Topiramate XR

Qudexy XR and Trokendi XR are the brand names used in the United States for the seizure medicine topiramate (toh-PEER-ah-mate).

Qudexy XR
Tablet

25 mg, 50 mg, 100 mg, 150 mg, and 200 mg extended-release capsules

Trokendi XR
Tablet
Trokendi 25mg

25 mg: Size 2 capsules, light green opaque body/yellow opaque cap (printed “SPN” on the cap, “25” on the body)

Trokendi 50mg

50 mg: light green opaque body/orange opaque cap (printed “SPN” on the cap, “50” on the body)

Trokendi 100mg

100 mg: green opaque body/blue opaque cap (printed “SPN” on the cap, “100” on the body)

Trokendi 200mg

200 mg: pink opaque body/blue opaque cap (printed “SPN” on the cap, “200” on the body)

Indications

Qudexy XR and Trokendi XR are currently indicated in the United States as monotherapy and adjunctive therapy for:

  • partial-onset seizures in adults and children ages 2-16 years
  • primary, generalized tonic-clonic seizures in adults and children ages 2-16 years
  • seizures associated with Lennox-Gastaut syndrome in people 2 years of age and older

Qudexy XR and Trokendi XR are currently approved by the Food and Drug Administration (FDA) as initial monotherapy for patients 10 years of age and older with partial-onset or primary generalized tonic-clonic seizures.

 

Forms

Qudexy XR is marketed in the United States by Upsher-Smith Laboratories. The name or appearance may differ in other countries. The dose (measured in milligrams, abbreviated "mg") will usually be the same. These descriptions apply to the U.S. versions:

Qudexy XR is available in 25 mg, 50 mg, 100 mg, 150 mg and 200 mg extended release capsuless.

Trokendi XR is marketed in the United States by Supernus.  The name or appearance may differ in other countries. The dose (measured in milligrams, abbreviated "mg") will usually be the same. These descriptions apply to the U.S. versions:

Qudexy and Tokendi XR are available in 25 mg, 50 mg, 100 mg, 150 mg and 200 mg extended release capsules.

How to take and store Topiramate XR?

Qudexy XR and Trokendi XR tablets should be swallowed whole.

Qudexy XR  or Trokendi XR can be taken either with food or without food. Food does not affect the bioavailability of Qudexy XR.

Qudexy XR tablets  and Trokendi XR should be stored at room temperature (59° to 86°F or 15° to 30°C). The sprinkle capsules may be especially vulnerable to heat, thus it's important to store the sprinkles below 77°F or 25°C. Keep all medicine in a tightly sealed container protected from moisture, heat and direct light.

All strengths of Qudexy™ XR and its AG may be swallowed whole or administered by carefully opening the capsule and sprinkling the entire contents on a spoonful of soft food.  This makes them the only approved extended-release topiramate products for patients who experience challenges swallowing whole capsules or tablets. 

Keep all medicines out of the reach of children.

Missed Doses

In general, tell patients that if they forget a dose, they should talk to their doctor for specific instructions on how to make it up. If it is almost time for the next dose, they should delay that dose for a few hours instead of taking two doses very close together.

Patients who often forget doses may benefit from using a special pillbox or watch with an alarm.

Mechanisms of actions of Topiramate XR

Qudexy XR has multiple mechanisms of action:

  • blocking voltage-dependent sodium channels
  • enhancing GABA activity at a nonbenzodiazepine site on GABA(A) receptors
  • antagonizing an NMDA–glutamate receptor
  • weakly inhibiting carbonic anhydrase in the central nervous system
Clinical Pharmacology of Topiramate XR

Absorption
Qudexy XR is absorbed well and peak plasma levels are reached in 6 to 8 hours.

Distribution and metabolism
Qudexy XR metabolism depends on the hepatic P450 system.

Nearly 70 to 80% of Qudexy XR is excreted unchanged in the urine, so the clearance of Qudexy XR is reduced by renal insufficiency. The half-life of Qudexy XR is approximately 21 hours with normal renal function.

Steady state
Steady state is reached after 4 to 5 days in patients with normal renal function. The dose that a patient takes should not be increased until steady state has been reached (or some time later), so that the effects of the previous dosage can be assessed.

