TOPIRAMATE tablet

Country: United States

Language: English

Source: NLM (National Library of Medicine)

Active ingredient:

TOPIRAMATE (UNII: 0H73WJJ391) (TOPIRAMATE - UNII:0H73WJJ391)

Available from:

NuCare Pharmaceuticals, Inc.

Administration route:

ORAL

Prescription type:

PRESCRIPTION DRUG

Therapeutic indications:

Topiramate tablets USP are indicated as initial monotherapy in patients 2 years of age and older with partial onset or primary generalized tonic-clonic seizures. 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 [see Clinical Studies (14.1)] .                                                                  Topiramate tablets USP are indicated as adjunctive therapy for adults and pediatric patients ages 2 to 16 years with partial onset seizures or primary generalized tonic-clonic seizures, and in patients 2 years of age and older with seizures associated with Lennox-Gastaut syndrome [see Clinical Studies (14.2)] . None Pregnancy Category D   [see   Warnings and Precautions 5.7 ] Topiramate tablets can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in utero have an increased risk for cleft lip and/or cleft palate (oral clefts). When multiple species of pregnant animals received topiramate at clinically relevant doses, structural malformations, including craniofacial defects, and reduced fetal weights occurred in offspring. Topiramate tablets should be used during pregnancy only if the potential benefit outweighs the potential risk. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations ( 8.9)] . Pregnancy Registry Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll-free number 1-888-233-2334. Information about the North American Drug Pregnancy Registry can be found at http://www.massgeneral.org/aed/ . Human Data Data from the NAAED Pregnancy Registry (425 prospective topiramate monotherapy-exposed pregnancies) indicate an increased risk of oral clefts in infants exposed during the first trimester of pregnancy. The prevalence of oral clefts among topiramate-exposed infants was 1.2% compared to a prevalence of 0.39% for infants exposed to a reference AED. In infants of mothers without epilepsy or treatment with other AEDs. The prevalence was 0.12%. For comparison, the Centers for Disease Control and Prevention (CDC) reviewed available data on oral clefts in the United States and found a similar background rate of 0.17%. The relative risk of oral clefts in topiramate-exposed pregnancies in the NAAED Pregnancy Registry was 9.6 (95% Confidence Interval [CI] 4.0 – 23.0) as compared to the risk in a background population of untreated women. The UK Epilepsy and Pregnancy Register reported a similarly increased prevalence of oral clefts of 3.2% among infants exposed to topiramate monotherapy. The observed rate of oral clefts was 16 times higher than the background rate in the UK, which is approximately 0.2%. Topiramate tablets treatment can cause metabolic acidosis [see Warnings and Precautions ( 5.4)] . The effect of topiramate-induced metabolic acidosis has not been studied in pregnancy; however, metabolic acidosis in pregnancy (due to other causes) can cause decreased fetal growth, decreased fetal oxygenation, and fetal death, and may affect the fetus' ability to tolerate labor. Pregnant patients should be monitored for metabolic acidosis and treated as in the nonpregnant state [see Warnings and Precautions ( 5.4)] . Newborns of mothers treated with topiramate tablets should be monitored for metabolic acidosis because of transfer of topiramate to the fetus and possible occurrence of transient metabolic acidosis following birth. Animal Data Topiramate has demonstrated selective developmental toxicity, including teratogenicity, in multiple animal species at clinically relevant doses. 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 2 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 2 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/m 2 basis). 