PREVAIL Epilepsy Trial

Qudexy® XR is an extended-release topiramate formulation backed by PREVAIL phase 3 data in patients with epilepsy.

Trial Design

The efficacy and safety of Qudexy® XR as adjunctive treatment for adults with partial-onset seizures were evaluated in PREVAIL.1,2

  • Randomized, double-blind, parallel-group, placebo-controlled trial
  • Enrolled patients with a history of partial-onset seizures (POS) on a stable dose of 1 to 3 AEDs
    • Seizure frequency during 8-week baseline: ≥8 POS, with or without secondary generalization, and ≤21 consecutive seizure-free days
    • 249 patients were randomly assigned to Qudexy® XR once daily or placebo in addition to their AEDs
    • Most common concomitant AEDs included carbamazepine, valproic acid, lamotrigine and/or levetiracetam*
  • Treatment consisted of an initial 3-week titration period followed by an 8-week maintenance period at 200 mg once daily of Qudexy® XR or placebo

*See Table 10 in the Qudexy® XR Prescribing Information for a summary of AED interactions with topiramate.

PREVAIL Titration Schedule

  • Initial Dose
  • Titration
  • Maintenance Dose
  • 50 mg once daily
  • Increased dose weekly by increments of 50 mg for 3 weeks
  • 200 mg once daily

Open-Label Extension of PREVAIL

96.8% of patients who completed PREVAIL continued into the open-label extension study.1,2

Patients who completed the PREVAIL treatment phase were eligible to enroll in the 1-year open-label extension.

  • Patients underwent a 3-week blinded-conversion phase followed by a 52-week open-label treatment phase
  • After 11 weeks of the open-label extension:
    • Qudexy® XR dose could be changed in 50 mg/week increments (maximum dose: 400 mg daily)
    • Concomitant AEDs could be added, removed or dose-adjusted as long as patients remained on 1 to 3 concomitant AEDs

Efficacy

Qudexy® XR demonstrated a nearly 40% reduction from baseline in refractory partial-onset seizures (POS) with only a 200 mg maintenance dose.1,2

PREVAIL Primary Endpoint During 11-Week Treatment Period

Although this controlled clinical trial was performed to assess the efficacy and safety of Qudexy® XR in patients, the basis for approval of Qudexy® XR included the studies using an immediate-release topiramate formulation and the demonstration of the pharmacokinetic equivalence of Qudexy® XR to immediate-release topiramate through the analysis of concentrations and cumulative AUCs at multiple time points.

POS=partial-onset seizure; AUC=area under the curve.

Qudexy® XR is an extended-release topiramate formulation with contemporary topiramate PREVAIL efficacy data when used with other AEDs, including carbamazepine, valproic acid, lamotrigine and levetiracetam.†2

† See Table 10 in the Qudexy® XR Prescribing Information for a summary of AED interactions with topiramate.

Favorable Safety and Tolerability Profile

Most treatment-emergent adverse events (TEAEs) reported were mild to moderate in intensity.1,2

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. In the Qudexy® XR trial, a dose of 200 mg/day was administered to a limited number of patients; therefore, these results cannot be directly compared to immediate-release topiramate experience.

Incidence (≥2%) of Treatment-Emergent Adverse Reactions in the PREVAIL Trial

Body System/Adverse Reaction Qudexy® XR (N=124) Placebo (N=125)

General disorders

Fatigue 6% 5%
Asthenia 2% 1%
Irritability 2% 1%

Nervous system disorders

Somnolence 12% 2%
Dizziness 7% 6%
Paresthesia 7% 2%
Aphasia 2% 0%
Dysarthria 2% 1%
Memory impairment 2% 1%

Psychiatric disorder

Psychomotor retardation 2% 0%

Cardiovascular disorders, general

Hypertension 3% 1%

Metabolic and nutritional disorders

Weight decrease 7% 0%
Decreased appetite 4% 2%
Anorexia 2% 1%

8.9% of patients who received Qudexy® XR and 4.0% who received placebo discontinued as a result of TEAEs.

References:

1. Qudexy® XR [package insert]. Maple Grove, MN: Upsher-Smith Laboratories, Inc.; February 2019.
2. Data on file. Maple Grove, MN: Upsher-Smith Laboratories, Inc.; 2019.

