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Topamax tablet
Topiramate
COMPOSITION
Topamax 25 contains 25 mg of topiramate per tablet
Topamax 50 contains 50 mg of topiramate per tablet
Topamax 100 contains 100 mg of topiramate per tablet
Topamax 200 contains 200 mg of topiramate per tablet
PROPERTIES
The precise mechanism by which topiramate exerts its antiseizure effect is unknown; however
electrophysiological and biochemical studies of the effects of topiramate on cultured neurons
have revealed three properties that may contribute to topiramate’s antiepileptic efficacy. First,
action potentials elicited repetitively by a sustained depolarization of the neurons are blocked by
topiramate in a time-dependent manner, suggestive of a state-dependent sodium channel
blocking action. Second, topiramate increases the frequency at which γ-aminobutyrate (GABA)
activates GABAA receptors and enhances the ability of GABA to induce a flux of chloride ions
into neurons, suggesting that topiramate potentiates the activity of this inhibitory neurotransmitter.
This effect was not blocked by flumazenil, a benzodiazepine antagonist, nor did topiramate
increase the duration of the channel open time, differentiating topiramate from barbiturates that
modulate GABAA receptors. Third, topiramate antagonizes the ability of kainate to activate the
kainate/AMPA (a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid; non-NMDA) subtype of
exitatory amino acid (glutamate) receptor, but has no apparent effect on the activity of N-methylD-aspartate (NMDA) at the NMDA receptor subtype. These effects of topiramate are
concentration-dependent within the range of 1 mM to 200 mM.
Topiramate also inhibits some isoenzymes of carbonic anhydrase (CA-II and CA-IV). This
pharmacologic effect is generally weaker than that of acetazolamide, a known carbonic
anhydrase inhibitor, and is not thought to be a major contributing factor to topiramate’s
antiepileptic activity.
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 GABAA
receptor 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.
Pharmacokinetics
Absorption of topiramate is rapid, with peak plasma concentrations occuring at approximately 2
hours following a 400 mg oral dose. The relative bioavailability of topiramate from the tablet
formulations 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 13-17% bound to human plasma proteins over
the concentration range of 1-250 µg/mL.
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, plasma clearance is approximately 20 to 30 mL/min in humans
following oral administration.
INDICATIONS
TOPAMAX (topiramate) is indicated as adjunctive therapy for the treatment of adults with partial
onset seizures.
DOSAGE AND ADMINISTRATION
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, and 1000 mg/day) have not been
shown to improve responses.
The recommended total daily dose of TOPAMAX (topiramate) as adjunctive therapy is 400
mg/day in two divided doses. A daily dose of 200 mg/day has inconsistent effects and is less
effective than 400 mg/day. It is recommended that therapy be initiated at 50 mg/day followed by
titration to an effective dose. Daily doses above 1,600 mg have not been studied.
The recommended titration rate for topiramate is :
AM DOSE
PM DOSE
Week 1
none
50 mg
Week 2
Week 3
50 mg
50 mg
50 mg
100 mg
Week 4
100 mg
100 mg
Week 5
100 mg
150 mg
Week 6
150 mg
150 mg
Week 7
150 mg
200 mg
Week 8
200 mg
200 mg
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.
Patients with renal impairment
In renally impaired subjects (creatinine clearance less than 70 mL/min/1.73m2), one half of the
usual adult dose is recommended. Such patients will require a longer time to reach steady-state
at each dose.
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.
Patients with hepatic disease
In hepatically impaired patients topiramate plasma concentrations may be increased. The
mechanism is not well understood.
WARNINGS AND PRECAUTIONS
Antiepileptic drugs, including TOPAMAX, should be withdrawn gradually to minimize the
potential of increased seizure frequency. In clinical trials, dosages were decreased by 100
mg/day at weekly intervals. In some patients, withdrawal was accelerated without complications.
The major route of elimination of unchanged topiramate and its metabolites is via the kidney.
Renal elimination is dependent on renal function and is independent of age. Patient with
moderate or severe renal impairment may take 10 to 15 days to reach steady-state plasma
concentrations as compared to 4 to 8 days in patients with normal renal function.
