Therapeutics

Galantamine

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Overview

Name: Galantamine
Synonyms: Razadyne™, Reminyl™, Nivalin®
Chemical Name: (4aS,6R,8aS)-4a,5,9,10,11,12-Hexahydro-3-methoxy-11-methyl-6H-benzofuro [3a,3,2-ef] [2] benzazepin-6-ol
Therapy Type: Small Molecule
Target Type: Cholinergic System
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Approved)
Company: Janssen, Ortho-McNeil Pharmaceutical, Sanochemia Pharmazeutika, Shire, Takeda Pharmaceutical Company
Approved for: Mild to Moderate Alzheimer's disease

Background

Discovered in the 1950s, galantamine is an alkaloid isolated from Galanthus nivalisthe common snowdrop. Galantamine crosses the blood-brain barrier and has been used in humans for decades in anaesthesia and the treatment of neuropathic pain. Galantamine enhances cholinergic function in two ways: It is a weak acetyl cholinesterase inhibitor and an allosteric potentiator of both nicotinic and muscarinic acetylcholine receptors. Synthetic galantamine was first registered for the treatment of Alzheimer's disease in Sweden in the year 2000; it was subsequently approved for this indication in the European Union, the United States, Canada, Japan, and many other countries around the world. 

Galantamine is available as a tablet, as solution, and, since 2005, as a once-daily extended-release capsule. Also in 2005, the trade name the name Reminyl® was replaced with RazadyneTM to avoid confusion and prescribing errors arising from the similarity of the name Reminyl® to the diabetes drug Amaryl® (glimepiride). Since then, several generic equivalents have been approved by the FDA.

In keeping with the other cholinesterase inhibitors approved to treat Alzheimer's—donepezil and rivastigmine—the most common side effects of galantamine are gastrointestinal, including nausea, vomiting, and diarrhea. Dizziness, insomnia or nightmares, agitation, mild arryhthmia, and other effects have also been reported. Adverse effects tend to be milder when the dose is titrated up to the final therapeutic dose slowly, over the course of two months. A study directly comparing galantamine and donepezil treatment for a year found a similar side effect profile for both drugs (Wilcock et al., 2003).

Findings

More than 90 clinical trials have evaluated galantamine's effect on Alzheimer's and other conditions. Overall, they find a consistent symptomatic benefit on cognition and clinical measures in AD for several years of treatment; however, as with all cholinesterase inhibitors, galantamine's effect size is small.

For example, in a six-month study of 653 patients with mild to moderate AD, 24 or 32 mg/day of galantamine led to a roughly 3-point treatment effect over placebo on both the ADAS-cognition scale and the CIBIC-plus and DAD scales of global clinical impression (Wilcock et al., 2000). A separate, five-month study of 978 patients with mild to moderate Alzheimer's compared placebo to galantamine slowly escalated up to final doses of 16 and 24 mg/day. It similarly showed a 3- to 3.6-point treatment effect on ADAS-cog, as well as benefits in global clinical function, behavioral symptoms, and activities of daily living (Tariot et al., 2000). 

After galantamine was approved, trials assessed whether it affected behavioral symptoms in patients with mild to moderate Alzheimer's disease. Post-hoc analysis of data on 2,033 patients, pooled from three separate studies, suggested a galantamine treatment benefit as measured by the Neuropsychiatric Inventory (NPI), particularly on symptoms of agitation, anxiety, disinhibition, and aberrant movements; a subsequent analysis of four trials found much the same result (Herrmann et al., 2005; Kavanagh et al., 2011). Other postmarketing studies evaluated additional aspects of galantamine treatment in Alzheimer’s disease, for example the drug’s effect on attention and its efficacy in mild AD (Vellas et al., 2005; Orgogozo et al., 2004). 

Several studies assessed galantamine's long-term efficacy. Overall, they reported modest but consistent cognitive and clinical benefits of continuous treatment over three to four years (e.g., Raskind et al., 2004). Claims that long-term galantamine treatment delays a patient's placement in a nursing home have been reported at conferences (see company press release); similar studies have been published in the peer-reviewed literature (Feldman et al., 2009).

A separate question concerns whether older patients and patients with advanced disease respond as well to cholinesterase treatment as do patients in their 70s and those with mild to moderate disease. An analysis of data on patients 80 and older, pooled from four different Phase 3 trials, suggested a treatment benefit for galantamine in patients in that age group (Marcusson et al., 2003). A retrospective analysis of data pooled from four three- to six-month trials reported a treatment benefit for moderate to severe Alzheimer's disease, as did the subsequent, international SERAD study specifically on severe AD (Wilkinson et al., 2002; Burns et al., 2009).

