Ranibizumab

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Ranibizumab
Mass / length primary structure 48.4  kDa
Identifier
External IDs
Drug information
ATC code S01 LA04
DrugBank DB01270
Drug class Monoclonal antibody

Ranibizumab (trade name Lucentis ® ; manufacturer Novartis ) is a drug that is indicated for the treatment of wet ( exudative ) age-related macular degeneration (AMD) and impaired visual acuity associated with diabetic macular edema .

Ranibizumab is a humanized, recombinant monoclonal antibody fragment ( Fab ) and inhibits the "Vascular Endothelial Growth Factor" (VEGF-A), a protein that plays a role in the formation of small blood vessels ( angiogenesis ).

Clinical information

Ranibizumab is given by an intravitreal injection into the vitreous humor of the eye after local anesthesia . The recommended dose is 0.5 mg (0.05 ml). In the first three months of therapy, the drug is injected at monthly intervals. In the subsequent maintenance phase, the ophthalmologist checks the patient's eyesight monthly using a standardized alphabet table. If the loss of vision is more than five letters, the preparation is given again. Much more precise tracking of the course of the disease and the decision to continue the therapy is possible with modern optical coherence tomography . AMD is the most common cause of blindness in old age in industrialized countries.

Visual acuity that is impaired as a result of diabetic macular edema is carried out with monthly injections of 0.05 ml until maximum visual acuity is achieved.

The drug may only be used by a qualified ophthalmologist who has the necessary practice infrastructure for aseptic use.

Adverse effects (side effects)

The most common undesirable effects during therapy with ranibizumab are eye problems with pain, bleeding, foreign body sensation, increased intraocular pressure ( glaucoma ) or floaters (small black dots, spots or thread-like structures in the visual field) as well as headache and arterial hypertension . Serious but rare are internal eye infections, retinal damage, or cataracts (cataracts). To reduce the risk of infection, the patient may use antibiotic eye drops .

Pharmacological properties

Ranibizumab is a humanized, recombinant, monoclonal antibody fragment that was specially developed for the treatment of exudative, age-related macular degeneration. The drug is used against human vascular endothelial growth factor A (VEGF-A). Ranibizumab binds all isoforms of VEGF-A with high affinity . This is considered to be the key molecule in the development of exudative AMD.

The binding of VEGF-A by ranibizumab prevents the activation of the VEGFR-1 and VEGFR-2 receptors on the surface of the endothelial cells . Due to its small size, it can penetrate all layers of the retina and reaches the choroidal neovascularizations (CNV), which are prone to bleeding. Ranibizumab's antibody fragment properties reduce the risk of inflammation. Since ranibizumab has a short plasma half-life after intravitreal injection, the risk of systemic side effects remains small.

Other Information

Chemical and pharmaceutical information

Ranibizumab is the Fab fragment of the humanized monoclonal antibody bevacizumab , which is produced in Escherichia coli using recombinant DNA technology . It differs from this in 6 amino acids, 4 of which are located in the VEGF binding site and are not glycosylated .

Red-hand letter

In November 2019, the manufacturer Novartis, in coordination with the European Medicines Agency (EMA) and the Paul Ehrlich Institute (PEI), published a red hand letter on the pre-filled syringe: The syringe plunger was stiff. As a result, less than the recommended dose of Lucentis® is administered into the patient's eye.

history

Ranibizumab was developed by Genentech , a subsidiary of the Swiss company Hoffmann-La Roche , and Novartis. Novartis has the worldwide distribution rights for ranibizumab with the exception of North America ( USA , Canada and Mexico ). Genentech holds the distribution rights for these countries. Production for all sales areas is carried out by Hoffmann-La Roche. Lucentis ® was approved in January 2007 by the European Commission for all countries of the European Union . Approval for the USA had already been granted in June 2006 and for Switzerland in September 2006.

In 2011, the National Health Service spoke out against reimbursement of the cost of therapy for type 2 diabetics for reasons of health economics . Availability for this patient population is therefore in question in the UK .