As with all patients, the titration schedule should be guided by clinical outcome (i.e., seizure
control, avoidance of side effects) with the knowledge that subjects with known renal impairment
may require a longer time to reach steady state of each dose.
Nephrolithiasis
Some patients, especially those with a predisposition to nephrolithiasis, may be at increased risk
for renal stone formation and associated signs and symptoms such as renal colic, renal pain or
flank pain. Adequate hydration is recommended to reduce this risk.
Risk factors for nephrolithiasis include prior stone formation, a family history of nephrolithiasis
and hypercalciuria. None of these risk factors can reliably predict stone formation during
topiramate treatment. In addition, patients taking other medication associated with nephrolithiasis
may be at increased risk.
Decreased Hepatic Function
In hepatically-impaired patients, topiramate should be administered with caution as the clearance
of topiramate may be decreased.
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 supracilliary effusion resulting in
anterior displacementof 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. Treatment includes
discontinuation of TOPAMAX, as rapidly as possible in the judgement of the treating physician,
and appropriate measures to reduce intraocular pressure. These measures generally result in a
decrease in intraocular pressure.
[Elevated intraocular pressure of any etiology, if left untreated, can lead to serious sequelae
including permanent vision less].
Nutritional supplementation
A dietary supplement or increased food intake may be considered if the patient is losing weight
while on this medication
Pregnancy and lactation
As with other antiepileptic drug, topiramate was teratogenic in mice, rats and rabbits. In rats,
topiramate crosses the placental barrier.
There are no studies using TOPAMAX in pregnant women. However, TOPAMAX should be used
during pregnancy only if the potential benefit outweighs the potential risk to the fetus. 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 suggests an extensive excretion
of topiramate into breast milk. Since many drugs are excreted in human milk, a decision should
be made whether to discontinue nursing or to discontinue the drug, taking into account the
importance of the drug to the mother.
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.
Effects on ability to drive and use machines
As with all antiepileptic drugs, TOPAMAX acts on the central nervous system and may produce
drowsiness, dizziness or other related symptoms. These otherwise mild or moderate adverse
events could potentially be dangerous in patients driving a vehicle or operating machinery,
particularly until such time as the individual patient’s experience with the drug is established.
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/m2 basis).
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 aberations 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/m2 basis).
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 (topiramate) on labor and delivery in humans is unknown.
Pediatric use
Safety and effectiveness in children have not been established. The pharmacokinetic profile of
TOPAMAX was studied in patients between the ages of 4 and 17 years.
Geriatric use
In clinical trials, 2% of patients were over 60. No age related difference in effectiveness or
adverse effects were seen. There were no pharmacokinetic differences related to age alone,
although the possibility of age-associated renal functional abnormalities should be considered.
Race and gender effects
Evaluation of efficacy and safety in clinical trials has shown no race or gender related effects.
SIDE EFFECTS
Reported adverse events were classified using a modified WHO-ART dictionary.
Adjunctive Therapy Clinical Trial
Since TOPAMAX has most frequently been co-administered with other antiepileptic agents, it is
not possible to determine which agents, if any, are associated with adverse events.
Adults
In double-blind clinical trials, some of which included a rapid titration period, adverse events
which occurred with a frequency greater than or equal to 5% and with a higher incidence in the
topiramate-treated adult patients than in the placebo group included: somnolence, dizziness,
nervousness, ataxia, fatigue, speech disorders/related speech problems, psychomotor slowing,
abnormal vision, difficulty with memory NOS*, confusion, paraesthesia, diplopia, anorexia,
nystagmus, nausea, weight decrease, language problems, difficulty with concentration/attention,
depression, abdominal pain, asthenia, and mood problems.
Adverse events that occurred less frequently but were considered potentially medically relevant
included: taste perversion, agitation, cognitive problems NOS*, emotional lability, coordination
problems, abnormal gait, apathy, psychosis/psychotic symptoms aggressive reaction/behavior,
leucopenia, and nephrolithiasis. Isolated cases of thromboembolic events have also been
reported, although a causal association with the drug has not been established.
CONTRAINDICATIONS
Hypersensitivity to any component of this product.
INTERACTIONS
Effect of TOPAMAX on other antiepileptic drugs.
