GabapentinClass: Anticonvulsants, MiscellaneousVA Class: CN400Chemical Name: 1-(Aminomethyl)-cyclohexaneacetic acidMolecul...
Has been used for the management of vasomotor symptoms (e.g., hot flashes) associated withmenopause†.31 34 54Gabapentin Do...
Children 3–12 years of age: Initially, 10–15 mg/kg daily in 3 divided doses.1 Maintenancedosage of 40 mg/kg daily in 3 div...
Children >12 years of age: Dosage of 3.6 g daily has been tolerated as adjunctive therapy in themanagement of partial seiz...
Warnings/PrecautionsWarningsPending revision, the material in this section should be considered in light of more recentlya...
Distributed into milk; use only if potential benefits outweigh the risks.1Pediatric UseSafety and efficacy as adjunctive t...
Not metabolized by CYP isoenzymes.1 Does not inhibit CYP isoenzymes 1A2, 2C9, 2C19, 2D6,2E1, or 3A4 in vitro; causes sligh...
DistributionExtentReadily crosses the blood-brain barrier and concentrates in brain tissue.29 Distributed into breastmilk....
Actions       Mechanism of anticonvulsant action is unknown.1 4 5 7 8 9 Does not bind to GABA       receptors,1 4 5 6 7 17...
References1. Parke-Davis. Neurontin (gabapentin) capsules prescribing information. New York, NY; 2005Dec.2. Anon. Parke-Da...
15. Hooper WD, Kavanagh MC, Herkes GK et al. Lack of a pharmacokinetic interactionbetween phenobarbitone and gabapentin. B...
29. Luer MS, Hamani C, Dujovny M et al. Saturable transport of gabapentin at the blood-brainbarrier. Neurol Res. 1999; 21:...
43. Simpson DA. Gabapentin and venlafaxine for the treatment of painful diabetic neuropathy. JClin Neuromusc Dis. 2001; 3:...
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Gabapentin

  1. 1. GabapentinClass: Anticonvulsants, MiscellaneousVA Class: CN400Chemical Name: 1-(Aminomethyl)-cyclohexaneacetic acidMolecular Formula: C9H17NO2CAS Number: 60142-96-3IntroductionAnticonvulsant; structurally related to the inhibitory CNS neurotransmitter GABA.1 4 6 7 8 9Uses for GabapentinPending revision, the material in this section should be considered in light of more recentlyavailable information in the MedWatch notification at the beginning of this monograph.Seizure DisordersManagement (in combination with other anticonvulsants) of partial seizures with or withoutsecondary generalization in adults and children >12 years of age.1 2 8 9Management (in combination with other anticonvulsants) of partial seizures in children 3–12years of age.1Neuropathic PainManagement of postherpetic neuralgia in adults.1 20 21 22 23 24 38 39 40Treatment of pain associated with diabetic neuropathy†.20 21 22 23 24 25 40 41 42 43 44 45 40% ofpatients who receive gabapentin for pain associated with diabetic neuropathy obtain good painrelief.40Some evidence of benefit for the relief of chronic neurogenic pain† in a variety of conditionsincluding trigeminal neuralgia†,20 21 46 47 pain and control of paroxysmal symptoms of multiplesclerosis†,20 21 48 49 complex regional pain syndromes†,20 52 53 HIV-related peripheralneuropathy†,20 21 50 and neuropathic pain associated with cancer†.20 21 51 Also has been used inthe treatment of restless legs syndrome†.26 27 28 Additional study needed to further elucidateprecise role in the management of these conditions.Vasomotor SymptomsHas been used for the management of vasomotor symptoms (e.g., hot flashes) in women withbreast cancer†.30
  2. 2. Has been used for the management of vasomotor symptoms (e.g., hot flashes) associated withmenopause†.31 34 54Gabapentin Dosage and AdministrationGeneralSeizure Disorders Monitoring of plasma gabapentin concentrations is not necessary to optimize therapy.1 Because addition of gabapentin to existing anticonvulsant therapy does not appreciably alter steady-state plasma concentrations of concomitantly administered anticonvulsants, additional monitoring of plasma concentrations of anticonvulsants generally is not necessary.1 (See Specific Drugs under Interactions.) Discontinuance of gabapentin and/or addition of an alternative anticonvulsant drug to therapy should be done gradually over ≥1 week.1AdministrationOral AdministrationAdminister orally without regard to meals.1If Neurontin film-coated scored tablets containing 600 or 800 mg of gabapentin are to be used inpatients requiring a 300- or 400-mg dose, divide the tablet in half to allow administration of theappropriate dose.1 Instruct patients to take one-half tablet and to use the remaining half-tablet forthe next dose.1 Half-tablets that are not used within several days should be discarded.1Seizure DisordersAdminister orally 3 times daily.1 The interval between doses in this schedule should not exceed12 hours.1DosagePending revision, the material in this section should be considered in light of more recentlyavailable information in the MedWatch notification at the beginning of this monograph.Pediatric PatientsSeizure DisordersPartial SeizuresOral
