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<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE" /><meta name="citation_inbook_title" content="LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]" /><meta name="citation_title" content="Amifampridine" /><meta name="citation_publisher" content="National Institute of Diabetes and Digestive and Kidney Diseases" /><meta name="citation_date" content="2019/05/15" /><meta name="citation_pmid" content="31643190" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK547851/" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="Amifampridine" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="National Institute of Diabetes and Digestive and Kidney Diseases" /><meta name="DC.Date" content="2019/05/15" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK547851/" /><meta name="description" content="Amifampridine is an orally available potassium channel blocker that increases acetylcholine in synaptic clefts of peripheral nerve endings and is used to treat the Lambert-Eaton myasthenic syndrome. Amifampridine is associated with a low rate of transient serum enzyme elevations during therapy but has not been linked with instances of clinically apparent acute liver injury." /><meta name="og:title" content="Amifampridine" /><meta name="og:type" content="book" /><meta name="og:description" content="Amifampridine is an orally available potassium channel blocker that increases acetylcholine in synaptic clefts of peripheral nerve endings and is used to treat the Lambert-Eaton myasthenic syndrome. Amifampridine is associated with a low rate of transient serum enzyme elevations during therapy but has not been linked with instances of clinically apparent acute liver injury." /><meta name="og:url" content="https://www.ncbi.nlm.nih.gov/books/NBK547851/" /><meta name="og:site_name" content="NCBI Bookshelf" /><meta name="og:image" content="https://www.ncbi.nlm.nih.gov/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-livertox-lrg.png" /><meta name="twitter:card" content="summary" /><meta name="twitter:site" content="@ncbibooks" /><meta name="bk-non-canon-loc" content="/books/n/livertox/Amifampridine/" /><link rel="canonical" href="https://www.ncbi.nlm.nih.gov/books/NBK547851/" /><link rel="stylesheet" href="/corehtml/pmc/css/figpopup.css" type="text/css" media="screen" /><link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books.min.css" type="text/css" /><link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books_print.min.css" type="text/css" /><style type="text/css">p a.figpopup{display:inline !important} .bk_tt {font-family: monospace} .first-line-outdent .bk_ref {display: inline} </style><script type="text/javascript" src="/corehtml/pmc/js/jquery.hoverIntent.min.js"> </script><script type="text/javascript" src="/corehtml/pmc/js/common.min.js?_=3.18"> </script><script type="text/javascript">window.name="mainwindow";</script><script type="text/javascript" src="/corehtml/pmc/js/bookshelf/2.26/book-toc.min.js"> </script><script type="text/javascript" src="/corehtml/pmc/js/bookshelf/2.26/books.min.js"> </script>
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<div class="pre-content"><div><div class="bk_prnt"><p class="small">NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.</p><p>LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. </p></div></div></div>
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<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><h1 id="_NBK547851_"><span class="title" itemprop="name">Amifampridine</span></h1><p class="small">Last Update: <span itemprop="dateModified">May 15, 2019</span>.</p></div><div class="body-content whole_rhythm" itemprop="text"><div id="Amifampridine.OVERVIEW"><h2 id="_Amifampridine_OVERVIEW_">OVERVIEW</h2><div id="Amifampridine.Introduction"><h3>Introduction</h3><p>Amifampridine is an orally available potassium channel blocker that increases acetylcholine in synaptic clefts of peripheral nerve endings and is used to treat the Lambert-Eaton myasthenic syndrome. Amifampridine is associated with a low rate of transient serum enzyme elevations during therapy but has not been linked with instances of clinically apparent acute liver injury.