Topiramate Tablets USP
Presentation

100 mg

For the use of a Registered Medical Practitioner or a Hospital or a Institution only.

Topiramate Tablets USP
DESCRIPTION:

TOPIRAMATE  TABLETS (Topiramate) is an antiepileptic agent classified as a sulfamate-substituted monosaccharide. Chemically, Topiramate is 2,3:4,5–Di–O–isopropylidene-b-D-fructopyranose sulfamate. The molecular formula is C12H21NO8S and molecular weight is 339.36.

STRUCTURAL  FORMULA :  
Its structural formula is :

Topiramate Tablets Structure

DESCRIPTION OF TABLET:

TOPIRAMATE  TABLETS  USP are yellow coloured, circular, biconvex, film coated tablets with breakline on one side and plain on other side.

COMPOSITION :
Each film coated tablet contains :
Topiramate USP    100 mg
Excipients                         q.s.
Colours : Yellow Ferric Oxide NF, Titanium Dioxide USP

 ACTIONS : 
The precise mechanism of action is unknown. Electrophysiological and biochemical studies on cultured neurons demonstrated that topiramate blocks the action potentials elicited repetitively by a sustained depolarization of the neurons in a time-dependent manner; this effect suggests a state-dependent sodium channel blocking action. Also, topiramate increases the frequency at which gamma-aminobutyric acid (GABA) activates GABA A receptors, thereby enhancing GABA-induced influx of chloride ions into neurons. Thus, it appears that topiramate exerts its effects by potentiation of the activity of the inhibitory neurotransmitter, GABA. In addition, topiramate antagonizes the ability of kainate to activate the kainate/AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid; non-NMDA) subtype of excitatory amino acid (glutamate) receptor, but has no apparent effect on the activity of N-methyl-D-aspartate (NMDA) at the NMDA receptor subtype. These effects of topiramate are concentration-dependent within the range of 1 to 200 micromoles. Topiramate also inhibits some isoenzymes of carbonic anhydrase (CA-II and CA-IV). This pharmacologic effect is generally weak and may not be a major contributing factor to the antiepileptic activity of Topiramate.

PHARMACOKINETICS :
Topiramate is readily absorbed after oral doses, with peak plasma concentrations achieved after about 2 hours. Bioavailability is not affected by the presence of food. Protein binding is about 9 to 17 %. The volume of distribution in women is about half that in men. In healthy subjects topiramate is not extensively metabolised; however, up to 50 % of a dose may undergo metabolism in the liver in patients also receiving enzyme-inducing drugs. It is eliminated chiefly in urine, as unchanged drug and metabolites; mean plasma elimination half-life is about 21 hours. Steady-state concentrations are achieved after about 4 to 8 days in patients with normal renal function. Clearance is decreased in patients with impaired renal or hepatic function, and steady-state plasma concentrations may not be achieved for 10 to 15 days in the former. Children exhibit a higher clearance and shorter elimination half-life than adults. The pharmacokinetics of topiramate may be affected by use with other antiepileptics.

INDICATIONS  : 
TOPIRAMATE  TABLETS is indicated as monotherapy in patients with newly diagnosed epilepsy or for conversion to monotherapy in patients with epilepsy. TOPIRAMATE  TABLETS is indicated as adjunctive therapy for adults and children older than 4 years of age who are inadequately controlled on conventional first-line antiepileptic medicines for :

  • Partial onset seizures with or without secondarily generalised seizures.
  • Seizures associated with Lennox-Gastaut syndrome.
  • Primary generalised tonic clonic seizures.
DOSAGE AND ADMINISTRATION:

Administration :
TOPIRAMATE  TABLETS  are for oral administration. TOPIRAMATE  TABLETS should be swallowed whole and can be taken without regard to meals.

Dosage :
Monotherapy : 
ADULT : 

Initially 25 mg at night for 1 week then increased in steps of 25 - 50 mg daily at intervals of 1 - 2 weeks taken in 2 divided doses; usual dose 100 mg daily in 2 divided doses; maximum 400 mg daily.

