Topiramate (topiramate)

Dosage of topiramate must be adjusted carefully and individualized according to patient response and tolerance and the condition being treated. The manufacturer states that titration of topiramate dosages too rapidly (e.g., over 3-6 weeks) to achieve target dosages and/or excessive target dosages may have contributed to an unnecessarily high incidence of adverse effects in clinical studies.

In patients with or without a history of seizures or epilepsy, anticonvulsant drugs, including topiramate, should be withdrawn gradually to minimize the risk of seizures or increased seizure frequency. In clinical studies for seizure disorders, daily dosages of topiramate were decreased in weekly intervals by 50-100 mg in adults and over a 2-8 week period in pediatric patients; transition to a new anticonvulsant regimen was permitted when clinically indicated. In clinical studies for migraine prophylaxis, daily dosages were decreased in weekly intervals by 25-50 mg. However, in situations where more rapid withdrawal of topiramate is clinically necessary, the manufacturers recommend appropriate monitoring.

Topiramate is administered orally; the drug is commercially available in various dosage forms for oral administration, including immediate-release tablets, sprinkle capsules, extended-release capsules, and an oral solution.

Store topiramate tablets at 15-30degreesC and topiramate sprinkle capsules at or below 25degreesC. Store Qudexy(R) XR extended-release capsules at 20-25degreesC (excursions permitted between 15-30degreesC). Store Trokendi XR(R) extended-release capsules at 25degreesC (excursions permitted between 15-30degreesC). Store Eprontia(R) oral solution at 20-25degreesC (excursions permitted between 15-30degreesC). Protect topiramate tablets, sprinkle capsules, and extended-release capsules from moisture during storage; additionally, protect Trokendi XR(R) from light during storage.

No dosing information is available for this tab.

No dosing information is available for this tab.

There is no enhanced messaging for this drug.

There are no contraindication interactions for this drug.

There are no severe interactions for this drug.

There are no moderate interactions for this drug.

*There are no known contraindications to the use of immediate-release topiramate and Qudexy(R) XR extended-release topiramate capsules. Trokendi XR(R) extended-release topiramate capsules are contraindicated in patients with recent alcohol use (i.e., within 6 hours prior to or 6 hours after topiramate use).

There are no contraindication contraindications for this drug.

There are no severe contraindications for this drug.

There are no moderate contraindications for this drug.

The most common adverse effects reported in adults and pediatric patients receiving topiramate for epilepsy (>=10% incidence and occurring more frequently with the drug than placebo) include paresthesia, anorexia, weight loss, speech disorders or other related speech problems, fatigue, dizziness, somnolence, nervousness, psychomotor slowing, abnormal vision, and fever.

The most common adverse effects reported in adults and pediatric patients receiving topiramate for migraine prophylaxis (5% or greater incidence and occurring more frequently with the drug than with placebo) include paresthesia, anorexia, weight loss, difficulty with memory, taste perversion, diarrhea, hypoesthesia, nausea, abdominal pain, and upper respiratory tract infection.

In controlled clinical trials evaluating topiramate for alcohol dependence+, paresthesia, taste perversion, fatigue, anorexia, insomnia, concentration and attention difficulties, memory impairment, nervousness, somnolence, diarrhea, dizziness, and pruritus were reported more frequently in patients receiving topiramate than in patients receiving placebo.

There are no severe adverse reactions for this drug.

There are no less severe adverse reactions for this drug.

No enhanced messaging available.

Safety and efficacy of topiramate for the management of seizure disorders have not been established in children younger than 2 years of age. In a randomized, double-blind, placebo-controlled study in infants 1-24 months of age, topiramate in fixed dosages of 5, 15, and 25 mg/kg daily was not shown to be more effective than placebo in controlling seizures after 20 days of treatment. Results of this study in addition to a long-term open-label study in infants and toddlers suggest that very young children may experience adverse effects not previously observed in older pediatric patients and adults or that occur with greater frequency or severity than in these older age groups. Such adverse effects included growth/length retardation, changes in certain laboratory parameters (e.g., increased serum creatinine concentrations, increased BUN, increased protein concentrations, decreased potassium concentrations, increased eosinophil count, increased alkaline phosphatase concentrations), and impairment of adaptive behavior. Although other preparations of topiramate may be used in children as young as 2 years of age for the management of seizure disorders, use of Trokendi XR(R) extended-release capsules is recommended only in children 6 years of age or older because this capsule formulation must be swallowed whole and cannot be sprinkled on food, crushed, or chewed.