</p></div><div id="Amifampridine.Background"><h3>Background</h3><p>Amifampridine (am" i fam' pri deen) is a diaminopyridine that acts on peripheral potassium channels and is used to treat the Lambert-Eaton myasthenic syndrome, a rare form of myasthenia suspected to be autoimmune in nature. The inhibition of the potassium channel on neuromuscular junctions causes depolarization of the presynaptic membrane resulting in prolonged action potentials and increased release of acetylcholine in the synaptic cleft. This increase in acetylcholine alleviates some of the neuromuscular dysfunction of myasthenia which is caused by defects in acetylcholine signaling. In small open-label and randomized controlled trials, amifampridine was found to alleviate the myasthenic symptoms in patients with the rare Lambert-Eaton myasthenic syndrome, but did not reverse the condition or its associated autoimmunity. In 2018, amifampridine was approved as symptomatic therapy for Lambert-Eaton syndrome in adults and is available in scored tablets of 10 mg under the brand name Firdapse. In 2019, amifampridine was approved as symptomatic therapy for Lambert-Eaton syndrome in children and became available as scored 10 mg tablets under the brand name Fuzurgi. The recommended starting dose is 15 to 30 mg in 3 to 4 divided doses daily with dose increases of 5 mg and a maximum total dose of 80 mg daily. A reduced dose is recommended for children weighing less than 45 kilograms. Common side effects are paresthesia, upper respiratory symptoms, abdominal pain, nausea, diarrhea, headache, back pain, hypertension and muscle spasm. Rare, but potentially serious adverse events include seizures and hypersensitivity reactions.</p></div><div id="Amifampridine.Hepatotoxicity"><h3>Hepatotoxicity</h3><p>Amifampridine has had limited clinical use, but adverse events have been largely neurologic and gastrointestinal. Serum ALT elevations were not reported in the prelicensure studies of amifampridine but were reported as occurring in a small proportion of patients in safety reviews by the Food and Drug Administration. Nevertheless, there have been no reports of clinically apparent liver injury associated with its use. Thus, liver injury from amifampridine must be rare if it occurs at all.</p><p>Likelihood score: E (unlikely cause of clinically apparent liver injury, but experience with its use is limited).</p></div><div id="Amifampridine.Mechanism_of_Injury"><h3>Mechanism of Injury</h3><p>The mechanism by which amifampridine might cause liver injury is not known. It is extensively metabolized by the liver largely by N-acetyltransferase (NAT) to an inactive metabolite. The NAT gene is highly polymorphic and activity rates range from slow to fast. Persons who are slow acetylators have 3- to 5-fold higher plasma levels than those who are fast acetylators. Nevertheless, there is no clinical evidence that acetylation status affects the efficacy or safety of amifampridine to a major extent.</p><p>Drug Class: Myasthenia Agents</p></div></div><div id="Amifampridine.PRODUCT_INFORMATION"><h2 id="_Amifampridine_PRODUCT_INFORMATION_">PRODUCT INFORMATION</h2><p>
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<b>REPRESENTATIVE TRADE NAMES</b>
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||
</p><p>Amifampridine – Generic, Firdapse®, Ruzurgi®</p><p>
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||
<b>DRUG CLASS</b>
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||
</p><p>Myasthenia Agents</p><p>
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||
<a href="https://dailymed.nlm.nih.gov/dailymed/search.cfm?labeltype=all&query=Amifampridine" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">COMPLETE LABELING</a>
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</p><p>Product labeling at DailyMed, National Library of Medicine, NIH</p></div><div id="Amifampridine.CHEMICAL_FORMULA_AND_STRUC"><h2 id="_Amifampridine_CHEMICAL_FORMULA_AND_STRUC_">CHEMICAL FORMULA AND STRUCTURE</h2><div id="Amifampridine.Tc" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK547851/table/Amifampridine.Tc/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__Amifampridine.Tc_lrgtbl__"><table><thead><tr><th id="hd_h_Amifampridine.Tc_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">DRUG</th><th id="hd_h_Amifampridine.Tc_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CAS REGISTRY NUMBER</th><th id="hd_h_Amifampridine.Tc_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MOLECULAR FORMULA</th><th id="hd_h_Amifampridine.Tc_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">STRUCTURE</th></tr></thead><tbody><tr><td headers="hd_h_Amifampridine.Tc_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Amifampridine</td><td headers="hd_h_Amifampridine.Tc_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="https://pubchem.ncbi.nlm.nih.gov/substance/134972106" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">54-96-6</a>