CHILD 6 – 16 years : 
Initially 0.5 – 1 mg/kg at night for 1 week then increased in steps of 0.5 – 1 mg/kg daily at intervals of 1 – 2 weeks taken in 2 divided doses; usual dose 3 – 6 mg/kg daily in 2 divided doses; maximum 15 mg/kg daily.

Adjunctive therapy :
ADULT : 

Initially 25 mg at night for 1 week then increased in steps of 25 – 50 mg daily at intervals of 1 – 2 weeks taken in 2 divided doses; usual  dose 200 – 400 mg daily in 2 divided doses; maximum 800 mg daily.

CHILD 2 – 16 years : 
Initially 25 mg at night for 1 week then increased in steps of 1 – 3 mg/kg daily at intervals of 1 – 2 weeks taken in 2 divided doses; recommended dose range 5 – 9 mg/kg daily in 2 divided doses; maximum 15 mg/kg daily.

Migraine prophylaxis : 
ADULT and CHILD over 16 years :
Initially 25 mg daily at night for 1 week then increased in steps of 25 mg daily at intervals of 1 week; usual dose 50 – 100 mg daily in 2 divided doses.
Note : If patient cannot tolerate titration regimens recommended above then smaller steps or longer interval between steps may be used.

CONTRAINDICATIONS : 
TOPIRAMATE  TABLETS is contraindicated in patients with hypersensitivity to the active substance or to any of the excipients. TOPIRAMATE  TABLETS is contraindicated in migraine prophylaxis in pregnancy and in women of childbearing potential if not using a highly effective method of contraception. TOPIRAMATE  TABLETS contains lactose which is contra-indicated in patients with galactosaemia, the glucose-galactose malabsorption  syndrome, or lactase deficiency. 

WARNINGS:

In situations where rapid withdrawal of topiramate is medically required, appropriate monitoring is recommended. As with other AEDs, some patients may experience an increase in seizure frequency or the onset of new types of seizures with topiramate. These
phenomena may be the consequence of an overdose, a decrease in plasma concentrations of concomitantly used AEDs, progress of the disease, or a paradoxical effect. Adequate hydration while using topiramate is very important. Hydration can reduce the risk of nephrolithiasis. Proper hydration prior to and during activities such as exercise or exposure to warm temperatures may reduce the risk of heat-related adverse reactions.

Oligohydrosis :
Oligohydrosis (decreased sweating) has been reported in association with the use of topiramate. Decreased sweating and hyperthermia (rise in body temperature) may occur especially in young children exposed to high ambient temperature.

Mood disturbances/depression :
An increased incidence of mood disturbances and depression has been observed during topiramate treatment.

Suicide/suicide ideation :
Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in several indications. A meta-analysis of randomised placebo-controlled trials of AEDs has shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for topiramate. In double blind clinical trials, suicide related events (SREs) (suicidal ideation, suicide attempts and suicide) occurred at a frequency of 0.5 % in topiramate treated patients (46 out of 8,652 patients treated) and at a nearly 3-fold higher incidence than those treated with placebo (0.2 %; 8 out of 4,045 patients treated). Patients therefore should be monitored for signs of suicidal ideation and behaviour and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.

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. 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 medicinal products associated with nephrolithiasis may be at increased risk.

Decreased renal function :
In patients with impaired renal function (CLCR d” 70 ml/min) topiramate should be administered with caution as the plasma and renal clearance of topiramate are decreased. For specific posology recommendations in patients with decreased renal function.

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 topiramate. 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 topiramate 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 topiramate, as rapidly as possible in the judgment 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. A determination should be made whether patients with history of eye disorders should be treated with topiramate. 

Visual field defects :
Visual field defects have been reported in patients receiving topiramate independent of elevated intraocular pressure. In clinical trials, most of these events were reversible after topiramate discontinuation. If visual field defects occur at any time during topiramate treatment, consideration should be given to discontinuing the drug.

