Brinzolamide + Timolol

Ophthalmic
Ocular hypertension, Open-angle glaucoma

CrCl (mL/min)	Dosage
<30	Contraindicated.

Hypersensitivity to brinzolamide, timolol, other β-blockers, or sulfonamides. Reactive airway disease, including current or history of bronchial asthma and severe COPD; sick sinus syndrome, sinus bradycardia, sino-atrial block, 2nd- or 3rd-degree AV block, overt cardiac failure, cardiogenic shock, severe allergic rhinitis and bronchial hyperreactivity, hyperchloraemic acidosis. Severe renal impairment (CrCl <30 mL/min).

Patient with CV disease (e.g. Prinzmetal's angina, coronary heart disease, compensated cardiac failure, hypotension, 1st-degree AV block), peripheral vascular disease (PVD), Raynaud's disease, mild to moderate COPD; myasthenia gravis, diabetes mellitus, thyroid disease; history of atopy or severe anaphylactic reaction to various allergens; pseudoexfoliative glaucoma, pigmentary glaucoma, corneal disease, compromised corneas (e.g. corneal dystrophy, patients with low endothelial cell counts), history of psychiatric illness. Patients subject to spontaneous hypoglycaemia and those undergoing major surgery. Avoid abrupt withdrawal. Timolol may mask signs of hypoglycaemia and hyperthyroidism (e.g. tachycardia). Not recommended for the treatment of narrow-angle glaucoma. Hepatic and mild to moderate renal impairment. Pregnancy and lactation.

Significant: Choroidal detachment (post-filtration procedures), dry eyes, increased risk of corneal oedema (in contact lenses wearers and patients with compromised corneas); acid-base disturbances (e.g. metabolic acidosis), CNS effects (e.g. CNS depression, impaired mental alertness and/or physical coordination); may precipitate or exacerbate arterial insufficiency symptoms (in patients with PVD and Raynaud's disease), may aggravate symptoms of myasthenia gravis (e.g. diplopia, ptosis, generalised weakness); hypersensitivity reactions, Stevens-Johnson syndrome, toxic epidermal necrolysis.
Cardiac disorders: Palpitation, chest pain.
Ear and labyrinth disorders: Tinnitus.
Eye disorders: Punctate keratitis, blurred vision, eye pain or irritation, foreign body sensation, eye allergy, eyelid oedema, conjunctivitis.
Gastrointestinal disorders: Dysgeusia, nausea, dry mouth, diarrhoea, abdominal discomfort.
General disorders and administration site conditions: Fatigue.
Investigations: Decreased heart rate and blood pressure.
Musculoskeletal and connective tissue disorders: Myalgia.
Nervous system disorders: Headache, dizziness, paraesthesia.
Psychiatric disorders: Hallucination, insomnia.
Respiratory, thoracic and mediastinal disorders: Asthma, cough, dyspnoea, epistaxis.
Skin and subcutaneous tissue disorders: Alopecia, erythema, rash, pruritus.
Potentially Fatal: Severe respiratory reactions due to bronchospasm (in patients with asthma); severe cardiac reactions, including cardiac failure.

Remove contact lenses before administration and wait for at least 15 minutes after instillation prior to reinsertion. This drug may cause transient blurred vision or other visual disturbances and may reduce mental alertness or physical coordination; if affected, do not drive or operate machinery.

Monitor IOP and perform ophthalmic exams periodically. Assess heart rate or signs of cardiac failure (in patients with severe cardiac disease), hypersensitivity reactions, and development of punctate and/or toxic ulcerative keratopathy (with frequent or long-term use).

Brinzolamide: May cause additive systemic effects with oral carbonic anhydrase inhibitors. Metabolism may be inhibited by CYP3A4 inhibitors (e.g. ketoconazole, ritonavir, troleandomycin).
Timolol: May cause additive effects leading to hypotension and/or marked bradycardia with oral Ca channel blockers, β-blockers, antiarrhythmic agents (e.g. amiodarone), digitalis glycosides, parasympathomimetics, and guanethidine. May result in mydriasis when given with epinephrine. May enhance the rebound hypertensive reaction of clonidine (when it is suddenly withdrawn). May result in enhanced systemic β-blockade (e.g. decreased heart rate, depression) with CYP2D6 inhibitors (e.g. fluoxetine, paroxetine, quinidine). May potentiate the hypoglycaemic effects of antidiabetic agents.

Description:
Mechanism of Action: Brinzolamide and timolol both reduce elevated intraocular pressure (IOP) mainly by lowering aqueous humour secretion but by different mechanisms of action.
Brinzolamide inhibits carbonic anhydrase in the ciliary process of the eye thereby decreasing the secretion of aqueous humour and leading to the reduction of IOP.
Timolol is a non-selective β-adrenergic receptor blocker that has no significant intrinsic sympathomimetic, direct myocardial depressant, or membrane-stabilising activity. The precise mechanism of action to reduce IOP is not clearly established; however, it may be by decreasing aqueous humour production or by increasing the outflow of aqueous humour.
Onset: Timolol: Reduction of IOP: 30 minutes.
Duration: Timolol: 24 hours.
Pharmacokinetics:
Absorption: Systemically absorbed through the cornea.
Distribution: Brinzolamide: Accumulates in RBCs and binds to carbonic anhydrase (brinzolamide and N-desethyl brinzolamide). Plasma protein binding: Approx 60%.
Timolol: Crosses the placenta and enters breast milk. Detectable in plasma at low concentrations.
Metabolism: Brinzolamide: Metabolised into N-desethyl brinzolamide.
Timolol: Extensively metabolised in the liver mainly by CYP2D6 isoenzyme.
Excretion: Brinzolamide: Via urine (as unchanged drug and metabolites).
Timolol: Via urine (approx 20% as unchanged drug; remainder as metabolites). Elimination half-life: Approx 4 hours.

Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 68844, Brinzolamide. https://pubchem.ncbi.nlm.nih.gov/compound/Brinzolamide. Accessed Oct. 23, 2023.

Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 33624, Timolol. https://pubchem.ncbi.nlm.nih.gov/compound/Timolol. Accessed Nov. 22, 2023.

Store below 30°C. Do not freeze. Use within 4 weeks after opening.

Antiglaucoma Preparations

S01ED51 - timolol, combinations ; Belongs to the class of beta blocking agents. Used in the treatment of glaucoma.

Anon. Brinzolamide and Timolol. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 14/02/2023.

Anon. Brinzolamide. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 14/02/2023.

Anon. Timolol (Ophthalmic). Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 14/02/2023.

Azarga 10 mg/mL + 5 mg/mL Eye Drops, Suspension (Novartis Corporation [Malaysia] Sdn. Bhd). National Pharmaceutical Regulatory Agency - Ministry of Health Malaysia. https://www.npra.gov.my. Accessed 14/02/2023.

Brinzolamide/Timolol Aspire 10 mg/mL + 5 mg/mL Eye Drops, Suspension (Aspire Pharma Limited). MHRA. https://products.mhra.gov.uk. Accessed 14/02/2023.

Buckingham R (ed). Timolol Maleate. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 14/02/2023.

Joint Formulary Committee. Brinzolamide with Timolol. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 21/11/2022.

Novartis New Zealand Limited. Azarga Eye Drops data sheet 28 July 2022. Medsafe. http://www.medsafe.govt.nz. Accessed 14/02/2023.