Vamorolone

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Vamorolone
Vamorolone.svg
Clinical data
Trade names Agamree
Other namesVBP; VBP-15; 17α,21-Dihydroxy-16α-methylpregna-1,4,9(11)-triene-3,20-dione
AHFS/Drugs.com Monograph
MedlinePlus a624005
License data
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Identifiers
  • (8S,10S,13S,14S,16R,17R)-17-Hydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-7,8,12,14,15,16-hexahydro-6H-cyclopenta[a]phenanthren-3-one
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.032.874 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C22H28O4
Molar mass 356.462 g·mol−1
3D model (JSmol)
  • C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@@]4(C3=CC[C@@]2([C@]1(C(=O)CO)O)C)C
  • InChI=1S/C22H28O4/c1-13-10-18-16-5-4-14-11-15(24)6-8-20(14,2)17(16)7-9-21(18,3)22(13,26)19(25)12-23/h6-8,11,13,16,18,23,26H,4-5,9-10,12H2,1-3H3/t13-,16-,18+,20+,21+,22+/m1/s1
  • Key:ZYTXTXAMMDTYDQ-DGEXFFLYSA-N

Vamorolone, sold under the brand name Agamree, is a synthetic corticosteroid, which is used for the treatment of Duchenne muscular dystrophy. [4] [5] [6] [7] [8] It is taken by mouth. [1] It is a dual atypical glucocorticoid and antimineralocorticoid. [9]

Contents

The most common adverse reactions include cushingoid features, psychiatric disorders, vomiting, increased weight, and vitamin D deficiency. [10]

Vamorolone was approved for medical use in the United States in October 2023, [11] [10] and in the European Union in December 2023. [2] [3]

Medical uses

Vamorolone is indicated for the treatment of Duchenne muscular dystrophy. [1] [10]

Available forms

Vamorolone is provided in the form of an oral suspension at a concentration of 40 mg/mL. [1]

Side effects

Side effects of vamorolone in clinical trials that occurred at a rate of 10% or greater included development of cushingoid features, psychiatric disorders, vomiting, weight gain, vitamin D deficiency, and cough. [1] The psychiatric disorders that occurred more frequently than with placebo included abnormal behavior, aggression, agitation, anxiety, irritability, altered mood, sleep disorder, and stereotypy. [1] In addition to the preceding side effects, vamorolone shows dose-dependent suppression of the hypothalamic–pituitary–adrenal axis (HPA axis) and hence has potential risks of adrenal suppression and adrenal insufficiency with discontinuation. [1] Vamorolone also shows immunosuppression and is expected to increase the risk of infection, among various other potential adverse effects. [1]

Adverse events observed more frequently in the treated cohort in clinical studies included adrenal suppression, cushingoid features, psychiatric disorders, vomiting, weight gain, and vitamin D deficiency, among others. [1]

Pharmacology

Pharmacodynamics

Vamorolone is a partial agonist of the glucocorticoid receptor with relative loss of transactivation activities, but retention of transrepression activities, compared to other glucocorticoids. As a result, it is described as possessing "dissociative" glucocorticoid properties. [9] In contrast to other corticosteroids, vamorolone is a potent antagonist of the mineralocorticoid receptor and hence has antimineralocorticoid activity. [9]

Vamorolone has anti-inflammatory and immunosuppressive effects as well as other glucocorticoid effects but is thought to lack certain other effects typical of glucocorticoids. [9] [1]

Chemistry

Vamorolone is a synthetic corticosteroid and is also known by the chemical name 17α,21-dihydroxy-16α-methylpregna-1,4,9(11)-triene-3,20-dione or as 16α-methyl-9,11-dehydroprednisolone. It is a derivative of cortisol (hydrocortisone) and prednisolone (1,2-dehydrocortisol).

