Ceftobiprole

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Ceftobiprole
Ceftobiprole2DCSD.svg
Clinical data
Trade names Zevtera, Mabelio
Other namesRO0639141-000, [1] BAL9141, [2] ceftobiprole medocaril
AHFS/Drugs.com Zevtera
License data
Routes of
administration 		Intravenous
Drug class Cephalosporin antibacterial
ATC code
Legal status
Legal status
Identifiers
  • (6R,7R)-7-[[(2Z)-2-(5-amino-1,2,4-thiadiazol-3-ylidene)- 2-nitroso-1-oxoethyl]amino]-8-oxo-3-[(E)-[2-oxo-1-[(3R)- 3-pyrrolidinyl]-3-pyrrolidinylidene]methyl]-5-thia-1- azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.129.666 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C20H22N8O6S2
Molar mass 534.57 g·mol−1
3D model (JSmol)
  • C1CNC[C@@H]1N2CC/C(=C\C3=C(N4[C@@H]([C@@H](C4=O)NC(=O)/C(=N\O)/c5nc(sn5)N)SC3)C(=O)O)/C2=O
  • InChI=1S/C20H22N8O6S2/c21-20-24-14(26-36-20)11(25-34)15(29)23-12-17(31)28-13(19(32)33)9(7-35-18(12)28)5-8-2-4-27(16(8)30)10-1-3-22-6-10/h5,10,12,18,22,34H,1-4,6-7H2,(H,23,29)(H,32,33)(H2,21,24,26)/b8-5+,25-11-/t10-,12-,18-/m1/s1 X mark.svgN
  • Key:VOAZJEPQLGBXGO-SDAWRPRTSA-N X mark.svgN
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Ceftobiprole, sold under the brand name Zevtera among others, is a fifth-generation [7] cephalosporin antibacterial used for the treatment of hospital-acquired pneumonia (excluding ventilator-associated pneumonia) and community-acquired pneumonia. It is marketed by Basilea Pharmaceutica under the brand names Zevtera and Mabelio. [8] [9] [10] [11] [12] [13] Like other cephalosporins, ceftobiprole exerts its antibacterial activity by binding to important penicillin-binding proteins and inhibiting their transpeptidase activity which is essential for the synthesis of bacterial cell walls. Ceftobiprole has high affinity for penicillin-binding protein 2a of methicillin-resistant Staphylococcus aureus strains and retains its activity against strains that express divergent mecA gene homologues (mecC or mecALGA251). Ceftobiprole also binds to penicillin-binding protein 2b in Streptococcus pneumoniae (penicillin-intermediate), to penicillin-binding protein 2x in Streptococcus pneumoniae (penicillin-resistant), and to penicillin-binding protein 5 in Enterococcus faecalis . [14]

Contents

For adults with Staphylococcus aureus bloodstream infections (bacteremia), the most common side effects include anemia, nausea, low levels of potassium in the blood (hypokalemia), vomiting, diarrhea, increased levels of certain liver tests (hepatic enzymes and bilirubin), increased blood creatinine, high blood pressure, low white blood cell count (leukopenia), fever, abdominal pain, fungal infection, headache and shortness of breath (dyspnea). [15] For adults with acute bacterial skin and skin structure infections, the most common side effects include nausea, diarrhea, headache, injection site reaction, increased levels of hepatic enzymes, rash, vomiting and altered taste (dysgeusia). [15] For adults with community-acquired bacterial pneumonia, the most common side effects include nausea, increased levels of hepatic enzymes, vomiting, diarrhea, headache, rash, insomnia, abdominal pain, vein inflammation (phlebitis), high blood pressure and dizziness. [15] For children with community-acquired bacterial pneumonia, the most common side effects include vomiting, headache, increased levels of hepatic enzymes, diarrhea, infusion site reaction, vein inflammation (phlebitis) and fever. [15]

Ceftobiprole medocaril was approved for medical use in the United States in April 2024. [15] [16]

Medical uses

In the US, ceftobiprole is indicated for the treatment of adults with Staphylococcus aureus bloodstream infections (bacteremia) including those with right-sided infective endocarditis; [6] adults with acute bacterial skin and skin structure infections; [6] and people with community-acquired bacterial pneumonia. [6] [15]

