Actions of Topimax in details
Pharmacology: Pharmacodynamics: Mechanism of Action: The precise mechanisms by which Topimax exerts its anticonvulsant and migraine prophylaxis effects are unknown; however, preclinical studies have revealed four properties that may contribute to Topimax's efficacy for epilepsy and migraine prophylaxis. Electrophysiological and biochemical evidence suggests that Topimax, at pharmacologically relevant concentrations, blocks voltage dependent sodium channels, augments the activity of the neurotransmitter gamma-aminobutyrate at some subtypes of the GABAA receptor, antagonizes the AMPA/kainate subtype of the glutamate receptor, and inhibits the carbonic anhydrase enzyme, particularly isozymes II and IV.
Topimax has anticonvulsant activity in rat and mouse maximal electroshock seizure (MES) tests. Topimax is only weakly effective in blocking clonic seizures induced by the GABAA receptor antagonist, pentylenetetrazole. Topimax is also 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.
Pharmacokinetics: Absorption and Distribution: Absorption of Topimax is rapid, with peak plasma concentrations occurring at approximately 2 hours following a 400 mg oral dose. The relative bioavailability of Topimax from the tablet formulation is about 80% compared to a solution. The bioavailability of Topimax is not affected by food.
The pharmacokinetics of Topimax are linear with dose proportional increases in plasma concentration over the dose range studied (200 to 800 mg/day). The mean plasma elimination half-life is 21 hours after single or multiple doses. Steady state is thus reached in about 4 days in patients with normal renal function. Topimax is 15 to 41 % bound to human plasma proteins over the blood concentration range of 0.5 to 250 μg/mL. The fraction bound decreased as blood concentration increased. Carbamazepine and phenytoin do not alter the binding of Topimax. Sodium valproate, at 500 μg/mL (a concentration 5 to 10 times higher than considered therapeutic for valproate) decreased the protein binding of Topimax from 23 to 13%. Topimax does not influence the binding of sodium valproate.
Metabolism and Excretion: Topimax is not extensively metabolized and is primarily eliminated unchanged in the urine (approximately 70% of an administered dose). Six metabolites have been identified in humans, none of which constitutes more than 5% of an administered dose. The metabolites are formed via hydroxylation, hydrolysis and glucuronidation. There is evidence of renal tubular re-absorption of Topimax. In rats, given probenecid to inhibit tubular reabsorption, along with Topimax, a significant increase in renal clearance of Topimax was observed. This interaction has not been evaluated in humans. Overall, oral plasma clearance (CL/F) is approximately 20 to 30 mL/minute in humans following oral administration.
How should I take Topimax?
Follow all directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results. Do not take this medicine in larger or smaller amounts or for longer than recommended.
Topimax can be taken with or without food.
Do not crush, chew, or break a Topimax tablet. Swallow it whole. The Trokendi XR extended-release capsule must be swallowed whole. Do not break or open.
The Topimax and Topimax Sprinkle Capsule can be swallowed whole. Or you may open the capsule and sprinkle the medicine into a spoonful of applesauce or other soft food. Swallow right away without chewing. Do not save the mixture for later use. Discard the empty capsule.
Carefully follow the swallowing instructions for your medicine.
While using Topimax, you may need frequent blood tests.
Drink plenty of liquids while you are taking Topimax, to prevent kidney stones or an electrolyte imbalance.
Do not stop using Topimax suddenly, even if you feel fine. Stopping suddenly may cause increased seizures. Follow your doctor's instructions about tapering your dose.
Call your doctor if your seizures get worse or you have them more often while taking Topimax.
Any medical care provider who treats you should know that you take seizure medication.
Store at cool room temperature away from moisture, light, and high heat. Keep the bottle tightly closed when not in use.
Topimax administration
Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results.
Topimax can be taken with or without food. The Topimax tablet should be swallowed whole. It has a bitter taste when chewed or broken.
