Topiramate Information
Topiramate () Dosage And Administration
In the controlled adjunctive (i.e., 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 1,000 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 () Tablets therapy. On occasion, the addition of Topiramate () Tablets 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 () Tablets. Because of the bitter taste, tablets should not be broken.
Topiramate () Tablets can be taken without regard to meals.
Monotherapy Use
The recommended dose for Topiramate () monotherapy in adults and pediatric patients 10 years of age and older is 400 mg/day in two divided doses. Approximately 58% of patients randomized to 400 mg/day achieved this maximal dose in the monotherapy controlled trial; the mean dose achieved in the trial was 275 mg/day. The dose should be achieved by titration according to the following schedule:
Adjunctive Therapy Use
Adults (17 Years of Age and Over) -Partial Onset Seizures, Primary Generalized Tonic-Clonic Seizures, or Lennox-Gastaut Syndrome The recommended total daily dose of Topiramate () Tablets as adjunctive therapy in adults with partial onset seizures is 200 to 400 mg/day in two divided doses, and 400 mg/day in two divided doses as adjunctive treatment in adults with primary generalized tonic-clonic seizures. It is recommended that therapy be initiated at 25 to 50 mg/day followed by titration to an effective dose in increments of 25 to 50 mg/day every week. Titrating in increments of 25 mg/day every week may delay the time to reach an effective dose. Daily doses above 1,600 mg have not been studied.
In the study of primary generalized tonic-clonic seizures the initial titration rate was slower than in previous studies; the assigned dose was reached at the end of 8 weeks [].
Pediatric Patients (Ages 2 -16 Years) – Partial Onset Seizures, Primary Generalized Tonic-Clonic Seizures, or Lennox-Gastaut Syndrome
The recommended total daily dose of Topiramate () Tablets as adjunctive therapy for pediatric patients with partial onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome is approximately 5 to 9 mg/kg/day in two divided doses. Titration should begin at 25 mg/day (or less, based on a range of 1 to 3 mg/kg/day) nightly for the first week. The dosage should then be increased at 1-or 2 week intervals by increments of 1 to 3 mg/kg/day (administered in two divided doses), to achieve optimal clinical response. Dose titration should be guided by clinical outcome.
In the study of primary generalized tonic-clonic seizures the initial titration rate was slower than in previous studies; the assigned dose of 6 mg/kg/day was reached at the end of 8 weeks [].
Topiramate () Dosage Forms And Strengths
Topiramate () Tablets, USP are available as debossed, coated, round tablets in the following strengths and colors:
25 mg white (debossed "USL" on one side; "25" on the other)
50 mg light-yellow (debossed "USL" on one side; "50" on the other)
100 mg dark-yellow (debossed "USL" on one side; "100" on the other)
200 mg dark-red (debossed "USL" on one side; "200" on the other)
Topiramate () Contraindications
Topiramate () Warnings And Precautions
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 judgment 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 (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 pediatric patients. 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 () Tablets are 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.
Antiepileptic drugs (AEDs), including Topiramate () , 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 1 shows absolute and relative risk by indication for all evaluated AEDs.
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
Anyone considering prescribing Topiramate () Tablets or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior or the emergence of suicidal thoughts, behavior or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
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 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 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 (2-16 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 Topiramate () (at approximately 6 mg/kg/day), and 10% 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 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.
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/d Topiramate () -placebo) was 5.9 mEq/L for bicarbonate. The incidence of metabolic acidosis (defined by a serum bicarbonate
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.
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 [].
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.
Topiramate () can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to Topiramate () 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 [.
Consider the benefits and risks of Topiramate () when administering this drug in women of childbearing potential, particularly when Topiramate () is considered for a condition not usually associated with permanent injury or death []. Topiramate () 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 [].
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. During long-term (up to 1 year) Topiramate () treatment in an open-label extension study of 284 pediatric patients 124 months old with epilepsy, 7% developed kidney or bladder stones that were diagnosed clinically or by sonogram. Topiramate () is not approved for pediatric patients less than 2 years old
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., zonisamide, acetazolamide or dichlorphenamide) can promote stone formation by reducing urinary citrate excretion and by increasing urinary pH []. The concomitant use to Topiramate () Tablets 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.