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</td><td headers="hd_h_Amifampridine.Tc_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">C5-H7-N3</td><td headers="hd_h_Amifampridine.Tc_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="https://pubchem.ncbi.nlm.nih.gov/substance/134972106" title="View this structure in PubChem" class="img_link" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem"><img src="https://pubchem.ncbi.nlm.nih.gov/image/imgsrv.fcgi?t=l&sid=134972106" alt="image 134972106 in the ncbi pubchem database" /></a>
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</td></tr></tbody></table></div></div></div><div id="Amifampridine.ANNOTATED_BIBLIOGRAPHY"><h2 id="_Amifampridine_ANNOTATED_BIBLIOGRAPHY_">ANNOTATED BIBLIOGRAPHY</h2><p>References updated: 15 May 2019</p><ul class="first-line-outdent"><li><div class="bk_ref" id="Amifampridine.REF.zimmerman.1999">Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999.<div><i>(Textbook of hepatotoxicity published in 1999, before the availability of amifampridine, does not discuss myasthenic syndromes and their therapy).</i></div></div></li><li><div class="bk_ref" id="Amifampridine.REF.kaplowitz.2013">Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013.<div><i>(Textbook of hepatotoxicity published in 2013, does not discuss amifampridine or other drugs for myasthenic syndromes).</i></div></div></li><li><div class="bk_ref" id="Amifampridine.REF.taylor.2018">Taylor P. Anticholinesterase Agents. In, Brunton LL, Hilal-Dandan R, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 13th ed. New York: McGraw-Hill, 2018, pp. 163-75.<div><i>(Textbook of pharmacology and therapeutics).</i></div></div></li><li><div class="bk_ref" id="Amifampridine.REF.fda">FDA. <a href="https://www.accessdata.fda.gov/scripts/cder/daf/" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">https://www<wbr style="display:inline-block"></wbr>.accessdata<wbr style="display:inline-block"></wbr>.fda.gov/scripts/cder/daf/</a><div><i>(FDA Drug Approvals website that has product labels [package inserts], letters of approval and full FDA scientific review of the new drug application for safety and efficacy; mentions that safety data were based upon 2 controlled withdrawal studies in 79 adults and that elevated liver enzymes occurred in 7 patients [13%], but all were self-limited and not accompanied by symptoms or jaundice).</i></div></div></li><li><div class="bk_ref" id="Amifampridine.REF.chalasani.2015.1340">Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al. United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. <span><span class="ref-journal">Gastroenterology. </span>2015;<span class="ref-vol">148</span>:1340–52.e7.</span> [<a href="/pmc/articles/PMC4446235/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4446235</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25754159" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25754159</span></a>]<div>
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<i>(Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, none were attributed to drugs used for myasthenic syndromes such as amifampridine).</i>
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</div></div></li><li><div class="bk_ref" id="Amifampridine.REF.verma.2016.809">Verma S, Mazell SN, Shah DA. Amifampridine phosphate in congenital myasthenic syndrome. <span><span class="ref-journal">Muscle Nerve. </span>2016;<span class="ref-vol">54</span>:809–10.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/27348204" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27348204</span></a>]<div>
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<i>(Two children [ages 4 and 5 years] with congenital myasthenic syndromes associated with mutations in the acetylcholine receptor had improvements in clinical symptoms [ptosis, dysarthria, energy level] with amifampridine treatment [10-20 mg daily], with only minor side effects; no mention of ALT levels or hepatotoxicity).</i>
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</div></div></li><li><div class="bk_ref" id="Amifampridine.REF.burns.2016.165">Burns TM, Smith GA, Allen JA, Amato AA, Arnold WD, Barohn R, Benatar M, et al. Editorial by concerned physicians: Unintended effect of the orphan drug act on the potential cost of 3,4-diaminopyridine. <span><span class="ref-journal">Muscle Nerve. </span>2016;<span class="ref-vol">53</span>:165–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/26662952" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26662952</span></a>]<div>