Efficacy of Topiramate XR

Qudexy XR's benefit was shown by the global phase 3 (PREVAIL) trial-- a randomized, multicenter, double-blind, placebo- controlled, parallel group study.  The study enrolled 249 patients worldwide at 66 centers.

Results showed that Qudexy XR significantly reduced partial onset seizures by 39.5%.

Children with Lennox-Gastaut syndrome have various types of difficult-to-control seizures, including tonic and atonic seizures with stiffening or falling. When Qudexy XR was added to previous medication, the frequency of major seizures was reduced by at least half for 33% of these patients. Only 8% of those who added a placebo had a similar improvement.

Some small studies suggest that Qudexy XR also may be effective when used alone, especially for control of partial seizures.

Trokendi XR's  benefit has also been shown by several studies that used immediate release topiramate.  Pharmacological studies were shown to show the equivalence of Trokendi XR to immediate release topiramate when given in an extended release capsule on a once daily basis.

Common side effects of Topiramate XR

Most people who take Qudexy XR or Trokendi XR (topiramate) have little or no problem with side effects. Those with problems most often complain of:

  • fatigue or drowsiness
  • difficulty with concentration
  • difficulty finding the right word (word retrieval)
  • confusion
  • dizziness
  • ataxia
  • paresthesias
  • anorexia and weight loss

Most of these problems are mild to moderate. Many of them are more common when higher doses of Qudexy XR  or Trokendsi XR are taken.

In December 2003, the labeling of Topiramate was changed to include a warning about metabolic acidosis, which usually occurs early in treatment but can occur at any time. In controlled clinical trials, some degree of this electrolyte imbalance was found in 67% of pediatric patients and 32% of adults. Values were markedly abnormal in 11% of children and 3% of adults. See further discussion in the page on serious side effects.

The side effect of anorexia and weight loss is now a focus of research on Qudexy XR and Trokendsi XR. Data show that at least 5-10% of patients will lose weight, and therefore it is sometimes used in combination with Depakote (valproate), Neurontin (gabapentin), or Tegretol (carbamazepine), which can cause weight gain in some patients. Weight loss can be a problem, however, especially in children and those who are already thin.

Some other, less-common side effects were

  • nervousness
  • depression
  • difficulty with memory

Idiosyncratic reactions
Idiosyncratic side effects include:

  • allergic dermatitis
  • oligohidrosis in children
  • acute myopia
  • secondary angle closure glaucoma
Serious Side effects of Topiramate XR

Most people who take Qudexy XR  or Trokendsi XR (topiramate) have no side effects or only mild or moderate side effects without sequelae. No fatal reactions have been associated with its use.

Glaucoma
In 2001, doctors in the United States were notified of the development of glaucoma in 23 patients (including one child) out of over 825,000 who had used Qudexy XR or Trokedni XR.  These symptoms usually occurred during the first month of treatment. Patients should be advised to notify their doctor if they experience blurred vision or difficulty seeing that comes on quickly, with or without eye pain.

Metabolic acidosis
As mentioned in the page on common side effects, warnings about metabolic acidosis (decreased serum bicarbonate) in patients taking Qudexy XR were issued in late 2003.

Certain circumstances predispose patients to acidosis:

  • renal disease
  • severe respiratory disorders
  • status epilepticus
  • diarrhea
  • ketogenic diet
  • other medications that inhibit carbonic anhydrase

Acidosis usually occurs early in treatment but can arise at any time. Physicians are advised to measure baseline serum bicarbonate before initiating treatment and to test levels periodically.

Metabolic acidosis can cause symptoms such as fatigue, loss of appetite, irregular heartbeat, and impaired consciousness. Patients should be advised to contact their doctor or other health care provider if these symptoms develop while taking topiramate.

Chronic, untreated acidosis may lead to conditions such as kidney stones, osteomalacia, or osteoporosis and may reduce growth rate (and maximal height) in pediatric patients.

If acidosis persists, discontinuation of Qudexy XR or the addition of alkali treatment should be considered.

