Topamax 25, 50, 100, 200

/ J-C Health Care Ltd

It is not necessary to monitor topiramate plasma concentrations to optimize therapy with topiramate. On rare occasions, the addition of topiramate to phenytoin may require an adjustment of the dose of phenytoin to achieve optimal clinical outcome. Addition or withdrawal of phenytoin and carbamazepine to adjunctive therapy with topiramate may require adjustment of the dose of topiramate.
In patients with or without a history of seizures or epilepsy, antiepileptic drugs (AEDs) including topiramate should be gradually withdrawn to minimize the potential for seizures or increased seizure frequency. In clinical trials, daily dosages were decreased in weekly intervals by 50-100 mg in adults with epilepsy and by 25-50 mg in adults receiving topiramate at doses up to 100 mg/day for migraine prophylaxis. In paediatric clinical trials, topiramate was gradually withdrawn over a 2–8-week period.
Adjunctive Therapy Epilepsy
Adults: Therapy should begin at 25 – 50 mg nightly for one week. Use of lower initial doses has been reported, but has not been studied systematically. Subsequently, at weekly or bi-weekly intervals, the dose should be increased by 25 – 50 to 100 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 as adjunctive therapy, 200 mg was effective and was the lowest dosage studied.
This is therefore considered the minimum effective dose.
The usual daily dose is 200 – 400 mg in two divided doses. Individual patients have received doses as high as 1600 mg/day.
These dosing recommendations apply to all adults, including the elderly, in the absence of underlying renal disease.
Children Aged 2 And Above: The recommended total daily dose of topiramate 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.
Daily doses up to 30 mg/kg/day have been studied and were generally well tolerated.
Monotherapy Epilepsy
General: When concomitant antiepileptic drugs (AEDs) are withdrawn to achieve monotherapy with topiramate, consideration should be given to the effects this may have on seizure control.
Unless safety concerns require an abrupt withdrawal of the concomitant AED, a gradual discontinuation at the rate of approximately one-third of the concomitant AED dose every 2 weeks is recommended.
When enzyme inducing drugs are withdrawn, topiramate levels will increase. A decrease in topiramate.
dosage may be required if clinically indicated.
Adults: Dose and titration should be guided by clinical response. Titration should begin at 25 mg nightly for 1 week. The dosage should then be increased at 1- or 2-week intervals by increments of 25 or 50 mg/day, administered in two divided doses. If the patient is unable to tolerate the titration regimen, smaller increments or longer intervals between increments can be used.
The recommended initial target dose for topiramate monotherapy in adults is 100 mg/day and the maximum recommended daily dose is 500 mg. Some patients with refractory forms of epilepsy have tolerated topiramate monotherapy at doses of 1,000 mg/day. These dosing recommendations apply to all adults including the elderly in the absence of underlying renal disease.
Children: Dose and titration rate in children should be guided by clinical outcome. Treatment of children aged 7 years and above should begin at 0.5 to 1 mg/kg nightly for the first week. The dosage should then be increased at 1- or 2-week intervals by increments of 0.5 to 1 mg/kg/day, administered in two divided doses. If the child is unable to tolerate the titration regimen, smaller increments or longer intervals between dose increments can be used.
The recommended initial target dose range for topiramate monotherapy in children aged seven years and above is 100 to 400 mg/day. Children with recently diagnosed partial onset seizures have received doses of up to 500 mg/day.
Migraine
Adults: The recommended total daily dose of topiramate for prophylaxis of migraine headache is 100 mg/day administered in two divided doses. Titration should begin at 25 mg nightly for 1 week.
The dosage should then be increased in increments of 25 mg/day administered at 1-week intervals. If the patient is unable to tolerate the titration regimen, longer intervals between dose adjustments can be used.
Some patients may experience a benefit at a total daily dose of 50 mg/day. Patients have received a total daily dose up to 200 mg/day. This dose may be benefit in some patients, nevertheless, caution is advised due to an increase incidence of side effects.
Dose and titration rate should be guided by clinical outcome.
Pediatric population: Topamax (topiramate) is not recommended for treatment or prevention of migraine in children due to insufficient data on safety and efficacy.
Special Populations
Renal Impairment: In patients with impaired renal function (CLCR ≤ 70 mL/min) topiramate should be administered with caution as the plasma and renal clearance of topiramate are decreased. Subjects with known renal impairment may require a longer time to reach steady-state at each dose. Half of the usual starting and maintenance dose is recommended.
In patients with end-stage renal failure, since topiramate 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.
Hepatic Impairment: In patients with moderate to severe hepatic impairment topiramate should be administered with caution as the clearance of topiramate is decreased.
Elderly: No dose adjustment is required in the elderly population providing renal function is intact.
Method of administration: Topamax is available in film-coated tablets for oral administration. It is recommended that filmcoated tablets not be broken.
Topamax can be taken without regard to meals.