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 Topiramate () treatment is recommended [].
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 laboratories (increased creatinine, BUN, alkaline phosphatase, total protein, total eosinophil count and decreased potassium) have been observed in a clinical investigational program in very young (
Topiramate () treatment with or without concomitant valproic acid (VPA) can cause hyperammonemia with or without encephalopathy [].
Topiramate () Adverse Reactions
The data described in the following section were obtained using Topiramate () Tablets.
The adverse reactions 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 [].
The adverse reactions 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 [].
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 reactions. Adverse reactions 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 reactions. Adverse reactions 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 reactions 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 reactions incidences in the population studied.
The most commonly observed adverse reactions 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 reactions 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 [].
Adverse reactions 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 [].
In controlled clinical trials in adults, 11% of patients receiving Topiramate () 200 to 400 mg/day as adjunctive therapy discontinued due to adverse reactions. 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 reactions.
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 reactions; an individual patient could have reported more than one adverse reaction. These adverse reactions were: psychomotor slowing (4.0%), 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 (2.0%). Approximately 11% of the 310 pediatric patients who received Topiramate () at dosages up to 30 mg/kg/day discontinued due to adverse reactions. Adverse reactions 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%).
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 reactions 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 reaction incidences in the population studied.
Study 119 was a randomized, double-blind, add-on/adjunctive, 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 reactions () did not differ significantly between the 2 Topiramate () regimens. Because the frequencies of adverse reactions 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.
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 reactions were recorded by the clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having adverse reactions, similar types of reactions were grouped into a smaller number of standardized categories using modified WHOART dictionary terminology. The frequencies presented represent the proportion of patients who experienced a reaction of the type cited on at least one occasion while receiving Topiramate () . Reported reactions 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.
Reactions 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: : vasodilation.
Body as a Whole: : syncope. : abdomen enlarged. : alcohol intolerance.
Cardiovascular Disorders, General: hypotension, postural hypotension, angina pectoris.
Central & Peripheral Nervous System Disorders: neuropathy, apraxia, hyperesthesia, dyskinesia, dysphonia, scotoma, ptosis, dystonia, visual field defect, encephalopathy, EEG abnormal. : upper motor neuron lesion, cerebellar syndrome, tongue paralysis.
Gastrointestinal System Disorders: : hemorrhoids, stomatitis, melena, gastritis, esophagitis. : tongue edema.
Heart Rate and Rhythm Disorders: : AV block.
Liver and Biliary System Disorders: : SGPT increased, SGOT increased.
Metabolic and Nutritional Disorders: Infrequent: dehydration, hypocalcemia, hyperlipemia, hyperglycemia, xerophthalmia, diabetes mellitus. : hypernatremia, hyponatremia, hypocholesterolemia, creatinine increased.
Musculoskeletal System Disorders: arthralgia. : arthrosis.
Neoplasms:: thrombocythemia. : polycythemia.Platelet,
Bleeding, and Clotting Disorders:gingival bleeding, pulmonary embolism.
Psychiatric Disorders: : impotence, hallucination, psychosis, suicide attempt. euphoria, paranoid reaction, delusion, paranoia, delirium, abnormal dreaming:libido increased, manic reaction.
Red Blood Cell Disordersanemiamarrow depression, pancytopenia.
Reproductive Disorders, Male: : ejaculation disorder, breast discharge.
Skin and Appendages Disorders: Infrequent: urticaria, photosensitivity reaction, abnormal hairtexture. Rare: chloasma.
Special Senses Other, Disorders:: taste loss, parosmia.
Urinary System Disorders: : urinary retention, face edema, renal pain, albuminuria, polyuria, oliguria.
Vascular (Extracardiac) Disorders:: flushing, deep vein thrombosis, phlebitis. : vasospasm.
Vision Disorders: : conjunctivitis.: abnormal accommodation, photophobia, strabismus. : mydriasis, iritis.
White Cell and Reticuloendothelial System Disorders: : lymphadenopathy, eosinophilia, lymphopenia, granulocytopenia. : lymphocytosis.
