Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/3796
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Topamax (Capsule, Coated Pellets)
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Epilepsy: 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 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 TOPAMAX therapy.
On occasion, the addition of TOPAMAX 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 TOPAMAX may require adjustment of the dose of
TOPAMAX. Because of the bitter taste, tablets should not
be broken. TOPAMAX can be taken without
regard to meals.<br/>Monotherapy Use: The recommended dose for topiramate monotherapy in adults
and children 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 titrating according to the
following schedule:<br/>Adjunctive Therapy Use:<br/>Migraine: The recommended total daily dose of TOPAMAX as
treatment for prophylaxis of migraine headache is 100 mg/day administered
in two divided doses. The recommended titration rate for topiramate for migraine
prophylaxis to 100 mg/day is: Dose and titration rate should be guided by clinical outcome.
If required, longer intervals between dose adjustments can be used.<br/>Administration of TOPAMAX Sprinkle
Capsules: TOPAMAX (topiramate capsules) Sprinkle Capsules
may be swallowed whole or may be administered by carefully opening the capsule
and sprinkling the entire contents on a small amount (teaspoon) of soft food.
This drug/food mixture should be swallowed immediately and not chewed. It
should not be stored for future use.<br/>Patients with Renal Impairment:: In renally impaired subjects (creatinine clearance less than
70 mL/min/1.73 m), one half of the usual adult dose is recommended.
Such patients will require a longer time to reach steady-state at each dose.<br/>Geriatric Patients (Ages 65 Years
and Over):: Dosage adjustment may be indicated in the elderly patient
when impaired renal function (creatinine clearance rate���70 mL/min/1.73
m) is evident (see DOSAGE AND ADMINISTRATION: Patients with Renal Impairment and CLINICAL
PHARMACOLOGY: Special Populations: Age, Gender, and Race).<br/>Patients Undergoing Hemodialysis:: Topiramate is cleared by hemodialysis at a rate that is 4
to 6 times greater than 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 may be
required. The actual adjustment should take into account 1) the duration of
dialysis period, 2) the clearance rate of the dialysis system being used,
and 3) the effective renal clearance of topiramate in the patient being dialyzed.<br/>Patients with Hepatic Disease:: In hepatically impaired patients topiramate plasma concentrations
may be increased. The mechanism is not well understood.
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Topiramate is a sulfamate-substituted monosaccharide. TOPAMAX (topiramate)
Tablets are available as 25 mg, 50 mg, 100 mg, and 200 mg round tablets for
oral administration. TOPAMAX (topiramate capsules) Sprinkle
Capsules are available as 15 mg and 25 mg sprinkle capsules for oral
administration as whole capsules or opened and sprinkled onto soft food. 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 has the molecular formula CHNOS
and a molecular weight of 339.36. Topiramate is designated chemically as 2,3:4,5-Di-O-isopropylidene-��-D-fructopyranose sulfamate
and has the following structural formula: TOPAMAX (topiramate)
Tablets contain the following inactive ingredients: lactose monohydrate, pregelatinized
starch, microcrystalline cellulose, sodium starch glycolate, magnesium stearate,
purified water, carnauba wax, hypromellose, titanium dioxide, polyethylene
glycol, synthetic iron oxide (50, 100, and 200 mg tablets) and polysorbate
80. TOPAMAX (topiramate capsules) Sprinkle
Capsules contain topiramate coated beads in a hard gelatin capsule. The inactive
ingredients are: sugar spheres (sucrose and starch), povidone, cellulose acetate,
gelatin, sorbitan monolaurate, sodium lauryl sulfate, titanium dioxide, and
black pharmaceutical ink.
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Mechanism of Action:: The precise mechanisms by which topiramate exerts its anticonvulsant
and migraine prophylaxis effects are unknown; however, preclinical studies
have revealed four properties that may contribute to topiramate's efficacy
for epilepsy and migraine prophylaxis. 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 somesubtypes of the GABA-A receptor, antagonizes the
AMPA/kainate subtype of the glutamate receptor, and inhibits the carbonic
anhydrase enzyme, particularly isozymes II and IV.<br/>Pharmacodynamics:: Topiramate has anticonvulsant activity in rat and mouse maximal
electroshock seizure (MES) tests. Topiramate is only weakly effective in blocking
clonic seizures induced by the GABAreceptor antagonist, pentylenetetrazole.