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 2 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 2 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 2 basis) and reductions in preand/or postweaning body weight gain at 2 mg/kg (0.05 times the RHD on a mg/m 2 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 2 basis) and persistent reductions in body weight gain at 30 mg/kg (1 times the RHD on a mg/m 2 basis) and higher. Although the effect of topiramate tablets on labor and delivery in humans has not been established, the development of topiramate-induced metabolic acidosis in the mother and/or in the fetus might affect the fetus' ability to tolerate labor [see   Use   in   Specific   Populations   ( 8.1 )] . Limited data on 5 breastfeeding infants exposed to topiramate showed infant plasma topiramate levels equal to 10–20% of the maternal plasma level. The effects of this exposure on infants are unknown. Caution should be exercised when administered to a nursing woman. Adjunctive Treatment for Partial Onset Epilepsy in Infants and Toddlers ( 1 to 24 months)             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. In a single randomized, double-blind, placebo-controlled investigational trial, the efficacy, safety, and tolerability of topiramate oral liquid and sprinkle formulations as an adjunct to concurrent antiepileptic drug therapy in infants 1 to 24 months of age with refractory partial onset seizures were assessed. After 20 days of double-blind treatment, topiramate (at fixed doses of 5, 15, and 25 mg/kg/day) did not demonstrate efficacy compared with placebo in controlling seizures. In general, the adverse reaction profile in this population was similar to that of older pediatric patients, although results from the above controlled study and an open-label, long-term extension study in these infants/toddlers (1 to 24 months old) suggested some adverse reactions/toxicities (not previously observed in older pediatric patients and adults; i.e., growth/length retardation, certain clinical laboratory abnormalities, and other adverse reactions/toxicities that occurred with a greater frequency and/or greater severity than had been recognized previously from studies in older pediatric patients or adults for various indications. These very young pediatric patients appeared to experience an increased risk for infections (any topiramate dose 12%, placebo 0%) and of respiratory disorders (any topiramate dose 40%, placebo 16%). The following adverse reactions were observed in at least 3% of patients on topiramate and were 3% to 7% more frequent than in patients on placebo: viral infection, bronchitis, pharyngitis, rhinitis, otitis media, upper respiratory infection, cough, and bronchospasm. A generally similar profile was observed in older children [see Adverse Reactions ( 6)] . Topiramate resulted in an increased incidence of patients with increased creatinine (any topiramate dose 5%, placebo 0%), BUN (any topiramate dose 3%, placebo 0%), and protein (any topiramate dose 34%, placebo 6%), and an increased incidence of decreased potassium (any topiramate dose 7%, placebo 0%). This increased frequency of abnormal values was not dose-related. Creatinine was the only analyte showing a noteworthy increased incidence (topiramate 25 mg/kg/day 5%, placebo 0%) of a markedly abnormal increase [see Warnings and Precautions ( 5.16)] . The significance of these findings is uncertain. Topiramate treatment also produced a dose-related increase in the percentage of patients who had a shift from normal at baseline to high/increased (above the normal reference range) in total eosinophil count at the end of treatment. The incidence of these abnormal shifts was 6 % for placebo, 10% for 5 mg/kg/day, 9% for 15 mg/kg/day, 14% for 25 mg/kg/day, and 11% for any topiramate dose [see Warnings and Precautions ( 5.16)] . There was a mean dose-related increase in alkaline phosphatase. The significance of these findings is uncertain. Topiramate produced a dose-related increased incidence of treatment-emergent hyperammonemia [see Warnings and Precautions ( 5.10)] . Treatment with topiramate for up to 1 year was associated with reductions in Z SCORES for length, weight, and head circumference [see Warnings and Precautions ( 5.4) and Adverse Reactions ( 