Janssen Products

Topiramate

Topamax^TM

Formulation
Each film coated tablet contains 25, 50 and 100 mg of topiramate.

Pharmaceutical Form
Topiramate is a novel antiepileptic agent classified as a sulfamate-substituted monosaccharide. Electrophysiological and biochemical studies on cultured neurons have identified three properties that may contribute to the antiepileptic efficacy of topiramate. Action potentials elicited repetitively by a sustained depolarization of the neurons were blocked by topiramate in a time-dependent manner, suggestive of a state-dependent sodium channel blocking action. Topiramate increased the frequency at which g-aminobutyrate (GABA) activated GABA_A receptors, and enhanced the ability of GABA to induce a flux of chloride ions into neurons, suggesting that topiramate potentiates the activity of this inhibitory neurotransmitter.

Because the antiepileptic profile of topiramate differs markedly from that of the benzodiazepines, it may modulate a benzodiazepine-insensitive subtype of GABA_A receptor. Topiramate antagonized the ability of kainate to activate the kainate/AMPA (a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) subtype of excitatory amino acid (glutamate) receptor, but had no apparent effect on the activity of N-methyl-D-aspartate (NMDA) at the NMDA receptor subtype. These effects of topiramate were concentration-dependent over a range of 1 mcM to 200 mcM, with minimum activity observed at 1 mcM to 10 mcM.

In addition, topiramate inhibits some isoenzymes of carbonic annhydrase. This pharmacologic effect is much weaker than that of acetazolamide, a known carbonic anhydrase inhibitor, and is not thought to be a major component of topiramate's antiepileptic activity.

Studies in mice receiving concomitant administration of topiramate and carbamazepine or phenobarbital showed synergistic anticonvulsant activity, while combination with phenytoin showed additive anticonvulsant activity. In well-controlled add-on trials, no correlation has been demonstrated between trough plasma concentrations of topiramate and its clinical efficacy. No evidence of tolerance has been demonstrated in man.

Pharmacokinetic Properties
Topiramate is rapidly and well absorbed. Following oral administration of 100 mg topiramate to healthy subjects, a mean peak plasma concentration (C_max) of 1.5 mg/mL was achieved within 2 to 3 hours (T_max). Based on the recovery of radioactivity from the urine the mean extent of absorption of a 100 mg oral dose of ¹⁴C-topiramate was at least 81%. There was no clinically significant effect of food on the bioavailability of topiramate. Generally, 13 to 17% of topiramate is bound to plasma protein. A low capacity binding site for topiramate in/on erythrocytes that is saturable above plasma concentrations of 4 mg/mL has been observed. The volume of distribution varied inversely with the dose. The mean apparent volume of distribution was 0.80 to 0.55 L/kg for a single dose range of 100 to 1200 mg. An effect of gender on the volume of distribution was detected, with values for females circa 50% of those for males. This was attributed to the higher percent body fat in female patients and is of no clinical consequence.

Topiramate is not extensively metabolized (~20%) in healthy volunteers. It is metabolized up to 50% in patients receiving concomitant antiepileptic therapy with known inducers of drug metabolizing enzymes. Six metabolites, formed through hydroxylation, hydrolysis and glucuronidation, have been isolated, characterized and identified from plasma, urine and feces of humans. Each metabolite represents less than 3% of the total radioactivity excreted following administration of ¹⁴C-topiramate. Two metabolites, which retained most of the structure of topiramate, were tested and found to have little or no anticonvulsant activity.

In humans, the major route of elimination of unchanged topiramate and its metabolites is via the kidney (at least 81% of the dose). Approximately 66% of a dose of ¹⁴C-topiramate was excreted unchanged in the urine within four days. Following twice a day dosing with 50 mg and 100 mg of topiramate the mean renal clearance was approximately 18 mL/min and 17 mL/min, respectively. There is evidence of renal tubular reabsoprtion of topiramate. This is supported by studies in rats where topiramate was co-administered with probenecid, and a significant increase in renal clearance of topiramate was observed. Overall, plasma clearance is approximately 20 to 30 mL/min in humans following oral administration.

Topiramate exhibits low intersubject variability in plasma concentrations and, therefore, has predictable pharmacokinetics. The pharmacokinetics of topiramate are linear with plasma clearance remaining constant and area under the plasma concentration curve increasing in a dose-proportional manner over a 100 to 400 mg single oral dose range in healthy subjects. Patients with normal renal function may take 4 to 8 days to reach steady-state plasma concentrations. The mean C_max following multiple, twice a day oral doses of 100 mg to healthy subjects was 6.76 mg/mL. Following administration of multiple doses of 50 mg and 100 mg of topiramate twice a day, the mean plasma elimination half-life was approximately 21 hours.

Concomitant multiple-dose administration of topiramate, 100 to 400 mg twice a day, with phenytoin or carbamazepine shows dose proportional increases in plasma concentrations of topiramate.

The plasma and renal clearance of topiramate are decreased in patients with impaired renal function (CL_CR £ 60 mL/min), and the plasma clearance is decreased in patients with end-stage renal disease. As a result, higher steady-state topiramate plasma concentrations are expected for a given dose in renal-impaired patients as compared to those with normal renal function. Topiramate is effectively removed from plasma by hemodialysis.

Plasma clearance of topiramate is unchanged in elderly subjects in the absence of underlying renal disease.

Plasma clearance of topiramate is decreased in patients with moderate to severe hepatic impairment.

