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ENA-713 Exelon TM Rivastigmine tartrate (Novartis (formerly Sandoz) Pharmaceuticals)

Primary medical role: Treatment of mild to moderate dementia of the Alzheimer's type.

Role in Alzheimer's disease: It improves cognition, participation in activities of daily living, and global evaluation ratings in patients with mild to moderately severe Alzheimer's disease.

Approved by FDA for Alzheimer's use?: Yes, in May 1999.

Pharmacological role: A phenyl-carbamate derivative, a brain-selective acetylcholinesterase inhibitor, thought to selectively target hippocampus and cerebral cortex. Studies in lesioned rats indicate that ENA-713 ameliorates impairment of ChAT activity. Rivastigmine preferentially inhibits the G1 enzymatic form of AChE, which predominates in the brains of patients with Alzheimer's disease (AD).

Contraindications: Too preliminary to know.

Side effects: At the high dose of 12 mg.day (note, in this study, 10% of the patients discontinued the study on the medication because of severe nausea and vomiting). Nausea (40% vs. 10% placebo); dizziness (40% vs. 30%); fatigue (25% vs. 0%); myalgia (20% vs. 0%); urinary incontinence(20% vs. 0%); sweating (10% vs. 0%); vision disorders (15% vs. 0%). Rivastigmine causes adverse events that are generally those expected from an acetylcholinesterase inhibitor. They are usually mild to moderate, of short duration and responsive to dosage reduction. One case of severe vomiting with esophageal rupture reported to have occurred after reinitiation of treatment at an inappropriate single dose of 4.5 mg following an interruption of treatment for eight weeks.

Evidence pro its efficacy: . In two large multicenter clinical trials, rivastigmine 6-12 mg/day was superior to placebo on three cognitive and functioning scales (p<0.001).

Evidence con its efficacy: Preliminary.

Dosage: Up to 12 mg/day. In a letter from Novartis Pharmaceuticals Corporation, posted on the FDA web site, the letter stated, "..to reduce the possibility of severe vomiting in patients who have interrupted Exelon therapy for longer than several days, treatment should be reinitiated with the lowest daily dose."

Cost: n/a

Selected References

Farlow M, Anand R, Messina J, Hartman R, Veach J. A 52-week study of the efficacy of rivastigmine in patients with mild to moderately severe Alzheimer's disease Eur Neurol. 2000;44(4):236-41. Abstract

Kumar V, Anand R, Messina J, Hartman R, Veach J. An efficacy and safety analysis of Exelon in Alzheimer's disease patients with concurrent vascular risk factors. Eur J Neurol. 2000 Mar;7(2):159-69. Abstract.

Grossberg GT, Stahelin HB, Messina JC, Anand R, Veach J. Lack of adverse pharmacodynamic drug interactions with rivastigmine and twenty-two classes of medications. Int J Geriatr Psychiatry. 2000 Mar;15(3):242-7. Abstract.

Rivastigmine for Alzheimer's disease. Drug Ther Bull. 2000 Feb;38(2):15-6. Abstract.

Birks J, Iakovidou V, Tsolaki M. Rivastigmine for Alzheimer's disease. Cochrane Database Syst Rev. 2000;(2):CD001191. Abstract.

Jann MW. Rivastigmine, a new-generation cholinesterase inhibitor for the treatment of Alzheimer's disease. Pharmacotherapy. 2000 Jan;20(1):1-12. Abstract.

Sim A. Rivastigmine: a review. Hosp Med. 1999 Oct;60(10):731-5. Abstract.

Rosler M, Anand R, Cicin-Sain A, Gauthier S, Agid Y, Dal-Bianco P, Stahelin HB, Hartman R, Gharabawi M. Efficacy and safety of rivastigmine in patients with Alzheimer's disease: international randomised controlled trial. BMJ 318(7184):633-8 (Mar. 1999) Abstract.

Spencer CM, Noble S. Rivastigmine. A review of its use in Alzheimer's disease. Drugs Aging 13(5):391-411 (Nov. 1998) Abstract.

Polinsky RJ. Clinical pharmacology of rivastigmine: a new-generation acetylcholinesterase inhibitor for the treatment of Alzheimer's disease. Clin Ther 20(4):634-47 (Jul-Aug 1998) Abstract.

Habucky K, Tse FL. Disposition of SDZ ENA 713, an acetylcholinesterase inhibitor, in the rabbit. Biopharm Drug Dispos 19(5):285-290 (July 1998). Abstract.

Cutler NR, Polinsky RJ, Sramek JJ, Enz A, Jhee SS, Mancione L, Hourani J, Zolnouni P. Dose-dependent CSF acetylcholinesterase inhibition by SDZ ENA 713 in Alzheimer's disease. Acta Neurol Scand. 1998 Apr;97(4):244-50. Abstract.

Ohara T, Tanaka K, Fukaya H, Demura N, Iimura A, Seno N. SDZ ENA 713 facilitates central cholinergic function and ameliorates spatial memory impairment in rats. Behav Brain Res 83 (1-2): 229-233 (Feb 1997). Abstract.

Schneider LS. New therapeutic approaches to Alzheimer's disease. J Clin Psychiatry 57 Suppl 14: 30-36 (1996). Abstract.

Sramek JJ, Anand R, Wardle TS, Irwin P, Hartman RD, Cutler NR. Safety/tolerability trial of SDZ ENA 713 in patients with probable Alzheimer's disease. Life Sci 58 (15): 1201-1207 (1996). Abstract.

Tanaka K, Mizukawa K, Ogawa N, Mori A. Post-ischemic administration of the acetylcholinesterase inhibitor ENA-713 prevents delayed neuronal death in the gerbil hippocampus. Neurochem Res 20 (6): 663-667 (Jun 1995). Abstract.

Niigawa H, Tanimukai S, Takeda M, Hariguchi S, Nishimura T. Effects of SDZ ENA 713, novel acetylcholinesterase inhibitor, on learning of rats with basal forebrain lesions. Prog Neuropsychopharmacol Biol Psychiatry 19 (1): 171-186 (Jan 1995). Abstract.

Tanaka K, Ogawa N, Mizukawa K, Asanuma M, Kondo Y, Nishibayashi S, Mori A. Acetylcholinesterase inhibitor ENA-713 protects against ischemia-induced decrease in pre- and postsynaptic cholinergic indices in the gerbil brain following transient ischemia. Neurochem Res 19 (2): 117-122 (Feb 1994). Abstract.

Holsboer-Trachsler E, Hatzinger M, Stohler R, Hemmeter U, Gray J, Muller J, Kocher R, Spiegel R. Effects of the novel acetylcholinesterase inhibitor SDZ ENA 713 on sleep in man. Neuropsychopharmacology 8 (1): 87-92 (Jan 1993). Abstract.

Tsujimoto S, Sakaki T, Morimoto T, Tominaga M. The effect of acetylcholinesterase inhibitor (SDZ ENA 713) for r-CBF and focal cerebral ischaemia. Acta Neurochir (Wien) 124 (2-4): 127-131 (1993). Abstract.