Brimonidine/timolol

Brimonidine/timolol

Combination of
Brimonidine	α2 adrenergic agonist
Timolol	Beta blocker
Clinical data
Trade names	Combigan
AHFS/Drugs.com	Professional Drug Facts
Pregnancy category	AU: C
Routes of administration	Eye drops
ATC code	S01ED51 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) US: ℞-only[1]
Identifiers
CAS Number	952743-07-6
PubChem CID	11387895
KEGG	D10298
CompTox Dashboard (EPA)	DTXSID20915041

Brimonidine/timolol, sold under the brand name Combigan among others, is a fixed-dose combination medication eye drop used for the treatment of glaucoma.^[1] It is a combination of brimonidine (an α₂ adrenergic agonist) and timolol (a β adrenergic blocker).^[1]

In 2020, it was the 256th most commonly prescribed medication in the United States, with more than 1 million prescriptions.^[2][3]

Medical uses

Brimonidine/timolol is used to reduce elevated intraocular pressure (IOP) in people with glaucoma or ocular hypertension who need adjunctive or replacement therapy.^[1]

Adverse effects

The most common adverse effects affecting 5 to 15% of the patients include allergic conjunctivitis, conjunctival folliculosis, conjunctival hyperemia, eye pruritus, ocular burning, and stinging. 1 to 5% of the patients in clinical trials experienced asthenia, blepharitis, corneal erosion, depression, epiphora, eye discharge, eye dryness, eye irritation, eye pain, eyelid edema, eyelid erythema, eyelid pruritus, foreign body sensation, headache, hypertension, oral dryness, somnolence, superficial punctate keratitis, and visual disturbance.^[1]

Contraindications

Contraindications of brimonidine/timolol include the following: reactive airway disease including bronchial asthma, a history of bronchial asthma, severe chronic obstructive pulmonary disease, sinus bradycardia, secondary or third degree atrioventricular block, overt cardiac failure, cardiogenic shock, age less than 2 years, and hypersensitivity to any component of brimonidine/timolol.^[1]

Pharmacology

Brimonidine/timolol is composed of brimonidine, a selective alpha-2 adrenergic receptor agonist, and timolol, a non-selective beta-adrenergic receptor inhibitor. Elevated IOP is considered the only modifiable risk factor in the pathogenesis of glaucoma.^[4] Brimonidine exerts its ocular hypotensive effect by decreasing aqueous humor production and increasing uveoscleral outflow, while timolol acts by reducing aqueous humor production.^[5] Brimonidine/timolol has a fast onset of action, and the peak IOP lowering effect occurs at two hours after administration.^[6]

History

Preclinical studies

No carcinogenic effects were found with brimonidine tartrate in mice or rats. With timolol maleate, 300 mg/kg/day in rats (equivalent to about 42,000 times systemic exposure following the maximum recommended ocular dose in human [MRHOD]) was associated with significantly increased incidence of adrenal pheochromocytomas in a two-year study; in a lifetime study in mice, 500 mg/kg/day (equivalent to about 71,000 times systemic exposure following the MRHOD) but not 5 or 50 mg/kg/day (about 700 or 7,000 times systemic exposure following the MRHOD) of timolol maleate was associated with significantly increased incidence of benign and malignant pulmonary tumors, benign uterine polyps and mammary adenocarcinomas.

Neither brimonidine tartrate nor timolol maleate was mutagenic in vitro and in vivo studies. Reproduction and fertility studies in rats did not reveal any adverse effects on male or female fertility with brimonidine tartrate or timolol maleate.^[7][8]

Clinical trials

Two prospective, randomized, double-blinded, phase III clinical trials were conducted at 53 sites in the United States to compare the IOP-lowering efficacy and safety of 0.2% brimonidine tartrate/0.5% timolol maleate fixed combination twice daily with 0.2% brimonidine tartrate three times daily or 0.5% timolol maleate twice daily in patients aged 18 or older who had ocular hypertension or glaucoma. When assessed over a 3-month period, pooled results from a total of 1159 patients showed significantly greater mean IOP decrease from baseline with the brimonidine/timolol combination (4.9-7.6 mmHg) than with brimonidine monotherapy (3.1-5.5 mmHg) or timolol monotherapy (4.3-6.2 mmHg) across all follow-up visits.^[9] Similar efficacy results were reported during 12-month follow-up: mean IOP decrease from baseline was 4.4-7.6 mmHg with brimonidine/timolol combination, compared to 2.7-5.5 mmHg with brimonidine and 3.9-6.2 mmHg with timolol. The incidence of treatment-related adverse events with the brimonidine/timolol combination was lower than that with brimonidine monotherapy but higher than that with timolol monotherapy.^[10]

A 12-week prospective, randomized, double-blinded study in 371 glaucoma and ocular hypertension patients with inadequate IOP control on monotherapy compared the efficacy and safety of 0.2% brimonidine tartrate/0.5% timolol fixed combination twice daily with the concomitant use of 0.2% brimonidine tartrate twice daily and timolol 0.5% twice daily. The IOP-lowering effect of the fixed combination group was shown to be non-inferior to that of concomitant therapy. Incidence of adverse events was similar between groups.^[11]

