INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
TOPAMAX

© J-C 2001        OF000000        ZAF.-P1602466E V

SCHEDULING STATUS:
Schedule 3.

PROPRIETARY NAME
(and dosage form):

TOPAMAX

TOPAMAX 25 mg
TOPAMAX 50 mg
TOPAMAX 100 mg
TOPAMAX 200 mg
TOPAMAX SC 15 mg sprinkle capsules
TOPAMAX SC 25 mg sprinkle capsules
TOPAMAX SC 50 mg sprinkle capsules

COMPOSITION
Each tablet contains 25 mg topiramate
Each tablet contains 50 mg topiramate
Each tablet contains 100 mg topiramate
Each tablet contains 200 mg topiramate
Each capsule contains 15 mg topiramate
Each capsule contains 25 mg topiramate
Each capsule contains 50 mg topiramate

PHARMACOLOGICAL CLASSIFICATION
A 2.5 Anticonvulsants, including anti-epileptics.

PHARMACOLOGICAL ACTION
TOPAMAX is an anti-epileptic agent classified as a sulfamate substituted monosaccharide.
Three pharmacological properties of topiramate have been identified that may contribute to its anticonvulsant activity:

•	Topiramate reduces the frequency at which action potentials are generated when neurones are subjected to a sustained depolarisation indicative of a state-dependent blockade of voltage-sensitive sodium channels.
•	Topiramate markedly enhances the activity of GABA at some types of GABA receptors
•	Topiramate weakly antagonises the excitatory activity of kainate/AMPA subtype of glutamate receptor but has no apparent effect on the activity of N-methyl-D-asparate (NMDA) at the NMDA receptor subtype.

In addition, topiramate inhibits some isoenzymes of carbonic anhydrase, however it is not thought to be a major component of topiramate's anti-epileptic activity.
Pharmacokinetics:
The tablet and sprinkle formulations are bioequivalent.
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.
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 1 200 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 anti-epileptic therapy with known inducers of drug metabolizing enzymes.
The major route of elimination of unchanged topiramate and its metabolites is via the kidney (at least 81% of the dose). 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. In healthy subjects, pharmacokinetics of topiramate are linear over a single oral dose range of 100 to 400 mg. Patients with normal renal function may take 4 to 8 days to reach steady-state plasma concentrations. 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 multi-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, and the plasma clearance is decreased in patients with end-stage renal disease. Topiramate is effectively removed from plasma by haemodialysis. Plasma clearance of topiramate is unchanged in elderly subjects in the absence of underlying renal disease.
Plasma clearance is decreased in patients with moderate to severe hepatic impairment.
The pharmacokinetics of topiramate in children (4-6 years), 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 consequently 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 anti-epileptic drugs decrease the steady state plasma concentration.

INDICATIONS
TOPAMAX is indicated as adjunctive therapy for adults and children over 4 years old who are inadequately controlled on conventional first line antiepileptic medicines for:

-	partial onset seizures with or without secondarily generalized seizures.
-	seizures associated with Lennox-Gastaut syndrome.
-	primary generalized tonic clonic seizures.

CONTRA-INDICATIONS
Hypersensitivity to any component of this product.
The safety and efficacy of TOPAMAX in children under 12 years has not yet been established.
Pregnancy:
Topiramate is teratogenic in mice, rats and rabbits. In rats, topiramate crosses the placental barrier.
There are no studies using TOPAMAX in pregnant women. Therefore, the safety in pregnancy has not been established.
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.

DOSAGE AND DIRECTIONS FOR USE
For optimal seizure control in both adults and children, it is recommended that therapy be initiated at a low dose, followed by titration to an effective dose.
TOPAMAX is available in tablets and a capsule sprinkle formulation. It is recommended that tablets not be broken. The sprinkle formulation is provided for those patients who cannot swallow tablets e.g. paediatrics and the elderly.
TOPAMAX 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.
Topamax can be taken without regard to meals.
Adults
Therapy should begin at 25-50 mg nightly for one week. Subsequently, at weekly intervals, the dose should be increased by 25-50 mg/day and taken in two divided doses. Dose titration should be guided by clinical outcome. Some patients may achieve efficacy with once-a-day dosing.
In clinical trials, 200 mg was effective and was the lowest dosage studied. This is therefore considered the minimal effective dose. The usual total daily dose is 200 mg to 400 mg in two divided doses. Some patients may require doses up to 800 mg per day which is the maximum dose. It is recommended that therapy be initiated at a low dose, followed by titration to an effective dose.
Since TOPAMAX is removed from plasma by haemodialysis, a supplemental dosage 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.
These dosing recommendations apply to all adults, including the elderly, in the absence of underlying renal disease. (see “Precautions”under heading “SIDE-EFFECTS AND SPECIAL PRECAUTIONS”).
Children 4 years and over
The recommended total daily dose of TOPAMAX as adjunctive therapy is approximately 5 to 9 mg/kg/day in two divided doses. Titration should begin at 25 mg (or less, based on a range of 1 to 3 mg/kg/day) nightly for the first week. The dosage should then be increased at 1- or 2- week intervals by increments of 1 to 3 mg/kg/day (administered in two divided doses) to achieve optimal clinical response. Dose titration should be guided by clinical outcome.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
Side-effects:
The most common adverse events in adults were mainly CNS-related and included:
Somnolence fatigue, nervousness, psychomotor slowing, paraesthesia, ataxia, dizziness, taste perversion, difficulty with memory NOS, confusion, speech disorders/related speech problems, difficulty with concentration/attention, weight decrease, anorexia, nausea, abnormal vision, nystagmus, depression, diplopia, language problems, tremor, mood problems, abdominal pain, dyspepsia, rhinitis, asthenia and pharyngitis.
Less frequently reported adverse events include: agitation, cognitive problems NOS, emotional lability, coordination problems, abnormal gait, apathy, psychosis/psychotic symptoms, psychomotor slowing, confusion, hallucination, depression, aggressive reaction/behaviour, leucopenia and nephrolithiasis.
The most common adverse events in paediatric patients included: somnolence, anorexia, fatigue, nervousness, injury, personality changes, difficulty with concentration/attention, aggressive reaction, weight decrease, insomnia, abnormal gait, purpura, mood problems, viral infection, ataxia, saliva increased, nausea, difficulty with memory NOS, pneumonia, hyperkinesia, constipation, confusion, dizziness, speech disorders/related speech problems, psychomotor slowing and paraesthesia.
Isolated cases of thromboembolic events have been reported, although a causal association with topiramate has not been established. 

