INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
TOPLEP 25 Tablets
TOPLEP 50 Tablets
TOPLEP 100 Tablets
TOPLEP 200 Tablets

SCHEDULING STATUS:
S3

PROPRIETARY NAME
(and dosage form):

TOPLEP 25 Tablets
TOPLEP 50 Tablets
TOPLEP 100 Tablets
TOPLEP 200 Tablets

COMPOSITION
TOPLEP 25
Each tablet contains topiramate 25 mg.
TOPLEP 50
Each tablet contains topiramate 50 mg.
TOPLEP 100
Each tablet contains topiramate 100 mg.
TOPLEP 200
Each tablet contains topiramate 200 mg.
Sugar free.

PHARMACOLOGICAL CLASSIFICATION
A.2.5 Anticonvulsants, including anti-epileptics.

PHARMACOLOGICAL ACTION
Mechanism of action
Topiramate is an antiepileptic 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 the neurons 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, thereby enhancing GABA-induced influx of chloride into neurons.
-	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.

Topiramate also inhibits some isoenzymes of carbonic anhydrase, This pharmacological effect is generally weak and may not be a major contributing factor to the antiepileptic activity of topiramate.
Pharmacokinetics
Topiramate is well absorbed after oral administration. The relative bioavailability is about 80%. Food does not affect the bioavailability of topiramate. Protein binding is low, 13 to 17%. The time to peak concentration (Tmax) is approximately 2 hours following administration of a 400 mg oral dose. The volume of distribution is 0,6 –0,8L/kg with values for women circa 50% of those for males.
In patients with normal renal function, steady state is reached in about 4 days. The pharmacokinetics of topiramate are linear, with dose-proportional increases in plasma concentration over the range of 200 to 800 mg a day. The mean elimination half-life (t½) is 21 hours, following single or multiple dosing. Approximately 70% of an administered dose is excreted unchanged in the urine and the remainder undergoes metabolism by hydroxylation, hydrolysis and glucuronidation with no one metabolite accounting for more than 5% of an oral dose. Topiramate clearance is reduced by 42% in patients with moderate renal function impairment and by 54% in patients with severe renal impairment as compared with the clearance in subjects with normal renal function. Children exhibit a higher clearance and shorter elimination half-life than adults.
Consequently, the plasma concentration of topiramate for the same mg/kg dose may be lower in children compared to adults.
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The clearance of topiramate may be decreased in patients with impaired hepatic function.

INDICATIONS
Toplep tablets are 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 Toplep or any components of the preparation.
Children under 4 years (as safety and efficacy of Toplep has not yet been established).
Pregnancy and lactation

WARNINGS
A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients receiving Toplep. Symptoms include acute onset of decreased visual acuity and/or ocular pain. Ophthalmic findings can include myopia, anterior chamber shallowing, ocular hyperemia (redness) and increased intraocular pressure. Mydriasis may or may not occur. 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 one month of initiating Toplep therapy. Secondary angle closure glaucoma associated with Toplep has been reported in paediatric patients as well as adult patients. Treatment includes discontinuation of Toplep, as rapidly as possible and appropriate measures to reduce intraocular pressure.
Metabolic Adidosis
Hyperchloremic, non-anion gap, metabolic acidosis (i.e. decreased serum bicarbonate below the normal reference range in the absence of respiratory alkalosis) is associated with topiramate treatment. This decrease in serum bicarbonate is due to the inhibitory effect of topiramate on renal carbonic anhydrase and consequent renal bicarbonate wasting. These decreases are usually mild to moderate (average decrease of 4 mmol/L at doses of 100 mg/day or above in adults and at approximately 6 mg/kg/day in paediatric patients). However, patients have experienced decreases to values below 10 mmol/l. Conditions or therapies that predispose to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhoea, surgery, ketogenic or certain drugs) may be addictive to bicarbonate lowering effects of topiramate.
Chronic metabolic acidosis in paediatric patients can reduce growth rate. Chronic metabolic acidosis can lead to nephrolithiasis and increased risk of fractures.
Evaluation of bicarbonate levels is recommended with topiramate therapy.
If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing topiramate. (see dose tapering)

INTERACTIONS
Effects of Toplep on other anti-epileptic medicines
If Toplep is taken concomitantly with other anti-epileptic medicines (phenytoin, carbamazepine, valproic acid, phenobarbital, primidone), there is no effect on their steady-state plasma concentrations, except in very rare cases where the addition of Toplep to phenytoin may result in an increase of plasma concentrations of phenytoin. Consequently, any patient on phenytoin, taking Toplep, in addition, should have phenytoin levels monitored.