Microbiology

Ceftobiprole has shown in vitro antimicrobial activity against a broad range of Gram-positive and Gram-negative pathogens. Among the Gram-positive pathogens, ceftobiprole has demonstrated good in vitro activity against methicillin-resistant Staphylococcus aureus, methicillin-susceptible Staphylococcus aureus and coagulase-negative staphylococci, as well as against strains of methicillin-resistant Staphylococcus aureus with reduced susceptibility to linezolid, daptomycin or vancomycin. [17] Ceftobiprole has also displayed potent activity against Streptococcus pneumoniae (including penicillin-sensitive, penicillin-resistant and ceftriaxone-resistant strains) and Enterococcus faecalis, but not against Enterococcus faecium . For Gram-negative pathogens, ceftobiprole has shown good in vitro activity against Haemophilus influenzae (including both ampicillin-susceptible and ampicillin-non-susceptible isolates), Pseudomonas aeruginosa and strains of Escherichia coli, Klebsiella pneumoniae and Proteus mirabilis that do not produce extended-spectrum β-lactamases (ESBL). Like all other cephalosporins, ceftobiprole was inactive against strains that produce extended-spectrum β-lactamases. [18]

The efficacy of ceftobiprole has been demonstrated in two large randomized, double-blind, phase 3 clinical trials in patients with hospital-acquired and community-acquired pneumonia. Ceftobiprole was non-inferior to ceftazidime plus linezolid in the treatment of hospital-acquired pneumonia (excluding ventilator-acquired pneumonia) and non-inferior to ceftriaxone with or without linezolid in the treatment of community-acquired pneumonia. [19] [20]

Pharmacology

Ceftobiprole medocaril Ceftobiprole medocaril.svg
Ceftobiprole medocaril
Zevtera Front UK(6)(1) (30204271666).jpg

Ceftobiprole is the active moiety of the prodrug ceftobiprole medocaril and is available for intravenous treatment only. It is mainly excreted via the kidney. [21]

History

The efficacy of ceftobiprole medocaril in treating Staphylococcus aureus bloodstream infections (bacteremia) was evaluated in a randomized, controlled, double-blind, multinational, multicenter trial. [15] In the trial, researchers randomly assigned 390 participants to receive ceftobiprole medocaril (192 participants) or daptomycin plus optional aztreonam [the comparator] (198 participants). [15] The primary measure of efficacy for this trial was the overall success (defined as survival, symptom improvement, S. aureus bacteremia bloodstream clearance, no new S. aureus bacteremia complications and no use of other potentially effective antibiotics) at the post-treatment evaluation visit, which occurred 70 days after being randomly assigned an antibiotic. [15] A total of 69.8% of participants who received ceftobiprole medocaril achieved overall success compared to 68.7% of participants who received the comparator. [15]

The efficacy of ceftobiprole medocaril in treating acute bacterial skin and skin structure infections was evaluated in a randomized, controlled, double-blind, multinational trial. [15] In the trial, researchers randomly assigned 679 participants to receive either ceftobiprole medocaril (335 participants) or vancomycin plus aztreonam [the comparator] (344 participants). [15] The primary measure of efficacy was early clinical response 48-72 hours after start of treatment. [15] Early clinical response required a reduction of the primary skin lesion by at least 20%, survival for at least 72 hours and the absence of additional antibacterial treatment or unplanned surgery. [15] Of the participants who received ceftobiprole medocaril, 91.3% achieved an early clinical response within the necessary timeframe compared to 88.1% of participants who received the comparator. [15]

The efficacy of ceftobiprole medocaril in treating adults with community-acquired bacterial pneumonia was evaluated in a randomized, controlled, double-blind, multinational, multicenter trial. [15] In the trial, researchers randomly assigned 638 adults hospitalized with community-acquired bacterial pneumonia and requiring IV antibacterial treatment for at least 3 days to receive either ceftobiprole medocaril (314 participants) or ceftriaxone with optional linezolid [the comparator] (324 participants). [15] The primary measurement of efficacy were clinical cure rates at test-of-cure visit, which occurred 7-14 days after end-of-treatment. [15] Of the participants who received ceftobiprole medocaril, 76.4% achieved clinical cure compared to 79.3% of participants who received the comparator. [15] An additional analysis considered an earlier timepoint of clinical success at Day 3, which was 71% in participants receiving ceftobiprole medocaril and 71.1% in participants receiving the comparator. [15]

