Chemistry:Eculizumab

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Short description: Pharmaceutical drug
Eculizumab
Monoclonal antibody
TypeWhole antibody
SourceHumanized (from mouse)
TargetComplement protein C5
Clinical data
Trade namesSoliris
AHFS/Drugs.comMonograph
MedlinePlusa612024
License data
Pregnancy
category
  • AU: B2
Routes of
administration		Intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Elimination half-life8 to 15 days (mean 11 days)
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
UNII
KEGG
ChEMBL
Chemical and physical data
Molar mass148 kg/mol
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Eculizumab, sold under the brand name Soliris among others, is a recombinant humanized monoclonal antibody used to treat paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), generalized myasthenia gravis, and neuromyelitis optica.[2][3] In people with PNH, it reduces both the destruction of red blood cells and need for blood transfusion, but does not appear to affect the risk of death.[8] Eculizumab was the first drug approved for each of its uses, and its approval was granted based on small trials.[9][10][11][12] It is given by intravenous infusion.[2]

Side effects include a risk for meningococcal infections and it is only prescribed to those who have enrolled in and follow a risk evaluation and mitigation strategy, which involves counseling people and ensuring that they are vaccinated.[2][13] It is a humanized monoclonal antibody functioning as a terminal complement inhibitor.[10]

It is developed, manufactured, and marketed by Alexion Pharmaceuticals.[14]:6

Medical uses

Eculizumab is used to treat atypical hemolytic uremic syndrome (aHUS) and paroxysmal nocturnal hemoglobinuria (PNH).[2][13][12] For people with PNH, it improves quality of life and decreases the need for blood transfusions but does not appear to affect the risk of death.[8] It does not appear to change the risk of blood clots, myelodysplastic syndrome, acute myelogenous leukemia, or aplastic anemia.[8] Eculizumab is also used to treat neuromyelitis optica spectrum disorder in adults who are anti-aquaporin-4 (AQP4) antibody positive.[9]

Eculizumab has also been explored as a treatment for CD55 deficiency, also known as CHAPLE syndrome, a rare genetic disorder of the immune system. With approval for compassionate off-label use, Kurolap and colleagues treated patients with the drug and found it to have positive clinical and laboratory outcomes over an 18-month period.[15]

Adverse effects

Eculizumab carries a black box warning for the risk of meningococcal infections and can only be prescribed by doctors who have enrolled in and follow a risk evaluation and mitigation strategy required by the FDA, which involves doctors counseling people to whom they are prescribing the drug, giving them educational materials, and ensuring that they are vaccinated, all of which must be documented.[2][13]

Eculizumab inhibits terminal complement activation and therefore makes people vulnerable to infection with encapsulated organisms. Life-threatening and fatal meningococcal infections have occurred in people who received eculizumab.[2] People receiving eculizumab have up to 2,000 times greater risk of developing invasive meningococcal disease.[16] Due to the increased risk of meningococcal infections, meningococcal vaccination is recommended at least 2 weeks prior to receiving eculizumab, unless the risks of delaying eculizumab therapy outweigh the risk of developing a meningococcal infection, in which case the meningococcal vaccine should be administered as soon as possible.[2] Both a serogroup A, C, W, Y conjugate meningococcal vaccine and a serogroup B meningococcal vaccine are recommended for people receiving eculizumab.[17] Receiving the recommended vaccinations may not prevent all meningococcal infections, especially from nongroupable N. meningiditis.[18] In 2017, it became clear that eculizumab has caused invasive meningococcal disease despite vaccination, because it interferes with the ability of antimeningococcal antibodies to protect against invasive disease.[18]

The drug's labels also carry warnings of severe anemia arising from the destruction of red blood cells as well as severe cases of blood clots forming in small blood vessels.[2][13]

Headaches are very common adverse effects, occurring in more than 10% of people who take the drug.[13]