Anti-inflammatory drugs of the corticosteroid class show a carbonyl (=O) or hydroxyl (-OH) group on the C11 carbon of the steroid backbone. In contrast, vamorolone contains a Δ9,11 double bond between the C9 and C11 carbons. This change in structure has been shown to remove a molecular contact site with the glucocorticoid receptor, and leads to dissociative properties. [12]

History

In phase I clinical trials of adult volunteers, vamorolone was shown to be safe and well tolerated, with blood biomarker data suggesting possible loss of safety concerns of the corticosteroid class. [13]

In phase IIa dose-ranging clinical trial of 48 children with Duchenne muscular dystrophy (2 weeks on drug, 2 weeks off drug), vamorolone was shown to be safe and well tolerated, and showed blood biomarker data consistent with a myofiber membrane stabilization and anti-inflammatory effects, and possible loss of safety concerns. [14] These children continued on to a 24-week open-label extension study at the same doses, and this showed dose-dependent improvement of motor outcomes, with 2.0 and 6.0 mg/kg/day suggesting benefit. [15] These same children continued on a long-term extension study with dose escalations, and this suggested continued clinical improvement through 18-months treatment. [16]

Population pharmacokinetics (PK) of vamorolone was shown to fit to a 1-compartment model with zero-order absorption, with both adult men and young boys showing dose-linearity of PK parameters for the doses examined, and no accumulation of the drug during daily dosing. Apparent clearance averaged 2.0 L/h/kg in men and 1.7 L/h/kg in boys. Overall, vamorolone exhibited well-behaved linear PK, with similar profiles in healthy men and boys with DMD, moderate variability in PK parameters, and absorption and disposition profiles similar to those of classical glucocorticoids. [17] Exposure/response analyses have suggested that the motor outcome of time to stand from supine velocity showed the highest sensitivity to vamorolone, with the lowest AUC value providing 50% of maximum effect (E50 = 186 ng·h/mL), followed by time to climb 4 stairs (E50 = 478 ng·h/mL), time to run/walk 10 m (E50 = 1220 ng·h/mL), and 6-minute walk test (E50 = 1770 ng·h/mL). Week 2 changes of proinflammatory PD biomarkers showed exposure-dependent decreases. The E50 was 260 ng·h/mL for insulin-like growth factor-binding protein 2, 1200 ng·h/mL for matrix metalloproteinase 12, 1260 ng·h/mL for lymphotoxin α1/β2, 1340 ng·h/mL for CD23, 1420 ng·h/mL for interleukin-22-binding protein, and 1600 ng·h/mL for macrophage-derived chemokine/C-C motif chemokine 22. [18]

The US Food and Drug Administration (FDA) approved vamorolone based on evidence from a single clinical trial of 121 boys with DMD who were 4 to <7 years of age. The trial (Study 1) was conducted at 33 sites in 11 countries in Australia, Belgium, Canada, the Czech Republic, Spain, the United Kingdom, Greece, Israel, Netherlands, Sweden, and the United States. [10] In addition to Study 1, safety was also evaluated in a separate, open-label study of children with DMD aged 2 to <4 years (N=16) and children with DMD aged 7 to <18 years (N=16). [10]

Society and culture

Santhera Pharmaceuticals signed an agreement with Catalyst Pharmaceuticals for the North American commercialization of vamorolone in July 2023. [19]

In October 2023, the FDA approved vamorolone (Agamree; Catalyst Pharmaceuticals) for the treatment of Duchenne muscular dystrophy. [11] [20] [21]

In October 2023, the Committee for Medicinal Products for Human Use adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Agamree, intended for the treatment of Duchenne muscular dystrophy. [2] The applicant for this medicinal product is Santhera Pharmaceuticals (Deutschland) GmbH. [2] Vamorolone was approved for medical use in the European Union in December 2023. [2] [3]

Brand names

Vamorolone is the international nonproprietary name. [22]

Vamorolone is sold under the brand name Agamree. [1] [2] [3]

Related Research Articles

<span class="mw-page-title-main">Muscular dystrophy</span> Diseases in which skeletal and visceral muscles breaks down over time

Muscular dystrophies (MD) are a genetically and clinically heterogeneous group of rare neuromuscular diseases that cause progressive weakness and breakdown of skeletal muscles over time. The disorders differ as to which muscles are primarily affected, the degree of weakness, how fast they worsen, and when symptoms begin. Some types are also associated with problems in other organs.