PREGNANCY AND LACTATION:

Pregnancy : Category C
TOPIRAMATE  TABLETS is contraindicated for use during pregnancy. TOPIRAMATE  TABLETS crosses the placenta and is teratogenic in animals. There is no adequate data in humans. It is recommended that women of child-bearing potential use adequate contraception. 

Nursing mothers :  
The safety of TOPIRAMATE  TABLETS during lactation has not been established. There is extensive excretion of topiramate into breast milk. Patients using TOPIRAMATE  TABLETS  should not breastfeed.

Paediatric Use : 
Safety and efficacy of topiramate in paediatric patients below 2 years of age have not been established. Pharmacokinetic profiles obtained after 1 week at topiramate doses of 1, 3, and 9 mg per kg of body weight per day in patients aged 4 to 17 years receiving one or two other antiepileptic medications showed that clearance was independent of dose. Paediatric patients have a 50 % higher clearance and shorter elimination half-life than adults. The plasma concentration for the same milligram/kilogram dose may be lower in paediatric patients compared to adults.

INTERACTIONS  AND  INCOMPATIBILITIES :
Effects of TOPIRAMATE  TABLETS  on other antiepileptic medicines :
The addition of TOPIRAMATE  TABLETS to other antiepileptic medicines such as phenytoin, carbamazepine, valproic acid, phenobarbital and primidone, has no effect on their steady-state plasma concentrations, except in the occasional patient where the addition of TOPIRAMATE  TABLETS  to phenytoin may result in an increase of plasma concentrations of phenytoin. This is possibly due to inhibition of a specific enzyme polymorphic isoform (CYP2Cmeph). Consequently, any patient on phenytoin should have phenytoin levels monitored. The addition of topiramate to lamotrigine has no effect of steady state plasma concentration on lamotrigine at topiramate doses of 100 to 400 mg/day. However, the incidence of adverse effects was meaningfully increased on the combination.

Effects of other antiepileptic medicines on TOPIRAMATE  TABLETS :
Phenytoin and carbamazepine decrease the plasma concentration of  TOPIRAMATE  TABLETS. The addition or withdrawal of phenytoin or carbamazepine to TOPIRAMATE  TABLETS  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 significant changes in plasma concentrations of topiramate and, therefore, does not warrant dosage adjustment of TOPIRAMATE  TABLETS .

Other medicine interactions :
Digoxin :

Concomitant administration has shown a decrease in serum digoxin. When TOPIRAMATE  TABLETS  is added or withdrawn in patients on digoxin therapy, careful attention should be given to the routine monitoring of serum digoxin.

Oral contraceptives :
The possibility of decreased contraceptive efficacy and increased breakthrough bleeding should be considered in patients taking combination oral contraceptive products with TOPIRAMATE  TABLETS. Patients taking oestrogen-containing contraceptives should be asked
to report any change in their bleeding patterns. Contraceptive efficacy can be decreased even in the absence of breakthrough bleeding.

Hydrochlorothiazide (HCTZ) :
The addition of HCTZ to TOPIRAMATE  TABLETS therapy may require adjustment of the TOPIRAMATE  TABLETS  USP dose as Cmax and AUC of TOPIRAMATE  TABLETS are increased. The steady-state pharmacokinetics of HCTZ are not significantly influenced by 
the concomitant administration of  TOPIRAMATE  TABLETS . Clinical laboratory results indicated decreases in serum potassium after TOPIRAMATE  TABLETS or HCTZ administration, which were greater when HCTZ and TOPIRAMATE  TABLETS  were administered in combination.

Metformin :
When metformin and TOPIRAMATE  TABLETS are given simultaneously, the metformin Cmax and AUC is increased. The clinical significance of this effect is unknown. When TOPIRAMATE  TABLETS 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.

SIDE EFFECTS:

Blood and lymphatic system disorders :

  • Frequent : Anaemia, purpura.
  • Less Frequent : Leucopenia, thrombocytopenia, hyperammonaemia.
  • Frequency not known : Thomboembolic events.