  3. 3. Children 3–12 years of age: Initially, 10–15 mg/kg daily in 3 divided doses.1 Maintenancedosage of 40 mg/kg daily in 3 divided doses for children 3 or 4 years of age and 25–35 mg/kgdaily in 3 divided doses for children 5–12 years of age.1Children >12 years of age: Initially, 300 mg 3 times daily.1 Maintenance dosage of 900 mg to 1.8g daily in 3 divided doses.1AdultsSeizure DisordersPartial SeizuresOralInitially, 300 mg 3 times daily.1 Maintenance dosage of 900 mg to 1.8 g daily in 3 divideddoses.1Neuropathic PainPostherpetic NeuralgiaOral300 mg on the first day, 300 mg twice daily on the second day, and 300 mg 3 times daily on thethird day.1 Increase dosage as needed for relief of pain up to a total daily dosage of 1.8 g in 3divided doses.1 No evidence of additional benefit with dosages >1.8 g daily.1Diabetic NeuropathyOralDosages of 900 mg to 3.6 g daily have been used; however, pain relief generally observed inpatients receiving dosages >1.8 g daily.24 25Vasomotor Symptoms†Oral300 mg 3 times daily has been effective; higher dosages may provide additional benefit.30 31 37Prescribing LimitsPediatric PatientsChildren 3–12 years of age: Dosages up to 50 mg/kg daily in divided doses have been toleratedas adjunctive therapy in the management of partial seizures.1
  4. 4. Children >12 years of age: Dosage of 3.6 g daily has been tolerated as adjunctive therapy in themanagement of partial seizures.1AdultsDosage of 3.6 g daily has been tolerated as adjunctive therapy in the management of partialseizures.1Special PopulationsRenal ImpairmentNot studied in children <12 years of age with renal impairment.1In adults and children ≥12 years of age, base dosage on measured or estimated Clcr:1 16a In patients with Clcr <15 mL/min, reduce dosage proportionally (e.g., a patient with a Clcr of 7.5mL/min should receive one-half the dosage that a patient with a Clcr of 15 mL/min shouldreceive).b Give maintenance doses based on Clcr, with supplemental doses (125–350 mg) given after each4-hour hemodialysis session.1 Dosage for Adults and Children ≤12 Years of Age with Renal Impairment Total Daily Dosage Clcr (mL/min) Dosage Regimen (mg/day) 300 –1200 mg 3 times≥60 900–3600 daily30–59 400–1400 200 –700 mg twice daily15–29 200–700 200 –700 mg once daily a15 100–300 100 –300 mg once dailyESRD patients undergoing — 125–350 mgbhemodialysisGeriatric PatientsSelect dosage carefully, usually initiating therapy at the low end of the dosage range.1 Adjustdosage based on Clcr.1Cautions for GabapentinContraindications Known hypersensitivity to gabapentin or any ingredient in the formulation.1
  5. 5. Warnings/PrecautionsWarningsPending revision, the material in this section should be considered in light of more recentlyavailable information in the MedWatch notification at the beginning of this monograph.Cognitive/Neuropsychiatric EffectsPending revision, the material in this section should be considered in light of more recentlyavailable information in the MedWatch notification at the beginning of this monograph.Emotional lability (primarily behavioral problems), hostility (including aggressive behaviors),thought disorders (including concentration and school performance changes), and hyperkinesia(primarily restlessness and hyperactivity) associated with use in children 3–12 years of age withepilepsy.1Withdrawal SeizuresAbrupt withdrawal may result in increased seizure frequency; withdraw gabapentin graduallyand reduce dosage slowly over ≥1 week.1Status EpilepticusNot established whether incidence of status epilepticus (1.5% in controlled and uncontrolledtrials of gabapentin) is higher or lower than would be expected in patients with epilepsy nottreated with the drug.1Tumorigenic PotentialUnexpectedly high incidence of pancreatic acinar adenocarcinomas in male but not female rats.1Clinical relevance unknown.1Sudden, Unexplained Deaths in EpilepsyHigher incidence of sudden and unexplained deaths than would be expected in a healthy(nonepileptic) population; however, incidence is within range of estimates for patients withepilepsy or refractory epilepsy.1Specific PopulationsPregnancyCategory C.1Lactation