Common adverse effects (occurring in between 1% and 10% of people who take the drug) include infections (pneumonia, upper respiratory tract infection, colds, and urinary tract infection), loss of white blood cells, loss of red blood cells, anaphylactic reaction, hypersensitivity reaction, loss of appetite, mood changes like depression and anxiety, a sense of tingling or numbness, blurred vision, vertigo, ringing in the ears, heart palpitations, high blood pressure, low blood pressure, vascular damage, peritonitis, constipation, upset stomach, swollen belly, itchy skin, increased sweating, blotches from small bleeds under the skin and skin redness, hives, muscle spasms, bone pain, back pain, neck pain, swollen joints, kidney damage, painful urination, spontaneous erections, general edema, chest pain, weakness, pain at the infusion site, and elevated transaminases.[13]

Pharmacology

Eculizumab specifically binds to the terminal complement component 5, or C5, which acts at a late stage in the complement cascade.[13] When activated, C5 is involved in activating host cells, thereby attracting pro-inflammatory immune cells, while also destroying cells by triggering pore formation. By inhibiting the complement cascade at this point, the normal, disease-preventing functions of proximal complement system are largely preserved, while the properties of C5 that promote inflammation and cell destruction are impeded.[19]

Eculizumab inhibits the cleavage of C5 by the C5 convertase into C5a, a potent anaphylatoxin with prothrombotic and proinflammatory properties, and C5b, which then forms the terminal complement complex C5b-9 which also has prothrombotic and proinflammatory effects. Both C5a and C5b-9 cause the complement-mediated events that are characteristic of PNH and aHUS.[19]

The metabolism of eculizumab is thought to occur via lysosomal enzymes that cleave the antibody to generate small peptides and amino acids. The volume of distribution of eculizumab in humans approximates that of plasma.[11]

Chemistry

Eculizumab is a recombinant humanized monoclonal antibody against the complement protein C5.[10] It is an immunoglobulin G-kappa (IgGκ) consisting of human constant regions and murine complementarity-determining regions grafted onto human framework light and heavy chain variable regions. The compound contains two 448-amino acid heavy chains and two 214-amino acid light chains, and has a molecular weight of approximately 148 kilodaltons (kDa).[11]

Society and culture

Legal status

Eculizumab was approved by the US Food and Drug Administration (FDA) in March 2007, for the treatment of PNH.[11] Eculizumab has exclusivity rights until 2017, which protects it from competition until 2017.[14]:6 When the FDA approved it in September 2011, for the treatment of aHUS, it designated it as an orphan drug.[20]

The 2011 FDA approval was based on two small prospective trials of 17 people and 20 people.[12][2][21]

The European Medicines Agency approved it for the treatment of PNH in June 2007,[13] and in November 2011, for the treatment of aHUS.[22] Health Canada approved it in 2009 to treat PNH and in 2013, as the only drug to treat aHUS.[23]

Eculizumab was approved by the FDA for AQP4+ NMO in 2019, based on the results of the PREVENT trial.[9]

Economics

A 2014 study showed that Eculizumab may provide substantive benefits to patients with PNH in terms of life expectancy and quality of life but at a high incremental cost.[24]

In 2010, Alexion priced Soliris as the most expensive drug in the world,[25] at approximately US$409,500 a year in the United States (2010),[25] €430,000 per year for ongoing treatment in the UK,[26][27] and $500,000 a year in Canada (2014).[28] In 2021, Soliris generated US$1.874 billion in sales.[29][30]

In April and May 2013, a controversy arose in Belgium when the media revealed that the government had refused to pay for a seven-year-old boy's treatment because Soliris was too expensive. The boy's medicine cost €9,000 every two weeks.[31] A public relations agency working for Alexion had reportedly been looking for such a story, and helped the boy's parents communicate their story to the press in order to pressure governments to reimburse the cost of the drug.[32][33][34] Several politicians stated that the company was attempting to 'blackmail' the government, charges which Alexion denied.[35] By 7 May 2013, an agreement had been reached for the government to reimburse the cost of the medicine beginning in July 2013.[36][37]

In December 2013, New Zealand's government pharmaceutical buyer Pharmac declined a proposal to subsidize the drug after Alexion refused to budge on a NZ$670,000 (US$590,000) per person per year price and Pharmac's economic analysis determined the price would need to be halved before the drug was cost-effective enough to subsidize.[38] Pharmac's decision upset many people with PNH in New Zealand PNH,[39] although Pharmac has not ruled out reviewing the decision at a later date, should the drug be made available at a lower price.[38]

