Question:

Who may be right for TOPAMAX for migraine prevention?

Answer:

Guidelines suggest that patients may be candidates for preventive therapy if any of the following criteria apply^2,3:

• Frequent attacks (≥ 2 per month with disability totaling 3 or more days)
• Recurring migraines that in the patient's opinion significantly interfere with daily routines
• Overuse of acute medications (≥ 2 times a week)
• Acute medications contraindicated, ineffective, or not tolerated

Adapted from the American Academy of Family Physicians and the American College of Physicians-American Society of Internal Medicine guidelines for the management of migraines.

TOPAMAX Tablets and TOPAMAX Sprinkle Capsules are indicated for adults for the prophylaxis of migraine headache. The usefulness of TOPAMAX in the acute treatment of migraine headache has not been studied.

Question:

What were the trial designs and inclusion/exclusion criteria for TOPAMAX in the pivotal studies?

Answer:

TOPAMAX was evaluated for migraine prevention in 2 large, 26-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trials. Patients included in these studies were required to have a history of migraine assessed by the International Headache Society (IHS), for at least 6 months prior to screening. ^5,6

They had to be between 12 and 70 years of age and experience between 3 and 12 migraines, but not more than 15 headache days (migraine or nonmigraine) during a 28-day prospective baseline period. Patients were excluded if they experienced headaches other than migraine (i.e., episodic tension or sinus headaches). Patients were also excluded if they failed to respond to more than 2 previous regimens of migraine prevention therapy, if their onset of migraine occurred after age 50, or if they overused analgesics or acute medications. ^5,6

Question:

How many patients were included in the trial when evaluating efficacy?

Answer:

Nine hundred thirty-seven patients were randomized to TOPAMAX 50 mg/day, 100 mg/day,
200 mg/day or placebo in 2 large well-controlled, phase 3, placebo-controlled clinical studies evaluating efficacy. These were the largest well-controlled trials conducted for migraine prevention to date. ^5,6

Question:

What were the primary efficacy results for TOPAMAX in these studies?

Answer:

The primary endpoint of the pivotal trials was change from baseline in mean monthly migraine frequency. TOPAMAX 50 mg BID (100 mg/day) effectively reduced migraines by 2.1 attacks per month from a baseline of approximately 5.5 migraines per month in both studies vs 0.8 and 11 with placebo. ^5,6

Question:

What was the first assessment point in these studies?

Answer:

The first assessment point was at 4 weeks. TOPAMAX 50 mg BID significantly reduced migraine frequency vs placebo at the first assessment point. ^5,6 However, guidelines suggest that migraine prevention therapy by maintained for 2 to 3 months before evaluating therapeutic effect. ²

Question:

Did the effect of TOPAMAX diminish over time in these studies?

Answer:

No, the reduction in migraine frequency was sustained through the double-blind treatment phase
(6 months).^5,6

Question:

What titration schedule was used during these trials?

Answer:

Patients were randomized to either TOPAMAX 50 mg/day, 100 mg/day, 200 mg/day, or placebo. Treatment was initiated at 25 mg/day for 1 week, then increased by 25 mg increments each week up to the recommended target maintenance dose. ^5,6

Question:

Is TOPAMAX useful in the acute treatment of migraines?

Answer:

TOPAMAX Tablets and TOPAMAX Sprinkle Capsules are indicated for adults for the prophylaxis of migraine headache. The usefulness of TOPAMAX in the acute treatment of migraine headache has not been studied.

Question:

What side effects are most commonly associated with TOPAMAX for migraine prevention?

Answer:

The most common adverse event associated with the use of TOPAMAX was paresthesia (defined as tingling in the extremities). However, severity was mild to moderate and discontinuation due to this effect was 7%. The most common adverse events associated with TOPAMAX 100 mg vs placebo were: paresthesia, 51% vs 6%; anorexia, 15% vs 6%; fatigue, 15% vs 11%; nausea, 13% vs 8%; diarrhea, 11% vs 4%; weight decrease, 9% vs 1%; taste alteration, 8% vs 1%. Of the 1135 patients exposed to topiramate in placebo-controlled studies, 25% discontinued due to adverse events, compared to 10% of the 445 placebo patients.

Question:

How can these adverse events be managed?

Answer:

If a patient experiences adverse events during the titration period of therapy, longer intervals between dosage adjustment may be used. Following the recommended titration schedule can help reduce the incidence of adverse events.