Given the similar course of community-acquired bacterial pneumonia in adults and children, the approval of ceftobiprole medocaril in children three months to less than eighteen years of age with community-acquired bacterial pneumonia was supported by evidence from the community-acquired bacterial pneumonia trial of ceftobiprole medocaril in adults and a trial in 138 children three months to less than eighteen years of age with pneumonia. [15]

The US Food and Drug Administration (FDA) granted the application for ceftobiprole medocaril priority review, fast track, and qualified infectious disease product designations for the community-acquired bacterial pneumonia, acute bacterial skin and skin structure infections, and Staphylococcus aureus bloodstream infections (bacteremia) indications. [15] The FDA granted the approval of Zevtera to Basilea Pharmaceutica International Ltd. [15]

Society and culture

500 mg powder Zevtera 1Vial UK(3)(1) (29608654394).jpg
500 mg powder

Ceftobiprole has been approved for the treatment of adults with hospital acquired pneumonia (excluding ventilator-acquired pneumonia) and community-acquired pneumonia in twelve European countries, Canada, and Switzerland. [22]

In February 2010, the Committee for Medicinal Products for Human Use of the European Medicines Agency adopted a negative opinion, recommending the refusal of the marketing authorization for the medicinal product Zeftera, intended for treatment of complicated skin and soft-tissue infections in adults. The company that applied for authorization is Janssen-Cilag International N.V. The applicant requested a re-examination of the opinion. After considering the grounds for this request, the CHMP re-examined the opinion, and confirmed the refusal of the marketing authorization in June 2010. [23]

Related Research Articles

<i>Staphylococcus aureus</i> Species of Gram-positive bacterium

Staphylococcus aureus is a Gram-positive spherically shaped bacterium, a member of the Bacillota, and is a usual member of the microbiota of the body, frequently found in the upper respiratory tract and on the skin. It is often positive for catalase and nitrate reduction and is a facultative anaerobe that can grow without the need for oxygen. Although S. aureus usually acts as a commensal of the human microbiota, it can also become an opportunistic pathogen, being a common cause of skin infections including abscesses, respiratory infections such as sinusitis, and food poisoning. Pathogenic strains often promote infections by producing virulence factors such as potent protein toxins, and the expression of a cell-surface protein that binds and inactivates antibodies. S. aureus is one of the leading pathogens for deaths associated with antimicrobial resistance and the emergence of antibiotic-resistant strains, such as methicillin-resistant S. aureus (MRSA), is a worldwide problem in clinical medicine. Despite much research and development, no vaccine for S. aureus has been approved.

Methicillin-resistant <i>Staphylococcus aureus</i> Bacterium responsible for difficult-to-treat infections in humans

Methicillin-resistant Staphylococcus aureus (MRSA) is a group of gram-positive bacteria that are genetically distinct from other strains of Staphylococcus aureus. MRSA is responsible for several difficult-to-treat infections in humans. It caused more than 100,000 deaths worldwide attributable to antimicrobial resistance in 2019.

Bloodstream infections (BSIs) are infections of blood caused by blood-borne pathogens. Blood is normally a sterile environment, so the detection of microbes in the blood is always abnormal. A bloodstream infection is different from sepsis, which is characterized by severe inflammatory or immune responses of the host organism to pathogens.

<span class="mw-page-title-main">Linezolid</span> Antibiotic medication

Linezolid is an antibiotic used for the treatment of infections caused by Gram-positive bacteria that are resistant to other antibiotics. Linezolid is active against most Gram-positive bacteria that cause disease, including streptococci, vancomycin-resistant enterococci (VRE), and methicillin-resistant Staphylococcus aureus (MRSA). The main uses are infections of the skin and pneumonia although it may be used for a variety of other infections including drug-resistant tuberculosis. It is used either by injection into a vein or by mouth.

<span class="mw-page-title-main">Cefazolin</span> Antibiotic medication

Cefazolin, also known as cefazoline and cephazolin, is a first-generation cephalosporin antibiotic used for the treatment of a number of bacterial infections. Specifically it is used to treat cellulitis, urinary tract infections, pneumonia, endocarditis, joint infection, and biliary tract infections. It is also used to prevent group B streptococcal disease around the time of delivery and before surgery. It is typically given by injection into a muscle or vein.

