TOPAMAX^®

topiramate

Presentation

Tablets

Topamax film-coated tablets for oral administration are supplied in bottles with tamper-evident closures:

25 mg, round and white, marked "TOP" on one side and "25" on the other

50 mg, round and light-yellow, marked "TOP" on one side and "50" on the other

100 mg, round and yellow, marked "TOP" on one side and "100" on the other

200 mg, round and salmon, marked "TOP" on one side and "200" on the other.

Sprinkle Capsules

Topamax Sprinkle capsules enclosing small, white to off-white spheres for oral administration and are supplied in bottles. Each gelatin capsule consists of a clear (natural) capsule cap and a white capsule body:

15 mg, imprinted "TOP" on cap and "15 mg" on body

25 mg, imprinted "TOP" on cap and "25 mg" on body

50 mg, imprinted "TOP" on cap and "50 mg" on body.

Uses

Actions

Topiramate is a novel antiepileptic agent classified as a sulfamate-substituted monosaccharide.

The precise mechanism by which topiramate exerts its antiseizure effect is unknown. 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 depolarisation 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 gama-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.

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 GABA_A receptors.

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 antagonised 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 micromol to 200 micromols, with minimum activity observed at 1 micromol to 10 micromols.

In addition, topiramate inhibits some isoenzymes of carbonic anhydrase. 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.

In animal studies, topiramate exhibits anticonvulsant activity in rat and mouse maximal electroshock seizure (MES) tests and is 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. Topiramate is only weakly effective in blocking clonic seizures induced by the GABA_A receptor antagonist, pentylenetetrazole.

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 humans.

Pharmacokinetics

The tablet and Sprinkle formulations are bioequivalent at equivalent doses.

The pharmacokinetic profile of topiramate compared to other antiepileptic medicines shows a long plasma half-life, linear pharmacokinetics, predominantly renal clearance, absence of significant protein binding, and lack of clinically relevant active metabolites.

Topiramate is not a potent inducer of drug metabolising enzymes. It can be administered without regard to meals, and routine monitoring of plasma topiramate concentrations is not necessary. In clinical studies, there was no consistent relationship between plasma concentrations and efficacy or adverse events.

Absorption

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 micrograms/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.

Distribution

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 micrograms/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. There is an effect of gender on the volume of distribution. Values for females are about 50% lower than those for males. This was attributed to the higher percentage body fat in female patients and is of no clinical consequence.

Metabolism

It is metabolised up to 50% in patients receiving concomitant antiepileptic therapy with known inducers of drug metabolising enzymes. Six metabolites, formed through hydroxylation, hydrolysis and glucuronidation, have been isolated, characterised and identified from plasma, urine and faeces 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.

Elimination

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 reabsorption 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 micrograms/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.

Patients with renal impairment

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 haemodialysis.

Patients with hepatic impairment

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

Elderly

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

Paediatric pharmacokinetics up to 12 years of age

The pharmacokinetics of topiramate in children, as in adults receiving add-on therapy, are linear, with clearance independent of dose and steady state plasma concentrations increasing in proportion to dose. Children, however, have a higher clearance and a shorter elimination half-life. Consequently, the plasma concentrations of topiramate for the same mg/kg dose may be lower in children compared to adults. As in adults, hepatic enzyme inducing antiepileptic medicines decrease the steady state plasma concentrations.

Indications

Topamax is indicated in adults and children, 2 years and over:

• as monotherapy in patients with newly diagnosed epilepsy
• for conversion to monotherapy in patients with epilepsy
• as add-on therapy in partial onset seizures, generalised tonic-clonic seizures or seizures associated with Lennox-Gastaut syndrome

Dosage and Administration

Topamax tablets should be swallowed whole.

Topamax Sprinkle capsules can be swallowed whole. However, for patients who cannot swallow the capsules (e.g. young children and the elderly), the content of the capsules should be sprinkled on a small amount of soft food and swallowed immediately without chewing. This mixture should not be stored for future use.

Topamax can be taken without regard to meals.

For optimum seizure control in both adults and children, it is recommended that therapy should be initiated at a low dose followed by slow titration to an effective dose. Dose titration should be guided by clinical outcome.

The recommended dosages of Topamax in adults and children are summarised in Table 1.

Monotherapy

In newly diagnosed epileptic patients, Topamax monotherapy should be initiated at a low dose (see Table 1).