Kidney stones
About 1.5% of adults taking Qudexy XR have developed kidney stones. They are more common in men and in those with a personal history. They also may be more likely if Diamox (acetazolamide) or Zonegran (zonisamide) is also taken or if the ketogenic diet is followed. Qudexy XR therefore should be used cautiously in patients taking Diamox or Zonegran or using the ketogenic diet. To help prevent kidney stones, patients should be advised to drink plenty of water, juice, or other fluids (8 glasses every day for adults) and should be told what to do if they feel the onset of a kidney stone, such as sharp pains in their side or lower back.

Psychiatric side effects
Psychiatric side effects reported with Qudexy XR include:

  • depression
  • psychosis, including delusions and hallucinations
  • aggressive or hostile behavior
  • agitated behavior

A study of 431 patients in England found that 103 (nearly 24%) had some kind of psychiatric effect (Mula 2003). This included 16 people (4%) with psychosis, 24 with aggressive behavior, 17 with other behavior abnormalities, and 46 with a mood disorder.

Another report of 91 patients in England found symptoms of psychosis in 12%, compared to less than 1% of patients who took Neurontin (gabapentin) or Lamictal (lamotrigine) (Crawford 1998). Seven patients (8%) were admitted to the hospital because of psychosis or depression.

Another group of doctors looking only for symptoms of psychosis found them in 5 (6%) of the first 80 patients they treated with Qudexy XR (Khan 1999).

Most reports have indicated that people with a history of psychiatric illness are much more likely than others to experience psychiatric disorders while taking Qudexy XR (Mula 2003, Trimble 2000). The disorder tends to be of the same type as before. That is, those who have had psychosis in the past are more likely to experience symptoms of psychosis again, and those with past mood disorders are more likely to have a similar mood disorder (Trimble 2000). People with no history of psychiatric disorders also can be affected, however (Khan 1999).

Other factors that have been implicated in the development of psychiatric side effects from Qudexy XR are:

  • high starting dose and rapid dose increases
  • family history of psychiatric illness and epilepsy
  • history of febrile seizures
  • presence of tonic-atonic seizures (Mula 2003)

On the other hand, it has been reported that psychiatric side effects are less likely in people with a low frequency of seizures before starting Qudexy XR and in those also taking Lamictal. (Mula 2003)

Osteopenia/osteoporosis
The effect of Qudexy XR on bone health is not fully known. However, a person who has metabolic acidosis can develop osteopenia which could lead to osteoporosis if the acidosis is not treated properly. Patients taking Qudexy XR should be instructed on the importance of regular exercise and diet to help bone health. Patients should talk to their doctor before taking calcium supplements, because too much calcium could increase the risk of kidney stones in some people who are taking topiramate.

On July 10, 2008, an advisory panel was convened by the Food and Drug Administration (FDA) to review data that the FDA had previously collected from drug studies showing an association between many of the antiepileptic drugs (AEDs) and suicidal ideation and behavior, which together are called suicidality. According to the FDA’s Alert, among the patients with epilepsy in these drug studies, 1 out of 1000 people taking the placebo (inactive substance) showed suicidality compared to approximately 3.5 out of 1000 people who took an AED. The FDA advisory panel voted to accept the FDA's data at its meeting on July 10.

  • Taking antiepileptic medicines may increase the risk of having suicidal thoughts or actions;
  • Do not make any changes to the medication regimen without first talking with the responsible healthcare professional;
  • Pay close attention to any day-to-day changes in mood, behavior and actions. These changes can happen very quickly so it is important to be mindful of any sudden differences.
  • Be aware of common warning signs that might be a signal for risk of suicide. Some of these are:
    • Talking or thinking about wanting to hurt yourself or end your life
    • Withdrawing from friends and family
    • Becoming depressed or having your depression get worse
    • Becoming preoccupied with death and dying
    • Giving away prized possessions

We again urge patients and families to contact their doctor before stopping an epilepsy medication because this may possibly lead to seizures and worsening of mood.

Impact of Topiramate XR on bone health

See package insert.