Metabolic and nutritional disorders :

  • Frequent : Weight loss, anorexia.
  • Less Frequent : Metabolic acidosis.

Psychiatric disorders :

  • Frequent : Depression, somnolence, nervousness, difficulty with memory, confusion, difficulty with concentration/attention, anorexia, emotional liability, insomnia, psychomotor slowing, mood changes, personality changes, aggressive reaction.
  • Less frequent : Agitation, cognitive problems NOS, psychomotor slowing, confusion, emotional liability with mood disorders, apathy, psychosis/ psychotic symptoms, hallucination, aggressive reaction/ behavior, suicidal ideation or attempts, anxiety.

Nervous system disorders :

  • Frequent : Paraesthesia, ataxia, dizziness, drowsiness, speech problems, hyperkinesia, tremor, language problems, abnormal gait.
  • Less Frequent : Hyperthermia, hemiparesis, hypoaesthesia, oligohidrosis.

Eye disorders :

  • Frequent : Abnormal vision, nystagmus, diplopia.
  • Less frequent : Acute myopia with secondary angle closure glaucoma.

Cardiac disorders :

  • Frequency not known : Hypotension, postural hypotension.

Respiratory, thoracic and mediastinal disorders :

  • Frequent : Rhinitis, pharyngitis, pneumonia.

Gastrointestinal disorders :

  • Frequent : Nausea, abdominal pain, dyspepsia, constipation, increased saliva, taste perversion.

Hepato-biliary disorders :

  • Frequency not known : Hepatotoxicity, hepatic failure, pancreatitis.

Skin and subcutaneous tissue disorders :

  • Less Frequent : Erythema multiforme, pemphigus, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Renal and urinary disorders :

  • Less Frequent : Nephrolithiasis.
  • Frequency not known : Renal failure.

General disorders and administration site conditions :

  • Frequent : Fatigue, asthenia.
  • Less Frequent : Viral infection.

EFFECTS  ON  ABILITY  TO  DRIVE  AND  USE  MACHINES : 
TOPIRAMATE  TABLETS has minor or moderate influence on the ability to drive and use machines. Topiramate acts on the central nervous system and may produce drowsiness, dizziness or other related symptoms. It may also cause visual disturbances and/or blurred vision. These adverse reactions could potentially be dangerous in patients driving a vehicle or operating machinery, particularly until such time as the individual patient’s experience with the medicinal products established.

OVERDOSAGE : 
Signs and symptoms :
Overdoses of topiramate have been reported. Signs and symptoms included convulsions, drowsiness, speech disturbances, blurred vision, diplopia, impaired mentation, lethargy, abnormal coordination, stupor, hypotension, abdominal pain, agitation, dizziness and depression. The clinical consequences were not severe in most cases, but deaths have been reported after overdoses with multiple medicinal products including topiramate. Topiramate overdose can result in severe metabolic acidosis.

TREATMENT  OF  OVERDOSAGE :
In acute topiramate overdose, if the ingestion is recent, the stomach should be emptied immediately by lavage or by induction of emesis. Activated charcoal has been shown to adsorb topiramate in vitro. Treatment should be appropriately supportive and the patient should be well hydrated. Haemodialysis has been shown to be an effective means of removing topiramate from the body.

STORAGE :
Store at controlled room temperature 15° - 30°C, protected from moisture and light. Do not refrigerate.

SHELF  LIFE :
24 months from the date of manufacture.

PRESENTATION :
TOPIRAMATE TABLETS contain Topiramate USP 100 mg.
60 Tablets per Bottle.

 

Disclaimer : For the use of a Registered Medical Practitioner or a Hospital or a Institution only. Also it is not intended to be used by healthcare professionals or patients for the purpose of prescribing or administering these products. Questions regarding the complete and current content of product labeling / specification / presentation should be directed to SGPharma.

 
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