Topiramate is also effective in rodent models of epilepsy, which include tonic
and absence-like seizures in the spontaneous epileptic rat (SER) and tonic
and clonic seizures induced in rats by kindling of the amygdala or by global
ischemia.<br/>Pharmacokinetics:: The sprinkle formulation is bioequivalent to the immediate
release tablet formulation and, therefore, may be substituted as a therapeutic
equivalent. 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 15-41%
bound to human plasma proteins over the blood concentration range of 0.5 -250��g/mL.
The fraction bound decreased as blood concentration increased. Carbamazepine
and phenytoin do not alter the binding of topiramate. Sodium valproate, at
500��g/mL (a concentration 5-10 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.<br/>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.<br/>Pharmacokinetic Interactions: (see also Drug Interactions):<br/>Antiepileptic Drugs: Potential interactions between topiramate and standard AEDs
were assessed in controlled clinical pharmacokinetic studies in patients with
epilepsy. The effect of these interactions on mean plasma AUCs are summarized
under PRECAUTIONS (Table 3).<br/>Special Populations::<br/>Renal Impairment:: The clearance of topiramate was reduced by 42% in moderately
renally impaired (creatinine clearance 30-69 mL/min/1.73m)
and by 54% in severely renally impaired subjects (creatinine clearance<30 mL/min/1.73m)
compared to normal renal function subjects (creatinine clearance>70 mL/min/1.73m).
Since topiramate is presumed to undergo significant tubular reabsorption,
it is uncertain whether this experience can be generalized to all situations
of renal impairment. It is conceivable that some forms of renal disease could
differentially affect glomerular filtration rate and tubular reabsorption
resulting in a clearance of topiramate not predicted by creatinine clearance.
In general, however, use of one-half the usual starting and maintenance dose
is recommended in patients with moderate or severe renal impairment (see PRECAUTIONS: Adjustment of Dose in
Renal Failure and DOSAGE AND ADMINISTRATION).<br/>Hemodialysis:: Topiramate is cleared by hemodialysis. Using a high efficiency,
counterflow, single pass-dialysate hemodialysis procedure, topiramate dialysis
clearance was 120 mL/min with blood flow through the dialyzer at 400
mL/min. This high clearance (compared to 20-30 mL/min total oral clearance
in healthy adults) will remove a clinically significant amount of topiramate
from the patient over the hemodialysis treatment period. Therefore, a supplemental
dose may be required (see DOSAGE
AND ADMINISTRATION).<br/>Hepatic Impairment:: In hepatically impaired subjects, the clearance of topiramate
may be decreased; the mechanism underlying the decrease is not well understood.<br/>Age, Gender, and Race:: The pharmacokinetics of topiramate in elderly subjects (65-85
years of age, N=16) were evaluated in a controlled clinical study. The elderly
subject population had reduced renal function [creatinine clearance (-20%)]
compared to young adults. Following a single oral 100 mg dose, maximum plasma
concentration for elderly and young adults was achieved at approximately 1-2 hours.
Reflecting the primary renal elimination of topiramate, topiramate plasma
and renal clearance were reduced 21% and 19%, respectively, in elderly
subjects, compared to young adults. Similarly, topiramate half-life was longer
(13%) in the elderly. Reduced topiramate clearance resulted in slightly higher
maximum plasma concentration (23%) and AUC (25%) in elderly subjects than
observed in young adults. Topiramate clearance is decreased in the elderly
only to the extent that renal function is reduced. As recommended for all
patients, dosage adjustment may be indicated in the elderly patient when impaired
renal function (creatinine clearance rate���70 mL/min/1.73 m)
is evident. It may be useful to monitor renal function in the elderly patient
(see Special Populations:
Renal Impairment, PRECAUTIONS: Adjustment of Dose in Renal Failure and DOSAGE AND ADMINISTRATION). Clearance of topiramate in adults was not
affected by gender or race.<br/>Pediatric Pharmacokinetics:: Pharmacokinetics of topiramate were evaluated in patients
ages 4 to 17 years receiving one or two other antiepileptic drugs. Pharmacokinetic
profiles were obtained after one week at doses of 1, 3, and 9 mg/kg/day.
Clearance was independent of dose. Pediatric patients
have a 50% higher clearance and consequently shorter elimination half-life
than adults. Consequently, the plasma concentration for the same mg/kg dose
may be lower in pediatric patients compared to adults. As in adults, hepatic
enzyme-inducing antiepileptic drugs decrease the steady state plasma concentrations
of topiramate.