The addition of TOPAMAX to other antiepileptic drugs (phenytoin, carbamazepine, valproic acid,
phenobarbital, primidone) has no effect on their steady-state plasma concentrations, except in
the occasional patient, where the addition of TOPAMAX to phenytoin may result in an increase of
plasma concentrations of phenytoin. This is possible due to inhibition of a specific enzyme
polymorphic isoform (CYP2C maph). Consequently, any patient on phenytoin showing clinical
signs of symptoms of toxicity should have phenytoin levels monitored.
Effects of other antiepileptic drugs on TOPAMAX
Phenytoin and carbamazepine decrease the plasma concentrations of TOPAMAX. The addition
or withdrawal of phenytoin or carbamazepine to TOPAMAX therapy may require an adjustment in
dosage of the latter. This should be done by titrating to clinical effect. The addition or withdrawal
of valproic acid does not produce clinically significant changes in plasma concentration of
TOPAMAX and, therefore, does not warrant dosage adjustment of TOPAMAX.
The results of these interactions are summarized in the following table:
AED Coadministered
AED Concentration
TOPAMAx Concentration
Phenytoin
↔
↓ 48%
Carbamazepine (CBZ)
↔
↓ 40%
Valproic acid
↔ 11% decrease
↔ 14% decrease
Phenobarbital
↔
NS
Primidone
↔
NS
↔
25% increase
= No effect
= Plasma concentrations increase in individual patients
↓
= Plasma concentration decrease
NS = Not studied
AED = Antiepileptic Drug
Other drug interactions
Digoxin : In a single-dose study, serum digoxin area under plasma concentration curve (AUC)
decreased 12% due to concomitant administration of TOPAMAX. The clinical relevance of this
observation has not been established. When TOPAMAX is added or withdrawn in patients on
digoxin therapy, careful attention should be given to the routine monitoring of serum digoxin.
CNS depressants: Concomitant administration of TOPAMAX and alcohol or other CNS
depressant drugs has not been evaluated in clinical studies. It is recommended that TOPAMAX
not be used concomitantly with alcohol or other CNS depressant drugs.
Oral Contraceptives: In a pharmacokinetic interaction study with oral contraceptives using a
combination product containing norethindrone plus ethinyl estradiol, TOP AMAX did not
significantly affect the oral clearance of norethindrone, but plasma clearance for the estrogenic
component increased significantly. Consequently, the efficacy of low dose (e.g., 20 mcg) oral
contraceptives may be reduced in this situation. Patients taking oral contraceptives should be
asked to report any change in their bleeding patterns.
Metformin: A drug-drug interaction study conducted in healthy volunteers evaluated the steadystate 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 C max and mean AUC 0-12h 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 or their diabetic
disease state.
Others: TOPAMAX, when used concomitantly with other agents predisposing to nephrolithiasis,
may increase the risk of nephrolithiasis. While using TOPAMAX, agents like these should be
avoided since they may create a physiological environment that increases the risk of renal stone
formation.
Overdose
Signs and Symptoms
Ingestion of between 6 and 40 g topiramate have been reported in a few patients. Signs
and symptoms included: headache, agitation, drowsiness, lethargy, metabolic acidosis
and hypokalemia. The clinical consequences were not severe. All patients recovered.
A patient who ingested a dose calculated to be 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.
Treatment
General supportive measures are indicated and an attempt should be made to remove
undigested drug from the gastro-intestinal tract using gastric lavage or activated charcoal.
Hemodialysis has been shown to be an effective means of removing topiramate from the
body. The patients should be well hydrated.
STORAGE
Store in dry place at or below 250C.
HOW SUPPLIED
TOPAMAX 25 mg tablet
Box 6 alu blister @ 10 tablet
TOPAMAX 50 mg tablet
Box 6 alu blister @ 10 tablet
TOPAMAX 100 mg tablet
Box 6 alu blister @ 10 tablet
TOPAMAX 200 mg tablet
Box 6 alu blister @ 10 tablet
HARUS DENGAN RESEP DOKTER
Manufactured by CILAG-AG, Switzerland
Imported and distributed by PBF Johnson & Johnson Indonesia
division of PT Johnson & Johnson Indonesia, Jakarta-Indonesia