Effects of other anti-epileptic medicines on Toplep
Phenytoin and carbamazepine decrease the plasma concentration of Toplep. The addition or withdrawal of phenytoin or carbamazepine to Toplep therapy may require an adjustment in dosage of Toplep. This should be done by titrating to clinical effect. The withdrawal or addition of valproic acid does not produce clinically significant changes in plasma concentrations of Toplep and, therefore, dosage adjustment of Toplep is not necessary.
Digoxin
Serum digoxin levels have decreased with concomitant administration of Toplep. When Toplep is added or withdrawn in patients on digoxin therapy, careful attention should be given to the routine monitoring of serum digoxin.
Oral Contraceptives
Efficacy of oral contraceptives may be compromised when used concurrently with Toplep. Bearing in mind the potential risk of teratogenicity, patients should receive a shapeType1fFlipH0fFlipV0lTxid131072dxTextLeft0dyTextTop0dxTextRight0dyTextBottom0fFilled0lineWidth0fLine0fShadow0

preparation containing not less than 50 micrograms of oestrogen or use some alternative non-hormonal method of contraception as Toplep increases plasma clearance of the oestrogenic component significantly. Patients on oral contraceptives are advised to report any change in their bleeding patterns.
Others
Concomitant use of Toplep with agents predisposing to nephrolithiasis (renal stone formation) should be avoided.

PREGNANCY AND LACTATION
Pregnancy (see Contra-indications)
Studies have not been done in humans, therefore, the safety in pregnancy has not been established. Hypospadias in male infants exposed in utero to Toplep, with or without other anticonvulsants, has been reported. However, a causal relationship has not been established.
Lactation (see Contra-indications)
It is not known if Toplep is excreted in human milk.
Mothers taking Toplep should not breast feed their babies.

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.
It is recommended that film-coated tablets not be broken.
Toplep can be taken without meals.
Adults
Therapy should begin at 25-50 mg nightly for one week. Subsequently, the dose should be increased at weekly intervals 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. The effective dose is usually within the range of 200 mg (minimum dose) to 400 mg daily taken in two divided doses; some patients may require up to 800 mg (maximum dose) daily. It is recommended that therapy be initiated at a low dose, followed by titration to an effective dose.
Since Toplep is removed from plasma by haemodialysis, an additional dosage equal to approximately one-half of the daily dose should be administered on haemodialysis days. The additional dose should be administered in divided doses at the beginning and completion of the haemodialysis procedure. The additional doses may vary based on the dialysis equipment being used.
No dosage adjustment is necessary in elderly patients. For patients with underlying renal disease, see “Special Precautions”.