6)] . In open-label, uncontrolled experience, increasing impairment of adaptive behavior was documented in behavioral testing over time in this population. There was a suggestion that this effect was dose-related. However, because of the absence of an appropriate control group, it is not known if this decrement in function was treatment-related or reflects the patient's underlying disease (e.g., patients who received higher doses may have more severe underlying disease) [see Warnings and Precautions ( 5.6)] . In this open-label, uncontrolled study, the mortality was 37 deaths/1000 patient years. It is not possible to know whether this mortality rate is related to topiramate treatment, because the background mortality rate for a similar, significantly refractory, young pediatric population (1-24 months) with partial epilepsy is not known. Monotherapy Treatment in Partial Onset Epilepsy in Patients <2 Years Old Safety and effectiveness in patients below the age of 2 years have not been established for the monotherapy treatment of epilepsy. Juvenile Animal Studies When topiramate (30, 90, or 300 mg/kg/day) was administered orally to rats during the juvenile period of development (postnatal days 12 to 50), bone growth plate thickness was reduced in males at the highest dose, which is approximately 5-8 times the maximum recommended pediatric dose (9 mg/kg/day) on a body surface area (mg/m 2 ) basis. In clinical trials, 3% of patients were over 60. No age-related differences 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 2 ) due to reduced clearance of topiramate [see   Clinical   Pharmacology   ( 12.3 )   and   Dosage   and   Administration   ( 2.5 )] . Evaluation of effectiveness and safety in clinical trials has shown no race- or gender-related effects. The clearance of topiramate was reduced by 42% in moderately renally impaired (creatinine clearance 30 to 69 mL/min/1.73m 2 ) and by 54% in severely renally impaired subjects (creatinine clearance <30 mL/min/1.73m 2 ) compared to normal renal function subjects (creatinine clearance >70 mL/min/1.73m 2 ). One-half the usual starting and maintenance dose is recommended in patients with moderate or severe renal impairment [see Dosage and Administration ( 2.6) and Clinical Pharmacology ( 12.3)] . Topiramate is cleared by hemodialysis at a rate that is 4 to 6 times greater than in a normal individual. Accordingly, a prolonged period of dialysis may cause topiramate concentration to fall below that required to maintain an anti-seizure effect. To avoid rapid drops in topiramate plasma concentration during hemodialysis, a supplemental dose of topiramate tablets may be required. The actual adjustment should take into account the duration of dialysis period, the clearance rate of the dialysis system being used, and the effective renal clearance of topiramate in the patient being dialyzed [see   Dosage   and   Administration   ( 2.4 )   and   Clinical   Pharmacology   ( 12.3 )]   Data from pregnancy registries indicate that infants exposed to topiramate tablets in utero have an increased risk for cleft lip and/or cleft palate (oral clefts) [see Warnings and Precautions ( 5.7) and Use in Specific Populations (8.1)] . Consider the benefits and the risks of topiramate tablets when prescribing this drug to women of childbearing potential, particularly when topiramate tablets is considered for a condition not usually associated with permanent injury or death. Because of the risk of oral clefts to the fetus, which occur in the first trimester of pregnancy before many women know they are pregnant, all women of childbearing potential should be apprised of the potential hazard to the fetus from exposure to topiramate tablets. If the decision is made to use topiramate tablets, women who are not planning a pregnancy should use effective contraception [see Drug Interactions ( 7.3)] . Women who are planning a pregnancy should be counselled regarding the relative risks and benefits of topiramate tablets use during pregnancy, and alternative therapeutic options should be considered for these patients [see Patient Counseling Information ( 17)] .