Vancomycin-resistant <i>Staphylococcus aureus</i> Antibiotica resistant bacteria

Vancomycin-resistant Staphylococcus aureus (VRSA) are strains of Staphylococcus aureus that have acquired resistance to the glycopeptide antibiotic vancomycin. Bacteria can acquire resistant genes either by random mutation or through the transfer of DNA from one bacterium to another. Resistance genes interfere with the normal antibiotic function and allow a bacteria to grow in the presence of the antibiotic. Resistance in VRSA is conferred by the plasmid-mediated vanA gene and operon. Although VRSA infections are uncommon, VRSA is often resistant to other types of antibiotics and a potential threat to public health because treatment options are limited. VRSA is resistant to many of the standard drugs used to treat S. aureus infections. Furthermore, resistance can be transferred from one bacterium to another.

A drug of last resort (DoLR), also known as a heroic dose, is a pharmaceutical drug which is tried after all other drug options have failed to produce an adequate response in the patient. Drug resistance, such as antimicrobial resistance or antineoplastic resistance, may make the first-line drug ineffective, especially in case of multidrug-resistant pathogens and tumors. Such an alternative may be outside of extant regulatory requirements or medical best practices, in which case it may be viewed as salvage therapy.

<span class="mw-page-title-main">Oritavancin</span> Pharmaceutical drug

Oritavancin, sold under the brand name Orbactiv among others, is a semisynthetic glycopeptide antibiotic medication for the treatment of serious Gram-positive bacterial infections. Its chemical structure as a lipoglycopeptide is similar to vancomycin.

<span class="mw-page-title-main">Cefoxitin</span> Chemical compound

Cefoxitin is a second-generation cephamycin antibiotic developed by Merck & Co., Inc. from Cephamycin C in the year following its discovery, 1972. It was synthesized in order to create an antibiotic with a broader spectrum. It is often grouped with the second-generation cephalosporins. Cefoxitin requires a prescription and as of 2010 is sold under the brand name Mefoxin by Bioniche Pharma, LLC. The generic version of cefoxitin is known as cefoxitin sodium.

<span class="mw-page-title-main">Cefditoren</span> Chemical to treat skin infections

Cefditoren, also known as cefditoren pivoxil is an antibiotic used to treat infections caused by Gram-positive and Gram-negative bacteria that are resistant to other antibiotics. It is mainly used for treatment of community acquired pneumonia. It is taken by mouth and is in the cephalosporin family of antibiotics, which is part of the broader beta-lactam group of antibiotics.

<span class="mw-page-title-main">Basilea Pharmaceutica</span> Swiss pharmaceutical company

Basilea Pharmaceutica is a multinational specialty biopharmaceutical company headquartered in Basel, Switzerland. It was formed as a spin-off entity from the drug giant Hoffmann–La Roche in October 2000. It is engaged in the development of antibiotics, antifungals and oncology drugs for treatment of invasive aspergillosis and mucormycosis. Basilea is publicly traded on the SIX Swiss exchange.

Targanta Therapeutics Corporation was a biopharmaceutical company headquartered in Cambridge, Massachusetts. The company also had operations in Indianapolis, Montreal and Toronto. Targanta completed its initial public offering on October 9, 2007 and traded on the Nasdaq market under the symbol: TARG. Targanta was acquired by The Medicines Company in 2009.

<span class="mw-page-title-main">Dalbavancin</span> Antibiotic used to treat MRSA

Dalbavancin, sold under the brand names Dalvance in the US and Xydalba in the EU among others, is a second-generation lipoglycopeptide antibiotic medication. It belongs to the same class as vancomycin, the most widely used and one of the treatments available to people infected with methicillin-resistant Staphylococcus aureus (MRSA).

<span class="mw-page-title-main">Telavancin</span> Pharmaceutical drug

Telavancin is a bactericidal lipoglycopeptide for use in MRSA or other Gram-positive infections. Telavancin is a semi-synthetic derivative of vancomycin.

