Eplerenone

Last updated

Eplerenone
Eplerenone.svg
Clinical data
Pronunciation /ɛpˈlɛrənoʊn/
Trade names Inspra, others
Other namesSC-66110; CGP-30083; 9-11α-Epoxymexrenone; 9,11α-Epoxy-7α-methoxycarbonyl-3-oxo-17α-pregn-4-ene-21,17-carbolactone
AHFS/Drugs.com Monograph
MedlinePlus a603004
License data
Pregnancy
category
  • AU:B3
Routes of
administration 		By mouth (tablets)
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability ~70% [2]
Protein binding ~50% (33–60%) (primarily to α1-acid glycoprotein) [2] [3]
Metabolism Liver (CYP3A4) [2] [3]
Metabolites 6β-OH-EPL, 6β,21-OH-EPL, 21-OH-EPL, 3α,6β-OH-EPL [2] (All inactive) [2]
Elimination half-life 4–6 hours [4]
Excretion Urine (67%), feces (32%) [5]
Identifiers
  • methyl (4aS,4bR,5aR,6aS,7R,9aS,9bR,10R)-4a,6a-dimethyl-2,5'-dioxo-2,4,4',4a,5',5a,6,6a,8,9,9a,9b,10,11-tetradecahydro-3H,3'H-spiro[cyclopenta[7,8]phenanthro[4b,5-b]oxirene-7,2'-furan]-10-carboxylate
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard 100.106.615 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C24H30O6
Molar mass 414.498 g·mol−1
3D model (JSmol)
  • COC(=O)[C@@H]4C\C1=C\C(=O)CC[C@]1(C)[C@@]65O[C@@H]6C[C@@]3(C)[C@@H](CC[C@]23CCC(=O)O2)[C@H]45
  • InChI=1S/C24H30O6/c1-21-7-4-14(25)10-13(21)11-15(20(27)28-3)19-16-5-8-23(9-6-18(26)30-23)22(16,2)12-17-24(19,21)29-17/h10,15-17,19H,4-9,11-12H2,1-3H3/t15-,16+,17-,19+,21+,22+,23-,24-/m1/s1 Yes check.svgY
  • Key:JUKPWJGBANNWMW-VWBFHTRKSA-N Yes check.svgY
   (verify)

Eplerenone, sold under the brand name Inspra, is an aldosterone antagonist type of potassium-sparing diuretic that is used to treat chronic heart failure and high blood pressure, particularly for people with resistant hypertension due to elevated aldosterone. It is a steroidal antimineralocorticoid of the spirolactone group and a selective aldosterone receptor antagonist (SARA). [6]

Contents

Medical uses

Heart failure

Eplerenone reduces risk of death in patients with heart failure, [7] particularly in patients with recent myocardial infarction (heart attack). [8]

Hypertension

Eplerenone lowers blood pressure in patients with primary hypertension. [9] Eplerenone also reduces arterial stiffness and vascular endothelial dysfunction. [10]

For persons with resistant hypertension, eplerenone is safe and effective for reducing blood pressure, [11] particularly in persons with resistant hypertension due to hyperaldosteronism. [12] [13]

Central serous chorioretinopathy

Eplerenone is often prescribed for people with central serous chorioretinopathy (CSC). However, the most recent and largest randomized controlled trial showed that eplerenone has no significant effect on chronic CSC that has been untreated for four months. [14] [15] There was one relatively large prospective, interventional case-control study that was tested in acute CSC that showed improved resolution of subretinal fluid in treatment group vs observational group (which is standard of care) with 45% resolution at end of 1st month, 55% at end of 2nd month, and 62% at end of 3rd month (vs 10%, 21%, and 31% in standard of care group). Study also showed faster resolution of visual acuity at the end of each month with 92% and 100% in the first two months vs 74% and 86% with resolution reaching 100% after the third month in standard of care group. [16]