Qudexy is a registered trademark of Upsher-Smith Laboratories, LLC. All other marks are property of their respective owners.
© 2024 Upsher-Smith Laboratories, LLC, Maple Grove, MN 55369

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IMPORTANT SAFETY INFORMATION WARNINGS & PRECAUTIONS
  • 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, with symptoms typically occurring within 1 month of therapy initiation. The primary treatment to reverse symptoms is discontinuation of Qudexy XR as rapidly as possible. If left untreated, elevated intraocular pressure 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. If visual problems occur at any time during topiramate treatment, consideration should be given to discontinuing the drug.
  • Oligohydrosis and Hyperthermia. Oligohydrosis, resulting in hospitalization in some cases, has been reported in association with topiramate use. The majority of reports have been in pediatric patients, but all patients should be monitored closely for evidence of decreased sweating and increased body temperature, especially in hot weather. Caution should be used when Qudexy XR is prescribed with other drugs that predispose patients to heat-related disorders.
  • Metabolic Acidosis. Qudexy XR can cause hyperchloremic, non-anion gap metabolic acidosis due to its inhibitory effect on carbonic anhydrase. Conditions that predispose patients to acidosis may be additive to the bicarbonate lowering effects of topiramate. Measurement of baseline and periodic serum bicarbonate during topiramate treatment is recommended. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing topiramate (using dose tapering).
  • Suicidal Behavior and Ideation. Antiepileptic drugs (AEDs), including Qudexy XR increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Patients, their caregivers, and families should be informed of these risks, and behaviors of concern should be immediately reported to healthcare providers.
  • Cognitive/Neuropsychiatric Adverse Reactions. Immediate-release topiramate can cause, and therefore, Qudexy XR is expected to cause, cognitive/neuropsychiatric adverse reactions. In adults, the most frequent of these can be classified into three general categories: cognitive-related dysfunction, psychiatric/behavioral disturbances, and somnolence/fatigue. In pediatric epilepsy trials, adverse reactions included psychomotor slowing, difficulty with concentration/attention, speech disorders/related speech problems, and language problems. In migraine preventive treatment-controlled trials, the most common cognitive adverse reaction was difficulty with memory. Patients should use caution when operating machinery including automobiles. Depression and mood problems may occur.
  • Fetal Toxicity. Topiramate can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in utero have an increased risk of major congenital malformations, including but not limited to cleft lip and/or cleft palate and of being small for gestational age. Qudexy XR should be used during pregnancy only if the potential benefit outweighs the potential risk. All women of childbearing potential should be informed of the potential hazard to the fetus and counseled to use effective contraception, keeping in mind that there is a potential for decreased contraceptive efficacy when using estrogen-containing birth control with topiramate.
  • Withdrawal of Antiepileptic Drugs. Antiepileptic drugs, including Qudexy XR, should be gradually withdrawn to minimize the potential for seizures or increased seizure frequency.
  • Decrease in Bone Mineral Density (BMD): Topiramate has been shown to decrease BMD and bone mineral content in pediatric patients.
  • Negative effects on Growth: Topiramate may slow height increase and weight gain; carefully monitor children receiving prolonged therapy.
  • Serious Skin Reactions. Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) have been reported in patients receiving topiramate. Qudexy XR should be discontinued at the first sign of a rash, unless the rash is clearly not drug related.
  • Hyperammonemia and Encephalopathy. Topiramate treatment can cause hyperammonemia, with and without encephalopathy. The risk for hyperammonemia with topiramate appears dose-related. Hyperammonemia has been reported more frequently when used concomitantly with valproic acid. Patients with inborn errors of metabolism or reduced mitochondrial activity may have an increased risk of hyperammonemia. Measure ammonia if encephalopathic symptoms occur.
  • Kidney Stones. Topiramate increases the risk of kidney stones. Topiramate is a carbonic anhydrase inhibitor. Carbonic anhydrase inhibitors can promote stone formation by reducing urinary citrate excretion and by increasing urinary pH. The concomitant use of Qudexy XR with any other drug producing metabolic acidosis, or potentially in patients on a ketogenic diet, may create a physiological environment that increases the risk of kidney stone formation, and should therefore be avoided. Increased fluid intake increases the urinary output, lowering the concentration of substances involved in stone formation. Hydration is recommended to reduce new stone formation.