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TOPAMAX is contraindicated in patients with
a history of hypersensitivity to any component of this product.
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TOPAMAX (topiramate) Tablets are available
as debossed, coated, round tablets in the following strengths and colors: 25
mg white (coded "TOP" on one side; "25" on the other)50 mg light-yellow
(coded "TOPAMAX" on one side; "50" on the other)100 mg yellow (coded
"TOPAMAX" on one side; "100" on the other)200 mg salmon (coded "TOPAMAX"
on one side; "200" on the other) They are supplied as
follows:25 mg tablets���bottles of 60 count with desiccant (NDC
0045-0639-65)50 mg tablets���bottles of 60 count with desiccant
(NDC 0045-0640-65)100 mg tablets���bottles of 60 count with desiccant
(NDC 0045-0641-65)200 mg tablets���bottles of 60 count with desiccant
(NDC 0045-0642-65) TOPAMAX (topiramate
capsules) Sprinkle Capsules contain small, white to off white spheres. The
gelatin capsules are white and clear. They are marked
as follows:15 mg capsule with���TOP���and���15 mg���on the side25 mg capsule with���TOP���and���25 mg���on the side The capsules are supplied as follows:15
mg capsules���bottles of 60 (NDC 0045-0647-65)25 mg capsules���bottles of 60 (NDC 0045-0645-65) TOPAMAX (topiramate)
Tablets should be stored in tightly-closed containers at controlled room temperature
(59 to 86��F, 15 to 30��C). Protect from moisture. TOPAMAX (topiramate
capsules) Sprinkle Capsules should be stored in tightly-closed containers
at or below 25��C (77��F). Protect from moisture. TOPAMAX (topiramate)
and TOPAMAX (topiramate capsules) are trademarks of Ortho-McNeil
Neurologics, Inc. TOPAMAX (topiramate)
and TOPAMAX (topiramate capsules) are manufactured by Janssen
Ortho, LLC Gurabo, Puerto Rico 00778 for Ortho-McNeil Neurologics, Division
of Ortho-McNeil-Janssen Pharmaceuticals, Inc. Titusville, NJ 08560.
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dailymed-ingredient:black_pharmaceutical_ink,
dailymed-ingredient:cellulose_acetate,
dailymed-ingredient:gelatin,
dailymed-ingredient:povidone,
dailymed-ingredient:sodium_lauryl_sulfate,
dailymed-ingredient:sorbitan_monolaurate,
dailymed-ingredient:sugar_spheres_(sucrose_and_starch),
dailymed-ingredient:titanium_dioxide
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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.<br/>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 2-4 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 TOPAMAX 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 TOPAMAX 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.<br/>Paresthesia: Paresthesia (usually tingling of the extremities), an effect
associated with the use of other carbonic anhydrase inhibitors, appears to
be a common effect of TOPAMAX. Paresthesia was more frequently
reported in the monotherapy epilepsy trials and migraine prophylaxis trials
versus the adjunctive therapy epilepsy trials. In the majority of instances,
paresthesia did not lead to treatment discontinuation.<br/>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 .<br/>Decreased Hepatic Function: In hepatically impaired patients, topiramate should be administered
with caution as the clearance of topiramate may be decreased.<br/>Information for Patients: Patients should be instructed to read the Patient Information
before starting treatment with TOPAMAX and each time their
prescription is renewed. Patients taking TOPAMAX should
be told to seek immediate medical attention if they experience blurred vision,
visual disturbances or periorbital pain. Patients, especially
pediatric patients, treated with TOPAMAX 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 PRECAUTIONS: Kidney Stones, for support regarding hydration as a preventative measure). Patientsshould be warned about the potential for somnolence, dizziness, confusion,
difficulty concentrating, and visual effects and advised not to drive or operate
machinery until they have gained sufficient experience on topiramate to gauge
whether it adversely affects their mental performance, motor performance,
and/or vision. Additional food intake may be considered
if the patient is losing weight while on this medication. Even
when taking TOPAMAX or other anticonvulsants, some patients
with epilepsy will continue to have unpredictable seizures. Therefore, all
patients taking TOPAMAX for epilepsy should be told to exercise
appropriate caution when engaging in any activities where loss of consciousness
could result in serious danger to themselves or those around them (including
swimming, driving a car, climbing in high places, etc.). Some patients with
refractory epilepsy will need to avoid such activities altogether. Physicians
should discuss the appropriate level of caution with their patients, before
patients with epilepsy engage in such activities. Please
refer to the end of the product labeling for important information on how
to take TOPAMAX (topiramate capsules) Sprinkle Capsules.<br/>Laboratory Tests:: Measurement of baseline and periodic serum bicarbonate during
topiramate treatment is recommended . In
double-blind trials hypokalemia defined as serum potassium decline below 3.5
mmol/L has been observed in 0.4% of subjects treated with topiramate compared
to 0.1% of subjects treated with placebo.<br/>Drug Interactions:: In vitro studies indicate
that topiramate does not inhibit enzyme activity for CYP1A2, CYP2A6,
CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4/5 isozymes.<br/>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 3. In Table 3, 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 TOPAMAX 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 PRECAUTIONS, Hyperammonemia
and Encephalopathy Associated with Concomitant Valproic Acid Use).<br/>Other Drug Interactions:<br/>Digoxin: In a single-dose study, serum digoxin AUC was decreased by