Other Uses of Topiramate XR

Anecdotal reports suggest that Qudexy XR  or Trokendsi XR may be efficacious for:

  • infantile spasms
  • migraine prophylaxis
  • painful peripheral neuropathy
  • weight loss
Topiramate XR Contraindications

Patients who are allergic to topiramate should not take Qudexy XR or Trokendi XR.

Patients with a history of kidney stones or those taking high-dose vitamin C or calcium supplementation should not take Qudexy XR  or Trokendi XR because of the increased risk of kidney stones.

Topiramate XR Interactions with other medications

Effects of Qudexy XR or Trokndi XR  on other drugs
Qudexy XR  and Trokendi XR may increase phenytoin plasma concentrations when phenytoin metabolism is near saturation, such as when phenytoin serum levels are in the upper teens.

Women taking an oral contraceptive for purposes of contraception should consider a barrier method or take a higher-strength pill. Qudexy XR  and Trokendi XR accelerates the metabolism of hormonal contraceptives, lessening their effectiveness.

Effects of other drugs on Qudexy XR or Trokendi XR
Because the metabolism of Qudexy XR  and Trokendi XR is dependent on the hepatic P450 microsomal enzymes, its clearance is increased in the setting of enzyme-inducing AEDs, resulting in decreased Qudexy XR  or Trokendi XR concentrations.

Therefore, some AEDs may decrease the blood level of Qudexy XR:

  • carbamazepine (Tegretol, Tegretol XR, Carbatrol)
  • phenytoin (Dilantin, Phenytek)
  • phenobarbital
  • primidone (Mysoline)
Topiramate XR effects on Children

In 1999, topiramate was approved by the FDA to treat partial-onset seizures in children over 2 years of age. In 2001, it was approved to treat children with the Lennox-Gastaut syndrome. In both instances, it is recommended as an adjunctive medication, but it can also be used as monotherapy. Doctors also commonly prescribe it (either as adjunctive therapy or monotherapy) for children with primary generalized tonic-clonic seizures. Its effectiveness in treating children with myoclonic epilepsy is less well established, but evidence suggests that it can be useful.

If the dosage is increased slowly and carefully monitored, side effects should not be a problem for most children. The most common side effects involve problems with thinking or behavior, such as difficulty with concentration and attention or memory difficulty. These side effects may be less frequent in children than in adults. Headache, sleepiness, fatigue, and weight loss are other common side effects. Children are also susceptible to glaucoma.

Oligohidrosis has been described in children taking Qudexy XR and Trokendi XR. Children should be monitored in hot weather to be sure they sweat appropriately.

Children often have the fewest problems from side effects with Qudexy XR  and Trokendi XR if they start at a dose of 15 to 25 mg or less, based on a range of 1 to 3 mg/kg per day. This dose is given nightly for the first week. The dose should then be increased every week or two by adding 1 to 3 mg/kg per day (given in two divided doses) to achieve the best response. Most children do best at about 5 to 9 mg/kg per day.

One advantage of using Qudexy XR  or Trokendi XR for children is that it comes in the form of a sprinkle capsule, which can be swallowed whole or given by carefully opening the capsule and sprinkling the entire contents on a small amount (teaspoon) of soft food. This mixture should be swallowed immediately and not chewed.

Topiramate XR and Pregnancy

The U.S. Food and Drug Administration (FDA) lists Qudexy XR  and Trokendi XR as Pregnancy Category C. This indicates that caution is advised, but the benefits of the medication may outweigh the potential risks. There have not been enough well-controlled studies in women, but studies in animals have shown some harm to the fetus.

The babies of women taking seizure medicines have a greater than usual number of major birth defects like cleft lip, cleft palate, and heart malformations. Defects like these occur in 2-3% of all pregnancies but affect 4-7% of the babies of women taking AEDs. Whether this is also true for Qudexy XR  or Trokendi XR is not yet known. The risk of birth defects is higher for women who take more than one AED and for women with a family history of birth defects.

Advise women who are capable of becoming pregnant to take at least 400 mcg (0.4 mg) of folic acid (folate) daily to help prevent neural tube defects. Women at high risk, such as those with a history of a neural tube defect in a previous pregnancy, should take 4000 mcg (4 mg) daily, beginning before they become pregnant.