In December 2014, the provincial government of Ontario, Canada, negotiated the price with the manufacturer, the only drug approved by Health Canada to treat aHUS. People can apply for it on "compassionate grounds" "on a case-by-case basis for example individuals who have been urgently hospitalized due to an immediate life-, limb-, or organ-threatening complication." It then was already "funded by the Ontario government for the treatment of another rare illness, paroxysmal nocturnal hemoglobinuria (PNH), through a bulk-buy deal reached by the provincial premiers in 2011."[28]

In February 2015, Canada's drug-price regulator took the rare step of calling a hearing into Soliris, accusing Alexion of exceeding the permissible price cap under the ""Highest International Price Comparison"" (HIPC).[40] In June 2015, the Patented Medicine Prices Review Board (PMPRB) under the Canadian Patent Act, held a preliminary hearing in Ottawa, Ontario to examine allegations. John Haslam, President and General Manager of Vaughan, Ontario-based Alexion Canada, was named as one of the respondents.[41] Alexion charges Canada $700,000 per person per year, more than anywhere else in the world.[42] Alexion denies the claim. In Canada "provincial drug plans have already negotiated secret discounts on Soliris for many of the patients they cover."[40]

As of 2015, while Eculizumab in PNH was associated with 1.13 additional life years and 2.45 quality of life years QALYs, there has been a high incremental cost (CAN$5.24 million) and a substantial opportunity cost. A 2014 Canadian study calculated the cost per life-year-gained with treatment as CAN$4.62 million (US$4,571,564) and cost per quality-adjusted-life-year as CAN$2.13 million (US$2,112,398)."The incremental cost per life year and per QALY gained is CAN$4.62 million and CAN$2.13 million, respectively. Based on established thresholds, the opportunity cost of funding eculizumab is 102.3 discounted QALYs per patient funded."[43]

By 2015, industry analysts and academic researchers agreed that the high price of orphan drugs, such as eculizumab, was not related to research, development, and manufacturing costs: their price is arbitrary and they have become more profitable than traditional medicines.[42]

The Brazilian universal health care system has annually provided it for its citizens. Initially patients got access to it by suing the government and demanding the right for treatment. In 2016 it was the medication that gave the biggest cost to the system by the judicial way, accounting to 625 million reais (about US$ 178 million at the time) to treat 364 patients,[44] but it was second when counting all the system regular medications, the biggest cost being sofosbuvir.[45] Brazil's supreme court ruled in April 2018 to break the patent of Soliris in Brazil, enabling it to be produced locally.[46] In December 2018 it was incorporated in the public health care system.[47]

Biosimilar competition

Main page: Biology:Biosimilar

A biosimilar developed by Amgen is prevented from entering the U.S. market until 2025.[48]

A biosimilar version, branded Elizaria, is available in Russia.[7]

On 23 February 2023, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Bekemv, intended for the treatment of adults and children in paroxysmal nocturnal hemoglobinuria.[49] The applicant for this medicinal product is Amgen Technology (Ireland) Unlimited Company.[49] Bekemv is a biosimilar medicinal product.[49] It is highly similar to the reference product Soliris (eculizumab), which was authorized in the EU on 20 June 2007.[49] Data show that Bekemv has comparable quality, safety and efficacy to Soliris.[49] Bekemv was approved for medical use in the European Union in April 2023.[50][4]

Epysqli was approved for medical use in the European Union in May 2023.[5]

