OVERVIEW

PRODUCT INFORMATION

CHEMICAL FORMULA AND STRUCTURE

ANNOTATED BIBLIOGRAPHY

References updated: 15 April 2019

Abbreviations: CGRP, calcitonin gene related protein.

• Zimmerman HJ. Drugs used to treat rheumatic and musculospastic disease. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 517-54.

  (Expert review of hepatotoxicity published in 1999, well before the availability of most monoclonal antibody therapies).
• Reuben A. Hepatotoxicity of immunosuppressive drugs. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2011, pp. 569-91.

  (Review of hepatotoxicity of monoclonal immunosuppressive agents; "the biological immuno-suppressants are largely free from hepatotoxicity, with the exception of the TNF alpha antagonists"; fremanezumab is not discussed).
• https://www​.accessdata​.fda.gov/scripts/cder/daf/

  (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).
• Bigal ME, Dodick DW, Rapoport AM, Silberstein SD, Ma Y, Yang R, Loupe PS, et al. Safety, tolerability, and efficacy of TEV-48125 for preventive treatment of high-frequency episodic migraine: a multicentre, randomised, double-blind, placebo-controlled, phase 2b study. Lancet Neurol 2015; 14: 1081-90. [PubMed: 26432182]

  (Among 297 patients with episodic migraine treated with injections of fremanezumab [225 mg or 675 mg] or placebo monthly, headache days decreased more with the monoclonal antibody [-6.1 and -6.3 vs -3.5 days per month] and adverse event rates were similar: “liver enzyme concentrations were stable in the treatment phase of the study”).
• Silberstein SD, Dodick DW, Bigal ME, Yeung PP, Goadsby PJ, Blankenbiller T, Grozinski-Wolff M, et al. Fremanezumab for the preventive treatment of chronic migraine. N Engl J Med 2017; 377: 2113-22. [PubMed: 29171818]

  (Among 1130 patients with chronic migraine treated with injections of fremanezumab [225 mg monthly or 675 mg every 3 months] or placebo, headache days decreased more with active drug than with placebo [-4.3 and -4.6 vs -2.5 days per month] and adverse event rates were similar, although 10 treated subjects [1.3%] had transient ALT elevations which were above 5 times ULN in 2, but all were without jaundice and resolved without dose adjustment or discontinuation).
• Dodick DW, Silberstein SD, Bigal ME, Yeung PP, Goadsby PJ, Blankenbiller T, Grozinski-Wolff M, et al. Effect of fremanezumab compared with placebo for prevention of episodic migraine: a randomized clinical trial JAMA 2018; 319: 1999-2008. [PMC free article: PMC6583237] [PubMed: 29800211]

  (Among 875 adults with episodic migraine treated with fremanezumab [225 mg monthly or 625 mg every 3 months] or placebo, headache days decreased more with active drug [-3.7 and -3.4 vs -2.2 days per month] and adverse event rates were similar except for injection site reactions; while ALT or AST elevations above 3 times ULN occurred in 0.7% and 0.3% on fremanezumab vs 0% on placebo, but none were associated with jaundice or led to early discontinuation).
• Edvinsson L. The CGRP pathway in migraine as a viable target for therapies. Headache 2018; 58 Suppl 1: 33-47. [PubMed: 29697153]

  (Review of the calcitonin gene related peptide [CGRP] and its receptor including their relationship to migraine headaches and development of small molecular inhibitors and monoclonal antibody therapies based upon their inhibition).
• Tepper SJ. History and review of anti-calcitonin gene-related peptide (CGRP) therapies: from translational research to treatment. Headache 2018; 58 Suppl 3: 238-75. [PubMed: 30242830]

  (Review of the role of CGRP in pathogenesis of migraine headaches and the development of small molecules and monoclonal antibody antagonists of CGRP actions).
• Hoy SM. Fremanezumab: First global approval. Drugs 2018; 78: 1829-34. [PMC free article: PMC6422958] [PubMed: 30406901]

  (Review of the mechanism of action, pharmacokinetics, clinical efficacy and safety of fremanezumab shortly after its approval in the United States; in pooled analyses of 1904 patients, the only adverse reaction occurring more frequently with fremanezumab was injection site reactions [43-45% vs 38%] and ALT elevations above 3 times ULN occurred in less than 1% of fremanezumab treated persons).
• Fremanezumab (Ajovy) and galcanezumab (Emgality) for migraine prevention. Med Lett Drugs Ther 2018; 60 (1559): 177-80. [PubMed: 30681655]

  (Concise review of the mechanism of action, clinical efficacy, safety and costs of fremanezumab and galcanezumab shortly after their approval for prevention of migraine; does not mention ALT elevations or hepatotoxicity).
• Silberstein SD, McAllister P, Ning X, Faulhaber N, Lang N, Yeung P, Schiemann J, et al. Safety and tolerability of fremanezumab for the prevention of migraine: a pooled analysis of phases 2b and 3 clinical trials. Headache 2019 Apr 12. [Epub ahead of print]. [PubMed: 30977520]

  (Among 2566 patients with migraine enrolled in 4 placebo controlled trials of fremanezumab, states that ALT or AST elevations of at least 3 times ULN "were infrequent" and similar in rates to those treated with placebo [<1% ] and that no patient developed clinically apparent liver injury).