Question:

When are adverse events most likely to occur during TOPAMAX therapy?

Answer:

Treatment-related adverse events occurred more frequently during the titration period than during the maintenance period and most were reported to be mild to moderate in severity.

Question:

What effect did TOPAMAX have on body weight in adults in the clinical trials?

Answer:

Nine hundred thirty-seven patients were randomized to TOPAMAX 50 mg/day, 100 mg/day, 200 mg/day or placebo in 2 large, phase 3, placebo-controlled clinical studies evaluation efficacy. These were the largest controlled trials conducted for migraine prevention to date. ^5,6

Question:

Is TOPAMAX associated with an increased incidence of impotence, hypotension, or urinary retention?

Answer:

TOPAMAX has no increased incidence of impotence and no significant incidence of hypotension or urinary retention vs placebo.⁵

Question:

Are there any contraindications or warnings of which I should be aware when prescribing TOPAMAX for migraine prevention?

Answer:

The only contraindication associated with the use of TOPAMAX for migraine prevention is patients having a history of hypersensitivity to any component of the product.

TOPAMAX has been associated with serious adverse events, including:

• Hyperchloremic, non-anion gap metabolic acidosis lowering of bicarbonate levels in the blood. Measurement of baseline and periodic serum bicarbonate is recommended.
• Acute myopia and secondary angle closure glaucoma patients should be cautioned to seek medical attention if they experience blurred vision or ocular pain.
• Oligohidrosis and hyperthermia decreased sweating and increased body temperature, especially in hot weather. The majority of reports have been in children.
• Cognitive/psychiatric side effects including cognitive dysfunction, psychiatric/behavioral disturbances including suicidal thoughts or behavior, and somnolence and fatigue.

Question:

How do I manage these serious adverse events?

Answer:

Generally, hyperchloremic, non-anion gap metabolic acidosis occurs early in treatment and serum bicarbonate decrements are usually mild to moderate. Measurement of baseline and periodic serum bicarbonate levels during treatment is recommended.

A syndrome consisting of acute myopia associated with secondary angle-closure glaucoma has been reported in patients receiving TOPAMAX. Symptoms typically occur within 1 month of initiating therapy. Patients should be cautioned to seek medical attention if they experience blurred vision or ocular pain. The primary treatment to reverse symptoms is discontinuation of treatment as rapidly as possible.

The majority of reports of oligohidrosis and hyperthermia have been in children. TOPAMAX for migraine prevention is indicated for use in adults.

TOPAMAX has also been associated with cognitive/psychiatric side effects including cognitive dysfunction, psychiatric/behavioral disturbances including suicidal thoughts or behavior, and somnolence and fatigue. These AEs were dose related. For more complete details, please refer to the Prescribing Information.

Question:

How many patients were included in clinical trials when evaluating safety?

Answer:

One thousand one hundred thirty-five patients were exposed to TOPAMAX in placebo-controlled clinical studies evaluating safety. However, more than 1700 patients were included in the development program for migraine prevention.⁶

Question:

Can TOPAMAX be used during pregnancy or when nursing?

Answer:

TOPAMAX is classified as Category C in terms of pregnancy risk, meaning that TOPAMAX should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus. TOPAMAX is excreted in human breast milk. However, pharmacologic significance of this exposure is not known.

Question:

What is the recommended titration for TOPAMAX?

Answer:

Question:

What is the recommended dosage of TOPAMAX during maintenance therapy?

Answer:

The recommended target maintenance dose for TOPAMAX is 50 mg BID for a total of 100 mg per day.

Question:

Can I titrate the dosage more slowly than recommended, if necessary?

Answer:

Yes. Dose and titration rate should be guided by clinical outcome. If required, longer intervals between dosage adjustments can be used for patients who may find the recommended schedule difficult to tolerate.

Question:

How long should I wait before evaluating the therapeutic effect of TOPAMAX?

Answer:

Guidelines suggest that migraine prevention therapy be maintained for 2 to 3 months before evaluating its therapeutic effect.²

Question:

Can TOPAMAX be taken with food?

Answer:

Yes. TOPAMAX can be taken without regard to meals.

Question:

How is TOPAMAX supplied?

Answer:

TOPAMAX is available as Tablets and Sprinkle Capsules. TOPAMAX Tablets are available in 25 mg, 50 mg, 100 mg, and 200 mg strengths. Sprinkle Capsules are available in 15 mg and 25 mg strengths.