Adverse effects

Common adverse drug reactions (ADRs) associated with the use of eplerenone include: hyperkalaemia, hypotension, dizziness, and reduced renal clearance. [17] Eplerenone may have a lower incidence than spironolactone of sexual side effects such as feminization, gynecomastia, impotence, low sex drive and reduction of size of male genitalia. [18] This is because other antimineralocorticoids have structural elements of the progesterone molecule, causing progestogenic and antiandrogenic outcomes. [4] When considering taking these medicines, it is important to note the variations in their ability to offset the nongenomic effects of aldosterone. [4]

Currently, there is not enough evidence available from the randomized controlled trials on side effects of eplerenone to do a benefit versus risk assessment in people with primary hypertension. [19]

Interactions

Eplerenone is primarily metabolized by the cytochrome P450 enzyme CYP3A4. Thus the potential exists for adverse drug interactions with other drugs that induce or inhibit CYP3A4. Specifically, the concomitant use of the CYP3A4 potent inhibitors ketoconazole and itraconazole is contraindicated. Other CYP3A4 inhibitors including erythromycin, saquinavir, and verapamil should be used with caution. Other drugs that increase potassium concentrations may increase the risk of hyperkalemia associated with eplerenone therapy, including salt substitutes, [20] potassium supplements and other potassium-sparing diuretics.

Pharmacology

Eplerenone is an antimineralocorticoid, or an antagonist of the mineralocorticoid receptor (MR). [21] Eplerenone is also known chemically as 9,11α-epoxy-7α-methoxycarbonyl-3-oxo-17α-pregn-4-ene-21,17-carbolactone and "was derived from spironolactone by the introduction of a 9α,11α-epoxy bridge and by substitution of the 17α-thoacetyl group of spironolactone with a carbomethoxy group." [22] The drug controls high blood pressure by blocking the binding of aldosterone to the mineralocorticoid receptor (MR) in epithelial tissues, such as the kidney. [4] Blocking the action of aldosterone decreases blood volume and lowers blood pressure. [23] It has 10- to 20-fold lower affinity for the MR relative to spironolactone, [21] and is less potent in vivo as an antimineralocorticoid. [4] However, in contrast to spironolactone, eplerenone has little affinity for the androgen, progesterone, and glucocorticoid receptors. [21] [4] It also has more consistently observed non-genomic antimineralocorticoid effects relative to spironolactone (see membrane mineralocorticoid receptor). [4] Eplerenone differs from spironolactone in its extensive metabolism, with a short half-life and inactive metabolites. [4]

Eplerenone seems to be about 50 to 75% as potent as spironolactone as an antimineralocorticoid. [24] Hence, 25 mg/day spironolactone may be equivalent to approximately 50 mg/day eplerenone. [25]

Society and culture

Eplerenone was patented in 1983 and approved for medical use in the United States in 2002. [26] [23] Eplerenone is approved for sale in Canada, the US, the EU, Netherlands, and Japan. [23]

Economics

Eplerenone costs an estimated $2.93 per day when treating congestive heart failure and $5.86 per day when treating hypertension. [18]

Brand names

In the US, Inspra is marketed by Viatris after Upjohn was spun off from Pfizer. [27] [28] [29]

Related Research Articles

<span class="mw-page-title-main">Primary aldosteronism</span> Excess production of aldosterone in the adrenal gland

Primary aldosteronism (PA), also known as primary hyperaldosteronism, refers to the excess production of the hormone aldosterone from the adrenal glands, resulting in low renin levels and high blood pressure. This abnormality is a paraneoplastic syndrome. About 35% of the cases are caused by a single aldosterone-secreting adenoma, a condition known as Conn's syndrome.

<span class="mw-page-title-main">Mineralocorticoid</span> Group of corticosteroids

Mineralocorticoids are a class of corticosteroids, which in turn are a class of steroid hormones. Mineralocorticoids are produced in the adrenal cortex and influence salt and water balances. The primary mineralocorticoid is aldosterone.

Antihypertensives are a class of drugs that are used to treat hypertension. Antihypertensive therapy seeks to prevent the complications of high blood pressure, such as stroke, heart failure, kidney failure and myocardial infarction. Evidence suggests that reduction of the blood pressure by 5 mmHg can decrease the risk of stroke by 34% and of ischaemic heart disease by 21%, and can reduce the likelihood of dementia, heart failure, and mortality from cardiovascular disease. There are many classes of antihypertensives, which lower blood pressure by different means. Among the most important and most widely used medications are thiazide diuretics, calcium channel blockers, angiotensin-converting enzyme inhibitors (ACEis), angiotensin II receptor blockers or antagonists (ARBs), and beta blockers.