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<i>(Commentary by academic neurologists concerned about the approval of amifampridine [3,4-diaminopyridine] as an orphan drug for Lambert-Eaton myasthenic syndrome and the possible result of a very expensive therapy that would replace the reasonably priced compassionate use product).</i>
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</div></div></li><li><div class="bk_ref" id="Amifampridine.REF.mcenany.2017.138">McEnany PJ. A response to a recent editorial by concerned physicians on 3,4-diaminopyridine. <span><span class="ref-journal">Muscle Nerve. </span>2017;<span class="ref-vol">55</span>:138.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/27756108" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27756108</span></a>]<div>
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<i>(Response to the commentary by Burns [2016] argues that the benefit of an FDA approved therapy for Lambert-Eaton syndrome far outweighs the possible negative effect of increase price).</i>
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</div></div></li><li><div class="bk_ref" id="Amifampridine.REF.schoser.2017.1854">Schoser B, Eymard B, Datt J, Mantegazza R. Lambert-Eaton myasthenic syndrome (LEMS): a rare autoimmune presynaptic disorder often associated with cancer. <span><span class="ref-journal">J Neurol. </span>2017;<span class="ref-vol">264</span>:1854–63.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/28608304" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28608304</span></a>]<div>
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<i>(Review of the history of discovery, epidemiology, pathophysiology, clinical features, electromyographic findings, autoimmune serology, diagnosis, management and therapy of Lambert-Eaton myasthenic syndrome; mentions that amifampridine may be effective for its symptomatic treatment [increasing neurotransmission] but that immunosuppressive therapy is needed to decrease disease progression).</i>
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</div></div></li><li><div class="bk_ref" id="Amifampridine.REF.sanders.2018.561">Sanders DB, Juel VC, Harati Y, Smith AG, Peltier AC, Marburger T, Lou JS, et al. Dapper Study Team. 3,4-diaminopyridine base effectively treats the weakness of Lambert-Eaton myasthenia. <span><span class="ref-journal">Muscle Nerve. </span>2018;<span class="ref-vol">57</span>:561–8.</span> [<a href="/pmc/articles/PMC5900968/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5900968</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/29280483" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 29280483</span></a>]<div>
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<i>(Among 32 adults with Lambert-Eaton myasthenia on compassionate use 3,4-diaminopyridine who were either continued on treatment or switched to placebo for at least 3 months, objective measurements of myasthenic symptoms worsened in those who were withdrawn and not in those who continued on therapy, and “there were no clinically meaningful laboratory value changes”).</i>
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</div></div></li><li><div class="bk_ref" id="Amifampridine.REF.bonanno.2018.2050312118819013">Bonanno S, Pasanisi MB, Frangiamore R, Maggi L, Antozzi C, Andreetta F, Campanella A, et al. Amifampridine phosphate in the treatment of muscle-specific kinase myasthenia gravis: a phase IIb, randomized, double-blind, placebo-controlled, double crossover study. <span><span class="ref-journal">SAGE Open Med. </span>2018;<span class="ref-vol">6</span>:2050312118819013. </span> [<a href="/pmc/articles/PMC6299310/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6299310</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/30574306" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30574306</span></a>]<div>
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<i>(Among 10 patients with muscle-specific kinase myasthenia gravis who were treated with amifampridine or placebo in a double-cross over study, myasthenia symptoms improved on amifampridine and deteriorated on placebo, and the only drug-specific adverse event was transient paresthesia; there were “no relevant differences between the two groups for…blood chemistries…over the duration of the study”).</i>
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