12% with concomitant TOPAMAX administration. The clinical
relevance of this observation has not been established.<br/>CNS Depressants: Concomitant administration of TOPAMAX 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.<br/>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), TOPAMAX 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, TOPAMAX (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 200-800 mg/day, there was no significant
dose dependent change in EE exposure for doses of 50-200 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 TOPAMAX.
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.<br/>Hydrochlorothiazide (HCTZ): A drug-drug interaction study conducted in healthy volunteers
evaluated the steady-state pharmacokinetics of HCTZ (25 mg q24h) and topiramate
(96 mg q12h) when administered alone and concomitantly. The results of this
study indicate that topiramate Cincreased 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.<br/>Metformin: A drug-drug interaction study conducted in healthy volunteers
evaluated the steady-state pharmacokinetics of metformin and topiramate in
plasma when metformin was given alone and when metformin and topiramate were
given simultaneously. The results of this study indicated that metformin mean
Cmax and mean AUC0-12h increased by 18% and 25%, respectively, while mean
CL/F decreased 20% when metformin was co-administered with topiramate. Topiramate
did not affect metformin tmax. The clinical significance of the effect of
topiramate on metformin pharmacokinetics is unclear. Oral plasma clearance
of topiramate appears to be reduced when administered with metformin. The
extent of change in the clearance is unknown. The clinical significance of
the effect of metformin on topiramate pharmacokinetics is unclear. When TOPAMAX is
added or withdrawn in patients on metformin therapy, careful attention should
be given to the routine monitoring for adequate control of their diabetic
disease state.<br/>Pilglitazone: 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 AUCof
pioglitazone with no alteration in Cwas observed. This
finding was not statistically significant. In addition, a 13% and 16% decrease
in Cand AUCrespectively, 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 TOPAMAX is added to
pioglitazone therapy or pioglitazone is added to TOPAMAX therapy,
careful attention should be given to the routine monitoring of patients for
adequate control of their diabetic disease state.<br/>Lithium: Multiple dosing of topiramate 100 mg every 12 hrs decreased
the AUC and cof Lithium (300 mg every 8 hrs) by 20% (N=12,
6M; 6F).<br/>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).<br/>Amitriptyline: There was a 12% increase in AUC and Cfor 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.<br/>Sumatriptan: Multiple dosing of topiramate (100 mg every 12 hrs) in 24
healthy volunteers (14 M, 10 F) did not affect the pharmacokinetics of single
dose sumatriptan either orally (100 mg) or subcutaneously (6 mg).<br/>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.<br/>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
(27M, 12F) had no effect on the exposure to topiramate at a dose of 200 mg/day
of topiramate.<br/>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.<br/>Others: Concomitant use of TOPAMAX, 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.<br/>Drug/Laboratory Test Interactions: There are no known interactions of topiramate with commonly
used laboratory tests.<br/>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/mbasis). Topiramate
did not demonstrate genotoxic potential when tested in a battery of in vitro and in
vivo assays. Topiramate was not mutagenic in the Ames test or the in vitro mouse lymphoma assay; it did not increase
unscheduled DNA synthesis in rat hepatocytes in
vitro; and it did not increase chromosomal aberrations in human
lymphocytes in vitro or in rat bone
marrow in vivo. 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/mbasis).<br/>Pregnancy: 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/mbasis. 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/mbasis) 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/mbasis) or greater, and teratogenic effects (primarily
rib and vertebral malformations) were observed at 120 mg/kg (6 timesthe
RHD on a mg/mbasis). 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/mbasis)
and reductions in pre- and/or postweaning body weight gain at 2 mg/kg
(0.05 times the RHD on a mg/mbasis) 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/mbasis) and persistent reductions in body
weight gain at 30 mg/kg (1 times the RHD on a mg/mbasis) and
higher. There are no studies using TOPAMAX in
pregnant women. TOPAMAX should be used during pregnancy only
if the potential benefit outweighs the potential risk to the fetus. In
post-marketing experience, cases of hypospadias have been reported in male
infants exposed in utero to topiramate, with or without other anticonvulsants;
however, a causal relationship with topiramate has not been established.<br/>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 TOPAMAX on labor and delivery in humans is unknown.<br/>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 TOPAMAX is unknown, the potential benefit to the mother
should be weighed against the potential risk to the infant when considering
recommendations regarding nursing.<br/>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 . Safety
and effectiveness in pediatric patients have not been established for the
prophylaxis treatment of migraine headache.<br/>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 .<br/>Race and Gender Effects:: Evaluation of effectiveness and safety in clinical trials
has shown no race or gender related effects.