<span class="mw-page-title-main">Ceftaroline fosamil</span> Chemical compound

Ceftaroline fosamil (INN), brand name Teflaro in the US and Zinforo in Europe, is a cephalosporin antibiotic with anti-MRSA activity. Ceftaroline fosamil is a prodrug of ceftaroline. It is active against methicillin-resistant Staphylococcus aureus (MRSA) and other Gram-positive bacteria. It retains some activity of later-generation cephalosporins having broad-spectrum activity against Gram-negative bacteria, but its effectiveness is relatively much weaker. It is currently being investigated for community-acquired pneumonia and complicated skin and skin structure infection.

Linopristin/flopristin is an experimental drug candidate under development by Novexel. It is an oral streptogramin antibiotic that has potent in vitro activity against certain Gram-positive bacteria including methicillin resistant Staphylococcus aureus (MRSA), as well as the important respiratory pathogens including penicillin-, macrolide- and quinolone-resistant strains. It is a combination of linopristin and flopristin.

Taksta is a front-loaded oral dosing regimen of sodium fusidate under development in the U.S. as an antibiotic for gram-positive infections including drug-resistant strains such as methicillin-resistant Staphylococcus aureus.

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Omadacycline, sold under the brand name Nuzyra, is a broad spectrum antibiotic medication belonging to the aminomethylcycline subclass of tetracycline antibiotics. In the United States, it was approved in October 2018, for the treatment of community-acquired bacterial pneumonia and acute skin and skin structure infections.

<span class="mw-page-title-main">Lefamulin</span> Chemical compound

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Kerry L. LaPlante is an American pharmacist, academic and researcher. She is the Dean at the University of Rhode Island College of Pharmacy. She is a Professor of Pharmacy and former department Chair of the Department of Pharmacy Practice at the University of Rhode Island, an Adjunct Professor of Medicine at Brown University, an Infectious Diseases Pharmacotherapy Specialist, and the Director of the Rhode Island Infectious Diseases Fellowship and Research Programs at the Veterans Affairs Medical Center in Providence, Rhode Island.