You may open the Topimax capsule and sprinkle the medicine into a spoonful of applesauce or other soft food to make swallowing easier. Swallow right away without chewing. Do not save the mixture for later use. Discard the empty capsule.
Drink plenty of liquids while you are taking Topimax. This will lower your risk of having kidney stones or an electrolyte imbalance. Call your doctor if you have ongoing vomiting or diarrhea. You can easily become dehydrated while taking this medication.
If you need surgery, tell the surgeon ahead of time that you are using Topimax. You may need to stop using the medicine for a short time.
Do not stop using Topimax without first talking to your doctor, even if you feel fine. You may have increased seizures if you stop using Topimax suddenly. You may need to use less and less before you stop the medication completely.
Contact your doctor if your seizures get worse or you have them more often while taking Topimax. To be sure this medication is not causing harmful effects, your blood may need to be tested often. Your kidney or liver function may also need to be tested. Visit your doctor regularly.
Wear a medical alert tag or carry an ID card stating that you take Topimax. Any medical care provider or dentist who treats you should know that you are taking a seizure medication.
Store at room temperature away from moisture and heat. Keep the bottle tightly closed when not in use.
Topimax pharmacology
Mechanism of Action
The precise mechanisms by which Topimax exerts its anticonvulsant effects are unknown; however, preclinical studies have revealed four properties that may contribute to Topimax's efficacy for epilepsy. Electrophysiological and biochemical evidence suggests that Topimax, at pharmacologically relevant concentrations, blocks voltage-dependent sodium channels, augments the activity of the neurotransmitter gamma-aminobutyrate at some subtypes of the GABA-A receptor, antagonizes the AMPA/kainate subtype of the glutamate receptor, and inhibits the carbonic anhydrase enzyme, particularly isozymes II and IV.
Pharmacodynamics
Topimax has anticonvulsant activity in rat and mouse maximal electroshock seizure (MES) tests. Topimax is only weakly effective in blocking clonic seizures induced by the GABA-A receptor antagonist, pentylenetetrazole. Topimax is also 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.
Pharmacokinetics
Absorption and Distribution
The pharmacokinetics of Topimax Extended-Release Capsules are linear with dose proportional increases in plasma concentration when administered as a single oral dose over the range of 50 mg to 1,400 mg. At 25 mg, the pharmacokinetics of Topimax Extended-Release Capsules are nonlinear, possibly due to the binding of Topimax to carbonic anhydrase in red blood cells.
Topimax Extended-Release Capsules sprinkled on a spoonful of soft food is bioequivalent to the intact capsule formulation.
Following a single 200 mg oral dose of Topimax Extended-Release Capsules, peak plasma concentrations (Tmax) occurred approximately 20 hours after dosing. Steady-state was reached in about 5 days following daily dosing of Topimax Extended-Release Capsules in subjects with normal renal function, with a Tmax of approximately 6 hours.
At steady-state, the plasma exposure (AUC0-24hr, Cmax, and Cmin) of Topimax from Topimax Extended-Release Capsules administered once daily and the immediate-release Topimax tablets administered twice-daily were shown to be bioequivalent. Fluctuation of Topimax plasma concentrations at steady-state for Topimax Extended-Release Capsules administered once daily was approximately 40% in healthy subjects, compared to approximately 53% for immediate-release Topimax.
Compared to the fasted state, high-fat meal had no effect on bioavailability (AUC and Cmax) but delayed the Tmax by approximately 4 hours following a single dose of Topimax Extended-Release Capsules. Topimax Extended-Release Capsules can be taken without regard to meals.
Topimax is 15% to 41% bound to human plasma proteins over the blood concentration range of 0.5 mcg/mL to 250 mcg/mL. The fraction bound decreased as blood concentration increased.