<span class="mw-page-title-main">Spironolactone</span> Steroidal antiandrogen and antimineralocorticoid

Spironolactone, sold under the brand name Aldactone among others, is a diuretic medication primarily used to treat fluid build-up due to heart failure, liver scarring, or kidney disease. It is also used in the treatment of high blood pressure, and low blood potassium that does not improve with supplementation, early puberty in boys, acne and excessive hair growth in women. Spironolactone is taken by mouth.

<span class="mw-page-title-main">Potassium-sparing diuretic</span> Drugs that cause diuresis without causing potassium loss in the urine and leading to hyperkalemia

Potassium-sparing diuretics or antikaliuretics refer to drugs that cause diuresis without causing potassium loss in the urine. They are typically used as an adjunct in management of hypertension, cirrhosis, and congestive heart failure. The steroidal aldosterone antagonists can also be used for treatment of primary hyperaldosteronism. Spironolactone, a steroidal aldosterone antagonist, is also used in management of female hirsutism and acne from PCOS or other causes.

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

Drospirenone is a progestin and antiandrogen medication which is used in birth control pills to prevent pregnancy and in menopausal hormone therapy, among other uses. It is available both alone under the brand name Slynd and in combination with an estrogen under the brand name Yasmin among others. The medication is an analog of the drug spironolactone. Drospirenone is taken by mouth.

<span class="mw-page-title-main">Hyperaldosteronism</span> Excess aldosterone in the body

Hyperaldosteronism is a medical condition wherein too much aldosterone is produced. High aldosterone levels can lead to lowered levels of potassium in the blood (hypokalemia) and increased hydrogen ion excretion (alkalosis). Aldosterone is normally produced in the adrenal glands.

<span class="mw-page-title-main">Mineralocorticoid receptor antagonist</span> Drug class

A mineralocorticoid receptor antagonist or aldosterone antagonist, is a diuretic drug which antagonizes the action of aldosterone at mineralocorticoid receptors. This group of drugs is often used as adjunctive therapy, in combination with other drugs, for the management of chronic heart failure. Spironolactone, the first member of the class, is also used in the management of hyperaldosteronism and female hirsutism. Most antimineralocorticoids, including spironolactone, are steroidal spirolactones. Finerenone is a nonsteroidal antimineralocorticoid.

Pseudohyperaldosteronism is a medical condition which mimics the effects of elevated aldosterone (hyperaldosteronism) by presenting with high blood pressure, low blood potassium levels (hypokalemia), metabolic alkalosis, and low levels of plasma renin activity (PRA). However, unlike hyperaldosteronism, this conditions exhibits low or normal levels of aldosterone in the blood. Causes include genetic disorders, acquired conditions, metabolic disorders, and dietary imbalances including excessive consumption of licorice. Confirmatory diagnosis depends on the specific cause and may involve blood tests, urine tests, or genetic testing; however, all forms of this condition exhibit abnormally low concentrations of both plasma renin activity (PRA) and plasma aldosterone concentration (PAC) which differentiates this group of conditions from other forms of secondary hypertension. Treatment is tailored to the specific cause and focuses on symptom control, blood pressure management, and avoidance of triggers.

<span class="mw-page-title-main">Mineralocorticoid receptor</span> Nuclear receptor that mediates the effects of the mineralocorticoid hormone Aldosterone

The mineralocorticoid receptor, also known as the aldosterone receptor or nuclear receptor subfamily 3, group C, member 2, (NR3C2) is a protein that in humans is encoded by the NR3C2 gene that is located on chromosome 4q31.1-31.2.

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

Potassium canrenoate or canrenoate potassium (USAN), also known as aldadiene kalium, the potassium salt of canrenoic acid, is an aldosterone antagonist of the spirolactone group. Like spironolactone, it is a prodrug, and is metabolized to active canrenone in the body.