Therapeutic Indications
Topiramate (Topamax^TM) is indicated as adjunctive therapy for adults and children with partial onset seizures, seizures associated with Lennox-Gastaut syndrome, and generalized tonic-clonic seizures.

Posology and Method of Administration
It is recommended that therapy be initiated at a low dose, followed by titration to an effective dose. Titration should begin at 50 mg nightly for one week. Subsequently, at weekly intervals, the dose should be increased by 50 to 100 mg and taken in two divided doses. Dose titration should be guided by clinical outcome. Some patients may achieve efficacy with once-a-day dosing.

Tablets should not be broken. Topiramate (Topamax^TM) can be taken without regard to meals. These dosing recommendations apply to all adults, including the elderly, in the absence of underlying renal disease. As yet there is limited experience on the use of topiramate (Topamax^TM) can be taken without regard to meals. These dosing recommendations apply to all adults, including the elderly, in the absence of underlying renal disease. As yet there is limited experience on the use of topiramate (Topamax^TM) in children aged 12 years and under.

Contraindications
Hypersensitivity to any component of this product.

Special Warnings and Special Precautions for Use
Antiepileptic drugs, including topiramate (Topamax^TM), should be withdrawn gradually to minimize the potential of increased seizure frequency. In adult 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. Patients 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 at each dose.

Some patients, especially those with a predisposition to nephrolithiasis, may be at increased risk for renal stone formation. 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.

Interaction with Other Medicaments and Other Forms of Interaction
Effects of Topiramate (Topamax^TM) on Other Antiepileptic Drugs
The addition of topiramate (Topamax^TM) 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 topiramate (Topamax^TM) to phenytoin may result in an increase of plasma concentrations of phenytoin. This is possibly due to inhibition of a specific enzyme polymorphic isoform (CYP2C_meph). Consequently, any patient on phenytoin showing clinical signs or symptoms of toxicity should have phenytoin levels monitored.

Effects of Other Antiepileptic Drugs on Topiramate (Topamax^TM)
Phenytoin and carbamazepine decrease the plasma concentration of topiramate (Topamax^TM). The addition or withdrawal of phenytoin or carbamazepine to topiramate (Topamax^TM) 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 concentrations of topiramate (Topamax^TM) and, therefore, does not warrant dosage adjustment of topiramate (Topamax^TM).

Other Drug Interactions
Digoxin: In a single-dose study, serum digoxin area under plasma concentration curve (AUC) decreased 12% due to concomitant administration of topiramate (Topamax^TM). The clinical relevance of this observation has not been established. When topiramate (Topamax^TM) is added or withdrawn in patients on digoxin therapy, careful attention should be given to the routine monitoring of serum digoxin.

Oral Contraceptives: In a pharmacokinetic interaction study with oral contraceptives using a combination product containing norethindrone plus ethinyl estradiol, topiramate (Topamax^TM) 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.

Others: Topiramate (Topamax^TM), when used concomitantly with other agents predisposing to nephrolithiasis, may increase the risk of nephrolithiasis. While using topiramate (Topamax^TM), agents like these should be avoided since they may create a physiological environment that increases the risk of renal stone formation.

Pregnancy and Lactation
As with other antiepileptic drugs, topiramate was teratogenic in mice, rats and rabbits. In rats, topiramate crosses the placental barrier.

There are no studies using topiramate (Topamax^TM) in pregnant women. However, topiramate (Topamax^TM) 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. It is not known if topiramate is excreted in human 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.

Effects on Ability to Drive and Use Machines
As with all antiepileptic drugs, topiramate (Topamax^TM) 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.

Adverse Events
The safety profile for topiramate (Topamax^TM) is based on experience in approximately 1800 subjects and patients. Reported adverse reactions were classified using the standard WHO-ART dictionary.

Since topiramate (Topamax^TM) 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. However, based on placebo-controlled trials in which there was a rapid titration period, the most common adverse reactions were mainly CNS-related and included, in alphabetical order: ataxia, impaired concentration, confusion, dizziness, fatigue, paresthesia, somnolence and thinking abnormal. Less common side effects included agitation, amnesia, anorexia, aphasia, depression, diplopia, emotional liability, nausea, nystagmus, speech disorder, taste perversion, vision abnormal and weight decrease.

Nephroliathiasis was reported rarely. Isolated cases of thromboembolic events have also been reported, a causal association with the drug has not been established.

Overdosage
In acute overdose with topiramate (Topamax^TM), if the ingestion is recent, the stomach should be emptied immediately by lavage or by induction of emesis. In vitro, activated charcoal has not been shown to absorb topiramate, therefore, its use in overdosage is not recommended. Supportive treatment should be used as appropriate. Hemodialysis, is an effective means of removing topiramate from the body. However, in cases of acute overdosage, including doses of over 20 g in one individual, hemodialysis has not been necessary.

Availability: Box of 20 tablets.
Store at a temperature not exceeding 30°C. Keep out of reach of children.

Caution: Food, Drugs, Devices and Cosmetics Act prohibits dispensing without prescription.

Manufactured by:
CILAG AG
Schaffhausen, Switzerland
Packed by:
INTERPHIL LABORATORIES, INC.
Canlubang Industrial Estate
Bo. Pittland, Cabuyao, Laguna
For: Johnson & Johnson (Philippines), Inc.
Edison Road, Bo. Ibayo
Parañaque, Metro Manila
Exclusively distributed by:
ZUELLIG PHARMA CORPORATION
Sen. Gil Puyat Avenue
Makati City