<span class="mw-page-title-main">Corticosteroid</span> Class of steroid hormones

Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are involved in a wide range of physiological processes, including stress response, immune response, and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte levels, and behavior.

<span class="mw-page-title-main">Dexamethasone</span> Corticosteroid medication

Dexamethasone is a fluorinated glucocorticoid medication used to treat rheumatic problems, a number of skin diseases, severe allergies, asthma, chronic obstructive pulmonary disease (COPD), croup, brain swelling, eye pain following eye surgery, superior vena cava syndrome, and along with antibiotics in tuberculosis. In adrenocortical insufficiency, it may be used in combination with a mineralocorticoid medication such as fludrocortisone. In preterm labor, it may be used to improve outcomes in the baby. It may be given by mouth, as an injection into a muscle, as an injection into a vein, as a topical cream or ointment for the skin or as a topical ophthalmic solution to the eye. The effects of dexamethasone are frequently seen within a day and last for about three days.

<span class="mw-page-title-main">Dystrophin</span> Rod-shaped cytoplasmic protein

Dystrophin is a rod-shaped cytoplasmic protein, and a vital part of a protein complex that connects the cytoskeleton of a muscle fiber to the surrounding extracellular matrix through the cell membrane. This complex is variously known as the costamere or the dystrophin-associated protein complex (DAPC). Many muscle proteins, such as α-dystrobrevin, syncoilin, synemin, sarcoglycan, dystroglycan, and sarcospan, colocalize with dystrophin at the costamere. It has a molecular weight of 427 kDa

<span class="mw-page-title-main">Duchenne muscular dystrophy</span> Type of muscular dystrophy

Duchenne muscular dystrophy (DMD) is a severe type of muscular dystrophy predominantly affecting boys. The onset of muscle weakness typically begins around age four, with rapid progression. Initially, muscle loss occurs in the thighs and pelvis, extending to the arms, which can lead to difficulties in standing up. By the age of 12, most individuals with Duchenne muscular dystrophy are unable to walk. Affected muscles may appear larger due to an increase in fat content, and scoliosis is common. Some individuals may experience intellectual disability, and females carrying a single copy of the mutated gene may show mild symptoms.

<span class="mw-page-title-main">Becker muscular dystrophy</span> Genetic muscle disorder

Becker muscular dystrophy (BMD) is an X-linked recessive inherited disorder characterized by slowly progressing muscle weakness of the legs and pelvis. It is a type of dystrophinopathy. The cause is mutations and deletions in any of the 79 exons encoding the large dystrophin protein, essential for maintaining the muscle fiber's cell membrane integrity. Becker muscular dystrophy is related to Duchenne muscular dystrophy in that both result from a mutation in the dystrophin gene, however the hallmark of Becker is milder in-frame deletions. and hence has a milder course, with patients maintaining ambulation till 50–60 years if detected early.

Antisense therapy is a form of treatment that uses antisense oligonucleotides (ASOs) to target messenger RNA (mRNA). ASOs are capable of altering mRNA expression through a variety of mechanisms, including ribonuclease H mediated decay of the pre-mRNA, direct steric blockage, and exon content modulation through splicing site binding on pre-mRNA. Several ASOs have been approved in the United States, the European Union, and elsewhere.

In medicine, myopathy is a disease of the muscle in which the muscle fibers do not function properly. Myopathy means muscle disease. This meaning implies that the primary defect is within the muscle, as opposed to the nerves or elsewhere.

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

Idebenone, sold under the brand name Raxone among others, is a medication that was initially developed by Takeda Pharmaceutical Company for the treatment of Alzheimer's disease and other cognitive defects. This has been met with limited success. The Swiss company Santhera Pharmaceuticals has started to investigate it for the treatment of neuromuscular diseases. In 2010, early clinical trials for the treatment of Friedreich's ataxia and Duchenne muscular dystrophy have been completed. As of December 2013 the drug is not approved for these indications in North America or Europe. It is approved by the European Medicines Agency (EMA) for use in Leber's hereditary optic neuropathy (LHON) and was designated an orphan drug in 2007.