In patients who are being converted to Topamax monotherapy, consideration should be given to the effects of seizure control when withdrawing concomitant antiepileptic agents (AEAs). Unless safety concerns require an abrupt withdrawal of the concomitant AEA, a gradual discontinuation at the rate of approximately one-third of the concomitant AEA dose every 2 weeks is recommended. When enzyme inducing medicines are withdrawn, topiramate levels will increase. A decrease in Topamax dosage may be required if clinically indicated.

Adults

Titration for monotherapy should begin at 25 mg as a single (nightly) dose for one week or longer. The dosage should then be increased by 25 to 50 mg/day at weekly or longer intervals to the recommended target dose of 100 mg/day. The maximum recommended dose is 500 mg/day. Some patients with refractory forms of epilepsy have tolerated doses of 1,000 mg/day. The daily dosage should be taken as two divided doses.

Children (2 years and over)

Titration for monotherapy should begin at 0.5 to 1 mg/kg as a single (nightly) dose for the first week. The dosage should then be increased by 0.5 to 1 mg/kg/day at weekly or longer intervals to the recommended target dose of 3 to 6 mg/kg/day. The daily dosage should be given as two divided doses.

Add-on therapy

Adults

Titration for add-on therapy should begin at 25 to 50 mg as a single (nightly) or divided dose for one week or longer. The dosage should then be increased by 25 to 100 mg/day at weekly or longer intervals to the target dose of 200 to 400 mg/day. The maximum recommended dose should not exceed 1000 mg/day. The daily dosage should be taken as two divided doses.

Children (2 years and over)

Titration for add-on therapy should begin at 1 to 3 mg/kg/day up to 25 mg/day as a single (nightly) dose for the first week. The dosage should then be increased by 1 to 3 mg/kg/day at weekly or longer intervals to the recommended total daily dose of 5 to 9 mg/kg/day. Daily doses up to 30 mg/kg have been studied and were generally well tolerated. The daily dosage should be given as two divided doses.

Table 1: Recommended dosages in adults and children

It is not necessary to monitor topiramate plasma concentrations to optimise Topamax therapy. For patients receiving concomitant phenytoin and carbamazepine, dosage adjustment for Topamax may be required (see Interactions ).

Use in patients with hepatic and/or renal impairment

Caution is advised during titration in the elderly and in patients with renal disease and/or hepatic impairment (see Warnings and Precautions ).

Use in patients undergoing haemodialysis

Since Topamax is removed from plasma by haemodialysis, a supplemental dose of Topamax equal to approximately one half the daily dose should be administered on haemodialysis days. The supplemental dose should be administered in divided doses at the beginning and completion of the haemodialysis procedure. The supplemental dose may differ based on the characteristics of the dialysis equipment being used.

Contraindications

Hypersensitivity to any component of this product.

Warnings and Precautions

Antiepileptic agents, including Topamax, should be withdrawn gradually to minimise 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.

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 or 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 patients with hepatic impairment, 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 hyperaemia (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 paediatric 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 aetiology, if left untreated, can lead to serious sequelae including permanent vision loss.

Nutritional supplementation

A dietary supplement or increased food intake may be considered if the patient is losing weight while on this medication.

Decreased renal function

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.

Pregnancy and lactation

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

There are no studies using Topamax in pregnant women. Topamax should be used during pregnancy only if the potential benefit outweighs the potential risk.

In post marketing experience, cases of hypospadias have been reported in male infants exposed in-utero to topiramate, with or without other anticonvulsants. A causal relationship with topiramate has not been established.

Topiramate is excreted in the milk of lactating rats. The excretion of topiramate in human milk has not been evaluated in controlled studies. Limited observation in patients suggests an extensive excretion of topiramate into breast milk. Since many medicines are excreted in human milk, a decision should be made whether to discontinue breastfeeding or to discontinue the medicine, taking into account the importance of the medicine to the mother.

Teratogenicity / Embryotoxicity

As with other antiepileptic agents, topiramate was teratogenic in mice, rats and rabbits. Overall numbers of foetal malformations in mice were increased for all topiramate treated groups, but no significant differences or dose-response relationships were observed for overall or specific malformations, suggesting that other factors such as maternal toxicity may be involved.

The teratogenic effects seen in rats and rabbits were similar to those seen with carbonic anhydrase inhibitors, which have not been associated with malformations in humans.

Mutagenicity

In a battery of in vitro and in vivo mutagenicity assays, topiramate did not show genotoxic potential.

Effects on ability to drive and use machines

As with all antiepileptic agents, Topamax acts on the central nervous system and may produce drowsiness, dizziness or other related symptoms. These otherwise mild or moderate adverse events are potentially dangerous in patients driving a vehicle or operating machinery, particularly until the individual patient's experience with the medicine is established.