  6. 6. Distributed into milk; use only if potential benefits outweigh the risks.1Pediatric UseSafety and efficacy as adjunctive therapy in the management of partial seizures not established inchildren <3 years of age.1Safety and efficacy for the management of postherpetic neuralgia not established in children.1Geriatric UseInsufficient experience with gabapentin for the management of partial seizures in patients ≥65years of age to determine whether they respond differently than younger adults.1 Select dosagecarefully.1 (See Geriatric Patients under Dosage and Administration.)Appeared to be more effective for the management of postherpetic neuralgia in patients >75years of age than in younger patients; apparent difference in efficacy may be related to decreasedrenal function in older patients.1Adverse effects in older patients with postherpetic neuralgia generally similar to those inyounger adults; however, the incidence of peripheral edema and ataxia appears to increase withage.1Geriatric patients may have decreased hepatic, renal, or cardiac function, with increased risk ofadverse effects.1 16 Use with caution; renal function monitoring may be useful.1Renal ImpairmentClearance decreased; adjust dosage in adults and children ≥12 years of age with renalimpairment.1 (See Renal Impairment under Dosage and Administration.)Use in children <12 years of age with renal impairment has not been studied.1Common Adverse EffectsChildren 3–12 years of age receiving gabapentin as adjunctive therapy for partial seizures: viralinfection, fever, nausea and/or vomiting, somnolence, hostility.1Adults and children >12 years of age receiving gabapentin as adjunctive therapy for partialseizures with or without secondary generalization: somnolence, dizziness, ataxia, fatigue,nystagmus.1Adults receiving gabapentin for management of postherpetic neuralgia: dizziness, somnolence,peripheral edema.1Interactions for Gabapentin
  7. 7. Not metabolized by CYP isoenzymes.1 Does not inhibit CYP isoenzymes 1A2, 2C9, 2C19, 2D6,2E1, or 3A4 in vitro; causes slight inhibition of CYP2A6 at high concentrations.1Specific Drugs Drug Interaction Comments Administer gabapentin at leastAntacids Reduced bioavailability of gabapentin1 2 hours after antacid1 Plasma concentrations of carbamazepine, phenytoin, valproic acid, phenobarbital, and diazepam in existing treatment regimens notAnticonvulsants affected by gabapentin;1 3 12 13 14 pharmacokinetics of gabapentin not affected by these drugs1 6 12 15 Not likely to be clinicallyCimetidine Possible decrease in gabapentin clearance 1 important1 Possible dose-dependent decrease in plasmaHydrocodone concentrations of hydrocodone; possible increase in plasma concentrations of gabapentin1 Decrease in dosage of morphine or gabapentin may Increase in plasma concentrations ofMorphine be required in patients with gabapentin1 symptoms of CNS depression (e.g., somnolence)1 Extent of interaction at usual Increased bioavailability of gabapentin atNaproxen 1 therapeutic dosages is subtherapeutic dosages of both drugs unknown1Oral Possible increase in peak plasma concentrations Not likely to be clinicallyContraceptives of norethindrone1 important1Probenecid No pharmacokinetic interaction observed1Gabapentin PharmacokineticsAbsorptionBioavailabilityBioavailability of 60–27% for doses ranging from 900 mg to 4.8 g daily.1 Bioavailability is notdose proportional.1FoodFood increases extent of absorption and peak plasma concentration by 14%.1
  8. 8. DistributionExtentReadily crosses the blood-brain barrier and concentrates in brain tissue.29 Distributed into breastmilk.1 Not known whether gabapentin crosses the placenta.1Plasma Protein Binding<3%.1EliminationMetabolismNot appreciably metabolized.1Elimination RouteExcreted renally as unchanged drug.1Half-life5–7 hours.1Special PopulationsIn children <5 years of age, clearance normalized for weight is higher than in adults and children≥5 years of age.1In patients with renal impairment, plasma clearance is decreased and half-life is prolonged.1 Inpatients with Clcr <30 mL/minute, half-life of 52 hours reported.1 In anuric patients, half-lifereported to be 132 hours on nondialysis days and 3.8 hours during hemodialysis.1StabilityStorageOralCapsules and Tablets : 25°C (may be exposed to 15–30°C).1 1Oral Solution : 2–8°C.