In 2005, safety flags were raised temporarily when more deaths occurred in the galantamine than placebo groups in two mild cognitive impairment trials, and the drug's prescribing information was updated accordingly (see Jan 2005 news storyWHO Pharmaceuticals newsletter). Subsequent meta-analysis contradicted this finding (e.g., Feldman et al., 2009). In 2012, a separate two-year trial of 2,051 patients with mild to moderate AD reportedly found 8 to 24 mg per day of galantamine to be associated not only with less decline in cognition and function, but also with lower mortality than placebo (see company press release). This last study has not been published in the peer-reviewed literature.

Even so, while galantamine is no longer seen as raising mortality in MCI, it was found to be ineffective in that population both in the two original MCI trials and in a broader meta-analysis of MCI patients in the cholinesterase inhibitor clinical trial literature (see Winblad et al., 2008Tricco et al., 2013).

Overall, the acetylcholinesterase therapies galantamine, donepezil, and rivastigmine are seen as having similar efficacy and safety, but few side-by-side comparisons have been conducted. One such trial, comparing galantamine to donepezil for one year, reported a slightly larger cognitive benefit and more caregiver relief for galantamine, with similar results on tolerability and activities of daily living (Wilcock et al., 2003). In clinical practice, galantamine—or donepezil or rivastigmine—is frequently prescribed in combination with the NMDA antagonist memantine (Atri 2011).

Phase 4 studies have also evaluated galantamine for conditions other than AD. These include vascular dementia, tardive dyskinesia, attention deficit hyperactivity disorder, post-traumatic headache, postoperative delirium, depression, Tourette’s syndrome, bipolar disorder, cognition in schizophrenia, and stroke. Development attempts for chronic fatigue and fibromyalgia have been discontinued. Galantamine is still being actively evaluated as a cognitive enhancer in bipolar disorder and schizophrenia, and as an aid to end nicotine or cocaine dependence. However, despite extensive testing of galantamine, as of 2014 its regulatory approval has not been expanded beyond its original indication of mild to moderate Alzheimer’s disease. 

For some years after cholinesterase inhibitor therapies were initially approved for Alzheimer's disease, their modest effect size created controversy about their cost-effectiveness (see Jul 2004 news story and extensive commentary). Pharmacoeconomic studies in the United States, Canada, and European countries have generally found that cholinesterase inhibitor treatment reduces the cost of care. In the United Kingdom, this debate called into question coverage of cholinesterase inhibitors by its universal health care system. The U.K.'s National Institute for Health and Care Excellence (NICE) in 2007 restricted use of these drugs, but in 2010 it re-evaluated the issue and in 2011 issued a guidance recommending the use of galantamine in the treatment of mild to moderate AD (see, e.g.,  Garfield et al., 2002; NICE guidance). Recent pharmacoeconomic studies confirm the cost-effectiveness of galantamine (e.g., Hyde et al., 2013).

For a comprehensive view of galantamine trials, see clinicaltrials.gov.