References

  1. ↑ Hebeisen P, Heinze-Krauss I, Angehrn P, Hohl P, Page MG, Then RL (March 2001). "In vitro and in vivo properties of Ro 63-9141, a novel broad-spectrum cephalosporin with activity against methicillin-resistant staphylococci". Antimicrobial Agents and Chemotherapy. 45 (3): 825–836. doi:10.1128/AAC.45.3.825-836.2001. PMC   90381 . PMID   11181368.
  2. ↑ Jones RN, Deshpande LM, Mutnick AH, Biedenbach DJ (December 2002). "In vitro evaluation of BAL9141, a novel parenteral cephalosporin active against oxacillin-resistant staphylococci". The Journal of Antimicrobial Chemotherapy. 50 (6): 915–932. doi: 10.1093/jac/dkf249 . PMID   12461013.
  3. ↑ "Prescription medicines: registration of new chemical entities in Australia, 2015". Therapeutic Goods Administration (TGA). 21 June 2022. Archived from the original on 10 April 2023. Retrieved 10 April 2023.
  4. ↑ "Zevtera Product information". Health Canada . 23 April 2010. Archived from the original on 19 February 2024. Retrieved 13 April 2024.
  5. ↑ "Zevtera Product information". Health Canada . 20 March 2018. Archived from the original on 30 April 2024. Retrieved 13 April 2024.
  6. 1 2 3 4 "Zevtera (ceftobiprole medocaril sodium for injection), for intravenous use" (PDF). Archived (PDF) from the original on 6 April 2024. Retrieved 6 April 2024.
  7. ↑ Scheeren TW (1 January 2015). "Ceftobiprole medocaril in the treatment of hospital-acquired pneumonia". Future Microbiology. 10 (12): 1913–1928. doi: 10.2217/fmb.15.115 . PMID   26573022.
  8. ↑ "Basilea announces distribution agreement with Cardiome to commercialize antibiotic Zevtera/Mabelio (ceftobiprole) in Europe and Israel". Basilea (Press release). 12 September 2017. Archived from the original on 7 April 2024. Retrieved 7 April 2024.
  9. ↑ "Basilea to launch Zevtera/Mabelio (ceftobiprole medocaril) in Europe through a commercial services provider" (Press release). Basilea Pharmaceutica. Archived from the original on 31 March 2019. Retrieved 20 September 2016.
  10. ↑ "Basilea announces launch of antibiotic Zevtera (ceftobiprole medocaril) in Germany". Basilea (Press release). 5 December 2014. Archived from the original on 7 April 2024. Retrieved 7 April 2024.
  11. ↑ "Swissmedic approves Basilea's antibiotic Zevtera (ceftobiprole medocaril) for the treatment of pneumonia". Basilea (Press release). 22 December 2014. Archived from the original on 7 April 2024. Retrieved 7 April 2024.
  12. ↑ "Basilea signs exclusive distribution agreement for Zevtera (ceftobiprole medocaril) in the Middle East and North Africa with Hikma Pharmaceuticals LLC". Basilea (Press release). 15 October 2015. Archived from the original on 7 April 2024. Retrieved 7 April 2024.
  13. ↑ "Basilea announces that Health Canada approved Zevtera for the treatment of bacterial lung infections". Basilea (Press release). 12 October 2015. Archived from the original on 7 April 2024. Retrieved 7 April 2024.
  14. ↑ Syed YY (September 2014). "Ceftobiprole medocaril: a review of its use in patients with hospital- or community-acquired pneumonia". Drugs. 74 (13): 1523–1542. doi: 10.1007/s40265-014-0273-x . PMID   25117196. S2CID   2925496.
  15. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 "FDA Approves New Antibiotic for Three Different Uses". U.S. Food and Drug Administration (FDA) (Press release). 3 April 2024. Archived from the original on 13 April 2024. Retrieved 12 April 2024.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  16. ↑ "Novel Drug Approvals for 2024". U.S. Food and Drug Administration (FDA). 29 April 2024. Archived from the original on 30 April 2024. Retrieved 30 April 2024.
  17. ↑ Zhanel GG, Lam A, Schweizer F, Thomson K, Walkty A, Rubinstein E, et al. (2008). "Ceftobiprole: a review of a broad-spectrum and anti-MRSA cephalosporin". American Journal of Clinical Dermatology. 9 (4): 245–254. doi:10.2165/00128071-200809040-00004. PMID   18572975. S2CID   24357533.
  18. ↑ Farrell DJ, Flamm RK, Sader HS, Jones RN (July 2014). "Ceftobiprole activity against over 60,000 clinical bacterial pathogens isolated in Europe, Turkey, and Israel from 2005 to 2010". Antimicrobial Agents and Chemotherapy. 58 (7): 3882–3888. doi:10.1128/AAC.02465-14. PMC   4068590 . PMID   24777091.
  19. ↑ Farrell DJ, Flamm RK, Sader HS, Jones RN (April 2014). "Activity of ceftobiprole against methicillin-resistant Staphylococcus aureus strains with reduced susceptibility to daptomycin, linezolid or vancomycin, and strains with defined SCCmec types". International Journal of Antimicrobial Agents. 43 (4): 323–327. doi:10.1016/j.ijantimicag.2013.11.005. PMID   24411474.
  20. ↑ Nicholson SC, Welte T, File TM, Strauss RS, Michiels B, Kaul P, et al. (March 2012). "A randomised, double-blind trial comparing ceftobiprole medocaril with ceftriaxone with or without linezolid for the treatment of patients with community-acquired pneumonia requiring hospitalisation". International Journal of Antimicrobial Agents. 39 (3): 240–246. doi:10.1016/j.ijantimicag.2011.11.005. PMID   22230331.
  21. ↑ Awad SS, Rodriguez AH, Chuang YC, Marjanek Z, Pareigis AJ, Reis G, et al. (July 2014). "A phase 3 randomized double-blind comparison of ceftobiprole medocaril versus ceftazidime plus linezolid for the treatment of hospital-acquired pneumonia". Clinical Infectious Diseases. 59 (1): 51–61. doi:10.1093/cid/ciu219. PMC   4305133 . PMID   24723282.
  22. ↑ "Zevtera 500 mg powder for concentrate for solution for infusion - Summary of Product Characteristics (SmPC)". (emc). 5 April 2023. Archived from the original on 2 June 2023. Retrieved 1 June 2023.
  23. ↑ "Zeftera (previously Zevtera) EPAR". European Medicines Agency (EMA). 18 February 2010. Archived from the original on 1 October 2023. Retrieved 6 April 2024. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
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