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, and pemphigus.
Topiramate () Drug Interactions
In vitro studies indicate that Topiramate () does not inhibit enzyme activity for CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1, and CYP3A4/5 isozymes. In vitro studies indicate that Topiramate () is a mild inhibitor of CYP2C19 and a mild inducer of CYP3A4. Drug interactions with some antiepileptic drugs, CNS depressants and oral contraceptives are described here. For other drug interactions, please refer to .
Potential interactions between Topiramate () and standard AEDs were assessed in controlled clinical pharmacokinetic studies in patients with epilepsy. Concomitant administration of phenytoin or carbamazepine with Topiramate () decreased plasma concentrations of Topiramate () by 48% and 40% respectively when compared to Topiramate () given alone [].
In addition, concomitant administration of valproic acid and Topiramate () has been associated with hyperammonemia with and without encephalopathy [].
Topiramate () Overdosage
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 [].
A patient who ingested a dose between 96 and 110 g Topiramate () was admitted to a hospital with a coma lasting 20 to 24 hours followed by full recovery after 3 to 4 days.
In acute Topiramate () Tablets 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 () in vitro. Treatment should be appropriately supportive. Hemodialysis is an effective means of removing Topiramate () from the body.
Topiramate () Description
Topiramate () , USP is a sulfamate-substituted monosaccharide. Topiramate () Tablets, USP are available as 25 mg, 50 mg, 100 mg, and 200 mg round tablets for oral administration.
Topiramate () , USP 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 () has the molecular formula CHNOS and a molecular weight of 339.36. Topiramate () is designated chemically as 2,3:4,5Di-O-isopropylidene-β-D-fructopyranose sulfamate and has the following structural formula:
Topiramate () Tablets, USP contain the following inactive ingredients: colloidal silicon dioxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, partially hydrolyzed polyvinyl alcohol, polyethylene glycol, sodium starch glycolate, talc, titanium dioxide, iron oxide yellow (50 mg and 100 mg only), and iron oxide red (50 mg and 200 mg only).
Topiramate () Clinical Pharmacology
Absorption of Topiramate () is rapid, with peak plasma concentrations occurring at approximately 2 hours following a 400 mg oral dose. The relative bioavailability of Topiramate () from the tablet formulation is about 80% compared to a solution. The bioavailability of Topiramate () is not affected by food.
The pharmacokinetics of Topiramate () are linear with dose proportional increases in plasma concentration over the dose range studied (200 to 800 mg/day). The mean plasma elimination half-life is 21 hours after single or multiple doses. Steady state is thus reached in about 4 days in patients with normal renal function. Topiramate () is 15% to 41% bound to human plasma proteins over the blood concentration range of 0.5 to 250 μg/mL. The fraction bound decreased as blood concentration increased.
Carbamazepine and phenytoin do not alter the binding of Topiramate () . Sodium valproate, at 500 μg/mL (a concentration 5 to 10 times higher than considered therapeutic for valproate) decreased the protein binding of Topiramate () from 23% to 13%. Topiramate () does not influence the binding of sodium valproate.
Metabolism and Excretion
Topiramate () is not extensively metabolized and is primarily eliminated unchanged in the urine (approximately 70% of an administered dose). Six metabolites have been identified in humans, none of which constitutes more than 5% of an administered dose. The metabolites are formed via hydroxylation, hydrolysis, and glucuronidation. There is evidence of renal tubular reabsorption of Topiramate () . In rats, given probenecid to inhibit tubular reabsorption, along with Topiramate () , a significant increase in renal clearance of Topiramate () was observed. This interaction has not been evaluated in humans. Overall, oral plasma clearance (CL/F) is approximately 20 to 30 mL/min in humans following oral administration.
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 Table 8.
In Table 8, 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 [].
CNS Depressants
Concomitant administration of Topiramate () 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 reactions, 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 and 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 () Tablets. 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 [].
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.