Carbamazepine and phenytoin do not alter the binding of immediate-release Topimax. Sodium valproate, at 500 mcg/mL (a concentration 5 to 10 times higher than considered therapeutic for valproate) decreased the protein binding of immediate-release Topimax from 23% to 13%. Immediate-release Topimax does not influence the binding of sodium valproate.
Metabolism and Excretion
Topimax is not extensively metabolized and is primarily eliminated unchanged in the urine (approximately 70% of an administered dose). Six metabolites have been identified in humans, none of which constitutes more than 5% of an administered dose. The metabolites are formed via hydroxylation, hydrolysis, and glucuronidation. There is evidence of renal tubular reabsorption of Topimax. In rats, given probenecid to inhibit tubular reabsorption, along with Topimax, a significant increase in renal clearance of Topimax was observed. This interaction has not been evaluated in humans. Overall, oral plasma clearance (CL/F) is approximately 20 mL/min to 30 mL/min in adults following oral administration. The mean effective half-life of Topimax Extended-Release Capsules is approximately 56 hours. Steady-state is reached in about 5 days after dosing with Topimax Extended-Release Capsules in subjects with normal renal function.
Specific Populations
Renal Impairment
The clearance of Topimax was reduced by 42% in subjects with moderate renal impairment (creatinine clearance 30 to 69 mL/min/1.73 m2) and by 54% in subjects with severe renal impairment (creatinine clearance less than 30 mL/min/1.73 m2) compared to subjects with normal renal function (creatinine clearance greater than70 mL/min/1.73 m2). Since Topimax is presumed to undergo significant tubular reabsorption, it is uncertain whether this experience can be generalized to all situations of renal impairment. It is conceivable that some forms of renal disease could differentially affect glomerular filtration rate and tubular reabsorption resulting in a clearance of Topimax not predicted by creatinine clearance. In general, however, use of one-half the usual starting and maintenance dose is recommended in patients with creatinine clearance less than 70 mL/min/1.73 m2.
Hemodialysis
Topimax is cleared by hemodialysis. Using a high-efficiency, counterflow, single pass-dialysate hemodialysis procedure, Topimax dialysis clearance was 120 mL/min with blood flow through the dialyzer at 400 mL/min. This high clearance (compared to 20 mL/min to 30 mL/min total oral clearance in healthy adults) will remove a clinically significant amount of Topimax from the patient over the hemodialysis treatment period. Therefore, a supplemental dose may be required.
Hepatic Impairment
In subjects with hepatic impairment, the clearance of Topimax may be decreased; the mechanism underlying the decrease is not well understood.
Age, Gender and Race
The pharmacokinetics of Topimax in elderly subjects (65 to 85 years of age, N=16) were evaluated in a controlled clinical study. The elderly subject population had reduced renal function (creatinine clearance [-20%]) compared to young adults. Following a single oral 100 mg dose, maximum plasma concentration for elderly and young adults was achieved at approximately 1 to 2 hours. Reflecting the primary renal elimination of Topimax, Topimax plasma and renal clearance were reduced 21% and 19%, respectively, in elderly subjects, compared to young adults. Similarly, Topimax half-life was longer (13%) in the elderly. Reduced Topimax clearance resulted in slightly higher maximum plasma concentration (23%) and AUC (25%) in elderly subjects than observed in young adults. Topimax clearance is decreased in the elderly only to the extent that renal function is reduced. Because of this, dosage adjustment may be necessary.
Clearance of Topimax in adults was not affected by gender or race.
Pediatric Pharmacokinetics
Pharmacokinetics of immediate-release Topimax were evaluated in patients ages 2 years to less than 16 years. Patients received either no or a combination of other antiepileptic drugs. A population pharmacokinetic model was developed on the basis of pharmacokinetic data from relevant Topimax clinical studies. This dataset contained data from 1217 subjects including 258 pediatric patients aged 2 years to less than 16 years (95 pediatric patients less than 10 years of age).