References

  1. ↑ "Soliris - Summary of Product Characteristics (SmPC)". 16 July 2021. https://www.medicines.org.uk/emc/product/362. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9 "Soliris- eculizumab injection, solution, concentrate". 20 April 2021. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ebcd67fa-b4d1-4a22-b33d-ee8bf6b9c722. 
  3. ↑ 3.0 3.1 "Soliris EPAR". 17 September 2018. https://www.ema.europa.eu/en/medicines/human/EPAR/soliris. 
  4. ↑ 4.0 4.1 4.2 "Bekemv". 15 May 2023. https://www.ema.europa.eu/en/medicines/human/EPAR/bekemv. 
  5. ↑ 5.0 5.1 5.2 "Epysqli EPAR". 31 May 2023. https://www.ema.europa.eu/en/medicines/human/EPAR/epysqli. 
  6. ↑ "Epysqli". 31 May 2023. https://ec.europa.eu/health/documents/community-register/html/h1735.htm. 
  7. ↑ 7.0 7.1 "Elizaria". https://www.generium.ru/en/products/elizaria/. 
  8. ↑ 8.0 8.1 8.2 "Eculizumab for treating patients with paroxysmal nocturnal hemoglobinuria". The Cochrane Database of Systematic Reviews 10 (10): CD010340. October 2014. doi:10.1002/14651858.CD010340.pub2. PMID 25356860. 
  9. ↑ 9.0 9.1 9.2 "FDA approves first treatment for neuromyelitis optica spectrum disorder, a rare autoimmune disease of the central nervous system" (Press release). U.S. Food and Drug Administration (FDA). 27 June 2019. Archived from the original on 14 September 2019. Retrieved 28 June 2019.
  10. ↑ 10.0 10.1 10.2 "Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria". Nature Biotechnology 25 (11): 1256–1264. November 2007. doi:10.1038/nbt1344. PMID 17989688. 
  11. ↑ 11.0 11.1 11.2 11.3 "FDA report: eculizumab (Soliris) for the treatment of patients with paroxysmal nocturnal hemoglobinuria". The Oncologist 13 (9): 993–1000. September 2008. doi:10.1634/theoncologist.2008-0086. PMID 18784156. 
  12. ↑ 12.0 12.1 12.2 "Eculizumab: a review of its use in atypical haemolytic uraemic syndrome". Drugs 73 (18): 2053–2066. December 2013. doi:10.1007/s40265-013-0147-7. PMID 24249647. 
  13. ↑ 13.0 13.1 13.2 13.3 13.4 13.5 13.6 13.7 "Soliris - Summary of Product Characteristics". UK Electronic Medicines Compendium. 23 March 2017. https://www.medicines.org.uk/emc/medicine/19966. 
  14. ↑ 14.0 14.1 An Outlook on Biosimilar Competition (Report). April 2015. http://thomsonreuters.com/content/dam/openweb/documents/pdf/pharma-life-sciences/white-paper/anoutlookonusbiosimilarcompetition-cwp-en.pdf. Retrieved 29 June 2015. 
  15. ↑ "Eculizumab Is Safe and Effective as a Long-term Treatment for Protein-losing Enteropathy Due to CD55 Deficiency". Journal of Pediatric Gastroenterology and Nutrition 68 (3): 325–333. March 2019. doi:10.1097/MPG.0000000000002198. PMID 30418410. 
  16. ↑ "HAN Archive - 00404|Health Alert Network (HAN)". 7 July 2017. https://emergency.cdc.gov/han/han00404.asp. 
  17. ↑ "Use of Serogroup B Meningococcal Vaccines in Persons Aged ≥10 Years at Increased Risk for Serogroup B Meningococcal Disease: Recommendations of the Advisory Committee on Immunization Practices, 2015". MMWR. Morbidity and Mortality Weekly Report 64 (22): 608–612. June 2015. PMID 26068564. PMC 4584923. https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6422a3.htm. Retrieved 9 September 2017. 
  18. ↑ 18.0 18.1 "High Risk for Invasive Meningococcal Disease Among Patients Receiving Eculizumab (Soliris) Despite Receipt of Meningococcal Vaccine". MMWR. Morbidity and Mortality Weekly Report 66 (27): 734–737. July 2017. doi:10.15585/mmwr.mm6627e1. PMID 28704351. 
  19. ↑ 19.0 19.1 "Paroxysmal nocturnal hemoglobinuria". Hematology: Basic Principles and Practice (5th ed.). Churchill Livingstone/Elsevier. 2009. pp. 385–395. ISBN 978-0-443-06715-0. 