Hydrochlorothiazide
A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of hydrochlorothiazide (HCTZ) (25 mg q24h) and Topiramate () (96 mg q12h) when administered alone and concomitantly. The results of this study indicate that Topiramate () Cmax increased by 27% and AUC increased by 29% when HCTZ was added to Topiramate () . The clinical significance of this change is unknown. The addition of HCTZ to Topiramate () therapy may require an adjustment of the Topiramate () dose. The steady-state pharmacokinetics of HCTZ were not significantly influenced by the concomitant administration of Topiramate () . Clinical laboratory results indicated decreases in serum potassium after Topiramate () or HCTZ administration, which were greater when HCTZ and Topiramate () were administered in combination.
Metformin
Topiramate () treatment can frequently cause metabolic acidosis, a condition for which the use of metformin is contraindicated.
A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of metformin (500 mg every 12 hr) and Topiramate () in plasma when metformin was given alone and when metformin and Topiramate () (100 mg every 12 hr) were given simultaneously. The results of this study indicated that the mean metformin C and AUCincreased by 17% and 25%, respectively, when Topiramate () was added. Topiramate () did not affect metformin t. The clinical significance of the effect of Topiramate () on metformin pharmacokinetics is not known. Oral plasma clearance of Topiramate () appears to be reduced when administered with metformin. The clinical significance of the effect of metformin on Topiramate () pharmacokinetics is unclear [ ].
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 C and AUC respectively, of the active hydroxy-metabolite was noted as well as a 60% decrease in C and AUC of the active keto-metabolite. The clinical significance of these findings is not known. When Topiramate () Tablets are added to pioglitazone therapy or pioglitazone is added to Topiramate () Tablets therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state.
Glyburide
A drug-drug interaction study conducted in patients with type 2 diabetes evaluated the steady-state pharmacokinetics of glyburide (5mg/day) alone and concomitantly with Topiramate () (150 mg/day). There was a 22% decrease in C and a 25% reduction in AUC for glyburide during Topiramate () administration. Systemic exposure (AUC) of the active metabolites, 4-trans-hydroxyglyburide (M1) and 3-cis-hydroxyglyburide (M2), was also reduced by 13% and 15%, and C was reduced by 18% and 25%, respectively. The steady-state pharmacokinetics of Topiramate () were unaffected by concomitant administration of glyburide.
Lithium
In patients, the pharmacokinetics of lithium were unaffected during treatment with Topiramate () at doses of 200 mg/day; however, there was an observed increase in systemic exposure of lithium (27% for Cand 26% for AUC) following Topiramate () doses up to 600 mg/day. Lithium levels should be monitored when co-administered with high-dose Topiramate () [].
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 males, 7 females).
Amitriptyline
There was a 12% increase in AUC and C for amitriptyline (25 mg per day) in 18 normal subjects (9 males; 9 females) 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 hrs) in 24 healthy volunteers (14 males, 10 females) did not affect the pharmacokinetics of single dose sumatriptan either orally (100 mg) or subcutaneously (6 mg).
Risperidone
When administered concomitantly with Topiramate () at escalating doses of 100, 250 and 400 mg/day, there was a reduction in risperidone (systemic exposure (16% and 33% for steady-state AUC at the 250 and 400 mg/day doses of Topiramate () ). No alterations of 9-hydroxyrisperidone levels were observed. Coadministration of Topiramate () 400 mg/day with risperidone resulted in a 14% increase in C and a 12% increase in AUC of Topiramate () . There were no clinically significant changes in the systemic exposure of risperidone plus 9-hydroxyrisperidone or of Topiramate () , therefore this interaction is not likely to be of clinical significance.
Propranolol
Multiple dosing of Topiramate () (200 mg/day) in 34 healthy volunteers (17 males, 17 females) did not affect the pharmacokinetics of propranolol following daily 160 mg doses. Propranolol doses of 160 mg/day in 39 volunteers (27 males, 12 females) 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 males, 12 females) 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.
Diltiazem
Co-administration of diltiazem (240 mg Cardizem CD) with Topiramate () (150 mg/day) resulted in a 10% decrease in C and a 25% decrease in diltiazem AUC, a 27% decrease in Cand an 18% decrease in des-acetyl diltiazem AUC, and no effect on N-desmethyl diltiazem. Coadministration of Topiramate () with diltiazem resulted in a 16% increase in C and a 19% increase in AUC of Topiramate () .