Adjunctive therapy for adults and children aged 2 and above with partial onset seizures or generalized tonic-clonic seizures.
In adults and children as adjunctive therapy for the treatment of seizures associated with Lennox Gastaut syndrome.
Monotherapy in patients with recently diagnosed epilepsy in adults and children aged 7 and above or for conversion to monotherapy in patient with epilepsy.
In adults for the prevention of migraines. The use of topiramate in the acute treatment of migraine has not been studied.

Hypersensitivity to the active substance or to any of the excipients.
Migraine prophylaxis in pregnancy and in women of childbearing potential if not using a highly effective method of contraception.

Epilepsy in pregnancy unless there is no suitable alternative treatment and in women of childbearing potential not using highly effective contraception. The only exception is a woman for whom there is no suitable alternative but who plans a pregnancy and who is fully informed about the risks of taking topiramate during pregnancy.

In situations where rapid withdrawal of topiramate is medically required, appropriate monitoring is recommended.
As with other antiepileptic drugs (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 antiepileptics, 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.
Pregnancy prevention programme
Topiramate can cause major congenital malformations and fetal growth restriction when administered to a pregnant woman. Pregnancy testing should be performed before initiating treatment with topiramate in a woman of childbearing potential.
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. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.
Serious skin reactions
Serious skin reactions (Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)) have been reported in patients receiving topiramate.
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.
Acute myopia and secondary angle closure glaucoma syndrome
Acute myopia and secondary angle closure glaucoma syndrome
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 some or all of the following: myopia, mydriasis, anterior chamber shallowing, ocular hyperaemia (redness), choroidal detachments, retinal pigment epithelial detachments, macular striae, and increased intraocular pressure. 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.
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.
Metabolic acidosis and sequelae
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. Generally, the decrease in bicarbonate occurs early in treatment although it can occur at any time during treatment. 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). Rarely, 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 diet, or certain medicinal products) may be additive to the bicarbonate lowering effects of topiramate.
Chronic, untreated metabolic acidosis increases the risk of nephrolithiasis and nephrocalcinosis, and may potentially lead to osteopenia.
Depending on underlying conditions, appropriate evaluation including serum bicarbonate levels is recommended with topiramate therapy. If signs or symptoms are present (e.g. Kussmaul’s deep breathing, dyspnoea, anorexia, nausea, vomiting, excessive tiredness, tachycardia or arrhythmia), indicative of metabolic acidosis, measurement of serum bicarbonate is recommended. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing topiramate (using dose tapering).
Topiramate should be used with caution in patients with conditions or treatments that represent a risk factor for the appearance of metabolic acidosis.
Impairment of cognitive function
Cognitive impairment in epilepsy is multifactorial and may be due to the underlying aetiology, due to the epilepsy or due to the anti-epileptic treatment. There have been reports in the literature of impairment of cognitive function in adults on topiramate therapy which required reduction in dosage or discontinuation of treatment. However, studies regarding cognitive outcomes in children treated with topiramate are insufficient and its effect in this regard still needs to be elucidated.
Hyperammonemia and encephalopathy
Hyperammonemia with or without encephalopathy has been reported with topiramate treatment. The risk for hyperammonemia with topiramate appears dose-related. Hyperammonemia has been reported more frequently when topiramate is used concomitantly with valproic acid. In patients who develop unexplained lethargy, or changes in mental status associated with topiramate monotherapy or adjunctive therapy, it is recommended to consider hyperammonemic encephalopathy and measuring ammonia levels.
Nutritional supplementation
Some patients may experience weight loss whilst on treatment with topiramate. It is recommended that patients on topiramate treatment should be monitored for weight loss. A dietary supplement or increased food intake may be considered if the patient is losing weight while on topiramate.
Sodium
Each tablet contains less than 1 mmol sodium (23 mg), and is essentially ‘sodium free’.
See prescribing information for full details.