Sarepta Therapeutics, Inc. is a medical research and drug development company with corporate offices and research facilities in Cambridge, Massachusetts, United States. Incorporated in 1980 as AntiVirals, shortly before going public the company changed its name from AntiVirals to AVI BioPharma soon with stock symbol AVII and in July 2012 changed name from AVI BioPharma to Sarepta Therapeutics and SRPT respectively. As of 2023, the company has four approved drugs.

<span class="mw-page-title-main">Omigapil</span> Drug developed by Novartis

Omigapil is a drug that was developed by Novartis and tested in clinical trials for its ability to help treat Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). The development for PD and ALS have been terminated due to lack of benefit, but Santhera Pharmaceuticals bought the compound for development for the treatment of congenital muscular dystrophy (CMD).

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

Deflazacort is a glucocorticoid belonging to acetonides or O-isopropylidene derivative. It is used as an anti-inflammatory and was patented in 1969 and approved for medical use in 1985. The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication for Duchenne Muscular Dystrophy.

Givinostat, sold under the brand name Duvyzat is a medication used for the treatment of Duchenne muscular dystrophy. It is a histone deacetylase inhibitor with potential anti-inflammatory, anti-angiogenic, and antineoplastic activities. It is a histone deacetylase (HDAC) inhibitor that works by targeting pathogenic processes to reduce inflammation and loss of muscle.

Drisapersen is an experimental drug that was under development by BioMarin, after acquisition of Prosensa, for the treatment of Duchenne muscular dystrophy. The drug is a 2'-O-methyl phosphorothioate oligonucleotide that alters the splicing of the dystrophin RNA transcript, eliminating exon 51 from the mature dystrophin mRNA.

<span class="mw-page-title-main">Eteplirsen</span> Medication

Eteplirsen is a medication to treat, but not cure, some types of Duchenne muscular dystrophy (DMD), caused by a specific mutation. Eteplirsen only targets specific mutations and can be used to treat about 14% of DMD cases. Eteplirsen is a form of antisense therapy.

Catalyst Pharmaceuticals, Inc. is a biopharmaceutical company based in Coral Gables, Florida, United States. The company develops medicines for rare diseases, including the phosphate salt of amifampridine for the treatment of Lambert–Eaton myasthenic syndrome (LEMS). The drug is referred to under the trade name Firdapse, which was approved by the FDA for approved use in children 6 years and older with LEMS in addition to the prior approval for use in adults with LEMS on November 28, 2018. Firdapse commercially launched in January 2019.

Kanneboyina Nagaraju is the Dean of the School of Pharmacy and Pharmaceutical Sciences at the State University of New York (SUNY), Binghamton. He holds the prestigious title of SUNY Distinguished Professor, the highest faculty rank awarded by the State University of New York system.

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

Ezutromid is an orally administered small molecule utrophin modulator involved in a Phase 2 clinical trial produced by Summit Therapeutics for the treatment of Duchenne muscular dystrophy (DMD). DMD is a fatal x-linked recessive disease affecting approximately 1 in 5000 males and is a designated orphan disease by the FDA and European Medicines Agency. Approximately 1/3 of the children obtain DMD as a result of spontaneous mutation in the dystrophin gene and have no family history of the disease. Dystrophin is a vital component of mature muscle function, and therefore DMD patients have multifarious forms of defunct or deficient dystrophin proteins that all manifest symptomatically as muscle necrosis and eventually organ failure. Ezutromid is theorized to maintain utrophin, a protein functionally and structurally similar to dystrophin that precedes and is replaced by dystrophin during development. Utrophin and dystrophin are reciprocally expressed, and are found in different locations in a mature muscle cell. However, in dystrophin-deficient patients, utrophin was found to be upregulated and is theorized to replace dystrophin in order to maintain muscle fibers. Ezutromid is projected to have the potential to treat all patients suffering with DMD as it maintains the production of utrophin to counteract the lack of dystrophin to retard muscle degeneration. Both the FDA and European Medicines Agency has given ezutromid an orphan drug designation. The FDA Office of Orphan Products and Development offers an Orphan Drug Designation program (ODD) that allows drugs aimed to treat diseases that affect less than 200,000 people in the U.S. monetary incentives such as a period of market exclusivity, tax incentives, and expedited approval processes.