Question:

Are TOPAMAX Tablets scored and/or can they be split?

Answer:

No. TOPAMAX Tablets are not scored and splitting of TOPAMAX Tablets is not recommended due to their bitter taste.

Question:

What are the recommended storage conditions for TOPAMAX?

Answer:

TOPAMAX Tablets should be stored in tightly closed containers at room temperature (59F to 86F, 15C to 30C) and protected from moisture.

Question:

What is the chemical structure of TOPAMAX?

Answer:

TOPAMAX (topiramate; 2,3:4,5-Di-O-isopropylidene-?-D-fructopyranose sulfamate) is a derivative of the naturally occurring monosaccharide D-fructose.

Question:

What is the mechanism of action of the migraine preventive effects of TOPAMAX?

Answer:

TOPAMAX may stabilize neuronal hyperexcitability. Multiple mechanisms of action may contribute to efficacy in migraine prevention by:

• Balancing GABA and glutamate
• Enhancing inhibitory effect of GABA
• Blocking excitatory effect of glutamate*
• Blocking Na+ channels, limiting repetitive firing
• Reducing the activity of Ca++ channels

* Via non-NMDA receptors.

TOPAMAX has also been shown to inhibit carbonic anhydrase activity. Exact mechanisms by which topiramate exerts its therapeutic effects are not established.

Question:

What is the half-life of TOPAMAX?

Answer:

The half-life of TOPAMAX is a function of clearance. In adults, the mean plasma elimination half-life is 21 hours after single or multiple doses. Steady state is reached in about 4 days in patients with normal renal function.

Question:

How is TOPAMAX metabolized and eliminated?

Answer:

In the absence of enzyme induction, TOPAMAX is not extensively metabolized (~30% metabolized) and is primarily eliminated unchanged in the urine. Overall, oral plasma clearance (CL/F) is approximately 20 to 30 mL/min in adults following oral administration.

Question:

How does renal disease affect the pharmacokinetics of TOPAMAX?

Answer:

Consistent with TOPAMAX being eliminated primarily by renal excretion, clearance of TOPAMAX was reduced 42% in subjects with moderately impaired renal function (creatinine clearance 30 to 69 mL/min/1.73 m2) and 54% in subjects with severe renal impairment (creatinine clearance <30 mL/min/1.73 m2). In general, use of one half the usual TOPAMAX dose is recommended for patients with moderate or severe renal impairment.

Question:

How does hepatic disease affect the pharmacokinetics of TOPAMAX?

Answer:

In hepatically impaired subjects, the clearance of TOPAMAX may be decreased. However, the underlying mechanism resulting in the decrease is not well understood.

Question:

How soon are steady-state plasma concentrations of TOPAMAX achieved?

Answer:

Based on elimination half-life, TOPAMAX steady state would be achieved in approximately 4 days in patients with normal renal function. The protein-bound fraction of TOPAMAX plasma concentration decreases as concentration increases. Over the broad plasma concentration range of 0.5 ?g/mL to 250 ?g/mL, which includes clinically relevant concentrations, TOPAMAX is 15% to 41% bound, respectively, to human plasma proteins.

Question:

Are there clinically significant interactions between TOPAMAX and other medications frequently used to treat migraine?

Answer:

The potential for pharmacokinetic interactions between TOPAMAX and other medications is somewhat limited because TOPAMAX is not highly protein bound nor is it extensively metabolized in the liver. TOPAMAX administration was not associated with clinically significant effects on sumatriptan, propranolol, or dihydroergotamine. TOPAMAX has been associated with an increase in amitriptyline and decreased valproic acid plasma concentrations.

Question:

How does TOPAMAX affect oral contraceptives?

Answer:

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), TOPAMAX given in the absence of other medications at doses of 50 mg/day to 200 mg/day was not associated with statistically significant changes in mean exposure (AUC) to either component of the oral contraceptive (1 mg norethindrone plus 35 mcg ethinyl estradiol [EE]).

• Although there was a dose-dependent decrease in EE exposure for doses between 200 mg/day and 800 mg/day, there were no significant dose-dependent changes in EE exposure for doses of 50 mg/day to 200 mg/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 productions with TOPAMAX.
• 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.

Question:

Does TOPAMAX cause renal stone formation?

Answer:

Patients, particularly those with predisposing factors, should be instructed to maintain an adequate fluid intake in order to minimize the risk of renal stone formation — the incidence is only 1.5%.