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

Canrenone, sold under the brand names Contaren, Luvion, Phanurane, and Spiroletan, is a steroidal antimineralocorticoid of the spirolactone group related to spironolactone which is used as a diuretic in Europe, including in Italy and Belgium. It is also an important active metabolite of spironolactone, and partially accounts for its therapeutic effects.

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

Spirolactones are a class of functional group in organic chemistry featuring a cyclic ester attached spiro to another ring system. The name is also used to refer to a class of synthetic steroids, called steroid-17α-spirolactones, 17α-spirolactosteroids, or simply 17α-spirolactones, which feature their spirolactone group at the C17α position. They are antimineralocorticoids, or antagonists of the mineralocorticoid receptor, and have been employed clinically as potassium-sparing diuretics. Some also possess progestogenic and/or antiandrogen properties, which have both contributed to side effects and been utilized for medical indications. The spirolactones were developed by G. D. Searle & Company in the 1950s and thereafter and were denoted as "SC" compounds.

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

Mexrenone is a steroidal antimineralocorticoid of the spirolactone group related to spironolactone that was never marketed. It is the lactonic form of mexrenoic acid (mexrenoate), and mexrenoate potassium (SC-26714), the potassium salt of mexrenoic acid, also exists. In addition to the mineralocorticoid receptor, mexrenone also binds to the glucocorticoid, androgen, and progesterone receptors. Relative to spironolactone, it has markedly reduced antiandrogen activity. Eplerenone is the 9-11α-epoxy analogue of mexrenone.

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

Finerenone, marketed under the brand name Kerendia 10 or 20 mg among others, is a medication used to reduce the risk of kidney function decline, kidney failure, cardiovascular death, non-fatal heart attacks, and hospitalization for heart failure in adults with chronic kidney disease associated with type 2 diabetes. Finerenone is a non-steroidal mineralocorticoid receptor antagonist (MRA). It is taken orally.

<span class="mw-page-title-main">SC-5233</span> Chemical compound

SC-5233, also known as 6,7-dihydrocanrenone or 20-spirox-4-ene-3,20-dione, is a synthetic, steroidal antimineralocorticoid of the spirolactone group which was developed by G. D. Searle & Company in the 1950s but was never marketed. It was the first synthetic antagonist of the mineralocorticoid receptor to have been identified and tested in humans. The drug was found to lack appreciable oral bioavailability and to be of low potency when administered parenterally, but it nonetheless produced a mild diuretic effect in patients with congestive heart failure. SC-8109, the 19-nor (19-demethyl) analogue, was developed and found to have improved oral bioavailability and potency, but still had low potency. Spironolactone followed and had both good oral bioavailability and potency, and was the first synthetic antimineralocorticoid to be marketed. It has about 46-fold higher oral potency than SC-5233.

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

Mespirenone (INN), also known as Δ1-15β,16β-methylenespironolactone, is a steroidal antimineralocorticoid of the spirolactone group related to spironolactone that was never marketed. Animal research found that it was 3.3-fold more potent as an antimineralocorticoid relative to spironolactone. In addition to its antimineralocorticoid properties, mespirenone is also a progestogen, antigonadotropin, and antiandrogen. It is 2- to 3-fold as potent as spironolactone as a progestogen and antigonadotropin but its antiandrogenic activity is markedly reduced and weak in comparison. Mespirenone is also a potent and specific enzyme inhibitor of 18-hydroxylase and thus of mineralocorticoid biosynthesis. The drug was under development by Schering and reached phase II clinical trials but was discontinued in 1989.

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

Esaxerenone is a nonsteroidal antimineralocorticoid which was discovered by Exelixis and developed by Daiichi Sankyo Company and is approved in Japan for the treatment of hypertension. It acts as a highly selective silent antagonist of the mineralocorticoid receptor (MR), the receptor for aldosterone, with greater than 1,000-fold selectivity for this receptor over other steroid hormone receptors, and 4-fold and 76-fold higher affinity for the MR relative to the existing antimineralocorticoids spironolactone and eplerenone.