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| dailymed-instance:overdosag... |
Overdoses of TOPAMAX 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 TOPAMAX. Topiramate
overdose has resulted in severe metabolic acidosis . A
patient who ingested a dose between 96 and 110 g topiramate was admitted to
hospital with coma lasting 20-24 hours followed by full recovery after 3 to
4 days. In acute TOPAMAX 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.
|
| dailymed-instance:genericMe... |
topiramate
|
| dailymed-instance:fullName |
Topamax (Capsule, Coated Pellets)
|
| dailymed-instance:adverseRe... |
The data described in the following section were obtained
using TOPAMAX (topiramate) Tablets.<br/>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 Table
4]. 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 Table 5]. 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.<br/>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 Table 6]. 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 Table
8]. 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 Table 9]. 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 (4.0%), 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 events. Adverse
events associated with discontinuing therapy included aggravated convulsions
(2.3%), difficulty with concentration/attention (1.6%), languageproblems
(1.3%), personality disorder (1.3%), and somnolence (1.3%).<br/>Incidence in Epilepsy Controlled Clinical
Trials���Adjunctive Therapy���Partial Onset Seizures, Primary
Generalized Tonic-Clonic Seizures, and Lennox-Gastaut Syndrome: Table
6 lists treatment-emergent adverse events that occurred
in at least 1% of adults treated with 200 to 400 mg/day topiramate in controlled
trials that were numerically more common at this dose than in the patients
treated with placebo. In general, most patients who experienced adverse events
during the first eight weeks of these trials no longer experienced them by
their last visit. Table
9 lists treatment-emergent adverse events that occurredin at least 1% of pediatric patients treated with 5 to 9 mg/kg topiramate
in controlled trials that were numerically more common than in patients treated
with placebo. The prescriber should be aware that these
data were obtained when TOPAMAX 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.<br/>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.<br/>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
for4 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
(Table 7)
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.<br/>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: frequent occurring in
at least 1/100 patients; infrequent occurring
in 1/100 to 1/1000 patients; rare occurring
in fewer than 1/1000 patients. Autonomic
Nervous System Disorders: Infrequent:
vasodilation. Body
as a Whole:Frequent: syncope. Infrequent: abdomen enlarged. Rare:
alcohol intolerance. Cardiovascular
Disorders, General:Infrequent: hypotension,
postural hypotension, angina pectoris. Central&Peripheral Nervous System Disorders:Infrequent
: neuropathy, apraxia, hyperaesthesia, dyskinesia, dysphonia, scotoma,
ptosis, dystonia, visual field defect, encephalopathy, EEG abnormal. Rare: upper motor neuron lesion, cerebellar
syndrome, tongue paralysis. Gastrointestinal
System Disorders:. Infrequent: hemorrhoids,
stomatitis, melena, gastritis, esophagitis. Rare:
tongue edema. Heart
Rate and Rhythm Disorders:Infrequent:
AV block. Liver
and Biliary System Disorders:Infrequent:
SGPT increased, SGOT increased. Metabolic and Nutritional Disorders:Infrequent:
dehydration, hypokalemia, alkaline phosphatase increased, hypocalcemia,
hyperlipemia, hyperglycemia, xerophthalmia, diabetes mellitus,. Rare:
hyperchloremia, hypernatremia, hyponatremia, hypocholesterolemia,
hypophosphatemia, creatinine increased. Musculoskeletal
System Disorders:Frequent: arthralgia. Infrequent: arthrosis. Neoplasms:Infrequent:
thrombocythemia. Rare: polycythemia. Platelet, Bleeding, and Clotting Disorders:Infrequent: gingival bleeding, pulmonary embolism. Psychiatric Disorders:Frequent:
impotence, hallucination, psychosis, suicide attempt. Infrequent: euphoria, paranoid reaction, delusion,
paranoia, delirium, abnormal dreaming. Rare:
libido increased, manic reaction. Red Blood Cell Disorders:Frequent:
anemia. Rare: marrow depression,
pancytopenia. Reproductive
Disorders, Male:Infrequent: ejaculation
disorder, breast discharge. Skin
and Appendages Disorders:Infrequent:
urticaria, photosensitivity reaction, abnormal hair texture. Rare: chloasma. Special Senses Other, Disorders:Infrequent:
taste loss, parosmia. Urinary
System Disorders:Infrequent: urinary
retention, face edema, renal pain, albuminuria, polyuria, oliguria. Vascular (Extracardiac) Disorders:Infrequent:
flushing, deep vein thrombosis, phlebitis. Rare:
vasospasm. Vision
Disorders:Frequent: conjunctivitis. Infrequent: abnormal accommodation, photophobia,
strabismus. Rare: mydriasis, iritis. White Cell and Reticuloendothelial System Disorders:Infrequent: lymphadenopathy, eosinophilia, lymphopenia,
granulocytopenia. Rare: lymphocytosis.<br/>Migraine: In the four multicenter, randomized, double-blind, placebo-controlled,
parallel group migraine prophylaxis clinical trials, most of the adverse events
with topiramate were mild or moderate in severity. Most adverse events occurred
more frequently during the titration period than during the maintenance period. Table 10 includes
those adverse events reported for patients in the placebo-controlled trials
where the incidence rate in any topiramate treatment group was at least 2
% and was greater than that for placebo patients. Of the 1,135 patients exposed to topiramate in the placebo-controlled
studies, 25% discontinued due to adverse events, compared to 10% of the
445 placebo patients. The adverse events associated with discontinuing therapy
in the topiramate-treated patients included paresthesia (7%), fatigue (4%),
nausea (4%), difficulty with concentration/attention (3%), insomnia (3%),
anorexia (2%), and dizziness (2%). Patients treated
with topiramate experienced mean percent reductions in body weight that were
dose-dependent. This change was not seen in the placebo group. Mean changes
of 0%,���2%,���3%, and���4% were seen for the placebo
group, topiramate 50, 100, and 200 mg groups, respectively. Table 11 shows
adverse events that were dose-dependent. Several central nervous system adverse
events, including some that represented cognitive dysfunction, were dose-related.
The most common dose-related adverse events were paresthesia, fatigue, nausea,
anorexia, dizziness, difficulty with memory, diarrhea, weight decrease, difficulty
with concentration/attention, and somnolence.<br/>Other Adverse Events Observed During
Migraine Clinical Trials: Topiramate, for the treatment of prophylaxis of migraine
headache, has been administered to 1,367 patients in all clinical studies
(includes double-blind and open-label extension). 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 following additional adverse events
that were not described earlier were reported by greater than 1% of the 1,367
topiramate-treated patients in the controlled clinical trials: Body as a Whole: Pain, chest pain, allergic reaction. Central&Peripheral Nervous System Disorders: Headache,
vertigo, tremor, sensory disturbance, migraine aggravated. Gastrointestinal System Disorders: Constipation,
gastroesophageal reflux, tooth disorder. Musculoskeletal
System Disorders: Myalgia. Platelet,
Bleeding, and Clotting Disorders: Epistaxis. Reproductive Disorders, Female: Intermenstrual
bleeding. Resistance Mechanism
Disorders: Infection, genital moniliasis. Respiratory System Disorders: Pneumonia, asthma. Skin and Appendages Disorders: Rash, alopecia. Vision Disorders: Abnormal accommodation, eye pain.<br/>Postmarketing and Other Experience: In addition to the adverse experiences reported during clinical
testing of TOPAMAX, the following adverse experiences have
been reported worldwide in patients receiving TOPAMAX 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.