Society and culture

Brand names

Allergan holds at least six active patents protecting Combigan from generic competition. Several generic companies challenged the validity of the patents and filed Abbreviated New Drug Applications (ANDA) seeking market entry. Allergan responded by filing a lawsuit against the ANDA filers.^[12] In Allergan, Inc. v. Sandoz, Inc., the US Court of Appeals for the Federal Circuit ruled that Allergan's composition-related patent claims were invalid based on obviousness, because brimonidine and timolol had already been marketed in the claimed concentrations. However, Allergan's method claim (US Patent No. 7,030,149), which states "reducing the number of daily topical ophthalmic doses of brimonidine administered topically to an eye of a person in need thereof for the treatment of glaucoma or ocular hypertension from 3 to 2 times a day without loss of efficacy", was held to be non-obvious. As a result, generic companies are prevented from marketing generic versions of Combigan until its patent expiration in 2022.^[13][14]

On February 2, 2022, Carlisle Medical issued a press release^[15] announcing that Apotex Corporation has launched the authorized generic version of Combigan (Brimonidine Timolol OPSO 0.2%/0.5%) in the United States subsequent to the FDA'a approval of the generic on December 13, 2021.^[16] On April 14, 2022, Novartis' Sandoz, Inc. issue a press release announcing the US launch of its generic combination.^[17]

References

1. "Combigan- brimonidine tartrate, timolol maleate solution/ drops". DailyMed. 1 October 2015. Retrieved 12 November 2022.
2. "The Top 300 of 2020". ClinCalc. Retrieved 7 October 2022.
3. "Brimonidine; Timolol - Drug Usage Statistics". ClinCalc. Retrieved 7 October 2022.
4. McMonnies CW (May 2017). "The importance of and potential for continuous monitoring of intraocular pressure". Clinical & Experimental Optometry. 100 (3): 203–207. doi:10.1111/cxo.12497. PMID 27813193. S2CID 205049171.
5. Larsson LI (April 2001). "Aqueous humor flow in normal human eyes treated with brimonidine and timolol, alone and in combination". Archives of Ophthalmology. 119 (4): 492–5. doi:10.1001/archopht.119.4.492. PMID 11296014.
6. Villarrubia HJ, Feldman RM (2007). "Topical fixed combination brimonidine-timolol therapy for glaucoma and ocular hypertension". Expert Review of Ophthalmology. 2 (5): 705–710. doi:10.1586/17469899.2.5.705. S2CID 73946491.
7. "BRIMONIDINE - brimonidine tartrate solution/ drops". DailyMed. Retrieved 21 November 2016.
8. "TIMOLOL MALEATE - timolol maleate solution". DailyMed. Retrieved 21 November 2016.
9. Craven ER, Walters TR, Williams R, Chou C, Cheetham JK, Schiffman R (August 2005). "Brimonidine and timolol fixed-combination therapy versus monotherapy: a 3-month randomized trial in patients with glaucoma or ocular hypertension". Journal of Ocular Pharmacology and Therapeutics. 21 (4): 337–48. doi:10.1089/jop.2005.21.337. PMID 16117698.
10. Sherwood MB, Craven ER, Chou C, DuBiner HB, Batoosingh AL, Schiffman RM, Whitcup SM (September 2006). "Twice-daily 0.2% brimonidine-0.5% timolol fixed-combination therapy vs monotherapy with timolol or brimonidine in patients with glaucoma or ocular hypertension: a 12-month randomized trial". Archives of Ophthalmology. 124 (9): 1230–8. doi:10.1001/archopht.124.9.1230. PMID 16966616.
11. Goñi FJ (2005). "12-week study comparing the fixed combination of brimonidine and timolol with concomitant use of the individual components in patients with glaucoma and ocular hypertension". European Journal of Ophthalmology. 15 (5): 581–90. doi:10.1177/112067210501500508. PMID 16167288. S2CID 12481940.
12. "Allergan Fights Back, Files Complaint Against Venture Fund That Filed IPR Petition". Patent Docs. Retrieved 21 November 2016.
13. Harrison C (June 2013). "Patent watch: one valid claim is all that is needed". Nature Reviews. Drug Discovery. 12 (6): 416–7. doi:10.1038/nrd4049. PMID 23722337. S2CID 29970897.
14. "Allergan Wins Out in Combigan Generics Case". FindLaw. 8 May 2013. Retrieved 21 November 2016.
15. "Generic Release of Combigan". Carlisle Medical. Retrieved 19 October 2022.
16. "Combigan First Time Generic Approval" (PDF). Nirvana Health. Retrieved 19 October 2022.
17. "Sandoz Launches Generic Version". Pharmacy Times. Retrieved 19 October 2022.