About 20% to 35% of women have seizures more often during pregnancy because of changes in hormones or changes in how their seizure medicine is handled by the body. Whether this applies to Qudexy XR  or Trokendi XR is not known, but it is advisable to check blood levels regularly during pregnancy so that the dosage can be adjusted as needed.

Some Qudexy XR  or Trokendi XR will probably appear in the milk of nursing mothers who take it, yet there is limited information on how much topiramate is passed through breast milk. The potential for seious side effects in nursing infants is unknown. See the package insert for more details.

Topiramate XR effects on Seniors

Because of aged-related reductions in renal function, older people excrete Qudexy XR and Trokendi XR more slowly than younger adults and they are often more susceptible to its side effects. Therefore, lower initial doses and caution in titration are advisable.

Topiramate XR Dosing and titration

The initial adult dosage is 25 to 50 mg/day, in one dose. The target dosage is 200 to 400 mg/day in a once a day dose. Up to 1000 mg daily has been given to patients also taking enzyme-inducing drugs.

In patients with renal insufficiency, doses should be reduced by half.

Therapeutic blood levels have not been established. Adjustments should depend on clinical response

Topiramate XR Package insert

In the United States, companies that manufacture medicines are required to publish certain kinds of information about each product. This document is commonly known as a “package insert” because it is usually included with each package of the medicine.

You can also read these documents (also called "prescribing information") online. The U.S. package insert for Qudexy XR (topiramate) is found at:

The package insert for Trokendi XR can be found at:

Some of the information may differ in other countries.

To learn how to read and understand a package insert, see  "How to read a package insert."

Topiramate XR References for Professionals

Abstracts of articles relevant to this topic are available through PubMed, a service of the National Library of Medicine:

Here are links to some articles relevant to this subject:

Biton V, Montouris GD, Ritter F, et al. A randomized, placebo-controlled study of topiramate in primary generalized tonic-clonic seizures. Topiramate YTC Study Group. Neurology 1999 Apr 22;52(7):1330-7. PMID: 10227614.

Topamax was effective as add-on therapy for primary generalized seizures in both adults and children, and side effects were not a serious problem.

Cramer JA, Ben Menachem E, French J. Review of treatment options for refractory epilepsy: new medications and vagal nerve stimulation. Epilepsy Res 2001 Nov;47(1-2):17-25. PMID: 11673017.

In a number of research studies, Topamax was more successful than six other new seizure medicines in controlling partial seizures as add-on therapy, but it had a higher rate of unwanted side effects at high doses.

Guberman A, Neto W, Gassmann-Mayer C; EPAJ-119 Study Group. Low-dose topiramate in adults with treatment-resistant partial-onset seizures. Acta Neurol Scand 2002;106:183-189. PMID: 12225311.

Topamax was effective and well tolerated as adjunctive therapy when added to carbamazepine (an enzyme-inducing AED) at a dosage of 200 mg/day.

Crawford P. An audit of topiramate use in a general neurology clinic. Seizure 1998 Jun;7(3):207-11. PMID: 9700833.

Khan A, Faught E, Gilliam F, Kuzniecky R. Acute psychotic symptoms induced by topiramate. Seizure 1999 Jun;8(4):235-7. PMID: 10452922.

Mula M, Trimble MR, Lhatoo SD, Sander JW. Topiramate and psychiatric adverse events in patients with epilepsy. Epilepsia 2003 May;44(5):659-63. PMID: 12752464.

Reife RA, Pledger GW: Topiramate as adjunctive therapy in refractory partial epilepsy: pooled analysis of data from five double-blind, placebo-controlled trials. Epilepsia 38 Suppl 1: S31, 1997. PMID 9092956.

Sachdeo RC, Glauser TA, Ritter F, et al. A double-blind, randomized trial of topiramate in Lennox-Gastaut syndrome. Topiramate YL Study Group. Neurology 1999 Jun 10;52(9):1882-7. PMID: 10371538.

Trimble MR, Rusch N, Betts T, Crawford PM. Psychiatric symptoms after therapy with new antiepileptic drugs: psychopathological and seizure related variables. Seizure 2000 Jun;9(4):249-54. PMID: 10880283.

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