Pediatric patients on adjunctive treatment exhibited a higher oral clearance (L/h) of Topimax compared to patients on monotherapy, presumably because of increased clearance from concomitant enzyme-inducing antiepileptic drugs. In comparison, Topimax clearance per kg is greater in pediatric patients than in adults and in young pediatric patients (down to 2 years) than in older pediatric patients. Consequently, the plasma drug concentration for the same mg/kg/day dose would be lower in pediatric patients compared to adults and also in younger pediatric patients compared to older pediatric patients. Clearance was independent of dose.
As in adults, hepatic enzyme-inducing antiepileptic drugs decrease the steady state plasma concentrations of Topimax.
Drug-Drug Interaction Studies
Antiepileptic Drugs
Potential interactions between immediate-release Topimax and standard AEDs were assessed in controlled clinical pharmacokinetic studies in patients with epilepsy. The effects of these interactions on mean plasma AUCs are summarized in Table 9. Interaction of Topimax Extended-Release Capsules and standard AEDs is not expected to differ from the experience with immediate-release Topimax products.
In Table 9, the second column (AED concentration) describes what happened to the concentration of the AED listed in the first column when Topimax was added. The third column (Topimax concentration) describes how the co-administration of a drug listed in the first column modified the concentration of Topimax in experimental settings when Topimax was given alone.
In addition to the pharmacokinetic interaction described in the above table, concomitant administration of valproic acid and Topimax has been associated with hyperammonemia with and without encephalopathy and hypothermia.
CNS Depressants or Alcohol
Concomitant administration of Topimax and alcohol or other CNS depressant drugs has not been evaluated in clinical studies.
Oral Contraceptives
In a pharmacokinetic interaction study in healthy volunteers with a concomitantly administered combination oral contraceptive product containing 1 mg norethindrone (NET) plus 35 mcg ethinyl estradiol (EE), Topimax, given in the absence of other medications at doses of 50 to 200 mg per day, was not associated with statistically significant changes in mean exposure (AUC) to either component of the oral contraceptive. In another study, exposure to EE was statistically significantly decreased at doses of 200, 400, and 800 mg per day (18%, 21%, and 30%, respectively) when given as adjunctive therapy in patients taking valproic acid. In both studies, Topimax (50 mg per day to 800 mg per day) did not significantly affect exposure to NET. Although there was a dose-dependent decrease in EE exposure for doses between 200 to 800 mg per day, there was no significant dose-dependent change in EE exposure for doses of 50 to 200 mg per day. 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 combination oral contraceptive products with Topimax Extended-Release Capsules. Patients taking estrogen-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.
Digoxin
In a single-dose study, serum digoxin AUC was decreased by 12% with concomitant Topimax administration. The clinical relevance of this observation has not been established.
Hydrochlorothiazide
A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of hydrochlorothiazide (HCTZ) (25 mg every 24 hours) and Topimax (96 mg every 12 hours) when administered alone and concomitantly. The results of this study indicate that Topimax Cmax increased by 27% and AUC increased by 29% when HCTZ was added to Topimax. The clinical significance of this change is unknown. The addition of HCTZ to Topimax Extended-Release Capsules therapy may require an adjustment of the Topimax Extended-Release Capsules dose. The steady-state pharmacokinetics of HCTZ were not significantly influenced by the concomitant administration of Topimax. Clinical laboratory results indicated decreases in serum potassium after Topimax or HCTZ administration, which were greater when HCTZ and Topimax were administered in combination.
Metformin
Topimax treatment can frequently cause metabolic acidosis, a condition for which the use of metformin is contraindicated. Topimax Extended-Release Capsules are expected to exhibit the same degree of metabolic acidosis as Topimax.
A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of metformin (500 mg every 12 hr) and Topimax in plasma when metformin was given alone and when metformin and Topimax (100 mg every 12 hr) were given simultaneously. The results of this study indicated that the mean metformin Cmax and AUC0-12h increased by 17% and 25%, respectively, when Topimax was added. Topimax did not affect metformin tmax. The clinical significance of the effect of Topimax on metformin pharmacokinetics is not known.