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References

News Citations

  1. Cholinesterase Inhibitors Not What They're Cracked Up To Be?

Paper Citations

  1. . Efficacy and safety of galantamine in patients with mild to moderate Alzheimer's disease: multicentre randomised controlled trial. Galantamine International-1 Study Group. BMJ. 2000 Dec 9;321(7274):1445-9. PubMed.
  2. . A 5-month, randomized, placebo-controlled trial of galantamine in AD. The Galantamine USA-10 Study Group. Neurology. 2000 Jun 27;54(12):2269-76. PubMed.
  3. . Galantamine treatment of problematic behavior in Alzheimer disease: post-hoc analysis of pooled data from three large trials. Am J Geriatr Psychiatry. 2005 Jun;13(6):527-34. PubMed.
  4. . Galantamine and behavior in Alzheimer disease: analysis of four trials. Acta Neurol Scand. 2011 Nov;124(5):302-8. PubMed.
  5. . Early onset effects of galantamine treatment on attention in patients with Alzheimer's disease. Curr Med Res Opin. 2005 Sep;21(9):1423-9. PubMed.
  6. . Effects of galantamine in patients with mild Alzheimer's disease. Curr Med Res Opin. 2004 Nov;20(11):1815-20. PubMed.
  7. . The cognitive benefits of galantamine are sustained for at least 36 months: a long-term extension trial. Arch Neurol. 2004 Feb;61(2):252-6. PubMed.
  8. . Treatment with galantamine and time to nursing home placement in Alzheimer's disease patients with and without cerebrovascular disease. Int J Geriatr Psychiatry. 2009 May;24(5):479-88. PubMed.
  9. . Galantamine demonstrates efficacy and safety in elderly patients with Alzheimer disease. Alzheimer Dis Assoc Disord. 2003 Jul-Sep;17 Suppl 3:S86-91. PubMed.
  10. . Galantamine provides broad benefits in patients with 'advanced moderate' Alzheimer's disease (MMSE < or = 12) for up to six months. Int J Clin Pract. 2002 Sep;56(7):509-14. PubMed.
  11. . Safety and efficacy of galantamine (Reminyl) in severe Alzheimer's disease (the SERAD study): a randomised, placebo-controlled, double-blind trial. Lancet Neurol. 2009 Jan;8(1):39-47. PubMed.
  12. . Analyses of mortality risk in patients with dementia treated with galantamine. Acta Neurol Scand. 2009 Jan;119(1):22-31. PubMed.
  13. . Safety and efficacy of galantamine in subjects with mild cognitive impairment. Neurology. 2008 May 27;70(22):2024-35. PubMed.
  14. . Efficacy and safety of cognitive enhancers for patients with mild cognitive impairment: a systematic review and meta-analysis. CMAJ. 2013 Nov 5;185(16):1393-401. PubMed.
  15. . A long-term comparison of galantamine and donepezil in the treatment of Alzheimer's disease. Drugs Aging. 2003;20(10):777-89. PubMed.
  16. . Effective pharmacological management of Alzheimer's disease. Am J Manag Care. 2011 Nov;17 Suppl 13:S346-55. PubMed.
  17. . Assessment of Health Economics in Alzheimer's Disease (AHEAD): treatment with galantamine in Sweden. Pharmacoeconomics. 2002;20(9):629-37. PubMed.
  18. . Evolution of the evidence on the effectiveness and cost-effectiveness of acetylcholinesterase inhibitors and memantine for Alzheimer's disease: systematic review and economic model. Age Ageing. 2013 Jan;42(1):14-20. PubMed.

External Citations

  1. company press release
  2. Jan 2005 news story
  3. WHO Pharmaceuticals newsletter
  4. ompany press release
  5. NICE guidance
  6. clinicaltrials.gov

Further Reading

Papers

  1. . Galantamine for vascular cognitive impairment. Cochrane Database Syst Rev. 2013;4:CD004746. PubMed.
  2. . A meta-analysis of the efficacy of donepezil, rivastigmine, galantamine, and memantine in relation to severity of Alzheimer's disease. J Alzheimers Dis. 2013 Jan 1;35(2):349-61. PubMed.
  3. . Galantamine enhances dopaminergic neurotransmission in vivo via allosteric potentiation of nicotinic acetylcholine receptors. Neuropsychopharmacology. 2007 Jan;32(1):43-53. Epub 2006 Apr 26 PubMed.
  4. . Cognitive Enhancement as a Treatment for Drug Addictions. Neuropharmacology. 2013 January; 64(1): 452–463.
  5. . Pharmacological aspects of the acetylcholinesterase inhibitor galantamine. J Pharmacol Sci. 2011;116(1):6-17. PubMed.
  6. . Galanthamine from Galanthus and other Amaryllidaceae--chemistry and biology based on traditional use. Alkaloids Chem Biol. 2010;68:157-65. PubMed.
  7. . Galantamine-ER for the treatment of mild-to-moderate Alzheimer's disease. Clin Interv Aging. 2010;5:1-6. PubMed.
  8. . Galanthamine, a natural product for the treatment of Alzheimer's disease. Recent Pat CNS Drug Discov. 2006 Jan;1(1):105-11. PubMed.
  9. . Effects of galantamine in a 2-year, randomized, placebo-controlled study in Alzheimer's disease. Neuropsychiatr Dis Treat. 2014;10:391-401. Epub 2014 Feb 21 PubMed.
  10. . Galantamine slows down plaque formation and behavioral decline in the 5XFAD mouse model of Alzheimer's disease. PLoS One. 2014;9(2):e89454. Epub 2014 Feb 21 PubMed.