  20. ↑ "FDA approves Soliris for rare pediatric blood disorder: Orphan drug receives second approval for rare disease" (Press release). U.S. Food and Drug Administration (FDA). 23 September 2011. Archived from the original on 18 January 2017. Retrieved 25 June 2015.
  21. ↑ "Orphan Drug Law Spurs Debate". The New York Times. 30 April 1990. https://www.nytimes.com/1990/04/30/business/orphan-drug-law-spurs-debate.html. 
  22. ↑ "EU/3/09/653". European Medicines Agency. http://www.ema.europa.eu/ema/index.jsp?curl=pages%2Fmedicines%2Fhuman%2Forphans%2F2009%2F11%2Fhuman_orphan_000657.jsp&mid=WC0b01ac058001d12b. 
  23. ↑ "In The Matter Of The Patent Act, R.S.C., 1985, C. P-4, As Amended". Patented Medicine Prices Review Board. 15 January 2015. http://www.pmprb-cepmb.gc.ca/CMFiles/Hearings%20and%20DecisionsDecisions%20and%20Orders/SOLIRIS_SofA_Abridged_EN_FINAL_Jan%2015,%202015.pdf. 
  24. ↑ "Opportunity cost of funding drugs for rare diseases: the cost-effectiveness of eculizumab in paroxysmal nocturnal hemoglobinuria". Medical Decision Making 34 (8): 1016–1029. November 2014. doi:10.1177/0272989X14539731. PMID 24990825. 
  25. ↑ 25.0 25.1 "The World's Most Expensive Drugs", Forbes, 19 February 2010, https://www.forbes.com/2010/02/19/expensive-drugs-cost-business-healthcare-rare-diseases.html, retrieved 25 June 2015 
  26. ↑ "Doctors must tell patients of errors, under new Varadkar law. Like a motoring 'hit and run' for doctors to fail to make such disclosures, says Minister". Irish Times. 5 February 2015. http://www.irishtimes.com/news/politics/doctors-must-tell-patients-of-errors-under-new-law-from-varadkar-1.2092525. 
  27. ↑ "High cost of treatment for rare blood disorder needs to be clarified, says NICE in draft guidance". National Institute for Health and Care Excellence.. UK. 4 March 2014. http://www.nice.org.uk/news/press-and-media/high-cost-of-treatment-for-rare-blood-disorder-needs-to-be-clarified-says-nice-in-draft-guidance. 
  28. ↑ 28.0 28.1 Toronto woman with rare disease fights province for life-saving but costly drug, The Toronto Star, 4 December 2014, https://www.thestar.com/news/gta/2014/12/04/toronto_woman_with_rare_disease_fights_province_for_lifesaving_but_costly_drug.html, retrieved 26 August 2017 
  29. ↑ "AAN: AstraZeneca touts new Ultomiris gMG data ahead of potential Argenx showdown". 6 April 2022. https://www.fiercepharma.com/pharma/astrazeneca-shows-data-enhance-ultomiris-case-approval-gmg. 
  30. ↑ Annual report 2021
  31. ↑ "Viktor (7) moet elke twee weken infuus krijgen van 9.000 euro" (in nl). VRT. 30 April 2013. https://www.vrt.be/vrtnws/nl/2013/04/30/viktor_7_moet_elketweewekeninfuuskrijgenvan9000euro-1-1617223/. 
  32. ↑ "Pr-bureau van farmabedrijf adviseerde ook ouders Viktor" (in nl). De Standaard. 4 May 2013. https://www.standaard.be/cnt/DMF20130504_00566977. 
  33. ↑ "Farmabedrijf Alexion heeft Viktor "gebruikt"" (in nl). VRT. 4 May 2013. https://www.vrt.be/vrtnws/nl/2013/05/04/farmabedrijf_alexionheeftviktorgebruikt-1-1620546/. 
  34. ↑ "Farmabaas fluit Alexion terug in zaak-Viktor" (in nl). De Standaard. 6 May 2013. https://www.standaard.be/cnt/DMF20130506_00568721. 
  35. ↑ "Detiège: "Dit is chantage van het farmabedrijf"" (in nl). VRT. 2 May 2013. https://www.vrt.be/vrtnws/nl/2013/05/02/detiege_dit_is_chantagevanhetfarmabedrijf-1-1619457/. 
  36. ↑ "Medicijn Viktor vanaf juli terugbetaald" (in nl). De Standaard. 7 May 2013. https://www.standaard.be/cnt/DMF20130507_00570744. 
