Dorzolamide/timolol

Dorzolamide/timolol, sold under the brand name Cosopt among others, is a medication used to treat high pressure inside the eye including glaucoma.[1] It is a combination of dorzolamide hydrochloride and timolol maleate.[1] It may be used when a beta blocker, like timolol, is not sufficient alone.[2] It is used as an eye drop.[1]

Dorzolamide hydrochloride/Timolol maleate eye drops
Combination of
Dorzolamide hydrochlorideCarbonic anhydrase inhibitor
Timolol maleateBeta blocker
Clinical data
Trade namesCosopt, others
AHFS/Drugs.comFDA Professional Drug Information
Pregnancy
category
  • US: C (Risk not ruled out)
    Routes of
    administration    		Eye drop
    ATC code
    Legal status
    Legal status
    Identifiers
    PubChem CID
    CompTox Dashboard (EPA)
      (verify)

    Common side effects include eye discomfort, eye redness, taste changes, and blurry vision.[1] Serious side effects may include allergic reactions and heart failure.[1] Use is not recommended in those with asthma, a sulfonamide allergy, or a slow heart rate.[1][2] Dorzolamide is a carbonic anhydrase inhibitor and timolol is a beta blocker.[1] Both work by decreasing the amount of aqueous humor made by the eye.[1]

    The combination was approved for medical use in the United States in 1998.[1] It is available as a generic medication.[2] A 5 milliliter bottle in the United Kingdom costs the NHS about 1.50 £ as of 2019.[2] In the United States the wholesale cost of this amount is about US$8.30.[3] In 2016 it was the 200th most prescribed medication in the United States with more than 2 million prescriptions.[4]

    Adverse effects

    Common adverse effects include temporarily blurred vision, cloudy vision, double vision, temporary burning/stinging/itching of the eye, watery eyes, feeling as if something is in the eye, drooping eyelid, sensitivity to light, cough, flu symptoms, nausea, and stomach pain.[5]

    More serious adverse effects include dizziness, slow or irregular heartbeat, muscle weakness, mental/mood changes, and coldness/numbness/pain in the hands or feet.[5]

    Pharmacology

    Dorzolamide is a human carboanydrase II inhibitor.[6] Inhibition of carboanhydrase in the ciliary processes of the eye decreases aqueous humor secretion supposedly by decreasing the formation rate of bicarbonate ions.[7] This results in reduction in both sodium and fluid transport.

    Timolol is a non-selective beta-adrenergic antagonist.[8]

    Comparison to other products

    Despite each of the active ingredients being availed in their own respective formulations, combination formulations are typically more convenient for the patient without sacrificing any quality in therapy. In the case of Cosopt, the combination formulation dosed twice daily provides equivalent treatment to both dorzolamide 2% dosed two times daily and timolol 0.5% dosed three times daily.[9] Specifically, the mean reduction in intraocular pressure was 27.4% for the combination product, 15.5% for dorzolamide 2%, and 22.2% for timolol 0.5%.

    Compared to other products such as latanoprost, both are equally efficacious with regard to lowering intraocular pressure and getting patients to reach their target intraocular pressure.[9] Cosopt, though, is typically less well tolerated than other treatments due to a well documented feeling of ocular burning upon administration.

    History

    Cosopt gained Food and Drug Administration (FDA) approval in April 1998 and was supplied initially by Merck.[10] In 2016, Merck & Co. had $95.3 billion in total assets, $40.3 billion in total equity, $24.3 billion in long term debt, and $13.4 billion in working capital.[11] This same year Merck & Co spent $20 billion total split virtually evenly between research and development (R&D) and marketing efforts.  Cosopt had annual sales of $342 million during the 12 months before June 2008.[12] In September 2013,  Merck & Co. sold the U.S. rights to their ophthalmic product line (including Cosopt) to Akorn Inc. for $52.8 million cash.[13]