Ranibizumab versus bevacizumab

Ranibizumab was approved for the treatment of AMD primarily based on the results of the MARINA and ANCHOR studies. The price of US $ 1,950 per injection was already felt by many ophthalmologists to be incredibly high when it was launched in the USA in June 2006 . Projections suggest that costs of several billion US $ or € annually due to this one drug alone for the health system appear possible. Many ophthalmologists avoided so as part of the medical therapy of freedom to the considerably cheaper, biochemically very similar bevacizumab (Avastin ® ) of which was not approved for this indication (so-called off-label use ).

However, the company that makes bevacizumab, Hoffmann-La Roche, which is 33% owned by Novartis, made no effort to get this drug approved for the treatment of AMD. Thereafter, on the initiative of ophthalmologists, therapy studies were initiated to compare the effectiveness of ranibizumab versus bevacizumab. In a first direct but small comparative study, there was no evidence of superiority over the much cheaper bevacizumab. Many observers found the attempt by Genentech in the USA to stop the sale of bevacizumab to ophthalmologists as scandalous (Genentech also sells bevacizumab in the USA). In a compromise in December 2007, bevacizumab could again be used by ophthalmologists under certain conditions. The possible liability risks for Genentech have been minimized.

The largest scientific society of German ophthalmologists, the German Ophthalmological Society , emphasized in a statement dated September 20, 2007 that “the treatment for the benefit of the patient must be based on the principles of evidence-based medicine ”, which is why “the therapy should be with a drug whose efficacy and safety has been tested in clinical studies for this indication. ”and advocated the implementation of a corresponding study to directly compare the efficacy and safety of Avastin with that of Lucentis.

In 2014, nine studies were evaluated in which the safety of both active ingredients was compared. As a result, the researchers came to the conclusion that compared to the more expensive ranibizumab (Lucentis ® ) bevacizumab (Avastin ® ) was equally effective and did not show an increased risk of death or serious side effects.

Comparative studies

A number of clinical studies are comparing the effectiveness of ranibizumab and bevacizumab for wet macular degeneration. In May 2011, the results of the CATT study were published in the New England Journal of Medicine . The results of the study showed that after one year of treatment, the effects of the two drugs were practically the same. With regard to the side effects that occurred, the authors recommended further scientific studies. On May 6, 2012, an interim result of the British IVAN study was published, which showed an equivalent effect of both substances after 12 months of treatment. The results of the German VIBERA and the Austrian Manta comparative study were still pending at the end of 2012.

The dispute over bevacizumab at AMD and the above Studies are followed with great interest by the public because important questions of principle regarding the off-label use of drugs are discussed here. However, it is not possible in the German health system to get an approved drug for another indication against the will of the approval holder (the manufacturer), which has met with criticism from the medical profession.