<span class="mw-page-title-main">7α-Thiomethylspironolactone</span> Chemical compound

←

<span class="mw-page-title-main">6β-Hydroxy-7α-thiomethylspironolactone</span> Chemical compound

6β-Hydroxy-7α-thiomethylspironolactone (6β-OH-7α-TMS) is a steroidal antimineralocorticoid of the spirolactone group and a major active metabolite of spironolactone. Other important metabolites of spironolactone include 7α-thiospironolactone, 7α-thiomethylspironolactone, and canrenone (SC-9376).

References

  1. ↑ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved 22 October 2023.
  2. 1 2 3 4 5 Lemke TL, Williams DA (24 January 2012). Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. pp. 743–. ISBN   978-1-60913-345-0.
  3. 1 2 Sica DA (January 2005). "Pharmacokinetics and pharmacodynamics of mineralocorticoid blocking agents and their effects on potassium homeostasis". Heart Failure Reviews. 10 (1): 23–9. doi:10.1007/s10741-005-2345-1. PMID   15947888. S2CID   21437788.
  4. 1 2 3 4 5 6 7 8 Struthers A, Krum H, Williams GH (April 2008). "A comparison of the aldosterone-blocking agents eplerenone and spironolactone". Clinical Cardiology. 31 (4): 153–8. doi:10.1002/clc.20324. PMC   6652937 . PMID   18404673.
  5. ↑ Frishman WH, Cheng-Lai A, Nawarskas J (4 January 2005). Current Cardiovascular Drugs. Springer Science & Business Media. pp. 246–. ISBN   978-1-57340-221-7.
  6. ↑ Delyani JA, Rocha R, Cook CS, Tobert DS, Levin S, Roniker B, et al. (2001). "Eplerenone: a selective aldosterone receptor antagonist (SARA)". Cardiovascular Drug Reviews. 19 (3): 185–200. doi: 10.1111/j.1527-3466.2001.tb00064.x . PMID   11607037.{{cite journal}}: CS1 maint: overridden setting (link)
  7. ↑ Frankenstein L, Seide S, Täger T, Jensen K, Fröhlich H, Clark AL, et al. (March 2020). "Relative Efficacy of Spironolactone, Eplerenone, and cAnRenone in patients with Chronic Heart failure (RESEARCH): a systematic review and network meta-analysis of randomized controlled trials". Heart Fail Rev. 25 (2): 161–171. doi:10.1007/s10741-019-09832-y. PMID   31364027. S2CID   198999728.
  8. ↑ De Luca L (October 2020). "Established and Emerging Pharmacological Therapies for Post-Myocardial Infarction Patients with Heart Failure: a Review of the Evidence". Cardiovasc Drugs Ther. 34 (5): 723–735. doi:10.1007/s10557-020-07027-4. PMID   32564304. S2CID   219936888.
  9. ↑ Tam TS, Wu MH, Masson SC, Tsang MP, Stabler SN, Kinkade A, et al. (February 2017). "Eplerenone for hypertension". The Cochrane Database of Systematic Reviews. 2017 (2): CD008996. doi:10.1002/14651858.CD008996.pub2. PMC   6464701 . PMID   28245343.{{cite journal}}: CS1 maint: overridden setting (link)
  10. ↑ Sakima A, Arima H, Matayoshi T, Ishida A, Ohya Y (March 2021). "Effect of Mineralocorticoid Receptor Blockade on Arterial Stiffness and Endothelial Function: A Meta-Analysis of Randomized Trials". Hypertension. 77 (3): 929–937. doi: 10.1161/HYPERTENSIONAHA.120.16397 . PMID   33461316.
  11. ↑ Dahal K, Kunwar S, Rijal J, Alqatahni F, Panta R, Ishak N, et al. (November 2015). "The Effects of Aldosterone Antagonists in Patients With Resistant Hypertension: A Meta-Analysis of Randomized and Nonrandomized Studies". American Journal of Hypertension. 28 (11): 1376–85. doi: 10.1093/ajh/hpv031 . PMID   25801902.
  12. ↑ Morimoto S, Ichihara A (August 2020). "Management of primary aldosteronism and mineralocorticoid receptor-associated hypertension". Hypertens Res. 43 (8): 744–753. doi:10.1038/s41440-020-0468-3. PMID   32424201. S2CID   218670505.