Children 4 years and over
The initial dose for children is 25 mg for the first week, increased at intervals of 1 –2 weeks by increments of 1 to 3 mg/kg/day, administered in two divided doses if more than 25 mg per day. The recommended dose thereafter is about 5 –9 mg/kg/day in two divided doses. Dose titration should be guided by clinical outcome.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
Side-effects
The adverse events considered at least possibly related to the treatment are listed below by body system, organ class and frequency (wherever applicable). Frequencies are defined as very common (>1/10), common (>1/100, =1/10), uncommon (>1/1000, =1/100), rare (>1/10000, =1/1000), very rare (=1/10000) or frequency unknown.
Blood and lymphatic system disorders
Less frequent: Leucopenia
Frequency unknown: Purpura. Anaemia and thrombocytopenia, alone or in combination with leucopenia. Thrombolic events have been reported although a causal association with Toplep has not been established.
Immune system disorders
Frequency unknown: Viral infection.
Metabolism and nutritional disorders
Less frequent: Weight decrease, anorexia.
Psychiatric disorders
Frequent: Somnolence, nervousness, psychomotor slowing, difficulty with memory not otherwise specified, confusion, difficulty with concentration/attention, anorexia, depression, mood problems, personality changes, insomnia.
Less frequent: Agitation, cognitive problems not otherwise specific, emotional lability, apathy, psychosis/psychotic symptoms, hallucination, aggressive reaction/behaviour, suicidal ideas or attempts.
Nervous system disorders
Frequent: Paresthesia, ataxia, dizziness, speech disorders/related speech problems, language problems, tremor, hyperkinesias.
Co-ordination problems.
Eye disorders
Frequent: Abnormal vision, diplopia, nystagmus, acute and secondary angle closure glaucoma.
Rare: Conjunctivitis.
Ear and labyrinth disorders
Rare: Tinnitus.
Vascular disorders
Frequency unknown: Hypotension and postural hypotension.
Respiratory, thoracic and mediastinal disorders
Less frequent: Pharyngitis.
Frequency unknown: Rhinitis, pneumonia, Dyspneoa.
Gastro-intestinal disorders
Frequent: Nausea.
Less frequent: Constipation, dyspepsia, abdominal pain.
Frequency unknown: Increased saliva production.
Hepato-biliary disorders
Frequency unknown: Hepatic failure, hepatitis.
Skin and subcutaneous tissue disorders
Less frequent: Gingivitis, increased sweating.
Rare: Pruritus.
Frequency unknown: Bullous skin and mucosal reactions, including erythema multiforme, pemphigus, Stevens-Johnson syndrome and toxic epidermal necrolysis.
Renal and urinary disorders
Less frequent: Nephrolithiasis (kidney stones).
Rare: Dysuria, urinary frequency, incontinence.
Frequency unknown: Renal failure, haematuria,
General disorders and administration site conditions
Frequent: Asthenia, fatigue.
Frequency unknown: Injury.

Special Precautions
Toplep should be withdrawn gradually to minimize the potential of increased seizure frequency.
Toplep should be used with caution in patients with renal or hepatic impairment. 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. The titration schedule should be guided by clinical outcome (i.e. seizure control and avoidance of side-effects).
In patients with hepatic impairment, Toplep should be administered with caution as it may be decreased.
Some patients, especially those with a predisposition to nephrolithiasis, may be at risk for renal stone formation. Concomitant use of Toplep with agents predisposing to nephrolithiasis (renal stone formation) should be avoided.
Adequate hydration while using Toplep is very important. Hydration can reduce the risk of nephrolithiasis or developing renal calculi. Proper hydration prior to and during activities such as exercise or exposure to warm temperatures may reduce the risk of heat related adverse events.
Effects on driving ability and use of machinery
Toplep may produce central nervous system related events such as: drowsiness, dizziness or other related symptoms. Caution is advised when driving or operating machinery.
Toplep may be more sedating than other antiepileptic medicines.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
Headache, agitation, drowsiness, lethargy, metabolic acidosis and hypokalemia occurred after overdosing. At very high doses, coma, lasting 20-24 hours followed by full recovery after 3 to 4 days, may occur.
Treatment is symptomatic and supportive. An attempt should be made to remove undigested Toplep from the gastro-intestinal tract using gastric lavage, induction of emesis or activated charcoal. Hemodialysis has been shown to be an effective means to removeToplep from the body. The patient should be well hydrated.

IDENTIFICATION
TOPLEP 25
White, film coated, circular tablets debossed with ‘TP1’ on one side and plain on the other side with intact coating.
TOPLEP 50
Yellow coloured, film coated, circular tablets debossed with ‘TP2’ on one side and plain on the other side with intact coating.
TOPLEP 100
Yellow coloured, film coated, circular tablets debossed with ‘TP3’ on one side and plain on the other side with intact coating.
TOPLEP 200
Peach coloured, film coated, circular tablets debossed with ‘TP4’ on one side and plain on the other side with intact coating.

PRESENTATION
Cartons contain a white opaque HDPE bottle containing 60 tablets.

STORAGE INSTRUCTIONS
Store below 25°C in the original package, protected from moisture.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBERS
TOPLEP 25: 40/2.5/0348
TOPLEP 50: 40/2.5/0349
TOPLEP 100: 40/2.5/0350
TOPLEP 200: 40/2.5/0351

NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION
RANBAXY (SA) (PTY) LTD
Third Floor
Outspan House
1006 Lenchen Avenue North
Centurion.

DATE OF PUBLICATION OF THE PACKAGE INSERT
June 2007

New addition to this site: December 2007
Source: Pharmaceutical Industry

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