Product summary:

Topiramate tablets USP Topiramate tablets USP are available in the following strengths and colors: 50 mg, Light orange colored, circular, biconvex, film-coated tablets, debossed with "123" on one side and "C" on the other side and are available in Bottles of 30 NDC 68071-3196-3 Bottles of 60 NDC 68071-3196-6 PHARMACIST: Dispense in a tight container as defined in the USP. Use child-resistant closure (as required). Store at 20°C to 25°C (68°F to 77°F) [See USP controlled room temperature]. Protect from moisture.

Authorization status:

Abbreviated New Drug Application

Patient Information leaflet

TOPIRAMATE- TOPIRAMATE TABLET
NuCare Pharmaceuticals, Inc.
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17 PATIENT COUNSELING
INFORMATION
Advise the patient to read the FDA-approved patient labeling
(Medication Guide).
Eye Disorders
Instruct patient taking topiramate tablets should be told to seek
immediate medical attention if they
experience blurred vision, visual disturbances, or periorbital pain
[see Warnings and Precautions
Oligohidrosis and Hyperthermia
Closely monitor topiramate tablets-treated pateints, especially
pediatric patients, for evidence of
decreased sweating and increased body temperature, especially in hot
weather. Counsel patient to contact
their healthcare professionals immediately if they develop a high or
persistent fever, or decreased
sweating [see Warnings and Precautions
Metabolic Acidosis
Warn patients about the potential significant risk for metabolic
acidosis that may be asymptomatic and
may be associated with adverse effects on kidneys (e.g., kidney
stones, nephrocalcinosis), bones (e.g.,
osteoporosis, osteomalacia, and/or rickets in children), and growth
(e.g., growth delay/retardation) in
pediatric patients, and on the fetus [see Warnings and Precautions (
and Use in Specific Populations
Suicidal Behavior and Ideation
Counsel patients, their caregivers, and families that AEDs, including
topiramate tablets, may increase the
risk of suicidal thoughts and behavior, and advise of the need to be
alert for the emergence or worsening
of the signs and symptoms of depression, any unusual changes in mood
or behavior or the emergence of
suicidal thoughts, or behavior or thoughts about self-harm. Instruct
patients to immediately report
behaviors of concern to their healthcare providers [see Warnings and
Precautions
Interference with Cognitive and Motor Performance
Warn patients about the potential for somnolence, dizziness,
confusion, difficulty concentrating, or visual
effects, and advise patients not to drive or operate machinery until
they have gained sufficient experience
on topiramate tablets to gauge whether it adversely

Summary of Product characteristics

TOPIRAMATE- TOPIRAMATE TABLET
NUCARE PHARMACEUTICALS, INC.
----------
HIGHLIGHTS OF PRESCRIBING INFORMATION
THESE HIGHLIGHTS DO NOT INCLUDE ALL THE INFORMATION NEEDED TO USE
TOPIRAMATE TABLETS, USP
SAFELY AND EFFECTIVELY. SEE FULL PRESCRIBING INFORMATION FOR
TOPIRAMATE TABLETS, USP.
TOPIRAMATE TABLETS USP, FOR ORAL USE.
INITIAL U.S. APPROVAL: 1996
RECENT MAJOR CHANGES
Warnings and Precautions, Visual Field Defects ( 5.2) 01/2014
INDICATIONS AND USAGE
Topiramate tablets USP is an antiepileptic (AED) agent indicated for:
Monotherapy epilepsy: Initial monotherapy in patients ≥ 2 years of
age with partial onset or primary
generalized tonic-clonic seizures ( 1.1)
Adjunctive therapy epilepsy: Adjunctive therapy for adults and
pediatric patients (2 to 16 years of age)
with partial onset seizures or primary generalized tonic-clonic
seizures, and in patients ≥2 years of age
with seizures associated with Lennox-Gastaut syndrome (LGS) ( 1.2)
DOSAGE AND ADMINISTRATION
See DOSAGE AND ADMINISTRATION, Epilepsy: Monotherapy and Adjunctive
Therapy Use for additional
details INITIAL DOSE
TITRATION
RECOMMENDED
DOSE
Epilepsy monotherapy:
children 2to<10years (2.1)
25mg/day
administered nightly
for the first week
The dosage should
betitratedover5–7 weeks
Daily doses in two
divided doses based
on weight(Table2)
Epilepsy monotherapy:
adults and pediatric patients≥10years
(2.1)
50mg/day in two
divided doses
The dosage should be
increased weekly by
increments of 50mg for the
first 4 weeks
then100mgfor weeks 5to6.
400 mg/day in two
divided doses
Epilepsy adjunctive
therapy :adults with
partial onset seizures or LGS( 2.1)
25to50mg/day
The dosage should be
increased weekly to an
effective dose by
incrementsof25to50mg.
200–400 mg/day in
two divided doses
Epilepsy adjunctive
therapy: adults with
primary generalized tonic- clonic
seizures (2.1)
25to50mg/day
The dosage should be
increased weekly to an
effective dose by
incrementsof25to50mg.
400 mg/day in two
divided doses
Epilepsy adjunctive therapy: pediatric
Patients with partial
on