Precautions:
Antiepileptic drugs, including TOPAMAX, 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, withdrawals was accelerated without complications
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 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.
In hepatically impaired patients, topiramate should be administered with caution as the clearance of topiramate may be decreased.

Interactions:
Effects of TOPAMAX on other anti-epileptic drugs
The addition of TOPAMAX to other anti-epileptic 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 possibly due to inhibition of a specific enzyme polymorphic isoform (CYP2C_meph). Consequently, any patient on phenytoin should have phenytoin levels monitored.
Effects of other anti-antiepileptic drugs on TOPAMAX
Phenytoin and carbamazepine decrease the plasma concentration 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 concentrations of TOPAMAX and, therefore, does not warrant dosage adjustment of TOPAMAX.
The above interactions are summarized in the following table:

AED         Co-administered	AED         Concentration	TOPAMAX-         Concentration
Phenytoin	<-> **	¯
Carbamazepine (CBZ)	<->	¯
Valproic acid	<->	<->
Phenobarbital	<->	NS
Primidone	<->	NS

<->	= No effect on plasma concentrations
**	= Plasma concentrations increase in individual patients
¯	= Plasma concentrations decrease
NS	= Not studied
AED	= Anti-epileptic drug

Digoxin
Concomitant administration has shown a decrease in serum digoxin. When TOPAMAX is added or withdrawn in patients on digoxin therapy, careful attention should be given to the routine monitoring of serum digoxin.
Oral Contraceptives
TOPAMAX increases plasma clearance of the oestrogenic component significantly. Consequently, and bearing in mind the potential risk of teratogenicity, patients should receive a preparation containing not less than 50 micrograms of oestrogen or use some alternative non-hormonal method of contraception. Patients taking oral contraceptives are advised to report any change in their bleeding patterns.
Others
Concomitant use of TOPAMAX with agents predisposing to nephrolithiasis (renal stone formation) should be avoided.
Concomitant use of TOPAMAX with alcohol or other central nervous system (CNS) depressant drugs should be avoided.
Pregnancy and Lactation
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.
It is not known if topiramate is excreted in human milk.
Effects on driving ability and use of machinery:
TOPAMAX may produce central nervous system related events such as: drowsiness, dizziness or other related symptoms. Caution is advised when driving or operating machinery.
TOPAMAX may be more sedating than other antiepileptic medicines.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
In acute overdose with TOPAMAX, if the ingestion is recent, the stomach should be emptied immediately by lavage or by induction of emesis.
Supportive treatment should be used as appropriate. Haemodialysis 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, haemodialysis has not been necessary.

IDENTIFICATION
TOPAMAX is available as embossed, round, coated tablets in the following strengths and colours: 25 mg white, 50 mg light yellow, 100 mg yellow and 200 mg salmon.
The tablets will be imprinted as follows:
25 mg “TOP”on one side, “25”on the other.
50 mg “TOP”on one side, “50”on the other.
100 mg “TOP”on one side, “100”on the other.
200 mg “TOP”on one side, “200”on the other.

TOPAMAX is available as a sprinkle formulation. The final product is supplied as small white to off-white spheres enclosed in gelatin capsules consisting of a white opaque body with a clear cap imprinted as follows:
15 mg: “TOP”on capsule cap with “15 mg”on capsule body.
25 mg: “TOP”on capsule cap with “25 mg”on capsule body.
50 mg: “TOP”on capsule cap with “50 mg”on capsule body.

PRESENTATION
TOPAMAX is available in HDPE opaque containers with tamper-evident closures containing 60 tablets or sprinkle capsules. Blister packs of 28, 56 or 100 tablets.

STORAGE INSTRUCTIONS
Store below 25°C in a dry place. Protect from moisture.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBER
30/2.5/0236/7/8/9
Sprinkle capsule - 32/2.5/0662/3/4

NAME AND BUSINESS ADDRESS OF THE APPLICANT
JANSSEN PHARMACEUTICA (PTY) LTD
(Reg No 1980/11122/07)
15th Road
HALFWAY HOUSE
1685

DATE OF PUBLICATION OF THIS PACKAGE INSERT
3 April 2001

JANSSEN - CILAG

Code No.: 024173
2002B
Britepak

Updated on this site: April 2002
Source: Pharmaceutical Industry
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