  13. ↑ Spence JD (May 2017). "Rational Medical Therapy Is the Key to Effective Cardiovascular Disease Prevention". The Canadian Journal of Cardiology. 33 (5): 626–634. doi:10.1016/j.cjca.2017.01.003. PMID   28449833.
  14. ↑ "Eplerenone does not improve vision in people with central serous chorioretinopathy". NIHR Evidence (Plain English summary). National Institute for Health and Care Research. 25 March 2020. doi:10.3310/signal-000893. S2CID   241440498.
  15. ↑ Lotery A, Sivaprasad S, O'Connell A, Harris RA, Culliford L, Ellis L, et al. (January 2020). "Eplerenone for chronic central serous chorioretinopathy in patients with active, previously untreated disease for more than 4 months (VICI): a randomised, double-blind, placebo-controlled trial". Lancet. 395 (10220): 294–303. doi: 10.1016/S0140-6736(19)32981-2 . hdl: 1983/c40782ba-12d7-428b-8724-bbffb45d7bcf . PMID   31982075.{{cite journal}}: CS1 maint: overridden setting (link)
  16. ↑ Venkatesh R, Pereira A, Jayadev C, Prabhu V, Aseem A, Jain K, et al. (29 July 2020). "Oral Eplerenone Versus Observation in the Management of Acute Central Serous Chorioretinopathy: A Prospective, Randomized Comparative Study". Pharmaceuticals (Basel, Switzerland). 13 (8): 170. doi: 10.3390/ph13080170 . ISSN   1424-8247. PMC   7463844 . PMID   32751370.
  17. ↑ Rossi S (2006). Australian Medicines Handbook 2006. Australian Medicines Handbook. ISBN   978-0-9757919-2-9.
  18. 1 2 Craft J (April 2004). "Eplerenone (Inspra), a new aldosterone antagonist for the treatment of systemic hypertension and heart failure". Proceedings. 17 (2): 217–20. doi:10.1080/08998280.2004.11927973. PMC   1200656 . PMID   16200104.
  19. ↑ Tam TS, Wu MH, Masson SC, Tsang MP, Stabler SN, Kinkade A, et al. (February 2017). "Eplerenone for hypertension". The Cochrane Database of Systematic Reviews. 2017 (2): CD008996. doi:10.1002/14651858.CD008996.pub2. PMC   6464701 . PMID   28245343.{{cite journal}}: CS1 maint: overridden setting (link)
  20. ↑ LoSalt Advisory Statement Archived 10 December 2005 at the Wayback Machine (PDF)
  21. 1 2 3 Delyani JA (April 2000). "Mineralocorticoid receptor antagonists: the evolution of utility and pharmacology". Kidney International. 57 (4): 1408–11. doi: 10.1046/j.1523-1755.2000.00983.x . PMID   10760075.
  22. ↑ Brown NJ (May 2003). "Eplerenone: cardiovascular protection". Circulation. 107 (19): 2512–8. doi:10.1161/01.CIR.0000071081.35693.9A. PMID   12756192. S2CID   13904574.
  23. 1 2 3 "Inspra (Eplerenone)". Drug Development Technology. Retrieved 19 April 2016.
  24. ↑ Struthers A, Krum H, Williams GH (April 2008). "A comparison of the aldosterone-blocking agents eplerenone and spironolactone". Clin Cardiol. 31 (4): 153–8. doi:10.1002/clc.20324. PMC   6652937 . PMID   18404673.
  25. ↑ Peter L. Thompson (28 January 2011). Coronary Care Manual. Elsevier Health Sciences. pp. 254–. ISBN   978-0-7295-7927-8.
  26. ↑ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 459. ISBN   9783527607495.
  27. ↑ "Pfizer Completes Transaction to Combine Its Upjohn Business with Mylan". Pfizer. 16 November 2020. Retrieved 17 June 2024– via Business Wire.
  28. ↑ "Inspra". Pfizer. Retrieved 17 June 2024.
  29. ↑ "Brands". Viatris. 16 November 2020. Retrieved 17 June 2024.
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