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

Viltolarsen, sold under the brand name Viltepso, is a medication used for the treatment of Duchenne muscular dystrophy (DMD). Viltolarsen is a Morpholino antisense oligonucleotide.

Toshifumi (Toshi) Yokota is a biomedical scientist and professor of medical genetics at the University of Alberta, holding the titles of the Friends of Garrett Cumming Research & Muscular Dystrophy Canada Endowed Research Chair and the Henri M. Toupin Chair in Neurological Science. Yokota is widely recognized for pioneering work in antisense therapy for muscular dystrophy and other genetic diseases, which led to the development of viltolarsen, an FDA-approved treatment for Duchenne muscular dystrophy (DMD). With over 100 peer-reviewed publications and several patents, Yokota has made significant contributions to the field of precision medicine. Yokota also co-edited three volumes in the Methods in Molecular Biology series by Humana Press, Springer-Nature and is on editorial boards of multiple scientific journals.

References

  1. 1 2 3 4 5 6 7 8 9 10 11 "Agamree- vamorolone kit". DailyMed. 26 October 2023. Retrieved 20 November 2023.
  2. 1 2 3 4 5 6 "Agamree EPAR". European Medicines Agency. 12 October 2023. Retrieved 27 December 2023. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  3. 1 2 3 4 "Agamree Product information". Union Register of medicinal products. 15 December 2023. Retrieved 26 December 2023.
  4. ↑ "Vamorolone - ReveraGen Biopharma". AdisInsight. Springer Nature Switzerland AG. Archived from the original on 7 October 2017. Retrieved 2 July 2017.
  5. ↑ Reeves EK, Hoffman EP, Nagaraju K, Damsker JM, McCall JM (April 2013). "VBP15: preclinical characterization of a novel anti-inflammatory delta 9,11 steroid". Bioorganic & Medicinal Chemistry. 21 (8): 2241–2249. doi:10.1016/j.bmc.2013.02.009. PMC   4088988 . PMID   23498916.
  6. ↑ Heier CR, Damsker JM, Yu Q, Dillingham BC, Huynh T, Van der Meulen JH, et al. (October 2013). "VBP15, a novel anti-inflammatory and membrane-stabilizer, improves muscular dystrophy without side effects". EMBO Molecular Medicine. 5 (10): 1569–1585. doi:10.1002/emmm.201302621. PMC   3799580 . PMID   24014378.
  7. ↑ Dadgar S, Wang Z, Johnston H, Kesari A, Nagaraju K, Chen YW, et al. (October 2014). "Asynchronous remodeling is a driver of failed regeneration in Duchenne muscular dystrophy". The Journal of Cell Biology. 207 (1): 139–158. doi:10.1083/jcb.201402079. PMC   4195829 . PMID   25313409.
  8. ↑ Damsker JM, Conklin LS, Sadri S, Dillingham BC, Panchapakesan K, Heier CR, et al. (September 2016). "VBP15, a novel dissociative steroid compound, reduces NFκB-induced expression of inflammatory cytokines in vitro and symptoms of murine trinitrobenzene sulfonic acid-induced colitis". Inflammation Research. 65 (9): 737–743. doi:10.1007/s00011-016-0956-8. PMID   27261270. S2CID   18698831.
  9. 1 2 3 4 Heier CR, Yu Q, Fiorillo AA, Tully CB, Tucker A, Mazala DA, et al. (February 2019). "Vamorolone targets dual nuclear receptors to treat inflammation and dystrophic cardiomyopathy". Life Sci Alliance. 2 (1): e201800186. doi:10.26508/lsa.201800186. PMC   6371196 . PMID   30745312.