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| dailymed-instance:warning |
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 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 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<20
mEq/L at two consecutive visits or at the final visit) in controlled clinical
trials for adjunctive treatment of epilepsy was 32% for 400 mg/day, and
1% for placebo. Metabolic acidosis has been observed at doses as low as 50
mg/day. The incidence of persistent treatment-emergent decreases in serum
bicarbonate in adults in the epilepsy controlled clinical trial for monotherapy
was 15% for 50 mg/day and 25% for 400 mg/day. The incidence of a markedly
abnormally low serum bicarbonate (i.e., absolute value<17 mEq/L and>5
mEq/L decrease from pretreatment) in the adjunctive therapy trials was 3%
for 400 mg/day, and 0% for placebo and in the monotherapy trial was 1% for
50 mg/day and 7% for 400 mg/day. Serum bicarbonate levels have not been systematically
evaluated at daily doses greater than 400 mg/day. In
pediatric patients (<16 years of age), the incidence of persistent treatment-emergent
decreases in serum bicarbonate in placebo-controlled trials for adjunctive
treatment of Lennox-Gastaut syndrome or refractory partial onset seizures
was 67% for TOPAMAX (at approximately 6 mg/kg/day),
and 10% for placebo. The incidence of a markedly abnormally low serum bicarbonate
(i.e., absolute value<17 mEq/L and>5 mEq/L decrease from pretreatment)
in these trials was 11% for TOPAMAX and 0% for placebo. Cases
of moderately severe metabolic acidosis have been reported in patients as
young as 5 months old, especially at daily doses above 5 mg/kg/day. 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<17 mEq/L and>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 for
prophylaxis of migraine was 44% for 200 mg/day, 39% for 100 mg/day, 23%
for 50 mg/day, and 7% for placebo. The incidence of a markedly abnormally
low serum bicarbonate (i.e., absolute value<17 mEq/L and>5 mEq/L
decrease from pretreatment) in these trials was 11% for 200 mg/day, 9% for
100 mg/day, 2% for 50 mg/day, and<1% for placebo. Some
manifestations of acute or chronic metabolic acidosis may include hyperventilation,
nonspecific symptoms such as fatigue and anorexia, or more severe sequelae
including cardiac arrhythmias or stupor. Chronic, untreated metabolic acidosis
may increase the risk for nephrolithiasis or nephrocalcinosis, and may also
result in osteomalacia (referred to as rickets in pediatric patients) and/or
osteoporosis with an increased risk for fractures. Chronic metabolic acidosis
in pediatric patients may also reduce growth rates. A reduction in growth
rate may eventually decrease the maximal height achieved. The effect of topiramate
on growth and bone-related sequelae has not been systematically investigated. 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.<br/>Acute Myopia and Secondary Angle Closure
Glaucoma: A syndrome consisting of acute myopia associated with secondary
angle closure glaucoma has been reported in patients receiving TOPAMAX.
Symptoms include acute onset of decreased visual acuity and/or ocular pain.
Ophthalmologic findings can include myopia, anterior chamber shallowing, ocular
hyperemia (redness) and increased intraocular pressure. Mydriasis may or may
not be present. This syndrome may be associated with supraciliary effusion
resulting in anterior displacement of the lens and iris, with secondary angle
closure glaucoma. Symptoms typically occur within 1 month of initiating TOPAMAX therapy.
In contrast to primary narrow angle glaucoma, which is rare under 40 years
of age, secondary angle closure glaucoma associated with topiramate has been
reported in pediatric patients as well as adults. The primary treatment to
reverse symptoms is discontinuation of TOPAMAX as rapidly
as possible, according to the judgment of the treating physician. Other measures,
in conjunction with discontinuation of TOPAMAX, may be helpful. Elevated
intraocular pressure of any etiology, if left untreated, can lead to serious
sequelae including permanent vision loss.<br/>Oligohidrosis and Hyperthermia: Oligohidrosis (decreased sweating), infrequently resulting
in hospitalization, has been reported in association with TOPAMAX use.