The most common adverse reactions include: anorexia, decreased appetite, bradyphrenia, depression, expressive language disorder, insomnia, coordination abnormal, disturbance in attention, dizziness, dysarthria, dysgeusia, hypoesthesia, lethargy, memory impairment, nystagmus, paresthesia, somnolence, tremor, diplopia, vision blurred, diarrhoea, nausea, fatigue, irritability, and weight decreased.
See prescribing information for full details.

Effects of this product on Other Antiepileptic Drugs: The addition of this product to other antiepileptic drugs (phenytoin, carbamazepine, valproic acid, phenobarbital, primidone) has no clinically relevant effect on their steady-state plasma concentrations, except in the occasional patient, where the addition of this product to phenytoin may result in an increase of plasma concentrations of phenytoin. This is possibly due to inhibition of a specific enzyme polymorphic isoform (CYP2C19). Consequently, any patient on phenytoin showing clinical signs or symptoms of toxicity should have phenytoin levels monitored. A pharmacokinetic interaction study of patients with epilepsy indicated the addition of topiramate to lamotrigine had no effect on steady state plasma concentration of lamotrigine at topiramate doses of 100 to 400 mg/day. In addition, there was no change in steady-state plasma concentration of topiramate during or after removal of lamotrigine treatment (mean dose of 327 mg/day). Topiramate inhibits the enzyme CYP2C19 and may interfere with other substances metabolised via this enzyme (e.g., diazepam, imipramin, moclobemide, proguanil, omeprazol).
Effects of Other Antiepileptic Drugs on topiramate:  Phenytoin and carbamazepine decrease the plasma concentration of this product. The addition or withdrawal of phenytoin or carbamazepine to this product 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 this product.
Other medicinal product interactions
Digoxin: In a single-dose study, serum digoxin area under plasma concentration curve (AUC) decreased 12% due to concomitant administration. The clinical relevance of this observation has not been established. When topiramate is added or withdrawn in patients on digoxin therapy, careful attention should be given to the routine monitoring of serum digoxin.
Systemic hormonal contraceptives: In both studies, topiramate (50-200 mg/day in healthy volunteers and 200-800 mg/day in epilepsy patients) did not significantly affect exposure to NET. Although there was a dose-dependent decrease in EE exposure for doses between 200-800 mg/day (in epilepsy patients), there was no significant dose-dependent change in EE exposure for doses of 50-200 mg/day (in healthy volunteers). The clinical significance of the changes observed is not known. The possibility of decreased contraceptive efficacy and increased breakthrough bleeding should be considered in patients taking systemic hormonal contraceptive products with topiramate. Women using systemic hormonal contraceptives should be advised to also use a barrier method.
Lithium: In healthy volunteers, there was an observed reduction (18% for AUC) in systemic exposure for lithium during concomitant administration with topiramate 200 mg/day. In patients with bipolar disorder, the pharmacokinetics of lithium were unaffected during treatment with topiramate at doses of 200 mg/day; however, there was an observed increase in systemic exposure (26% for AUC) following topiramate doses of up to 600 mg/day. Lithium levels should be monitored when co-administered with topiramate.
Risperidone: When topiramate was added to existing risperidone (1-6 mg/day) treatment, adverse events were reported more frequently than prior to topiramate (250-400 mg/day) introduction (90% and 54% respectively). The most frequently reported AE’s when topiramate was added to risperidone treatment were: somnolence (27% and 12%), paraesthesia (22% and 0%) and nausea (18% and 9% respectively).