Venlafaxine
Multiple dosing of Topiramate () (150 mg/day) in healthy volunteers did not affect the pharmacokinetics of venlafaxine or O-desmethyl venlafaxine. Multiple dosing of venlafaxine (150 mg Effexor XR) did not affect the pharmacokinetics of Topiramate () .
Other Carbonic Anhydrase Inhibitors
Concomitant use of Topiramate () , a carbonic anhydrase inhibitor, with any other carbonic anhydrase inhibitor (e.g., zonisamide, acetazolamide or dichlorphenamide), may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation. Therefore, if Topiramate () is given concomitantly with another carbonic anhydrase inhibitor, the patient should be monitored for the appearance or worsening of metabolic acidosis [].
Drug/Laboratory Tests Interactions
There are no known interactions of Topiramate () with commonly used laboratory tests.
Topiramate () Clinical Studies
The studies described in the following sections were conducted using Topiramate () Tablets.
Topiramate () How Supplied/storage And Handling Topiramate Tablets
Topiramate () Tablets, USP are available as debossed, coated, round tablets in the following strengths and colors:
25 mg white tablet (debossed "USL" on one side; "25" on the other) and are available in bottles of 60 count with desiccant (NDC 0245-0707-60)
50 mg light-yellow tablet (debossed "USL" on one side; "50" on the other) and are available in bottles of 60 count with desiccant (NDC 0245-0708-60)
100 mg dark-yellow tablet (debossed "USL" on one side; "100" on the other) and are available in bottles of 60 count with desiccant (NDC 0245-0709-60)
200 mg dark-red tablet (debossed "USL" on one side; "200" on the other) and are available in bottles of 60 count with desiccant (NDC 0245-0710-60)
Topiramate () Patient Counseling Information
Patients and their caregivers should be informed of the availability of a Medication Guide, and they should be instructed to read the Medication Guide prior to taking Topiramate () Tablets.
Patients should be instructed to take Topiramate () Tablets only as prescribed. See FDA approved Medication Guide.
Topiramate ()
Topiramate () Medication Guide
Read this Medication Guide before you start taking Topiramate () Tablets, USP and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. If you have any questions about Topiramate () Tablets, talk to your healthcare provider or pharmacist.
People, especially children, should be watched for signs of decreased sweating and fever, especially in hot temperatures. Some people may need to be hospitalized for this condition.
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Topiramate () Tablets is a prescription medicine used:
Before taking Topiramate () Tablets, tell your healthcare provider about all your medical conditions, including if you:
Tell your healthcare provider about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Topiramate () Tablets and other medicines may affect each other causing side effects.
Especially, tell your healthcare provider if you take:
Ask your healthcare provider if you are not sure if your medicine is listed above.
Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist each time you get a new medicine. Do not start a new medicine without talking with your healthcare provider.
Topiramate () Tablets may cause serious side effects including:
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Call your healthcare provider right away if you have any of the symptoms above.
The most common side effects of Topiramate () Tablets include:
Tell your healthcare provider about any side effect that bothers you or that does not go away.
These are not all the possible side effects of Topiramate () Tablets. For more information, ask your healthcare provider or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1800-FDA-1088.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Topiramate () Tablets for a condition for which it was not prescribed. Do not give Topiramate () Tablets to other people, even if they have the same symptoms that you have. It may harm them.
This Medication Guide summarizes the most important information about Topiramate () Tablets. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Topiramate () Tablets that is written for health professionals.
For more information call 1-800-654-2299.
colloidal silicon dioxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, partially hydrolyzed polyvinyl alcohol, polyethylene glycol, sodium starch glycolate, talc, titanium dioxide, iron oxide yellow (50 mg and 100 mg only), and iron oxide red (50 mg and 200 mg only).
Manufactured by: Upsher-Smith Laboratories, Inc.
Minneapolis, MN 55447
102909-05 Revised 0311
Topiramate ()
Topiramate ()
Topiramate ()
Topiramate ()
