraelManufactured For:TEVA PHARMACEUTICALS USASellersville, PA 18960This Product was Repackaged By:State of Florida DOH Central PharmacyTopiramate tablets are available as follows:25 mg – white to off-white, capsule-shaped tablets, debossed with “93” on one side and “155” on the other side. 50 mg – light-yellow, capsules-shaped tablets, debossed with “93” on one side and “7540” on the other side. 100 mg – yellow, capsule-shaped tablets, debossed with “93” on one side and “7219” on the other side. 200 mg – salmon, capsule-shaped tablets, debossed with “93” on one side and “7220” on the other side. They are supplied by as follows:Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].Protect from moisture.Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).Manufactured In Israel By:TEVA PHARMACEUTICAL IND. LTD.Jerusalem, 91010, IsraelManufactured For:TEVA PHARMACEUTICALS USASellersville, PA 18960This Product was Repackaged By:State of Florida DOH Central PharmacyTopiramate tablets are available as follows:25 mg – white to off-white, capsule-shaped tablets, debossed with “93” on one side and “155” on the other side. 50 mg – light-yellow, capsules-shaped tablets, debossed with “93” on one side and “7540” on the other side. 100 mg – yellow, capsule-shaped tablets, debossed with “93” on one side and “7219” on the other side. 200 mg – salmon, capsule-shaped tablets, debossed with “93” on one side and “7220” on the other side. They are supplied by as follows:Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].Protect from moisture.Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).Manufactured In Israel By:TEVA PHARMACEUTICAL IND. LTD.Jerusalem, 91010, IsraelManufactured For:TEVA PHARMACEUTICALS USASellersville, PA 18960This Product was Repackaged By:State of Florida DOH Central PharmacyTopiramate tablets are available as follows:25 mg – white to off-white, capsule-shaped tablets, debossed with “93” on one side and “155” on the other side. 50 mg – light-yellow, capsules-shaped tablets, debossed with “93” on one side and “7540” on the other side. 100 mg – yellow, capsule-shaped tablets, debossed with “93” on one side and “7219” on the other side. 200 mg – salmon, capsule-shaped tablets, debossed with “93” on one side and “7220” on the other side. They are supplied by as follows:Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].Protect from moisture.Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).Manufactured In Israel By:TEVA PHARMACEUTICAL IND. LTD.Jerusalem, 91010, IsraelManufactured For:TEVA PHARMACEUTICALS USASellersville, PA 18960This Product was Repackaged By:State of Florida DOH Central PharmacyTopiramate tablets are available as follows:25 mg – white to off-white, capsule-shaped tablets, debossed with “93” on one side and “155” on the other side. 50 mg – light-yellow, capsules-shaped tablets, debossed with “93” on one side and “7540” on the other side. 100 mg – yellow, capsule-shaped tablets, debossed with “93” on one side and “7219” on the other side. 200 mg – salmon, capsule-shaped tablets, debossed with “93” on one side and “7220” on the other side. They are supplied by as follows:Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].Protect from moisture.Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).Manufactured In Israel By:TEVA PHARMACEUTICAL IND. LTD.Jerusalem, 91010, IsraelManufactured For:TEVA PHARMACEUTICALS USASellersville, PA 18960This Product was Repackaged By:State of Florida DOH Central PharmacyTopiramate tablets are available as follows:25 mg – white to off-white, capsule-shaped tablets, debossed with “93” on one side and “155” on the other side. 50 mg – light-yellow, capsules-shaped tablets, debossed with “93” on one side and “7540” on the other side. 100 mg – yellow, capsule-shaped tablets, debossed with “93” on one side and “7219” on the other side. 200 mg – salmon, capsule-shaped tablets, debossed with “93” on one side and “7220” on the other side. They are supplied by as follows:Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].Protect from moisture.Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).Manufactured In Israel By:TEVA PHARMACEUTICAL IND. LTD.Jerusalem, 91010, IsraelManufactured For:TEVA PHARMACEUTICALS USASellersville, PA 18960This Product was Repackaged By:State of Florida DOH Central Pharmacy


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Clinical Information

Chemical Structure

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Clinical Pharmacology

The precise mechanism by which topiramate exerts its anticonvulsant effect is unknown; however, preclinical studies have revealed four properties that may contribute to topiramate’s efficacy for epilepsy. Electrophysiological and biochemical evidence suggests that topiramate, at pharmacologically relevant concentrations, blocks voltage-dependent sodium channels, augments the activity of the neurotransmitter gamma-aminobutyrate at some subtypes of the GABA receptor, antagonizes the AMPA/kainate subtype of the glutamate receptor, and inhibits the carbonic anhydrase enzyme, particularly isoenzymes II and IV.

Non-Clinical Toxicology
Topiramate tablets are contraindicated in patients with a history of hypersensitivity to any component of this product.

In vitro

Concomitant administration of topiramate and valproic acid has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone. 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 event is not due to a pharmacokinetic interaction.

It is not known if topiramate monotherapy is associated with 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, an interaction of topiramate and valproic acid may exacerbate existing defects or unmask deficiencies in susceptible persons.

In patients who develop unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured.

The data described in the following section were obtained using topiramate tablets.

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Reference

This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"

While we update our database periodically, we cannot guarantee it is always updated to the latest version.

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Professional

Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72
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Tips

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Interactions

Interactions

A total of 440 drugs (1549 brand and generic names) are known to interact with Imbruvica (ibrutinib). 228 major drug interactions (854 brand and generic names) 210 moderate drug interactions (691 brand and generic names) 2 minor drug interactions (4 brand and generic names) Show all medications in the database that may interact with Imbruvica (ibrutinib).