  9. 9. Actions Mechanism of anticonvulsant action is unknown.1 4 5 7 8 9 Does not bind to GABA receptors,1 4 5 6 7 17 affect GABA reuptake or metabolism, 1 6 7 17 or act as a precursor of GABA or other substances active at GABA receptors.1 17 Mechanism of analgesic action is unknown.1 20 21 22 23 Prevents allodynia (pain-related behavior in response to normally innocuous stimuli) and hyperalgesia (exaggerated response to painful stimuli) in several animal models of neuropathic pain.1 20 Decreases pain-related responses after peripheral inflammation in animals; however, has not altered immediate pain-related behaviors.1 Clinical relevance of these findings is not known.1Advice to PatientsPending revision, the material in this section should be considered in light of more recentlyavailable information in the MedWatch notification at the beginning of this monograph. Importance of taking gabapentin exactly as prescribed.1 Importance of not abruptly discontinuing therapy.1 Potential for drug to impair mental alertness or physical coordination; avoid driving or operating machinery until effects on individual are known.1 Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1 Importance of informing patients of other important precautionary information. (See Cautions.)1PreparationsRoutes Dosage Forms StrengthsOral Capsules 100 mg* 300 mg* 400 mg* Solution 250 mg/5 mL Tablets 100 mg* 300 mg* 400 mg* 600 mg 800 mg
  10. 10. References1. Parke-Davis. Neurontin (gabapentin) capsules prescribing information. New York, NY; 2005Dec.2. Anon. Parke-Davis’ Neurontin recommended for approval as ―add on‖ therapy for refractoryseizures in epilepsy; gabapentin monotherapy trials under way. F-D-C Rep. 1992 Dec:7-8.3. Anon. Warner Lambert’s Neurontin approved for adjunctive therapy in epilepsy patients Dec30; ―1P‖ drug does not interact with other anticonvulsants. F-D-C Rep. 1994 Jan:11.4. Ramsay ER. Advances in the pharmacotherapy of epilepsy. Epilepsia. 1993; 34(Suppl 5):S9-16. [PubMed 8339715]5. MacDonald RL, Kelly KM. Antiepileptic drug mechanisms of action. Epilepsia. 1993;34(Suppl 5):S1-8. [IDIS 319353] [PubMed 7687957]6. Goa KL, Sorkin EM. Gabapentin: a review of its pharmacological properties and clinicalpotential in epilepsy. Drugs. 1993; 46:409-27. [PubMed 7693432]7. Graves NM, Leppik IE. Antiepileptic medications in development. DICP Ann Pharmacother.1991; 25:978-86. [IDIS 285278] [PubMed 1949977]8. UK Gabapentin Study Group. Gabapentin in partial epilepsy. Lancet. 1990; 335:1114-7. [IDIS266256] [PubMed 1971862]9. US Gabapentin Study Group. Gabapentin as add-on therapy in refractory partial epilepsy: adouble blind, placebo-controlled, parallel-group study. Neurology. 1993; 43:2292-8. (IDIS321974) [IDIS 321974] [PubMed 8232945]10. Suman-Chauhan N, Webdale L, Hill DR et al. Characterisation of [3H] gabapentin binding toa novel site in rat brain: homogenate binding studies. Eur J Pharmacol. 1993; 244:293-301.11. Hill DR, Suman-Chauhan N, Woodruff GN. Localization of [3H] gabapentin to a novel sitein rat brain: autoradiogaphic studies. Eur J Pharmacol. 1993; 244: 303-9. [PubMed 8384571]12. Anhut H, Leppik I, Schmidt B et al. Drug interaction study of the new anticonvulsantgabapentin with phenytoin in epileptic patients. Naunyn- Schmiedeberg Arch Pharmacol. 1988;337(Suppl):R127. Abstract No. 507.13. Graves NM, Leppik IE, Wagner ML et al. Effect of gabapentin on carbamazepine levels.Epilepsia. 1990; 31:644. Abstract.14. Uthman BM, Hammond EJ, Wilder BJ. Absence of gabapentin and valproate interaction: anevoked potential and pharmacokinetic study. Epilepsia. 1990; 31:645. Abstract.