  10. 1 2 3 4 5 "Drug Trials Snapshots: Agamree". U.S. Food and Drug Administration (FDA). 16 February 2024. Retrieved 14 March 2024.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  11. 1 2 "Drug Approval Package: Agamree". U.S. Food and Drug Administration (FDA). 7 November 2023. Archived from the original on 13 November 2023. Retrieved 13 November 2023.
  12. ↑ Liu X, Wang Y, Gutierrez JS, Damsker JM, Nagaraju K, Hoffman EP, et al. (September 2020). "Disruption of a key ligand-H-bond network drives dissociative properties in vamorolone for Duchenne muscular dystrophy treatment". Proceedings of the National Academy of Sciences of the United States of America. 117 (39): 24285–24293. Bibcode:2020PNAS..11724285L. doi: 10.1073/pnas.2006890117 . PMC   7533876 . PMID   32917814.
  13. ↑ Hoffman EP, Riddle V, Siegler MA, Dickerson D, Backonja M, Kramer WG, et al. (June 2018). "Phase 1 trial of vamorolone, a first-in-class steroid, shows improvements in side effects via biomarkers bridged to clinical outcomes". Steroids. 134: 43–52. doi:10.1016/j.steroids.2018.02.010. PMC   6136660 . PMID   29524454.
  14. ↑ Conklin LS, Damsker JM, Hoffman EP, Jusko WJ, Mavroudis PD, Schwartz BD, et al. (October 2018). "Phase IIa trial in Duchenne muscular dystrophy shows vamorolone is a first-in-class dissociative steroidal anti-inflammatory drug". Pharmacological Research. 136: 140–150. doi:10.1016/j.phrs.2018.09.007. PMC   6218284 . PMID   30219580.
  15. ↑ Hoffman EP, Schwartz BD, Mengle-Gaw LJ, Smith EC, Castro D, Mah JK, et al. (September 2019). "Vamorolone trial in Duchenne muscular dystrophy shows dose-related improvement of muscle function". Neurology. 93 (13): e1312 –e1323. doi:10.1212/WNL.0000000000008168. PMC   7011869 . PMID   31451516.
  16. ↑ Smith EC, Conklin LS, Hoffman EP, Clemens PR, Mah JK, Finkel RS, et al. (September 2020). "Efficacy and safety of vamorolone in Duchenne muscular dystrophy: An 18-month interim analysis of a non-randomized open-label extension study". PLOS Medicine. 17 (9): e1003222. doi: 10.1371/journal.pmed.1003222 . PMC   7505441 . PMID   32956407.
  17. ↑ Mavroudis PD, van den Anker J, Conklin LS, Damsker JM, Hoffman EP, Nagaraju K, et al. (July 2019). "Population Pharmacokinetics of Vamorolone (VBP15) in Healthy Men and Boys With Duchenne Muscular Dystrophy". Journal of Clinical Pharmacology. 59 (7): 979–988. doi:10.1002/jcph.1388. PMC   6548694 . PMID   30742306.
  18. ↑ Li X, Conklin LS, van den Anker J, Hoffman EP, Clemens PR, Jusko WJ (October 2020). "Exposure-Response Analysis of Vamorolone (VBP15) in Boys With Duchenne Muscular Dystrophy". Journal of Clinical Pharmacology. 60 (10): 1385–1396. doi:10.1002/jcph.1632. PMC   7494537 . PMID   32434278.
  19. ↑ Deswal P. "Santhera and Catalyst to market DMD drug vamorolone in North America". Pharmaceutical Technology.
  20. ↑ "FDA Approves Vamorolone for Treatment of Duchenne Muscular Dystrophy in Patients Aged 2 Years and Older". Pharmacy Times. 26 October 2023. Archived from the original on 27 October 2023. Retrieved 27 October 2023.
  21. ↑ "Santhera Receives U.S. FDA Approval of Agamree (vamorolone) for the Treatment of Duchenne Muscular Dystrophy" (Press release). Santhera Pharmaceuticals Holding AG. 27 October 2023. Archived from the original on 31 October 2023. Retrieved 13 November 2023– via GlobeNewswire.
  22. ↑ World Health Organization (2017). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 77". WHO Drug Information. 31 (1). hdl: 10665/330984 .
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