  • Hypothermia with Concomitant Valproic Acid Use. Hypothermia has been reported in association with topiramate use with concomitant valproic acid, both in the presence and in the absence of hyperammonemia. Consideration should be given to stopping topiramate or valproate in patients who develop hypothermia.
USE IN SPECIFIC POPULATIONS
  • Lactation: Topiramate is excreted in human milk. The effects of topiramate on milk production are unknown. Diarrhea and somnolence have been reported in breastfed infants whose mothers receive topiramate treatment. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Qudexy XR and any potential adverse effects on the breastfed infant from Qudexy XR or from the underlying maternal condition.
  • Females of Reproductive Potential: Women of childbearing potential who are not planning a pregnancy should use effective contraception because of the risks to the fetus of major congenital malformations, including but not limited to oral clefts and of being small for gestational age.
  • Pediatric Use: The adverse reactions (both common and serious) in pediatric patients are similar to those seen in adults. Qudexy XR is not indicated for any use in patients less than 2 years of age.
  • Pregnancy: Increased risk of major congenital malformations, including but not limited to cleft lip and/or palate and for being small for gestational age.
  • Patients with Renal Impairment: One-half of the usual adult dose is recommended.
  • Patients Undergoing Hemodialysis: To avoid rapid drops in topiramate plasma concentration, a supplemental dose of topiramate may be required.
  • Geriatric use: Dosage adjustment may be necessary for elderly with impaired renal function.
DRUG INTERACTIONS
  • Antiepileptic Drugs: Concomitant administration of phenytoin or carbamazepine with topiramate resulted in a clinically significant decrease in plasma concentrations of topiramate. A dosage adjustment may be needed. Concomitant administration of valproic acid and topiramate has been associated with hypothermia and hyperammonemia with or without encephalopathy.
  • Other Carbonic Anhydrase Inhibitors: Patients should be monitored for the appearance or worsening of metabolic acidosis when Qudexy XR is given concomitantly with another carbonic anhydrase inhibitor.
  • CNS Depressants: Qudexy XR should be used with extreme caution if used in combination with alcohol and other CNS depressants.
  • Oral Contraceptives: The possibility of decreased contraceptive efficacy and increased breakthrough bleeding may occur.
  • Hydrochlorothiazide (HCTZ): The addition of HCTZ to Qudexy XR may require a decrease in the Qudexy XR dose.
  • Pioglitazone: When Qudexy XR is added to pioglitazone therapy or pioglitazone is added to Qudexy XR therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state.
  • Lithium: Lithium levels should be monitored when co-administered with high-dose Qudexy XR.
  • mitriptyline: Some patients may experience a large increase in amitriptyline concentration in the presence of Qudexy XR and any adjustments in amitriptyline dose should be made according to the patient’s clinical response and not on the basis of plasma levels.
ADVERSE REACTIONS
  • Epilepsy: The most common adverse reactions in adult and pediatric controlled, clinical trials of immediate-release topiramate were: paresthesia, anorexia, weight loss, speech disorders and related speech problems, fatigue, dizziness, somnolence, nervousness, psychomotor slowing, abnormal vision, and fever.
  • Migraine: The most common adverse reactions at recommended doses in adult and adolescent controlled, clinical trials were: paresthesia, anorexia, weight loss, difficulty with memory, taste perversion, diarrhea, hypoesthesia, nausea, abdominal pain, and upper respiratory tract infection.
  • Qudexy XR has been studied in a randomized, placebo-controlled, phase 3 clinical study in 249 adult patients with a history of partial-onset seizures with or without secondary generalization. See the ADVERSE REACTIONS section of the Qudexy XR full prescribing information for adverse reaction rates from this clinical trial.
  • The most serious adverse reactions are listed above in the WARNINGS AND PRECAUTIONS section.

This safety information is not comprehensive.  Please refer to the full Prescribing Information for Qudexy XR and Medication Guide. You can also visit www.upsher-smith.com or call 1-888-650-3789.

You are encouraged to report suspected adverse reactions to Upsher-Smith Laboratories, LLC at 1-855-899-9180 or to the FDA by visiting www.fda.gov/medwatch.

INDICATIONS

Qudexy XR (topiramate) Extended-Release Capsules are indicated for:

  • Migraine: Preventive treatment of migraine in patients 12 years and older.
  • Epilepsy: Initial monotherapy for the treatment of partial-onset or primary generalized tonic-clonic seizures in patients 2 years and older. Adjunctive therapy for the treatment of partial-onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut Syndrome in patients 2 years and older.

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