  11. 11. 15. Hooper WD, Kavanagh MC, Herkes GK et al. Lack of a pharmacokinetic interactionbetween phenobarbitone and gabapentin. Br J Clin Pharmacol. 1991; 31:171-4. [IDIS 277831][PubMed 2049232]16. Parke-Davis, Morris Plains, NJ: Personal communication.17. Taylor CP. Mechanism of action of new anti-epileptic drugs. In: Chadwick D, ed. New trendsin epilepsy management: the role of gabapentin. London: Royal Society of Medicine ServicesLtd; 1993:13-40.18. Appleton R, Fichtner K, LaMoreaux L et al. Gabapentin as add-on therapy in children withrefractory partial seizures: a 12-week, multicentre, double-blind, placebo-controlled study.Epilepsia. 1999; 40:1147-54. [IDIS 432135] [PubMed 10448830]19. Pfizer, Morris Plains, NJ: Personal communication.20. Rose MA, Kam PCA. Gabapentin: pharmacology and its use in pain management.Anaesthesia. 2002; 57:451-62. [IDIS 483415] [PubMed 11966555]21. Tremont-Lukats IW, Megeff C, Backonja MM. Anticonvulsants for neuropathic painsyndromes. Drugs. 2000; 60:1029-1052. [PubMed 11129121]22. Ross EL. The evolving role of antiepileptic drugs in treating neuropathic pain. Neurology.2000; 55(supp 1):S41-S46. [IDIS 453200] [PubMed 11001361]23. Wiffen P, Collins S, McQuay H et al. Anticonvulsant drugs for acute and chronic pain(Cochrane Review). In: The Cochrane Library, Issue 3. Oxford, United Kingdom: updatesoftware 2002.24. Backonja MM. Use of anticonvulsants for treatment of neuropathic pain. Neurology. 2002;59(suppl 2):S14-S17.25. Backonja M, Beydoun A, Edwards KR et al. Gabapentin for the symptomatic treatment ofpainful neuropathy in patients with diabetes mellitus. JAMA. 1998; 280:1831-6. [IDIS 418038][PubMed 9846777]26. Garcia-Borreguero D, Larrosa O, de la Llave Y, et al. Treatment of restless legs syndromewith gabapentin. Neurology. 2002;59:1573-79.27. Happe S, Klosch G, Saletu, et al. Treatment of restless legs syndrome (RLS) withgabapentin. Neurology. 2001;57:1717-19.28. Thorp MK, Morris DC, Bagby SP. A crossover study of gabapentin in treatment of restlesslegs syndrome among hemodialysis patients. Am J of Kidney Diseases. 2001;38:104-8.