Oral plasma clearance of Topimax appears to be reduced when administered with metformin. The clinical significance of the effect of metformin on Topimax Extended-Release Capsules pharmacokinetics is unclear.
Pioglitazone
A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of Topimax and pioglitazone when administered alone and concomitantly. A 15% decrease in the AUCτ,ss of pioglitazone with no alteration in Cmax,ss was observed. This finding was not statistically significant. In addition, a 13% and 16% decrease in Cmax,ss and AUCτ,ss respectively, of the active hydroxy-metabolite was noted as well as a 60% decrease in Cmax,ss and AUCτ,ss of the active keto-metabolite. The clinical significance of these findings is not known.
When Topimax Extended-Release Capsules are added to pioglitazone therapy or pioglitazone is added to Topimax Extended-Release Capsules therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state.
Glyburide
A drug-drug interaction study conducted in patients with type 2 diabetes evaluated the steady-state pharmacokinetics of glyburide (5 mg per day) alone and concomitantly with Topimax (150 mg per day). There was a 22% decrease in Cmax and 25% reduction in AUC24 for glyburide during Topimax administration. Systemic exposure (AUC) of the active metabolites, 4-trans-hydroxy glyburide (M1) and 3-cis-hydroxyglyburide (M2), was also reduced by 13% and 15%, reduced Cmax by 18% and 25%, respectively. The steady-state pharmacokinetics of Topimax were unaffected by concomitant administration of glyburide.
Lithium
In patients, the pharmacokinetics of lithium were unaffected during treatment with Topimax at doses of 200 mg per day; however, there was an observed increase in systemic exposure of lithium (27% for Cmax and 26% for AUC) following Topimax doses up to 600 mg per day. Lithium levels should be monitored when co-administered with high-dose Topimax Extended-Release Capsules.
Haloperidol
The pharmacokinetics of a single dose of haloperidol (5 mg) were not affected following multiple dosing of Topimax (100 mg every 12 hr) in 13 healthy adults (6 males, 7 females).
Amitriptyline
There was a 12% increase in AUC and Cmax for amitriptyline (25 mg per day) in 18 normal subjects (9 males, 9 females) receiving 200 mg per day of Topimax. Some subjects may experience a large increase in amitriptyline concentration in the presence of Topimax Extended-Release Capsules and any adjustments in amitriptyline dose should be made according to the patient's clinical response and not on the basis of plasma levels.
Sumatriptan
Multiple dosing of Topimax (100 mg every 12 hrs) in 24 healthy volunteers (14 males, 10 females) did not affect the pharmacokinetics of single-dose sumatriptan either orally (100 mg) or subcutaneously (6 mg).
Risperidone
When administered concomitantly with Topimax at escalating doses of 100, 250, and 400 mg per day, there was a reduction in risperidone systemic exposure (16% and 33% for steady-state AUC at the 250 and 400 mg per day doses of Topimax). No alterations of 9-hydroxyrisperidone levels were observed. Coadministration of Topimax 400 mg per day with risperidone resulted in a 14% increase in Cmax and a 12% increase in AUC12 of Topimax. There were no clinically significant changes in the systemic exposure of risperidone plus 9- hydroxyrisperidone or of Topimax; therefore, this interaction is not likely to be of clinical significance.
Propranolol
Multiple dosing of Topimax (200 mg per day) in 34 healthy volunteers (17 males, 17 females) did not affect the pharmacokinetics of propranolol following daily 160 mg doses. Propranolol doses of 160 mg per day in 39 volunteers (27 males, 12 females) had no effect on the exposure to Topimax at a dose of 200 mg per day of Topimax.