Adverse Effects

Monotherapy

The types of adverse events observed in monotherapy trials were generally similar to those observed during add-on therapy trials. With the exception of paraesthesia and fatigue, the incidence rates of the adverse events were similar or lower in the monotherapy trials when compared to the add-on therapy trials.

In double-blind clinical trials, the following adverse events occurred at an incidence greater than or equal to 10% in Topamax-treated patients:

Adults

paraesthesia, headache, fatigue, dizziness, somnolence, weight decrease, nausea and anorexia.

Children

headache, fatigue, anorexia and somnolence.

Add-on therapy

Table 2 and 3 list adverse events reported during the add-on clinical trials. Since Topamax has most frequently been co-administered with other antiepileptic agents, it is not possible to determine which agents are associated with adverse events.

Table 2: Adverse events for add-on trials in adults

¹ The frequency of these adverse events was lower at the usual dosage of 200 to 400 mg/day.
² Leg pain and isolated cases of thromboembolic events have been reported, although a causal association with Topamax has not been established.
³ A dietary supplement or increased food intake may be considered if the patient is losing weight while on Topamax.

Table 3: Adverse events for add-on trials in children

¹ Psychiatric adverse events, such as agitation, apathy, cognitive problems, hallucination and depression have also been reported as uncommon events (<1%).
² A dietary supplement or increased food intake may be considered if the patient is losing weight while on Topamax.

Post-marketing and other experience

Reports of increases in liver function tests in patients taking Topamax with and without other medications have been received. Isolated reports have been received of hepatitis and hepatic failure occurring in patients taking multiple medications while being treated with Topamax.

Interactions

Effects Of Topamax On Other Antiepileptic Agents

The addition of Topamax to other antiepileptic agents (phenytoin, carbamazepine, valproic acid, phenobarbitone, 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 possibly due to inhibition of a specific enzyme polymorphic isoform (CYP2C ₁₉ ). Consequently, any patient on phenytoin showing clinical signs or symptoms of toxicity should have phenytoin levels monitored.

Effects Of Other Antiepileptic Agents On Topamax

Topiramate is metabolised up to 50% in patients receiving concomitant antiepileptic therapy with known inducers of enzymes which metabolise medicines.

Phenytoin and carbamazepine decrease the plasma concentration of topiramate. 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 concentrations of topiramate and, therefore, does not warrant dosage adjustment of Topamax.

The results of these interactions are summarised in Table 4:

Table 4: Summary of AEA interactions with Topamax

<-> = No effect on plasma concentration (< 15% change)
** = Plasma concentrations increase in occasional patients
↓ = Plasma concentrations decrease
NS = Not studied
AEA = antiepileptic agent

No data are available on the use of Topamax with vigabatrin, lamotrigine or gabapentin.

Other Interactions

Digoxin

In a single dose study, the 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 medicines has not been evaluated in clinical studies. It is recommended that Topamax not be used concomitantly with alcohol or other CNS depressant medicines.

Oral Contraceptives

In a pharmacokinetic interaction study with oral contraceptives using a combination product containing norethisterone plus ethinyl oestradiol, Topamax did not significantly affect the oral clearance of norethisterone, but plasma clearance for the oestrogenic component increased significantly. Consequently, the efficacy of low dose (e.g. 20 micrograms) 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 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 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 t_max. 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.

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.

Overdosage

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 hypokalaemia. 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. Haemodialysis has been shown to be an effective means of removing topiramate from the body. The patient should be well hydrated.

Pharmaceutical Precautions

Shelf Life

Sprinkle capsules - 2 years

Tablets in bottles - 30 months

Special Precautions for Storage

Sprinkle capsules - Store at or below 25°C (77°F) in a dry place.

Tablets - Store below 25°C (77°F) in a dry place.

Package Quantities

Supplied in opaque bottles with tamper-evident closures.

Each bottle contains 60 tablets or Sprinkle capsules.

Further Information

Topamax tablets contain lactose, pregelatinised maize starch, purified water, carnauba wax, microcrystalline cellulose, sodium starch glycollate, magnesium stearate, and the OPADRY® coating and colouring for each tablet comprising titanium dioxide, hypromellose, lauromacrogol 400 and polysorbate 80. Additionally, in the coating, the 50 mg and 100 mg tablets contain iron oxide yellow, and the 200 mg tablets contain iron oxide red.

Topamax Sprinkle capsules consist of sugar spheres enclosed in a gelatin capsule. The sugar spheres contain topiramate, povidone, cellulose acetate and sucrose. The capsule shells contain gelatin and titanium dioxide, and are imprinted with black ink.

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