Topirva XR

Approved Indications:

• Epilepsy (as monotherapy or adjunctive therapy):
• Partial-onset seizures in patients ≥2 years of age
• Primary generalized tonic-clonic seizures in patients ≥2 years of age
• Seizures associated with Lennox-Gastaut syndrome (LGS) in patients ≥2 years of age
• Migraine Prophylaxis:
• Prevention of migraine headaches in adults and adolescents (≥12 years of age)

Clinically Accepted Off-Label Uses:

• Bipolar disorder (as adjunctive therapy for mood stabilization)
• Post-traumatic stress disorder (PTSD)
• Alcohol use disorder (to reduce cravings and relapse rates)
• Weight management and obesity (commonly in fixed-dose combination with phentermine)
• Essential tremor
• Cluster headache prevention
• Idiopathic intracranial hypertension (IIH) – to reduce cerebrospinal fluid production
• Tardive dyskinesia – investigational use

Route of Administration: Oral
Available Forms: Film-coated tablets (25 mg, 50 mg, 100 mg, 200 mg); Sprinkle capsules (15 mg, 25 mg)

Epilepsy (Monotherapy or Adjunctive Therapy):

Adults (Monotherapy):

• Initial dose: 25 mg once daily at night
• Titrate in 25–50 mg increments every 1–2 weeks
• Target dose: 400 mg/day in two divided doses

Children (2–9 years):

• Start at 0.5–1 mg/kg/day at bedtime
• Titrate to 5–9 mg/kg/day in 2 divided doses

Lennox-Gastaut Syndrome (Adjunctive):

• Children ≥2 years: Initial 1 mg/kg/day → titrate to 5–9 mg/kg/day in 2 divided doses
• Adults: Target dose 200–400 mg/day in divided doses

Migraine Prophylaxis:

Adults and Adolescents (≥12 years):

• Start with 25 mg once daily at bedtime
• Titrate weekly by 25 mg to reach target dose of 100 mg/day, divided into two doses

Special Populations:

Renal Impairment (CrCl <70 mL/min):

• Reduce dose by 50%
• Slower titration is recommended

Hepatic Impairment:

• Use with caution; slower dose escalation may be needed due to reduced clearance

Elderly:

• Use standard adult dosing with close monitoring; consider renal function when dosing

Administration Instructions:

• Can be taken with or without food
• Tablets should be swallowed whole; do not crush or chew
• Sprinkle capsules can be opened and sprinkled on a small amount of soft food and consumed immediately

Topiramate exerts its therapeutic effects through multiple mechanisms. It blocks voltage-dependent sodium channels, thereby stabilizing neuronal membranes and reducing repetitive firing. It enhances GABA-A receptor activity, increasing inhibitory neurotransmission. It also inhibits excitatory glutamate pathways by antagonizing AMPA/kainate receptors and inhibits carbonic anhydrase isoenzymes (especially II and IV), contributing to its anticonvulsant and antimigraine actions. These combined effects decrease neuronal hyperexcitability and prevent seizure propagation and migraine initiation.

• Absorption: Rapid and nearly complete after oral administration
• Bioavailability: Approximately 80%
• Time to Peak Concentration: 2 to 4 hours
• Protein Binding: Low (~15%)
• Volume of Distribution: 0.6–0.8 L/kg
• Metabolism: Limited hepatic metabolism; more pronounced in patients on enzyme-inducing drugs
• Active Metabolites: None
• Half-life:
• ~21 hours (monotherapy)
• ~12–15 hours (with enzyme inducers like phenytoin or carbamazepine)
• Elimination: Primarily renal (about 70% excreted unchanged in urine)
• Steady-State: Achieved in approximately 4 to 5 days

Pregnancy:

• FDA Category D
• Associated with increased risk of oral clefts (e.g., cleft lip/palate) and fetal growth restriction
• Use only when potential benefit outweighs known teratogenic risks

Lactation:

• Excreted in breast milk
• May cause sedation, diarrhea, or poor feeding in nursing infants
• Breastfeeding is not recommended without careful risk-benefit assessment

• Primary Class: Antiepileptic (AED)
• Subclass: Broad-spectrum anticonvulsant; carbonic anhydrase inhibitor

• Known hypersensitivity to Topiramate or any formulation component
• Recent alcohol intake within 6 hours before or after extended-release formulation
• Use with phentermine during pregnancy (for weight loss)
• History of metabolic acidosis with Topiramate
• Anuria or severe renal impairment (caution advised)
• Glaucoma or nephrolithiasis (relative contraindications)

• Cognitive Dysfunction: Can cause attention/memory impairment, speech/language difficulties
• Visual Disturbances: Acute myopia and secondary angle-closure glaucoma may occur
• Metabolic Acidosis: Monitor serum bicarbonate regularly
• Hyperammonemia: May cause encephalopathy, especially with valproate
• Suicidal Behavior: Increased risk of suicidal ideation; monitor mood and behavior
• Kidney Stones: Risk increased by carbonic anhydrase inhibition
• Oligohidrosis and Hyperthermia: Seen in pediatric patients during hot weather
• Weight Loss and Nutritional Concerns: Monitor weight and growth in pediatric patients

Common:

• Central Nervous System:
• Somnolence, fatigue, dizziness, confusion, slowed cognition, speech difficulties
• Sensory: Paresthesia (tingling)
• Gastrointestinal: Anorexia, nausea, diarrhea, weight loss
• Renal: Nephrolithiasis
• Psychiatric: Mood changes, anxiety, depression

Serious or Rare:

• Metabolic acidosis
• Angle-closure glaucoma
• Hyperammonemic encephalopathy (especially with valproate)
• Suicidal ideation
• Stevens-Johnson Syndrome (very rare)
• Visual field defects

Onset:

• Cognitive and sensory effects often occur during titration
• Serious metabolic or ocular effects may develop over weeks or months

Major Interactions:

• Enzyme-inducing AEDs (phenytoin, carbamazepine): Reduce Topiramate levels
• Valproic acid: ↑ risk of hyperammonemia and encephalopathy
• Oral contraceptives (ethinylestradiol): Reduced efficacy at Topiramate doses ≥200 mg/day
• Carbonic anhydrase inhibitors (acetazolamide, zonisamide): Additive risk of metabolic acidosis or nephrolithiasis
• CNS depressants: Enhanced sedation and psychomotor impairment

Drug-Food Interactions:

• High-fat meals may delay absorption of extended-release forms

Drug-Alcohol Interactions:

• Alcohol should be avoided within 6 hours before or after extended-release doses due to CNS and metabolic risks

Metabolic Pathways:

• Weak inducer of CYP3A4
• Moderate inhibitor of CYP2C19

• FDA 2023 Update: Reinforced teratogenicity risks, especially oral clefts and advised against weight loss use during pregnancy
• AAN/AES Epilepsy Guidelines (2023): Topiramate remains first-line for focal and generalized tonic-clonic seizures
• Migraine Prophylaxis (AHS 2023): Topiramate remains a first-choice for prevention of chronic or episodic migraines
• Weight Management Use: FDA emphasizes avoidance in pregnant women and advises strict monitoring when used in combination with phentermine

• Storage Temperature: 20°C to 25°C (68°F to 77°F)
• Permitted Excursion: 15°C to 30°C for brief periods
• Humidity: Store in a dry place
• Light: Protect from excessive light exposure
• Handling Instructions:
• Do not crush or chew tablets
• Sprinkle capsules should be consumed immediately after mixing with soft food
• Refrigeration/Reconstitution: Not required