Decreased sweating and an elevation in body temperature above normal characterized
these cases. Some of the cases were reported after exposure to elevated environmental
temperatures. The majority of the reports have been
in children. Patients, especially pediatric patients, treated with TOPAMAX should
be monitored closely for evidence of decreased sweating and increased body
temperature, especially in hot weather. Caution should be used when TOPAMAX is
prescribed with other drugs that predispose patients to heat-related disorders;
these drugs include, but are not limited to, other carbonic anhydrase inhibitors
and drugs with anticholinergic activity.<br/>Withdrawal of AEDs: In patients with or without a history of seizures or epilepsy,
antiepileptic drugs including TOPAMAX should be gradually
withdrawn to minimize the potential for seizures or increased seizure frequency
. In situations where
rapid withdrawal of TOPAMAX is medically required, appropriate
monitoring is recommended.<br/>Cognitive/Neuropsychiatric Adverse
Events:<br/>Adults: Adverse events most often associated with the use of TOPAMAX were
related to the central nervous system and were observed in both the epilepsy
and migraine populations. In adults, the most frequent of these can be classified
into three general categories: 1) Cognitive-related dysfunction (e.g.
confusion, psychomotor slowing, difficulty with concentration/attention, difficulty
with memory, speech or language problems, particularly word-finding difficulties);
2) Psychiatric/behavioral disturbances (e.g. depression or mood problems);
and 3)Somnolence or fatigue.<br/>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 ADVERSE
REACTIONS, Table
4, Table 6, and Table 10]. In the original
add-on epilepsy controlled trials (using rapid titration such as 100-200 mg/day
weekly increments), the proportion of patients who experienced one or more
cognitive-related adverse 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 TOPAMAX 50 mg/day
and 26% for 400 mg/day. In the 6-month migraine prophylaxis
controlled trials using a slower titration regimen (25 mg/day weekly increments),
the proportion of patients who experienced one or more cognitive-related adverse
events was 19% for TOPAMAX 50 mg/day, 22% for 100 mg/day,
28% for 200 mg/day, and 10% for placebo. These dose-related adverse reactions
typically began in the titration phase and often persisted into the maintenance
phase, but infrequently began in the maintenance phase. Some patients experienced
a recurrence of one or more of these cognitive adverse events and this recurrence
was typically in the titration phase. A relatively small proportion of topiramate-treated
patients experienced more than one concurrent cognitive adverse event. The
most common cognitive adverse events occurring together included difficulty
with memory along with difficulty with concentration/attention, difficulty
with memory along with language problems, and difficulty with concentration/attention
along with language problems. Rarely, topiramate-treated patients experienced
three concurrent cognitive events.<br/>Psychiatric/Behavioral Disturbances: Psychiatric/behavioral disturbances (depression or mood problems)
were dose-related for both the epilepsy and migraine populations. In
the double blind phases of clinical trials with topiramate in approved and
investigational indications, suicide attempts occurred at a rate of 3/1000
patient years (13 events/3999 patient years) on topiramate versus 0 (0 events/1430
patient years) on placebo. One completed suicide was reported in a bipolar
disorder trial in a patient on topiramate.<br/>Somnolence/Fatigue: Somnolence and fatigue were the adverse events most frequently
reported during clinical trials of TOPAMAX for adjunctive
epilepsy. For the adjunctive epilepsy population, the incidence of somnolence
did not differ substantially between 200 mg/day and 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). For the migraine population, fatigue
and somnolence were dose-related and more common in the titration phase. Additional
nonspecific CNS events commonly observed with topiramate in the add-on epilepsy
population include dizziness or ataxia.<br/>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 themonotherapy 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.<br/>Sudden Unexplained Death in Epilepsy
(SUDEP): During the course of premarketing development of TOPAMAX (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 TOPAMAX (ranging from 0.0005 for the
general population of patients with epilepsy, to 0.003 for a clinical trial
population similar to that in the TOPAMAX program, to 0.005
for patients with refractory epilepsy).
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| dailymed-instance:indicatio... |
Monotherapy Epilepsy: TOPAMAX (topiramate) Tablets and TOPAMAX (topiramate
capsules) Sprinkle Capsules 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.<br/>Adjunctive Therapy Epilepsy: TOPAMAX (topiramate) Tablets and TOPAMAX (topiramate
capsules) Sprinkle Capsules are indicated as adjunctive therapy for adults
and pediatric patients ages 2 - 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.<br/>Migraine: TOPAMAX (topiramate) Tablets and TOPAMAX (topiramate
capsules) Sprinkle Capsules are indicated for adults for the prophylaxis of
migraine headache. The usefulness of TOPAMAX in the acute
treatment of migraine headache has not been studied.
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Topamax
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