Hydrochlorothiazide (HCTZ): A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of HCTZ (25 mg every 24 h) and topiramate (96 mg every 12 h) when administered alone and concomitantly. The results of this study indicate that topiramate Cmax increased by 27% and AUC increased by 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The addition of HCTZ to topiramate therapy may require an adjustment of the topiramate dose. The steady-state pharmacokinetics of HCTZ were not significantly influenced by the concomitant administration of topiramate. Clinical laboratory results indicated decreases in serum potassium after topiramate or HCTZ administration, which were greater when HCTZ and topiramate were administered in combination.
Glibenclamide: A drug-drug interaction study conducted in patients with type 2 diabetes evaluated the steady-state pharmacokinetics of glibenclamide (5 mg/day) alone and concomitantly with topiramate (150 mg/day). There was a 25% reduction in glibenclamide AUC24 during topiramate administration. Systemic exposure of the active metabolites, 4-trans-hydroxy-glyburide (M1) and 3-cis-hydroxyglyburide (M2), were also reduced by 13% and 15%, respectively. The steady-state pharmacokinetics of topiramate were unaffected by concomitant administration of glibenclamide.
When topiramate is added to glibenclamide therapy or glibenclamide is added to topiramate therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state.
Other forms of interactions
Agents predisposing to nephrolithiasis: Topiramate, when used concomitantly with other agents predisposing to nephrolithiasis, may increase the risk of nephrolithiasis. While using topiramate, agents like these should be avoided since they may create a physiological environment that increases the risk of renal stone formation.
Valproic acid: Concomitant administration of topiramate and valproic acid has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either medicinal product alone. In most cases, symptoms and signs abated with discontinuation of either medicinal product. This adverse reaction is not due to a pharmacokinetic interaction.
Hypothermia, defined as an unintentional drop in body core temperature to <35°C, has been reported in association with concomitant use of topiramate and valproic acid (VPA) both in conjunction with hyperammonemia and in the absence of hyperammonemia. This adverse event in patients using concomitant topiramate and valproate can occur after starting topiramate treatment or after increasing the daily dose of topiramate.
Warfarin: Decreased Prothrombin Time/International Normalised Ratio (PT/INR) has been reported in patients treated with topiramate in combination with warfarin. Therefore, INR should be carefully monitored in patients concomitantly treated with topiramate and warfarin.
For full details see prescribing information.

Pregnancy:
Risk related to epilepsy and AEDs in general: In women being treated for epilepsy, sudden discontinuation of AED therapy should be avoided as this may lead to breakthrough seizures that could have serious consequences for the woman and the unborn child.
Risk related to topiramate: Topiramate was teratogenic in mice, rats and rabbits. In rats, topiramate crosses the placental barrier. It is recommended that women of child bearing potential use highly effective contraception and consider alternative therapeutic options.
Topiramate is contraindicated in pregnancy and in women of childbearing potential if a highly effective method of contraception is not used.
See prescribing information for full details.
Lactation: Animal studies have shown excretion of topiramate in milk. The excretion of topiramate in human milk has not been evaluated in controlled studies. Limited observations in patients suggest an extensive excretion of topiramate into breast milk. Since many medicinal products are excreted in human milk, a decision should be made whether to suspend breast feeding or to discontinue/ abstain from topiramate therapy taking into account the importance of the medicinal product to the mother.

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: 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. Hemodialysis has been shown to be an effective means of removing topiramate from the body.