Brimonidine/timolol

Brimonidine/timolol (INNs, trade name Combigan) are combination eye drops indicated for the treatment of glaucoma. It is a combination of brimonidine (an α2 adrenergic agonist) and timolol (a β adrenergic blocker), in concentrations of 0.2% and 0.5% respectively. Both substances work by decreasing the synthesis of aqueous humor.

Brimonidine/timolol
Combination of
Brimonidineα2 adrenergic agonist
TimololBeta blocker
Clinical data
Trade namesCombigan
AHFS/Drugs.comcombigan
Pregnancy
category
  • US: C (Risk not ruled out)
    Routes of
    administration    		Eye drops
    ATC code
    Legal status
    Legal status
    Identifiers
    PubChem CID
    KEGG

    Combigan is marketed and sold by Allergan. It has been approved by regulatory authorities in Europe, Canada, and the United States for reduction of intraocular pressure (IOP) in patients with glaucoma or ocular hypertension. Although clinical studies showed that the IOP-lowering effect was slightly greater (1-2 mmHg) with concomitant administration of 0.5% timolol twice daily and 0.2% brimonidine tartrate three times daily than with Combigan twice daily, the safety profile of latter was more favorable.[1][2]

    Medical uses

    Combigan (brimonidine tartrate/timolol maleate) 0.2%/0.5% is used to reduce IOP in patients with glaucoma or ocular hypertension who need adjunctive or replacement therapy. The recommended dosage is one drop administered to the affected eye(s) twice a day, approximately every 12 hours.[3]

    Both brimonidine 0.2% and timolol 0.5% are commonly used ophthalmic solutions for lowering IOP.[4] Timolol 0.5% is dosed one drop once or twice daily, while brimonidine 0.2% is dosed one drop three times daily. For patients who need more than one medication to lower IOP, the fixed combination product offers the advantages of reducing the number of drops and medication bottles, improving patient compliance, and decreasing ocular exposure to preservatives in ophthalmic solutions.[5]

    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.[6]

    Contraindications

    Contraindications of Combigan 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 Combigan.[7]

    Pharmacology

    Combigan 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.[8] Brimonidine exerts its ocular hypotensive effect by decreasing aqueous humor production and increasing uveoscleral outflow, while timolol acts by reducing aqueous humor production.[9] Combigan has a fast onset of action, and the peak IOP lowering effect occurs at two hours after administration.[10]

    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 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.[11][12]

    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.[13] 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.[14]

    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.[15]

    Society and culture

    Commercial aspects

    Allergan is the New Drug Application (NDA) holder of brimonidine tartrate/timolol maleate ophthalmic solution 0.2%/0.5%, which is sold under the COMBIGAN® trademark. The New Drug Application (NDA) for Combigan was approved by the US Food and Drug Administration (FDA) in October 2007.[16] Allergan, Plc is a global specialty pharmaceutical company which develops, manufactures, markets and distributes branded pharmaceutical products, aesthetic products, biosimilar and over-the-counter pharmaceutical products. In 2015, Actavis, Plc acquired Allergan, Inc. for approximately $77 billion and subsequently changed its name to Allergan, Plc. In 2015, the global revenues for Alphagan and Combigan totaled $411.1 million ($285 million from the US market), which accounted for 2.7% of Allergan’s total net revenues.[17]

    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.[18] 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.[19][20]

    Combigan is supplied in 5 mL, 10 mL, and 15 mL bottles. In the United States, the cash price of one 5-mL eye dropper of Combigan ranges from $160 to $190.[21]

    References
    1. "Prescribing Information - Combigan". Allergan. Retrieved 21 November 2016.
    2. Frampton, JE (2006). "Topical brimonidine 0.2%/timolol 0.5% ophthalmic solution: in glaucoma and ocular hypertension". Drugs Aging. 23 (9): 753–61. doi:10.2165/00002512-200623090-00005. PMID 17020399.
    3. "COMBIGAN - brimonidine tartrate, timolol maleate solution/drops". DailyMed. Retrieved 21 November 2016.
    4. "New drug information. Combigan". JAAPA. 21 (2): 14. 2008. PMID 18326089.
    5. Lee, AJ; McCluskey, P (2008). "Fixed combination of topical brimonidine 0.2% and timolol 0.5% for glaucoma and uncontrolled intraocular pressure". Clin Ophthalmol. 2 (3): 545–55. PMC 2694019. PMID 19668752.
    6. "Patient Tolerability". Combigan. Retrieved 21 November 2016.
    7. "Safety Information". Combigan. Retrieved 21 November 2016.
    8. McMonnies, CW (2016). "The importance of and potential for continuous monitoring of intraocular pressure". Clin Exp Optom. 100: 203–207. doi:10.1111/cxo.12497. PMID 27813193.
    9. Larsson, LI (2001). "Aqueous humor flow in normal human eyes treated with brimonidine and timolol, alone and in combination". Arch Ophthalmol. 119 (4): 492–5. doi:10.1001/archopht.119.4.492. PMID 11296014.
    10. 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.
    11. "BRIMONIDINE - brimonidine tartrate solution/ drops". DailyMed. Retrieved 21 November 2016.
    12. "TIMOLOL MALEATE - timolol maleate solution". DailyMed. Retrieved 21 November 2016.
    13. Craven, ER; Walters, TR; Williams, R; Chou, C; et al. (2005). "Brimonidine and timolol fixed-combination therapy versus monotherapy: a 3-month randomized trial in patients with glaucoma or ocular hypertension". J Ocul Pharmacol Ther. 21 (4): 337–48. doi:10.1089/jop.2005.21.337. PMID 16117698.
    14. Sherwood, MB; Craven, ER; Chou, C; DuBiner, HB (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". Arch Ophthalmol. 124 (9): 1230–8. doi:10.1001/archopht.124.9.1230. PMID 16966616.
    15. Goñi, FJ; Brimonidine/Timolol Fixed Combination Study Group (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". Eur J Ophthalmol. 15 (5): 581–90. PMID 16167288.
    16. Guttman, C (2007). "Fixed combination approval may boost adherence". Ophthalmology Times. 32 (22): 1.
    17. "Financial Information - Annual Reports". Allergan. Retrieved 21 November 2016.
    18. "Allergan Fights Back, Files Complaint Against Venture Fund That Filed IPR Petition". Patent Docs. Retrieved 21 November 2016.
    19. Harrison, C (2013). "Patent watch: one valid claim is all that is needed". Nat Rev Drug Discov. 12 (6): 416–7. doi:10.1038/nrd4049. PMID 23722337.
    20. "Allergan Wins Out in Combigan Generics Case". FindLaw. Retrieved 21 November 2016.
    21. "Combigan Prices and Combigan Coupons". GoodRx. Retrieved 21 November 2016.
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