Repaglinide

Repaglinide
Names
Trade namesPrandin, GlucoNorm, NovoNorm, Enyglid, others
IUPAC name
  • (S)-(+)-2-ethoxy-4-[2-(3-methyl-1-[2-(piperidin-1-yl)phenyl]butylamino)-2-oxoethyl]benzoic acid
Clinical data
Drug classMeglitinide[1]
Main usesType 2 diabetes[2]
Side effectsLow blood sugar, headache, joint pain, nausea, back pain[2]
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Pregnancy
category
  • AU: C
  • US: C (Risk not ruled out)
    Routes of
    use    		By mouth
    Typical dose0.5 to 2 mg TID[2]
    External links
    AHFS/Drugs.comMonograph
    MedlinePlusa600010
    Legal
    License data
    Legal status
    Pharmacokinetics
    Bioavailability56% (by mouth)
    Protein binding>98%
    MetabolismLiver oxidation and glucuronidation (CYP3A4-mediated)
    Elimination half-life1 hour
    ExcretionFecal (90%) and kidney (8%)
    Chemical and physical data
    FormulaC27H36N2O4
    Molar mass452.595 g·mol−1
    3D model (JSmol)
    Melting point126 to 128 °C (259 to 262 °F)
    SMILES
    • O=C(O)c1ccc(cc1OCC)CC(=O)N[C@H](c2ccccc2N3CCCCC3)CC(C)C
    InChI
    • InChI=1S/C27H36N2O4/c1-4-33-25-17-20(12-13-22(25)27(31)32)18-26(30)28-23(16-19(2)3)21-10-6-7-11-24(21)29-14-8-5-9-15-29/h6-7,10-13,17,19,23H,4-5,8-9,14-16,18H2,1-3H3,(H,28,30)(H,31,32)/t23-/m0/s1 checkY
    • Key:FAEKWTJYAYMJKF-QHCPKHFHSA-N checkY

    Repaglinide, sold under the brand name Prandin among others, is a medication used to control blood sugar in type 2 diabetes.[2] It is used together with diet and exercise.[2] It is taken by mouth.[2] Maximum effects occur in about 3 hours.[1]

    Common side effects include low blood sugar, headache, joint pain, nausea, and back pain.[2] Use in pregnancy is not generally recommended.[1] It is in the meglitinide class of medication and works by promoting insulin release from the pancreas in response to blood sugar.[1]

    Repaglinide was developed in 1983 and approved for medical use in the United States in 1997.[2][3] It is available as a generic medication.[4] In the United Kingdom a month of medication costs around £5 as of 2021.[4] This amount in the United States is about 25 USD.[5]

    Medical uses

    Repaglinide is an oral medication used in addition to diet and exercise for blood sugar control in type 2 diabetes mellitus.[2]

    Special groups

    Caution should be taken in people with liver disease and decreased kidney function.[2]

    Dosage

    It is typically taken at a dose of 0.5 to 2 mg before each meal.[2]

    Contraindications

    Repaglinide is contraindicated in people with:

    1. Diabetic ketoacidosis, with or without coma
    2. Type 1 diabetes
    3. Co-administration with gemfibrozil
    4. Known hypersensitivity to drug or inactive ingredients [2]

    Side events

    Common side effects include:[2]

    Metabolic

    • Hypoglycemia (31%)

    Respiratory

    • Upper respiratory infection (16%)
    • Sinusitis (6%)
    • Rhinitis (3%)

    Gastrointestinal

    • Nausea (5%)
    • Diarrhea (5%)
    • Constipation (3%)
    • Vomiting (3%)

    Musculoskeletal

    • Arthralgia (6%)
    • Back Pain (5%)

    Other

    • Headache (11%)
    • Paresthesia (3%)

    Serious adverse events include:[2]

    • Cardiac ischemia (2%)
    • Angina (1.8%)
    • Deaths due to cardiovascular events (0.5%)

    Pregnancy

    Pregnancy category C: safety in pregnant women has not been established.[2] Data is limited, and there is only one case report that notes no complications with the use of repaglinide during pregnancy.[6]

    Interactions

    Repaglinide is a major substrate of CYP3A4 and should not be administered concomitantly with gemfibrozil, clarithromycin or azole antifungals such as itraconazole or ketoconazole.[2] Administration of both repaglinide and one or more of these drugs results in an increase in plasma concentration of repaglinide and may lead to hypoglycemia. Co-administration of repaglinide and clopidogrel (a CYP2C8 inhibitor) may lead to a significant decrease in blood glucose levels due to a drug-drug interaction.[7] In fact, using these drugs together for even one day can cause repaglinide levels to increase over 5-fold...and may lead to significant hypoglycemia. Repaglinide should not be combined with sulfonylurea, because they have the same mechanism of action.[2]

    Mechanism of action

    Repaglinide lowers blood glucose by stimulating the release of insulin from the beta islet cells of the pancreas. It achieves this by closing ATP-dependent potassium channels in the membrane of the beta cells. This depolarizes the beta cells, opening the cells' calcium channels, and the resulting calcium influx induces insulin secretion.[2]

    Pharmacokinetics

    Absorption: repaglinide has a 56% bioavailability when absorbed from the gastrointestinal tract. Bioavailability is reduced when taken with food; the maximum concentration decreases by 20%.