Safety and efficacy of topiramate for migraine prophylaxis have not been established in pediatric patients younger than 12 years of age. In a controlled study in pediatric patients 6-16 years of age, topiramate 2-3 mg/kg daily was not more effective than placebo for preventing migraine headaches.

As in adults, cognitive/neuropsychiatric effects are commonly reported in pediatric patients receiving topiramate, although the incidence appears to be lower than that observed in adults. Such effects include psychomotor slowing, difficulty with concentration or attention, speech disorders, and language problems. The most common adverse CNS effects reported in pediatric patients receiving topiramate as initial monotherapy for seizure disorders include dizziness, headache, anorexia, and somnolence. The most common adverse CNS effects reported in pediatric patients receiving the drug as adjunctive therapy for seizure disorders include somnolence and fatigue. In migraine prophylaxis studies in pediatric patients 12-17 years of age, difficulty with concentration/attention was the most commonly reported adverse CNS effect. Adverse cognitive effects observed in pediatric migraine studies were dose dependent and occurred with greater frequency in younger (6-11 years of age) compared with older (12-17 years of age) children. Topiramate may cause psychomotor slowing and decreased verbal fluency based on results of a standard neuropsychological test that was administered to adolescents 12-17 years of age.

Hyperchloremic, non-anion gap, metabolic acidosis (i.e., decreased serum bicarbonate concentrations to below the normal reference range in the absence of chronic respiratory alkalosis) has been reported in pediatric patients receiving topiramate. In pediatric studies evaluating topiramate as adjunctive therapy for refractory partial-onset seizures or Lennox-Gastaut syndrome, the incidence of decreased serum bicarbonate concentrations was as high as 67 or 10% for patients receiving topiramate (approximately 6 mg/kg daily) or placebo, respectively. Markedly abnormally low serum bicarbonate concentrations (defined as concentrations of less than 17 mEq/L and a decrease from pretreatment values exceeding 5 mEq/L) were observed in up to 11% of patients receiving topiramate in these studies compared with no more than 2% of those receiving placebo. Similar reductions in serum bicarbonate were reported in an open-label, active-controlled study of pediatric patients treated with topiramate monotherapy for partial-onset seizures. Markedly low serum bicarbonate concentrations and persistent metabolic acidosis were reported in 35 and 76% of patients treated with topiramate, respectively. Chronic, untreated metabolic acidosis may have potentially serious sequelae, including development of osteomalacia (rickets), reduction of growth rates, and a decrease in maximal height achieved in pediatric patients. Although the effects of topiramate on growth and bone-related sequelae have not been systematically evaluated in long-term, placebo-controlled trials, results of an open-label study demonstrated that pediatric patients 1-24 months old who received topiramate for up to 1 year had reduced length, weight, and head circumference compared with age- and sex-matched normative data; reductions in length and weight were correlated with the degree of acidosis. Because of the potential risk of metabolic acidosis, the manufacturers state that serum bicarbonate concentrations should be measured at baseline and periodically during topiramate therapy.

Reductions in bone mineral density and growth have been reported in a 1-year active-controlled study of pediatric patients receiving monotherapy with topiramate for treatment of partial-onset seizures. In an open-label, active-controlled study of pediatric patients aged 4-15 years with partial-onset seizures, statistically significant reductions in weight and bone mineral density in the lumbar spine and total body less head were reported among patients treated with topiramate monotherapy compared to those treated with levetiracetam monotherapy.

Oligohidrosis (decreased sweating) and hyperthermia have been reported in clinical trials and during postmarketing surveillance of topiramate. Because oligohidrosis and hyperthermia typically occurred in children and may have potentially serious sequelae, the manufacturers state that patients, particularly pediatric patients, receiving topiramate should be monitored closely for evidence of decreased sweating and increased body temperature, especially in hot weather.

Clearance of topiramate is higher in pediatric patients than in adults, and also higher in younger versus older pediatric patients, presumably because of age-related changes in the rate of drug metabolism. Pediatric patients (2 to younger than 16 years of age) receiving adjunctive therapy with topiramate exhibited higher oral topiramate clearance than those receiving topiramate monotherapy; the observed difference was presumably due to concomitant use of enzyme-inducing anticonvulsant agents.