Studies

  • J. Gaudreault, D. Fei, J. Rusit, P. Suboc, V. Shiu: Preclinical pharmacokinetics of Ranibizumab (rhuFabV2) after a single intravitreal administration . In: Invest. Ophthalmol. Vis. Sci. tape 46 , no. 2 , February 2005, p. 726-733 , doi : 10.1167 / iovs.04-0601 , PMID 15671306 .
  • IK Kim, D. Husain, N. Michaud et al .: Effect of intravitreal injection of ranibizumab in combination with verteporfin PDT on normal primate retina and choroid . In: Invest. Ophthalmol. Vis. Sci. tape 47 , no. 1 , January 2006, p. 357-363 , doi : 10.1167 / iovs.04-0087 , PMID 16384985 .
  • G. Coscas, F. Coscas, G. Soubrane: Traitement par injection intra-vitréenne de Ranibizumab (Lucentis®) pour des néovaisseaux choroïdiens occultes prédominants liés à la DMLA. In: Journal Français d'Ophtalmologie. Volume 29, No. 7, September 2006, pp. 731-737 ( em-consulte.com ).
  • RH Guymer: Managing neovascular age-related macular degeneration: a step into the light . In: Med. J. Aust. tape 186 , no. 6 , March 2007, p. 276–277 , PMID 17371204 ( ( Page no longer available , search in web archives: mja.com.au )).@1@ 2Template: Dead Link / www.mja.com.au
  • P. Epstein: Trials that matter: two faces of progress in the treatment of age-related macular degeneration . In: Ann. Intern. Med. Band 146 , no. 7 , April 2007, p. 532-534 , PMID 17404357 .
  • TC Smith, L. Lee: Age related macular degeneration - new developments in treatment . In: Aust Fam Physician . tape 36 , no. 5 , May 2007, pp. 359-361 , PMID 17492074 ( racgp.org.au ).
  • G. Landa, W. Amde, V. Doshi et al: Comparative study of intravitreal bevacizumab (Avastin) versus ranibizumab (Lucentis) in the treatment of neovascular age-related macular degeneration . In: Ophthalmologica . tape 223 , no. 6 , 2009, p. 370-375 , doi : 10.1159 / 000227783 , PMID 19590252 .
  • DS Fong, P. Custis, J. Howes, JW Hsu: Intravitreal bevacizumab and ranibizumab for age-related macular degeneration a multicenter, retrospective study . In: Ophthalmology . tape 117 , no. 2 , February 2010, p. 298-302 , doi : 10.1016 / j.ophtha.2009.07.023 , PMID 19969368 .
  • Ranibizumab and Bevacizumab for Neovascular Age-Related Macular Degeneration . In: N Engl J Med . April 2011, doi : 10.1056 / NEJMoa1102673 , PMID 21526923 .
  • Philip J. Rosenfeld: Bevacizumab versus Ranibizumab for AMD. In: New England Journal of Medicine. 364, 2011, pp. 1966-1967, doi: 10.1056 / NEJMe1103334 .