    Distribution: The protein binding of repalglinide to albumin is greater than 98%.

    Metabolism: repaglinide is primarily metabolized by the liver - specifically CYP450 2C8 and 3A4 - and to a lesser extent via glucuronidation. Metabolites of repaglinide are inactive and do not display glucose-lowering effects.

    Excretion: repaglinide is 90% excreted in the feces and 8% in the urine. 0.1% is cleared unchanged in the urine. Less than 2% is unchanged in the feces.[2]

    History

    Precursor drugs to repaglinide were invented in late 1983 by scientists at Dr Karl Thomae GmbH, a German drug manufacturer located at Biberach an der Riß in southern Germany which was acquired by Boehringer Ingelheim in 1990. The drug that became repaglinide was later licensed by Boehringer to Novo Nordisk, which filed an Investigational New Drug application for the compound with the Food and Drug Administration (FDA) in April 1992. Novo Nordisk filed its New Drug Application (NDA) for Prandin in July 1997 and it was quickly approved, gaining FDA approval in December 1997. The drug was the first of the meglitinide class. It was branded Prandin because its quick onset and short duration of action concentrates its effect around meal time (the prandium was the Roman meal which is comparable to the modern lunch).[8]

    Society and culture

    Intellectual property

    After several attempts to file for U.S. patent protection, a filing was made in March 1990 which eventually became U.S. Patents 5,216,167 (June 1993), 5,312,924 (May 1994) and 6,143,769 (November 2000). After filing its NDA for repaglinide in 1997, Novo Nordisk applied for patent extension under the Hatch-Waxman Act. This process, called patent term restoration, allows drug patents to be extended based on the time that a drug spent in clinical trials and in the approval process. Previously it had been decided by the U.S. Patent and Trademark Office that the expiration date of U.S. Patents 5,216,167 and 5,312,924 would be 5 September 2006. In February 2001 Prandin's patent life was extended to 14 March 2009 in response to Novo Nordisk's patent term restoration application, with U.S. Patent 5,216,167 having been reissued as RE37035.[9]

    Prior to the end of repaglinide's patent term, Novo Nordisk obtained a new patent, U.S. Patent 6,677,358 (January 2004), covering the combination therapy of repaglinide together with the generic anti-diabetic drug metformin. This new patent was due to expire June 2018. In January 2011, a federal court ruled Novo Nordisk's new patent invalid on the grounds of obviousness, and unenforceable on the grounds of inequitable conduct on the part of Novo Nordisk's patent attorneys.[10]

    References

    1. 1 2 3 4 "Repaglinide Monograph for Professionals". Drugs.com. Archived from the original on 17 May 2021. Retrieved 16 October 2021.
    2. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 "DailyMed - REPAGLINIDE - repaglinide tablet". dailymed.nlm.nih.gov. Archived from the original on 2015-10-19. Retrieved 2015-11-04.
    3. ↑ Engel, Jürgen; Kleemann, Axel; Kutscher, Bernhard; Reichert, Dietmar (14 May 2014). Pharmaceutical Substances, 5th Edition, 2009: Syntheses, Patents and Applications of the most relevant APIs. Georg Thieme Verlag. p. 1199. ISBN 978-3-13-179275-4. Archived from the original on 17 October 2021. Retrieved 16 October 2021.
    4. 1 2 BNF (80 ed.). BMJ Group and the Pharmaceutical Press. September 2020 – March 2021. p. 740. ISBN 978-0-85711-369-6.{{cite book}}: CS1 maint: date format (link)
    5. ↑ "Repaglinide Prices, Coupons & Patient Assistance Programs". Drugs.com. Archived from the original on 6 August 2020. Retrieved 16 October 2021.
    6. ↑ Mollar-Puchades MA, Martin-Cortes A, Perez-Calvo A, Diaz-Garcia C (January 2007). "Use of repaglinide on a pregnant woman during embryogenesis". Diabetes, Obesity & Metabolism. 9 (1): 146–7. doi:10.1111/j.1463-1326.2006.00629.x. PMID 17199735. S2CID 34476970.
    7. ↑ "Gluconorm (repaglinide) - New Contraindication for Concomitant Use with Clopidogrel". Health Canada. Archived from the original on 2019-06-02. Retrieved 2020-10-19.
    8. ↑ "Welcome to Novo Nordisk A/S". Novo Nordisk A/S. Archived from the original on 2014-10-02. Retrieved 2015-11-05.
    9. ↑ "Details for Patent: RE37035". Archived from the original on 2012-03-16. Retrieved 2020-10-19.
    10. ↑ Frankel A (2011-01-27). "Judge Finds Novo Nordisk Diabetes Drug Patent Invalid and Unenforceable, Questions In-House Patent Lawyer's Conduct". Archived from the original on 2020-01-27. Retrieved 2011-02-05.
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