Topiramate

From Anvita Health Wiki

Contents 1 Indications 2 Contraindications 3 Dosage 4 Dosage-adjustment-in-renal-failure 5 Pharmacokinetics 6 Monitor 7 Adverse-effects 8 Drug-interactions 9 Mechanism-of-action 10 Notes 11 More General Terms 12 Additional Terms 13 Internet Database 14 References

Indications

• adjunctive therapy in the treatment of partial seizures
• effective for tonic-clonic seizures, myoclonic seuzures & absence seizures [11]
• treatment of Lennox-Gastaut syndrome
• migraine prophylaxis [7,8]
• used for obesity, but not approved or recommended [5,6]
• alcohol dependence [5]
• tremors [6]
• painful diabetic neuropathy (NOT drug of choice) [9]
• neuropathic pain

Contraindications

• Caution:
• AVOID abrupt withdrawal
• increase risk of renal stones; maintain adequate fluid intake
• use cautiously in patient with hepatic or renal insufficiency
• watch for metabolic acidosis [6]
  

• pregnancy category = d
• safety in lactation = ?

Dosage

• start 25-50 mg/day in 2 divided doses
• 1st dose HS ( at bedtime)
• increase daily dose by 25-50 mg weekly
• maintenance dose:

• 200-400 mg/day divided BID
• 50-100 mg PO BID ( migraine prophylaxis) [7,8]
• 300 mg/day ( alcohol dependence) [5]

• maximum dose: 400 mg/day
• reduce dose by 25-50% in patients with renal insufficiency
• patients may require supplemental doses post dialysis

• Tabs: 25 mg, 100 mg, 200 mg.

Dosage-adjustment-in-renal-failure

• creatinine clearance < 70 mL/min:

• administer 25-50% of dose
• titrate more slowly

Pharmacokinetics

• oral bioavailability is about 80%, unaffected by food
• 13-17% of drug is bound to plasma proteins
• time to peak serum concentration is 2-4 hours
• not extensively metabolized
• excreted unchanged in the urine
• elimination 1/2life is about 21 hours
• clearance is reduced 42-54% with renal insufficiency
• 30% dialyzable
• about 4 weeks before effective for migraine propylaxis [8]
  

• elimination via kidney
• 1/2life = 21 hours
• protein binding = 13-17 %
• 1/2life = 21 hours
• elimination by hemodialysis = +/-

Monitor

• serum bicarbonate baseline, periodically & when increasing dose (may cause metabolic acidosis) [15]
• plasma ammonia if evidence of encephalopathy [15]
  
• monitor with anticonvulsants

Adverse-effects

• common (> 10%)

• fatigue (8%), dizziness, ataxia, somnolence, psychomotor slowing, nervousness, anxiety, memory difficulties [10], speech problems, nausea, paresthesia (8%), tremor, nystagmus, upper respiratory tract infections

• less common (1-10%)

• chest pain, edema, language problems, abnormal coordination, confusion, depression, difficulty concentrating, hypoesthesia, hot flashes, dyspepsia, abdominal pain, anorexia, constipation, xerostomia, gingivitis, weight loss, myalgia, weakness, back pain, leg pain, rigors, decreased hearing, nephrolithiasis, pharyngitis, sinusitis, epistaxis, flu-like syndrome

• other

• kidney stones (2-4 fold increased risk)
• visual problems generally within 1st month of therapy [3]

• acute myopia
• angle-closure glaucoma

• metabolic acidosis [6]
• cognitive impairment [10]
• 3-fold increased risk of suicide [13]
• increased risk of cleft lip &/or cleft palate in infants born to women treated with topiramate during pregnancy
  
• drug adverse effects of anticonvulsants

Drug-interactions

• phenytoin:

• 25% increase in phenytoin concentration
• 48% decrease in topiramate concentration

• carbamazepine: 40% decrease in topiramate concentration
• valproic acid:

• 11% decrease in valproic acid concentration
• 14% decrease in topiramate concentration

• CNS depressants: increased CNS depression
• carbonic anhydrase inhibitors: increased incidence of renal stone formation
• oral contraceptives: decreased effectiveness of oral contraceptives

Mechanism-of-action

• sulfamate-substituted monosaccharide with a broad spectrum of anticonvulsant activity
• mechanism not fully understood
• inhibits carbonic anhydrase

• increases renal excretion of bicarbonate

• some effects may be due to

• blockage of Na+ channels
• enhancement of GABA's inhibitory effects
• antagonsim of kainate receptor responses

Notes

• cost nearly $200 per month for migraine prophylaxis [8]

More General Terms

• monosaccharide
• anticonvulsant
• enzyme inhibitor

Additional Terms

• Lennox-Gastaut syndrome (epileptic encephalopathy, Lennox-Gastaut type)
• partial seizure

Internet Database

PubChem: 5514
PubChem: 5284627

References

1. Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
2. Kaiser Permanente Northern California Regional Drug Formulary, 1998
3. Prescriber's Letter 8(11):65 2001
4. Prescriber's Letter 9(12):69 2002
5. Prescriber's Letter 10(9):53 2003
6. Prescriber's Letter 11(3):14 2004 Detail-Document#: [1] (subscription needed) [2]
7. Journal Watch 24(7):54, 2004 Brandes JL et al, Topiramate for migraine prevention: a randomized controlled trial. JAMA 291:965, 2004 PMID: [3]
8. Prescriber's Letter 11(10): 2004 Topamax for Migraine Prevention Detail-Document#: [4] (subscription needed) [5]
9. Journal Watch 24(21):165, 2004
   - Raskin P, Donofrio PD, Rosenthal NR, Hewitt DJ, Jordan DM, Xiang J, Vinik AI; CAPSS-141 Study Group. Topiramate vs placebo in painful diabetic neuropathy: analgesic and metabolic effects. Neurology. 2004 Sep 14;63(5):865-73. PMID: [6]
   - Thienel U, Neto W, Schwabe SK, Vijapurkar U; Topiramate Diabetic Neuropathic Pain Study Group. Topiramate in painful diabetic polyneuropathy: findings from three double-blind placebo-controlled trials. Acta Neurol Scand. 2004 Oct;110(4):221-31. PMID: [7]
10. Journal Watch 25(9):74, 2005 Salinsky MC, Storzbach D, Spencer DC, Oken BS, Landry T, Dodrill CB. Effects of topiramate and gabapentin on cognitive abilities in healthy volunteers. Neurology. 2005 Mar 8;64(5):792-8. PMID: [8]
11. Medical Knowledge Self Assessment Program (MKSAP) 15, American College of Physicians, Philadelphia 2009
12. Prescriber's Letter 17(7): 2010 Recommended Lab Monitoring for Common Medications Detail-Document#: [9] (subscription needed) [10]
13. Andersohn F et al, Use of antiepileptic drugs in epilepsy and the risk of self-harm or suicidal behavior Neurology 2010;75:335-340 <PubMed> PMID: [11] <Internet> [12]
14. FDA MedWatch: 3/3/2011 Topamax (topiramate): Label Change - Risk For Development of Cleft Lip and/or Cleft Palate in Newborns [13]
    - FDA Drug Safety Communication: Risk of oral clefts in children born to mothers taking Topamax (topiramate 03-04-2011 [14]
    - Hunt S et al Topiramate in pregnancy: Preliminary experience from the UK Epilepsy and Pregnancy Register Neurology 2008 71:272-276 <PubMed> PMID: [15] <Internet> [16]

topiramate (Topamax)