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topiramate (Topamax, Qudexy XR, Trokendi XR)

Indications: 1) adjunctive therapy in the treatment of partial seizures 2) generalized seizures - effective for tonic-clonic seizures, myoclonic seizures & absence seizures [11] 3) treatment of Lennox-Gastaut syndrome 4) migraine prophylaxis [7,8,15] 5) used for obesity, but not approved or recommended [5,6] 6) alcohol dependence, alcoholism [5] 7) tremors [6] 8) painful diabetic neuropathy (NOT drug of choice) [9] 9) neuropathic pain 10) idiopathic intracranial hypertension (pseudotumor cerebri) [11] Contraindications: Caution: 1) AVOID abrupt withdrawal 2) increase risk of renal stones; maintain adequate fluid intake 3) use cautiously in patient with hepatic or renal insufficiency 3) watch for metabolic acidosis [6] 4) pregnancy - avoid use during pregnancy [18] - use with caution in women of child-bearing age [11,18] Dosage: 1) start 25-50 mg/day in 2 divided doses 2) 1st dose HS (at bedtime) 3) increase daily dose by 25-50 mg weekly 4) maintenance dose: a) 200-400 mg/day divided BID b) 50-100 mg PO BID (migraine prophylaxis) [7,8] c) 300 mg/day (alcohol dependence) [5] 5) maximum dose: 400 mg/day 6) reduce dose by 25-50% in patients with renal insufficiency 7) patients may require supplemental doses post dialysis Tabs: 25 mg, 100 mg, 200 mg. * dosage adjustment for liver failure uncertain [11] Dosage adjustment in renal failure: - creatinine clearance < 70 mL/min: a) administer 25-50% of dose b) titrate more slowly - supplemental dosage after dialysis Pharmacokinetics: 1) oral bioavailability is about 80%, unaffected by food 2) 13-17% of drug is bound to plasma proteins 3) time to peak serum concentration is 2-4 hours 4) not extensively metabolized 5) excreted unchanged in the urine 6) elimination 1/2life is about 21 hours 7) clearance is reduced 42-54% with renal insufficiency 8) 30% dialyzable 9) about 4 weeks before effective for migraine propylaxis [8] Monitor: - serum bicarbonate baseline, periodically & when increasing dose (may cause metabolic acidosis) [15] - plasma ammonia if evidence of encephalopathy [15] Adverse effects: 1) common (> 10%) - fatigue (8%), somnolence, psychomotor slowing, dizziness, ataxia, nervousness, anxiety, memory difficulties [10], upper respiratory tract infections, speech problems (word-finding difficulty), nausea, anorexia, paresthesia (8%), tremor, nystagmus 2) less common (1-10%) - chest pain, edema, language problems, incoordination, 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, pharyngitis, sinusitis, nephrolithiasis (calcium phosphate stones), epistaxis, flu-like syndrome 3) other - kidney stones (2-4 fold increased risk) [11,15] - calcium phosphate stones - visual problems generally within 1st month of therapy [3] - acute myopia - acute angle-closure glaucoma - metabolic acidosis [6], hypokalemia (RTA1 ?) - heat stroke [11] - cognitive impairment [10,16] affecting verbal fluency - increased risk of cleft lip &/or cleft palate in infants born to women treated with topiramate during pregnancy - associated with low birth weight & small for gestational age [18] Drug interactions: 1) phenytoin: a) 25% increase in phenytoin concentration b) 48% decrease in topiramate concentration 2) carbamazepine: 40% decrease in topiramate concentration 3) valproic acid: a) 11% decrease in valproic acid concentration b) 14% decrease in topiramate concentration 4) CNS depressants: increased CNS depression 5) carbonic anhydrase inhibitors: increased incidence of renal stone formation 6) oral contraceptives: decreased effectiveness of oral contraceptives Mechanism of action: 1) sulfamate-substituted monosaccharide with broad spectrum anticonvulsant activity 2) mechanism not fully understood 3) inhibits carbonic anhydrase - increases renal excretion of bicarbonate 4) some effects may be due to a) blockage of Na+ channels b) enhancement of GABA's inhibitory effects c) antagonsim of kainate receptor responses Notes: cost nearly $200 per month for migraine prophylaxis [8]

Interactions

drug interactions drug adverse effects (more general classes) monitor with drug (more general classes)

Related

Lennox-Gastaut syndrome (epileptic encephalopathy, Lennox-Gastaut type) partial seizure; focal seizure topiramate in serum/plasma

General

anticonvulsant carbonic anhydrase inhibitor monosaccharide

Properties

INHIBITS: carbonic anhydrase (dehydratase) MISC-INFO: elimination route KIDNEY 1/2life 21 HOURS protein-binding 13-17% 1/2life 21 HOURS elimination by hemodialysis +/- pregnancy-category D safety in lactation ?

Database Correlations

PUBCHEM correlations

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#: 200307 (subscription needed) http://www.prescribersletter.com
  7. Journal Watch 24(7):54, 2004 Brandes JL et al, Topiramate for migraine prevention: a randomized controlled trial. JAMA 291:965, 2004 PMID: 14982912
  8. Prescriber's Letter 11(10): 2004 Topamax for Migraine Prevention Detail-Document#: 201009 (subscription needed) http://www.prescribersletter.com
  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: 15365138 - 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: 15355485
  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: 15753411
  11. Medical Knowledge Self Assessment Program (MKSAP) 15, 16, 17. American College of Physicians, Philadelphia 2009, 2012, 2015
  12. Prescriber's Letter 17(7): 2010 Recommended Lab Monitoring for Common Medications Detail-Document#: 260704 (subscription needed) http://www.prescribersletter.com
  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 PMID: 20660863 http://www.neurology.org/cgi/content/abstract/75/4/335
  14. FDA MedWatch: 3/3/2011 Topamax (topiramate): Label Change - Risk For Development of Cleft Lip and/or Cleft Palate in Newborns http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm245777.htm - FDA Drug Safety Communication: Risk of oral clefts in children born to mothers taking Topamax (topiramate 03-04-2011 http://www.fda.gov/Drugs/DrugSafety/ucm245085.htm - Hunt S et al Topiramate in pregnancy: Preliminary experience from the UK Epilepsy and Pregnancy Register Neurology 2008 71:272-276 PMID: 18645165 http://www.neurology.org/content/71/4/272.abstract
  15. Welch BJ, Graybeal D, Moe OW, Maalouf NM, Sakhaee K. Biochemical and stone-risk profiles with topiramate treatment. Am J Kidney Dis. 2006 Oct;48(4):555-63. PMID: 16997051 FDA approves Topamax for migraine prevention in adolescents. First approved treatment for ages 12 to 17. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm391026.htm
  16. Wandschneider B et al. Effect of topiramate and zonisamide on fMRI cognitive networks. Neurology 2017 Feb 17 PMID: 28213372
  17. Dell'Orto VG, Belotti EA, Goeggel-Simonetti B ET AL Metabolic disturbances and renal stone promotion on treatment with topiramate: a systematic review. Br J Clin Pharmacol. 2014 Jun;77(6):958-64. Review. PMID: 24219102 Free PMC Article
  18. Kirkner RM Three Antiseizure Medications Join List for Newborn Risks. Medscape. Dec 13, 2022 https://www.medscape.com/viewarticle/985504

Component-of

phentermine/topiramate (Qnexa, Qsymia)