Topiramate can cause fetal harm when administered to pregnant patients. Exposure to the drug in utero has been associated with an increased risk of oral clefts (cleft lip and/or palate) and for neonates being SGA (i.e., birth weight less than 10th percentile). Data from pregnancy registries, including the North American Antiepileptic Drug (NAAED) pregnancy registry, indicate that infants exposed to topiramate in utero have a higher prevalence of oral cleft birth defects than those with no such exposure. The prevalence of oral clefts among infants in the NAAED registry who were exposed to topiramate in utero was 1.1% compared with a prevalence of 0.36% in infants exposed to a reference anticonvulsant and a prevalence of 0.12% in infants born to women without epilepsy and without exposure to anticonvulsant agents. For comparison, the estimated background rate of oral clefts in the US as estimated by the US Centers for Disease Control and Prevention (CDC) is 0.17%. Based on NAAED data, the relative risk of developing an oral cleft defect in topiramate-exposed pregnancies was 9.6 compared with the risk in a background population of untreated women. The United Kingdom Epilepsy and Pregnancy Registry reported a similarly increased prevalence of oral clefts of 3.2% among infants exposed in utero to topiramate monotherapy; the reported rate was 16 times higher than the background rate in the United Kingdom, which is approximately 0.2%.

Data from the NAAED registry indicate that 19.7% of infants who were exposed to topiramate in utero were SGA compared with 7.9% of infants exposed to a reference anticonvulsant and 5.4% of infants born to women without epilepsy and without exposure to anticonvulsant agents. In another population-based birth registry, 25% of topiramate-exposed infants were SGA compared with 9% of infants who were not exposed to anticonvulsants. The prevalence of this adverse effect is higher in infants born to women who received higher dosages of topiramate during pregnancy or who continued to receive topiramate through the third trimester. SGA has been observed at all dosages of topiramate and appears to be dose dependent; however, the long-term consequences of these findings are not known.

Topiramate has demonstrated selective developmental toxicity, including teratogenicity and embryotoxicity, in multiple species of animals (rats, rabbits, mice). Structural malformations, including craniofacial defects, and reduced fetal weights have occurred in the offspring of pregnant animals exposed to topiramate at clinically relevant dosages in the absence of maternal toxicity. However, there also was some evidence of maternal toxicity (e.g., decreased maternal body weight gain, increased mortality).

Topiramate therapy can cause metabolic acidosis. The effect of topiramate-induced metabolic acidosis has not been specifically studied during pregnancy; however, metabolic acidosis from other causes during pregnancy can result in decreased fetal growth, decreased fetal oxygenation, and fetal death, and also may affect the ability of the fetus to tolerate labor. Therefore, pregnant women receiving topiramate should be monitored and treated for metabolic acidosis in the same manner as nonpregnant patients. In addition, neonates born to women treated with topiramate should be monitored for metabolic acidosis because of possible drug transfer to the fetus and possible occurrence of transient metabolic acidosis following birth.

The benefits and risks of topiramate therapy should be carefully considered when use of the drug in females of reproductive potential is contemplated, particularly for conditions not usually associated with permanent injury or death. All females of reproductive potential should be informed of the potential risks to the fetus from exposure to topiramate. Alternative options should be considered in patients who are planning a pregnancy. If a decision is made to use topiramate in a female of reproductive potential who is not planning a pregnancy, clinicians should recommend use of effective contraception. The potential for decreased efficacy of estrogen-containing oral contraceptives should be considered.

Women who become pregnant while receiving topiramate should be encouraged to enroll in the NAAED pregnancy registry; patients can enroll by calling 888-233-2334. Information on the registry also can be found on the website https://www.aedpregnancyregistry.org.

Limited data indicate that topiramate distributes into human milk at concentrations similar to those in maternal plasma. The effects of topiramate on milk production are not known. Diarrhea and somnolence have been reported in breast-fed infants whose mothers were receiving topiramate treatment. The known benefits of breast-feeding should be considered along with the clinical importance of the drug to the mother and any potential adverse effects on the breast-fed infant from topiramate or the underlying maternal condition.

The manufacturers make no specific dosage recommendations for geriatric patients.

While clinical studies evaluating topiramate did not include sufficient numbers of adults 65 years of age or older to determine whether geriatric patients respond differently than younger adults, approximately 3% of patients receiving the drug in clinical trials were older than 60 years of age. Although no age-related differences in efficacy or safety were evident in these patients, pharmacokinetic data from one controlled clinical study revealed a decreased clearance of topiramate in geriatric patients with reduced renal function (i.e., creatinine clearance reduced by 20% compared with that in younger adults). Following administration of a single 100-mg dose of topiramate in these patients, plasma clearance and renal clearance of topiramate were reduced by 21 and 19%, respectively; half-life was prolonged by 13%; and peak plasma concentrations and area under the plasma concentration-time curve (AUC) were increased by 23 or 25%, respectively, compared with younger adults. Therefore, the manufacturers state that it may be useful to monitor renal function in geriatric patients; dosage adjustment may be necessary in geriatric patients with impaired renal function (i.e., creatinine clearance less than 70 mL/minute per 1.73 m2).