  12. 12. 29. Luer MS, Hamani C, Dujovny M et al. Saturable transport of gabapentin at the blood-brainbarrier. Neurol Res. 1999; 21:559-62. [PubMed 10491815]30. Pandya KJ, Morrow GR, Roscoe JA et al. Gabapentin for hot flashes in 420 women withbreast cancer: a randomised double-blind placebo-controlled trial. Lancet. 2005;366:818-24.31. Guttuso T, Kurlan R, McDermott MP, Kieburtz K. Gabapentin’s effects on hot flashes inpostmenopausal women: a randomized controlled trial. Obstet Gynecol. 2003;101:337-45.32. Jeffery SM, Pepe JJ, Popovich LM et al. Gabapentin for hot flashes in prostate cancer. AnnPharmacother. 2002; 36:433-6. [IDIS 477342] [PubMed 11895055]33. Stearns V. Management of hot flashes in breast cancer survivors and men with prostatecancer. Curr Oncol Rep. 2004; 6:285-90. [PubMed 15161582]34. Fugate SE, Church CO. Nonestrogen treatment modalities for vasomotor symptomsassociated with menopause. Ann Pharmacother. 2004; 38:1482-99. [IDIS 528920] [PubMed15292498]35. Loprinzi CL, Kugler JW, Sloan JA et al. Venlafaxine in management of hot flashes insurvivors of breast cancer: a randomized controlled trial. Lancet. 2000; 356:2059-63. [IDIS459837] [PubMed 11145492]36. Reviewers’ comments (personal observations).37. North American Menopause Society. Treatment of menopause-associated vasomotorsymptoms: position statement of the North American Menopause Society. Menopause. 2004;11:11-33. [PubMed 14716179]38. Rice AS, Maton S, . Gabapentin in postherpetic neuralgia: a randomised, double blind,placebo controlled study. Pain. 2001; 94:215-24. [PubMed 11690735]39. Rowbotham M, Harden N, Stacey B et al. Gabapentin for the treatment of postherpeticneuralgia: a randomized controlled trial. JAMA. 1998; 280:1837-42. [PubMed 9846778]40. Wiffen PJ, McQuay HJ, Edwards JE et al. Gabapentin for acute and chronic pain. CochraneDatabase Syst Rev. 2005; 3:CD005452. [PubMed 16034978]41. Gorson KC, Schott C, Herman R, Ropper AH. Gabapentin in the treatment of painfuldiabetic neuropathy: a placebo controlled, double blind, crossover trial. J Neurol NeurosurgPsychiatry. 1999; 66 :251-2. (Letter) [PubMed 10071116]42. Pérez HE, Sánchez GF. Gabapentin therapy for diabetic neuropathic pain. Am J Med. 2000;108; 689. (Letter)
  13. 13. 43. Simpson DA. Gabapentin and venlafaxine for the treatment of painful diabetic neuropathy. JClin Neuromusc Dis. 2001; 3:53-62.44. Dallocchio C, Buffa C, Mazzarello P et al. Gabapentin vs. amitriptyline in painful diabeticneuropathy: an open-label pilot study. J Pain Symptom Manage. 2000; 20:280-5. [PubMed11027910]45. Morello CM, Leckband SG, Stoner CP et al. Randomized double-blind study comparing theefficacy of gabapentin with amitriptyline on diabetic peripheral neuropathy pain. Arch InternMed. 1999; 159:1931-7. [PubMed 10493324]46. Khan OA. Gabapentin relieves trigeminal neuralgia in multiple sclerosis patients. Neurology.1998; 51:611-4. [PubMed 9710050]47. Cheshire WP. Defining the role for gabapentin in the treatment of trigeminal neuralgia: aretrospective study. J Pain. 2002; 3:137-42. [PubMed 14622800]48. Solaro C, Lunardi GL, Capello E et al. An open-label trial of gabapentin treatment ofparoxysmal symptoms in multiple sclerosis patients. Neurology. 1998; 51:609-11. [PubMed9710049]49. Yetimalar Y, Gürgör N, Basoglu M. Clinical efficacy of gabapentin for paroxysmalsymptoms in multiple sclerosis. Acta Neurol Scand. 2004; 109; 430-1. (Letter) [PubMed15147470]50. Hahn K, Arendt G, Braun JS et al. A placebo-controlled trial of gabapentin for painful HIV-associated sensory neuropathies. J Neurol. 2004; 251:1260-6. [PubMed 15503108]51. Caraceni A, Zecca E, Bonezzi C et al. Gabapentin for neuropathic cancer pain: a randomizedcontrolled trial from the Gabapentin Cancer Pain Study Group. J Clin Oncol. 2004; 22:2909-17.[PubMed 15254060]52. Serpell MG, . Gabapentin in neuropathic pain syndromes: a randomised, double-blind,placebo-controlled trial. Pain. 2002; 99:557-66. [PubMed 12406532]53. van der Vusse AC, Stomp-van den Berg SG, Kessels AH, Weber WE. Randomisedcontrolled trial of gabapentin in complex regional pain syndrome type 1. BMC Neurology. 2004.From Bio Med Central website (.)54. Reddy SY, Warner H, Guttuso T et al. Gabapentin, estrogen, and placebo for treating hotflushes: a randomized controlled trial. Obstet Gynecol. 2006; 108:41-8. [PubMed 16816054]

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