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Dorzolamide/timolol

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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
License data
Routes of
administration		Eye drop
ATC code
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
CompTox Dashboard (EPA)
  (verify)

Dorzolamide/timolol, sold under the brand name Cosopt among others, is a medication used to treat high pressure inside the eye including glaucoma.[3][4][5] It is a combination of dorzolamide hydrochloride and timolol maleate.[3] It may be used when a beta blocker, like timolol, is not sufficient alone.[6] It is used as an eye drop.[3]

Common side effects include eye discomfort, eye redness, taste changes, and blurry vision.[3] Serious side effects may include allergic reactions and heart failure.[3] Use is not recommended in those with asthma, a sulfonamide allergy, or a slow heart rate.[3][6] Dorzolamide is a carbonic anhydrase inhibitor and timolol is a beta blocker.[3] Both work by decreasing the amount of aqueous humor made by the eye.[3]

The combination was approved for medical use in the United States in 1998.[3] It is available as a generic medication.[6] In 2020, it was the 195th most commonly prescribed medication in the United States, with more than 2 million prescriptions.[7][8]

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.[9]

More serious adverse effects include dizziness, slow or irregular heartbeat, muscle weakness, mental/mood changes, and coldness/numbness/pain in the hands or feet.[9]

Pharmacology

Dorzolamide is a human carboanydrase II inhibitor.[10] Inhibition of carboanhydrase in the ciliary processes of the eye decreases aqueous humor secretion supposedly by decreasing the formation rate of bicarbonate ions.[11] This results in reduction in both sodium and fluid transport.

Timolol is a non-selective beta-adrenergic antagonist.[12]

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.[13] 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.[13] 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.[14] 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.[15] 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.[16] 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.[17]

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.[18] Hi-Tech Pharma's ANDA was approved on 28 October 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."[18] The FDA upheld their previous exclusivity decisions on acarbose and granisetron, allowing both Hi-Tech and Apotex to make a generic version of Cosopt.[16] Soon after, ANDAs from Sandoz, Bausch & Laumb, TEVA and others were also approved.[19]

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.[20]

References

  1. ^ "Cosopt- dorzolamide hydrochloride and timolol maleate solution/ drops". DailyMed. 2 December 2022. Archived from the original on 24 January 2022. Retrieved 7 June 2023.
  2. ^ "Cosopt PF- dorzolamide hydrochloride and timolol maleate solution/ drops". DailyMed. 8 November 2022. Retrieved 7 June 2023.
  3. ^ a b c d e f g h i "Dorzolamide Hydrochloride and Timolol Maleate Solution". DailyMed. Archived from the original on 27 March 2019. Retrieved 26 March 2019.
  4. ^ He M, Wang W, Huang W (2013). "Efficacy and tolerability of the fixed combinations latanoprost/timolol versus dorzolamide/timolol in patients with elevated intraocular pressure: a meta-analysis of randomized controlled trials". PLOS ONE. 8 (12): e83606. Bibcode:2013PLoSO...883606H. doi:10.1371/journal.pone.0083606. PMC 3859645. PMID 24349536.
  5. ^ Konstas AG, Schmetterer L, Katsanos A, Hutnik CM, Holló G, Quaranta L, et al. (January 2021). "Dorzolamide/Timolol Fixed Combination: Learning from the Past and Looking Toward the Future". Advances in Therapy. 38 (1): 24–51. doi:10.1007/s12325-020-01525-5. PMC 7854404. PMID 33108623.
  6. ^ a b c British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. p. 1149. ISBN 9780857113382.
  7. ^ "The Top 300 of 2020". ClinCalc. Archived from the original on 12 February 2021. Retrieved 7 October 2022.
  8. ^ "Dorzolamide; Timolol - Drug Usage Statistics". ClinCalc. Archived from the original on 11 October 2022. Retrieved 7 October 2022.
  9. ^ a b "Common Side Effects of Cosopt (Dorzolamide Hydrochloride-Timolol Maleate Ophthalmic Solution) Drug Center - RxList". RxList. Archived from the original on 7 November 2017. Retrieved 30 October 2017.
  10. ^ "Dorzolamide". www.drugbank.ca. Archived from the original on 2 July 2017. Retrieved 27 October 2017.
  11. ^ "Cosopt - FDA prescribing information, side effects and uses". Drugs.com. Archived from the original on 7 November 2017. Retrieved 30 October 2017.
  12. ^ "Timolol". www.drugbank.ca. Archived from the original on 28 October 2017. Retrieved 27 October 2017.
  13. ^ a b Bartlett J (2008). Clinical Ocular Pharmacology. Elsevier Health Sciences. p. 166. ISBN 978-0750675765.
  14. ^ "Merck Receives FDA Approval to Market 'Cosopt'". www.newswise.com. Archived from the original on 21 October 2017. Retrieved 20 October 2017.
  15. ^ "Merck Form 10-K" (PDF). Merck. Archived (PDF) from the original on 28 October 2017. Retrieved 27 October 2017.
  16. ^ a b "FDA Says Hi-Tech Forfeited Exclusivity; Way Paved for Approval of All Cosopt ANDAs". Leydig. 7 November 2008. Archived from the original on 28 October 2017. Retrieved 27 October 2017.
  17. ^ "Akorn Acquires Three Branded Ophthalmic Products from Merck". Business Wire. 15 November 2013. Archived from the original on 28 October 2017. Retrieved 27 October 2017.
  18. ^ a b "Hi-Tech Sues FDA To Get Generic Cosopt Exclusivity". Law360. 4 August 2008. Archived from the original on 28 October 2017. Retrieved 27 October 2017.
  19. ^ "Generic Cosopt Availability". Drugs.com. Archived from the original on 28 October 2017. Retrieved 27 October 2017.
  20. ^ "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. Archived from the original on 7 November 2017. Retrieved 29 October 2017.
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