Trokendi XR - Drug Monograph

Introduction

Trokendi XR (topiramate extended-release) is an antiepileptic drug (AED) approved for migraine prophylaxis and epilepsy management. It is an extended-release formulation designed to provide once-daily dosing with more stable plasma concentrations compared to immediate-release topiramate. Trokendi XR belongs to the sulfamate-substituted monosaccharide class and exhibits multiple mechanisms of action.

Mechanism of Action

Topiramate demonstrates multiple pharmacological actions:

• Voltage-dependent sodium channel blockade
• Enhancement of GABAergic activity through GABA-A receptor modulation
• Antagonism of AMPA/kainate glutamate receptors
• Weak inhibition of carbonic anhydrase isoenzymes CA-II and CA-IV
• Modulation of voltage-gated calcium channels (L-type)

These multifaceted mechanisms contribute to its antiepileptic and migraine-preventive effects.

Indications

FDA-approved indications:

• Monotherapy or adjunctive therapy for partial-onset seizures, primary generalized tonic-clonic seizures, and seizures associated with Lennox-Gastaut syndrome in patients aged 2 years and older
• Prophylaxis of migraine headaches in adults

Off-label uses (not FDA-approved):

• Bipolar disorder maintenance
• Neuropathic pain conditions
• Alcohol dependence
• Essential tremor

Dosage and Administration

• Adults: Initial dose 25-50 mg daily, titrate by 25-50 mg weekly to target 200-400 mg daily
• Pediatrics (2-16 years): Initial dose 25 mg once nightly, titrate by 1-3 mg/kg/week to target 5-9 mg/kg/day

• Adults: Initial dose 25 mg daily, titrate by 25 mg weekly to target 100 mg daily

• Renal impairment (CrCl <70 mL/min): Reduce dose by 50%
• Hepatic impairment: Use with caution, consider dose reduction
• Geriatric patients: Initiate at lower doses
• Dialysis: Supplemental dose may be needed after dialysis

• Swallow whole; do not crush, chew, or split
• Administer in the morning with or without food
• Avoid evening dosing due to potential CNS effects

Pharmacokinetics

• Bioavailability: ~80%
• Tmax: 21 hours (extended-release formulation)
• Food effect: None significant
• Steady-state: Achieved in 4 days

• Protein binding: 15-41%
• Vd: 0.6-0.8 L/kg
• Crosses blood-brain barrier and placenta

• Hepatic metabolism: ~50% (not CYP-dependent)
• Metabolites: Not pharmacologically active
• Minimal autoinduction

• Half-life: 21 hours (Trokendi XR)
• Renal excretion: ~70% unchanged drug
• Clearance: 20-30 mL/min

Contraindications

• Hypersensitivity to topiramate or any component of the formulation
• Acute metabolic acidosis with concomitant metformin use
• History of nephrolithiasis with previous topiramate use
• Pregnancy (for migraine prophylaxis) due to teratogenic risk

Warnings and Precautions

• Teratogenicity: Increased risk of cleft lip/palate and other major congenital malformations
• Cognitive/neuropsychiatric effects: Word-finding difficulties, memory impairment, confusion
• Metabolic acidosis: May decrease serum bicarbonate; monitor periodically
• Acute myopia and secondary angle-closure glaucoma: Requires immediate discontinuation
• Oligohidrosis and hyperthermia: Especially in children
• Suicidal behavior and ideation: Monitor for emergence or worsening depression
• Hyperammonemia and encephalopathy: Particularly with concomitant valproic acid

• Renal stone formation: Maintain adequate hydration
• Hypothermia: Reported with concomitant valproic acid
• Hepatic impairment: Use with caution
• Withdrawal seizures: Taper gradually (reduce by 25-50 mg/week)

Drug Interactions

• Oral contraceptives: Decreased efficacy (estrogen component); use alternative contraception
• CNS depressants: Additive sedation (alcohol, benzodiazepines, opioids)
• Carbonic anhydrase inhibitors: Increased risk of nephrolithiasis (avoid concomitant use)
• Valproic acid: Increased risk of hyperammonemia and hypothermia
• Phenytoin: Decreased topiramate concentrations
• Metformin: Increased risk of metabolic acidosis
• Lithium: Possible increased lithium concentrations

• Enzyme inducers (carbamazepine, phenytoin): Decrease topiramate concentrations by 40-50%
• CYP2C19 inhibitors: May increase topiramate concentrations

Adverse Effects

• Paresthesia (49%)
• Fatigue (14%)
• Anorexia (13%)
• Weight loss (12%)
• Nausea (11%)
• Taste perversion (10%)

• Metabolic acidosis (1-3%)
• Acute angle-closure glaucoma (0.1%)
• Nephrolithiasis (1.5%)
• Oligohidrosis and hyperthermia
• Cognitive dysfunction (memory impairment, word-finding difficulty)
• Psychiatric symptoms (depression, anxiety)
• Visual field defects
• Hepatic failure (rare)

Monitoring Parameters

• Comprehensive metabolic panel (including bicarbonate)
• Renal function tests
• Pregnancy test in women of childbearing potential
• Body weight
• Ophthalmologic examination (if symptoms develop)

• Serum bicarbonate: Every 3-6 months
• Renal function: Annually
• Body weight: Monthly for first 6 months
• Therapeutic drug monitoring: Not routinely required (therapeutic range 5-20 mg/L)
• Mental status and cognitive function: At each visit
• Signs of glaucoma: At each visit

• Pediatric patients: Height, weight, and development regularly
• Elderly patients: Renal function and cognitive status frequently

Patient Education

• Take medication exactly as prescribed; do not stop abruptly
• Swallow capsules whole; do not crush or chew
• Report any visual changes immediately
• Maintain adequate fluid intake (6-8 glasses daily) to prevent kidney stones
• Be aware of potential cognitive effects (memory problems, word-finding difficulty)
• Use effective contraception; discuss pregnancy planning with provider
• Monitor for mood changes, depression, or suicidal thoughts
• Avoid alcohol and other CNS depressants
• Be cautious when driving or operating machinery until effects are known
• Report signs of infection or decreased sweating, especially in children
• Regular follow-up appointments are essential for monitoring

• Missed dose: Take as soon as remembered unless close to next dose
• Storage: Room temperature (15-30°C); keep in original container
• Pregnancy registry: Encourage enrollment in North American Antiepileptic Drug Pregnancy Registry (1-888-233-2334)

References

1. FDA Prescribing Information: Trokendi XR (topiramate) extended-release capsules. Revised 2022. 2. Glauser TA, et al. Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia. 2013;54(3):551-563. 3. Silberstein SD, et al. Topiramate in migraine prevention: results of a large controlled trial. Archives of Neurology. 2004;61(4):490-495. 4. Brandes JL, et al. Topiramate for migraine prevention: a randomized controlled trial. JAMA. 2004;291(8):965-973. 5. French JA, et al. Efficacy and tolerability of the new antiepileptic drugs I: treatment of new onset epilepsy. Neurology. 2004;62(8):1252-1260. 6. Perucca E. Pharmacological and therapeutic properties of topiramate. CNS Drugs. 2003;17(7):463-484. 7. Johannessen Landmark C, et al. Clinical pharmacokinetics of antiepileptic drugs in paediatric patients. Clinical Pharmacokinetics. 2018;57(3):315-334. 8. Wiegand F, et al. Topiramate extended release: a review in epilepsy. CNS Drugs. 2016;30(6):559-566. 9. American Academy of Neurology guidelines for antiepileptic drug selection. Neurology. 2020;94(10):1-15. 10. North American Antiepileptic Drug Pregnancy Registry. Massachusetts General Hospital.