Individual evidence

  1. ↑ GB Jaissle, KU Bartz-Schmidt: Recommendation of the German Ophthalmological Society for the implementation of intravitreal injections (IVI). (PDF; 349 kB) In: www.augeninfo.de. Professional Association of Ophthalmologists in Germany, April 2007, archived from the original on October 19, 2010 ; Retrieved May 7, 2011 .
  2. ↑ JS Heier, DS Boyer, TA Ciulla et al .: Ranibizumab combined with verteporfin photodynamic therapy in neovascular age-related macular degeneration: year 1 results of the FOCUS Study . In: Arch. Ophthalmol. tape 124 , no. 11 , November 2006, p. 1532-1542 , doi : 10.1001 / archopht.124.11.1532 , PMID 17101999 .
  3. ↑ Summary of the product features. (PDF; 610 kB) In: www.emea.europa.eu. European Medicines Agency, accessed May 7, 2011 .
  4. ↑ Lucentis factsheet. In: www.gene.com. Genentech, Inc, accessed May 7, 2011 .
  5. ↑ RHB on the stiffness of the syringe plunger , accessed on November 15, 2019
  6. ↑ Press release of the NICE Committee of the NHS of July 11, 2011, available as ranibizumab (Lucentis) - Full submission - July 11, 2011 , scottishmedicines.org.uk ( Memento of April 9, 2016 in the Internet Archive ) PDF; last accessed on July 16, 2011.
  7. ↑ PJ Rosenfeld, DM Brown, JS Heier et al .: Ranibizumab for neovascular age-related macular degeneration . In: N. Engl. J. Med. Band 355 , no. October 14 , 2006, p. 1419-1431 , doi : 10.1056 / NEJMoa054481 , PMID 17021318 .
  8. ↑ DM Brown, PK Kaiser, M. Michels et al .: Ranibizumab versus verteporfin for neovascular age-related macular degeneration . In: N. Engl. J. Med. Band 355 , no. October 14 , 2006, p. 1432-1444 , doi : 10.1056 / NEJMoa062655 , PMID 17021319 .
  9. ^ R. Steinbrook: The price of sight - ranibizumab, bevacizumab, and the treatment of macular degeneration . In: N. Engl. J. Med. Band 355 , no. October 14 , 2006, p. 1409-1412 , doi : 10.1056 / NEJMp068185 , PMID 17021315 .
  10. ↑ C. Baumgärtel: Label against off-label use. (PDF; 11.0 MB) March 29, 2010, archived from the original on December 18, 2015 ; Retrieved May 7, 2011 .
  11. ↑ ML Subramanian, G. Abedi, S. Ness et al .: Bevacizumab vs ranibizumab for age-related macular degeneration: 1-year outcomes of a prospective, double-masked randomized clinical trial . In: Eye (Lond) . tape 24 , no. 11 , November 2010, p. 1708-1715 , doi : 10.1038 / eye.2010.147 , PMID 20885427 .
  12. ↑ Susan Desmond-Hellmann: Letter to Physicians. Avastin Distribution Update. In: www.gene.com. Genentech, Inc, October 11, 2007, archived from the original on June 12, 2011 ; Retrieved May 7, 2011 : "As of November 30, 2007, Genentech will no longer allow compounding pharmacies to purchase this product directly from wholesale distributors."
  13. ↑ Age-related macular degeneration: US ophthalomologists may use Avastin® again. In: www.aerzteblatt.de. Deutsches Ärzteblatt, December 21, 2007, accessed May 7, 2011 .
  14. ↑ Barbara Ritzert: Statement of the DOG on the current discussion of therapy for macular degeneration 105th (PDF) DOG Congress in Berlin. In: www.dog.de. Deutsche Ophthalmologische Gesellschaft eV, September 20, 2007, accessed on May 7, 2011 (press release): "The DOG Deutsche Ophthalmologische Gesellschaft advocates the direct comparison of the two drugs Avastin and Lucentis in a study."
  15. ↑ L. Moja et al .: Systemic safety of bevacizumab versus ranibizumab for neovascular age-related macular degeneration. In: Cochrane Database Syst Rev. 9, 2014, p. CD011230; PMID 25220133 ; doi: 10.1002 / 14651858.CD011230.pub2
  16. ↑ Juliane Ziegler, Doris Uhl: Avastin ® not riskier than Lucentis ® . In: Deutsche Apothekerzeitung . 154, 39, Stuttgart, September 25, 2014, p. 28.
  17. ↑ CATT Research Group, DF Martin, MG Maguire, GS Ying, JE Grunwald, SL Fine, GJ Jaffe: Ranibizumab and bevacizumab for neovascular age-related macular degeneration. In: NEJM. 364, 2011, pp. 1897-1908. PMID 21526923
  18. ↑ One Year Findings: ( Memento from April 19, 2013 in the web archive archive.today ) CTEU Bristol.
  19. ↑ Prevention of Vision Loss in Patients With Age-Related Macular Degeneration (AMD) by Intravitreal Injection of Bevacizumab and Ranibizumab (VIBERA). ClinicalTrials.gov, accessed December 26, 2012 .
  20. ↑ Manta Study: Avastin Versus Lucentis in Age Related Macular Degeneration (MANTA). ClinicalTrials.gov, accessed December 26, 2012 .
  21. ↑ Maximilian Gaßner: Off-label use: instrumentalization for economic purposes . In: Dtsch Arztebl. 110 (31-32), 2013, pp. A-1474 / B-1298 / C-1282.
  22. ↑ Bernd Kirchhof, Walter Lehmacher, Sascha Thomas: Bevacizumab versus Ranibizumab: Is off-label use advisable? In: Dtsch Arztebl. 110 (15), 2013, pp. A-708 / B-619 / C-619.
  23. ^ Bernd Kirchhoff: Drug therapy: arbitrariness of the manufacturer. In: Dtsch Arztebl. 110 (40), 2013, pp. A-1856 / B-1637 / C-1607.

Web links

Wikibooks: Ophthalmology: Retina and Visual Pathway  - Learning and Teaching Materials