  37. ↑ "Contract van Onkelinx met farmareus opent doos van Pandora". De Morgen. 23 March 2015. https://www.demorgen.be/nieuws/contract-van-onkelinx-met-farmareus-opent-doos-van-pandora~b412db4e/. 
  38. ↑ 38.0 38.1 "Citing unreasonable price, PHARMAC declines eculizumab funding proposal". Pharmaceutical Management Agency. 11 December 2013. http://www.pharmac.health.nz/news/media-2013-12-11-eculizumab/. 
  39. ↑ "Plea to Pharmac for pricey life-saver". 3 News NZ. 24 January 2013. http://www.3news.co.nz/Plea-to-Pharmac-for-pricey-life-saver/tabid/423/articleID/284198/Default.aspx. 
  40. ↑ 40.0 40.1 "World's most expensive drug — which costs up to $700,000 per year — too expensive, Canada says", National Post, 3 February 2015, http://news.nationalpost.com/health/worlds-most-expensive-drug-prescription-that-costs-up-to-700000-per-year-too-expensive-canada-says, retrieved 25 June 2015 
  41. ↑ "Motions and Exhibits", Government of Canada (Ottawa, Ontario), 2015, http://pmprb-cepmb.gc.ca/CMFiles/Hearings%20and%20Decisions/Decisions%20and%20Orders/Notice_of_Motion_and_exhibits.pdf, retrieved 25 June 2015 
  42. ↑ 42.0 42.1 "How pharmaceutical company Alexion set the price of the world's most expensive drug: Cost of one of world's most expensive drugs shrouded in corporate secrecy", CBC News, 25 June 2015, http://www.cbc.ca/news/health/how-pharmaceutical-company-alexion-set-the-price-of-the-world-s-most-expensive-drug-1.3125251, retrieved 25 June 2015 
  43. ↑ "Opportunity cost of funding drugs for rare diseases: the cost-effectiveness of eculizumab in paroxysmal nocturnal hemoglobinuria". Medical Decision Making 34 (8): 1016–1029. November 2014. doi:10.1177/0272989X14539731. PMID 24990825. 
  44. ↑ Xavier, C (2018). "Judicialização da Saúde: Perspectiva crítica sobre os gastos da União para o cumprimento das ordens judiciais." (in pt). Coletânea direito à saúde: Dilemas do fenômeno da judicialização da saúde 2: 52–61. https://gestaosus.suprema.edu.br/Direito%20a%20Saude%20Dilemas%20da%20Judic.pdf. Retrieved 4 May 2022. 
  45. ↑ (in pt) Medicamentos em situação de exclusividade financiados pelo Ministério da Saúde: análise da situação patentária e das compras públicas. Rio de Janeiro: Fiocruz, ENSP. 2018. ISBN 978-85-9511-029-8. https://naf.ensp.fiocruz.br/sites/default/files/relatorio_projeto_monopolio_v_final_divulgacao_18_12_2018.pdf. Retrieved 4 May 2022. 
  46. ↑ "STJ atende a pedido da AGU e quebra patente do medicamento Soliris" (in Portuguese). Reuters. 19 April 2019. https://br.reuters.com/article/domesticNews/idBRKBN1HQ31S-OBRDN. 
  47. ↑ "Torna pública a decisão de incorporar o eculizumabe para tratamento de pacientes com hemoglobinúria paroxística noturna (HPN) no âmbito do Sistema Único de Saúde - SUS" (in pt). 77, Ordinance of 14 December 2018. https://www.in.gov.br/materia/-/asset_publisher/Kujrw0TZC2Mb/content/id/55443289.  "PORTARIA Nº 77, DE 14 DE DEZEMBRO DE 2018 - Imprensa Nacional". https://www.in.gov.br/materia/-/asset_publisher/Kujrw0TZC2Mb/content/id/55443289. 
  48. ↑ "Alexion delays Soliris biosimilar until 2025". https://www.gabionline.net/policies-legislation/Alexion-delays-Soliris-biosimilar-until-2025. 
  49. ↑ 49.0 49.1 49.2 49.3 49.4 "Bekemv: Pending EC decision". European Medicines Agency (EMA). 24 February 2023. https://www.ema.europa.eu/en/medicines/human/summaries-opinion/bekemv.  Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  50. ↑ "Bekemv". 20 April 2023. https://ec.europa.eu/health/documents/community-register/html/h1727.htm. 



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