    Upon the original patent expiration, Hi-Tech Pharma was the first of many generic competitors to submit an abbreviated new drug application (ANDA) for dorzolamide hydrochloride/timolol maleate eye drops.[14] Hi-Tech Pharma's ANDA was approved on October 28, 2008.  At the time, controversy surrounded the approval of this first ANDA.  Hi-Tech sued the FDA for their right to 180 market exclusivity as laid out in the Hatch-Waxman Act. Apotex, another firm seeking an ANDA approval for generic Cosopt, argued that Hi-Tech "forfeited its rights to market exclusivity because it has failed to market the drug within 30 months of its ANDA submission or within 75 days after Merck withdrew its patent information."[14] The FDA upheld their previous exclusivity decisions on acarbose and granisetron, allowing both Hi-Tech and Apotex to make a generic version of Cosopt.[12] Soon after, ANDAs from Sandoz, Bausch & Laumb, TEVA and others were also approved.[15]

    Just over a year before Merck sold their ophthalmic line to Akorn, Akorn developed a new formulation of dorzolamide hydrochloride/timolol maleate called Cosopt PF, which is simply a preservative free formulation of Cosopt.[16] It gained FDA approval in July 2012 and is currently protected by market exclusivity.

    Society and culture

    Legality

    In the United States, Cosopt, as well as its generics, is only available to patients with a valid prescription.[15]

    Cost

    The brand name Cosopt currently costs upwards of $200 after discounts[17] while the generic formulation costs around $70 cash.[18] The more recent preservative free formulation can be purchased for less than the original brand name formulation at around $160[19]

    References
    1. "Dorzolamide Hydrochloride and Timolol Maleate Solution". DailyMed. Retrieved 26 March 2019.
    2. British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. p. 1149. ISBN 9780857113382.
    3. "NADAC as of 2019-02-27". Centers for Medicare and Medicaid Services. Retrieved 3 March 2019.
    4. "The Top 300 of 2019". clincalc.com. Retrieved 22 December 2018.
    5. "Common Side Effects of Cosopt (Dorzolamide Hydrochloride-Timolol Maleate Ophthalmic Solution) Drug Center - RxList". RxList. Retrieved 2017-10-30.
    6. "Dorzolamide". www.drugbank.ca. Retrieved 2017-10-27.
    7. "Cosopt - FDA prescribing information, side effects and uses". Drugs.com. Retrieved 2017-10-30.
    8. "Timolol". www.drugbank.ca. Retrieved 2017-10-27.
    9. Bartlett, Jimmy (2008). Clinical Ocular Pharmacology. https://books.google.com/books?id=Eybg7fbs65MC&pg=PA166&lpg=PA166&dq=cosopt+pharmacology&source=bl&ots=gFP7IEk7yz&sig=QznLSog1YWagh_FKcB3D5TkcWnA&hl=en&sa=X&ved=0ahUKEwjM2qPr3ZbXAhVCLyYKHa0UBrEQ6AEIVzAJ#v=onepage&q=cosopt%20pharmacology&f=false. p. 166.
    10. "Merck Receives FDA Approval to Market 'Cosopt'". www.newswise.com. Retrieved 2017-10-20.
    11. "Merck Form 10-K" (PDF). Merck. Retrieved 2017-10-27.
    12. "FDA Says Hi-Tech Forfeited Exclusivity; Way Paved for Approval of All Cosopt ANDAs". Leydig. 2008-11-07. Retrieved 2017-10-27.
    13. "Akorn Acquires Three Branded Ophthalmic Products from Merck". Business Wire. 2013-11-15. Retrieved 2017-10-27.
    14. "Hi-Tech Sues FDA To Get Generic Cosopt Exclusivity". Law360. 2008-08-04. Retrieved 2017-10-27.
    15. "Generic Cosopt Availability". Drugs.com. Retrieved 2017-10-27.
    16. "October 2017 - When do the COSOPT PF patents expire, and when will generic COSOPT PF be available?". Deep knowledge on small-molecule drugs and the 120,000 global patents covering them. Retrieved 2017-10-29.
    17. "Prices and Coupons for Cosopt". Retrieved 2017-10-29.
    18. "Prices and Coupons for Cosopt". www.goodrx.com. Retrieved 2017-10-29.
    19. "Prices and Coupons for Cosopt PF". www.goodrx.com. Retrieved 2017-10-29.
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