Dihydroergotamine
Multiple dosing of Topimax (200 mg per day) in 24 healthy volunteers (12 males, 12 females) did not affect the pharmacokinetics of a 1 mg subcutaneous dose of dihydroergotamine. Similarly, a 1 mg subcutaneous dose of dihydroergotamine did not affect the pharmacokinetics of a 200 mg per day dose of Topimax in the same study.
Diltiazem
Co-administration of diltiazem (240 mg) with Topimax (150 mg per day) resulted in a 10% decrease in Cmax and 25% decrease in diltiazem AUC, 27% decrease in Cmax and 18% decrease in des-acetyl diltiazem AUC, and no effect on N-desmethyl diltiazem. Co-administration of Topimax with diltiazem resulted in a 16% increase in Cmax and a 19% increase in AUC12 of Topimax.
Venlafaxine
Multiple dosing of Topimax (150 mg per day) in healthy volunteers did not affect the pharmacokinetics of venlafaxine or O-desmethyl venlafaxine. Multiple dosing of venlafaxine (150 mg) did not affect the pharmacokinetics of Topimax.
Other Carbonic Anhydrase Inhibitors
Concomitant use of Topimax Extended-Release Capsules, a carbonic anhydrase inhibitor, with any other carbonic anhydrase inhibitor (e.g., zonisamide, acetazolamide, or dichlorphenamide), may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation. Therefore, if Topimax Extended-Release Capsules are given concomitantly with another carbonic anhydrase inhibitor, the patient should be monitored for the appearance or worsening of metabolic acidosis.
Drug/Laboratory Tests Interactions
There are no known interactions of Topimax Extended-Release Capsules with commonly used laboratory tests.
Relative Bioavailability of Topimax Extended-Release Capsules Compared to Immediate-Release Topimax in Healthy Volunteers
Topimax Extended-Release Capsules, taken once daily, provides similar steady-state Topimax concentrations to immediate-release Topimax taken every 12 hours, when administered at the same total daily dose. In a healthy volunteer, multiple-dose crossover study, the 90% CI for the ratios of AUC0-24, Cmax and Cmin, as well as partial AUC (the area under the concentration-time curve from time 0 to time p (post dose)) for multiple time points were within the 80 to 125% bioequivalence limits, indicating no clinically significant difference between the two formulations. In addition, the 90% CI for the ratios of Topimax plasma concentration at each of multiple time points over 24 hours for the two formulations were within the 80 to 125% bioequivalence limits, except for the initial time points before 3 hours and at 8 hours post-dose, which is not expected to have a significant clinical impact.
The effects of switching between Topimax Extended-Release Capsules and immediate-release Topimax were also evaluated in the same multiple-dose, crossover, comparative bioavailability study. In healthy subjects switched from immediate-release Topimax given every 12 hours to Topimax Extended-Release Capsules given once daily, similar concentrations were maintained immediately after the formulation switch. On the first day following the switch, there were no significant differences in AUC0-24, Cmax, and Cmin, as the 90% CI for the ratios were contained within the 80 to 125% equivalence limits.
References
- DailyMed. "TOPIRAMATE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailyme... (accessed September 17, 2018).
- NCIt. "Topiramate: NCI Thesaurus (NCIt) provides reference terminology for many systems. It covers vocabulary for clinical care, translational and basic research, and public information and administrative activities.". https://ncit.nci.nih.gov/ncitbrowser... (accessed September 17, 2018).
- EPA DSStox. "Topiramate: DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.". https://comptox.epa.gov/dashboard/ds... (accessed September 17, 2018).
Reviews
The results of a survey conducted on ndrugs.com for Topimax are given in detail below. The results of the survey conducted are based on the impressions and views of the website users and consumers taking Topimax. We implore you to kindly base your medical condition or therapeutic choices on the result or test conducted by a physician or licensed medical practitioners.User reports
Consumer reported administration
No survey data has been collected yetConsumer reviews
There are no reviews yet. Be the first to write one! |
Information checked by Dr. Sachin Kumar, MD Pharmacology
