Brinzolamide/ Brimonidine Tartrate

Registered South African indications:

• Decrease of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension for whom monotherapy provides insufficient IOP reduction

Contraindications

Registered contraindications in South Africa & other jurisdictions

• Hypersensitivity to the active ingredients or any of the excipients in this combination product
• Hypersensitivity to sulphonamides
• Patients receiving monoamine oxidase (MAO) inhibitor therapy
• Patients on antidepressants which affect noradrenergic transmission (e.g., tricyclic antidepressants and mianserin)
• Patients with severe renal impairment
• Patients with hyperchloraemic acidosis
• Neonates and infants under the age of 2 years

Cautions

Recommendations in South Africa & other jurisdictions

• Pregnancy
• Women of childbearing potential
• Breastfeeding
• Mild to moderate renal impairment (CrCl>30ml/min)
• Hepatic impairment
• Elderly
• Children 2 years and above (especially those in the 2-7 age range and/or weighing <20kg)
• Narrow-angle glaucoma 
• Compromised corneas (particularly in patients with low endothelial cell count)
• Diabetes mellitus
• Corneal dystrophies
• Concomitant use with contact lens (including soft contact lens)
• Severe or unstable and uncontrolled cardiovascular disease
• Depression
• Cerebral insufficiency
• Coronary insufficiency
• Raynaud's phenomenon
• Orthostatic hypotension
• Thromboangiitis obliterans 
• Pre-existing dry eye 
• Pre-existing compromised cornea 
• Prolonged or repeated usage
• Pre-existing extensive ocular surface disease (South African manufacturer recommendations)
• May impair ability to drive and operate machinery  

Forms avail. in SA and covered in this monograph: opd

South African registered indications and dosages

Decrease of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension for whom monotherapy provides insufficient IOP reduction

• Ophthalmic (opd): 1 drop into affected eye(s), 2 times dly

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Missed dose: If a dose is missed, treatment should be continued with the next dose as planned

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Method of administration:
For ocular use. Advise patients to shake the bottle gently before use. When nasolacrimal occlusion is used and the eyelids are closed for 2 minutes, systemic absorption is reduced. This may result in a decrease in systemic side effects and an increase in local activity. To prevent contamination of the dropper tip and solution, care must be taken not to touch the eyelids, surrounding areas or other surfaces with the dropper tip of the bottle. Keep the bottle tightly closed when not in use

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Brinzolamide/ brimonidine may be coadministered with other topical ophthalmic medicines to lower intraocular pressure. If more than one topical ophthalmic agent is being used, the administration should be at least 5 minutes apart

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This agent should not be injected

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Patients should be instructed not to swallow brinzolamide/ brimonidine

Younger than 2 years: Contraindicated
Between 2-17 years: Not established for use

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Not recommended: Treatment of children 2 years and above (especially those in the 2-7 age range and/or weighing <20kg) because of the potential for central nervous system related side effects

Pregnancy

South African recommendations 

• Caution; not recommended
• The safety of brinzolamide/ brimonidine tartrate in pregnancy have not been established
• Use of brinzolamide/ brimonidine tartrate is not recommended during pregnancy and in women of childbearing potential not using contraception
• Brinzolamide was not teratogenic in rats and rabbits, following systemic administration (oral gavage). Animal studies with oral brimonidine tartrate do not indicate direct harmful effects with respect to reproductive toxicity. In animal studies, brimonidine tartrate crossed the placenta and entered into the foetal circulation to a limited extent

Recommendations in other jurisdictions

• Caution; not recommended
• There are no or limited amount of data from the use of brinzolamide/ brimonidine tartrate in pregnant women
• Use of brinzolamide/ brimonidine tartrate is not recommended during pregnancy and in women of childbearing potential not using contraception
• Brinzolamide was not teratogenic in rats and rabbits, following systemic administration (oral gavage). Animal studies with oral brimonidine tartrate do not indicate direct harmful effects with respect to reproductive toxicity. In animal studies, brimonidine tartrate crossed the placenta and entered into the foetal circulation to a limited extent 

Breastfeeding

South African recommendations 

• Caution; not recommended 
• Brinzolamide/ brimonidine tartrate should not be used by women who are breastfeeding their infants
• Animal studies have shown that following oral administration, minimal levels of brinzolamide are excreted in breastmilk and that brimonidine tartrate administered orally is excreted in breastmilk

Recommendations in other jurisdictions

• Caution; not recommended 
• It is unknown whether topical brinzolamide/ brimonidine tartrate is excreted in human milk
• Available pharmacodynamic/toxicological data in animals have shown that following oral administration, minimal levels of brinzolamide are excreted in breast milk. Brimonidine tartrate administered orally is excreted in breast milk. Brinzolamide/ brimonidine tartrate should not be used by women who are breastfeeding

Fertility

Recommendations below are applicable to South Africa and other jurisdictions

• Non-clinical data do not show any effects of brinzolamide or brimonidine tartrate on fertility. There are no data on the effect of topical ocular administration of brinzolamide/ brimonidine tartrate on human fertility

Recommendations below are applicable to South Africa and other jurisdictions

• Mild to moderate (CrCl>30ml/min): Caution; no dose adjustment recommended
• Severe (CrCl<30ml/min): Contraindicated
  Brinzolamide/ brimonidine tartrate has not been studied in patients with hyperchloraemic acidosis. Since the brinzolamide component of Brinzolamide/ brimonidine tartrate and its metabolite are excreted predominantly by the kidney, brinzolamide/ brimonidine tartrate is contraindicated in such patients

Recommendations below are applicable to South Africa and other jurisdictions

• Caution; no information available

Recommendations below are applicable to South Africa and other jurisdictions

• Caution; no dose adjustment recommended

Brinzolamide/ Brimonidine Tartrate
Central Nervous System Disorders

• Headache
• Somnolence

Cardiovascular Disorders 

• Hypotension

Respiratory Disorders 

• Nasal congestion
• Nasal dryness
• Postnasal drip

Gastrointestinal Disorders 

• Dry throat
• Dry mouth
• Dyspepsia
• Abdominal discomfort
• Oral paraesthesia

Skin and Subcutaneous Tissue Disorders 

• Contact dermatitis

Sensory Disorders 

• Dysgeusia
• Eye allergy
• Keratitis
• Eye pain
• Ocular discomfort
• Blurred vision
• Ocular hyperaemia
• Corneal erosion
• Blepharitis
• Corneal deposits (keratic precipitates)
• Conjunctival disorder (papillae)
• Photophobia
• Eyelid oedema
• Conjunctival oedema
• Dry eye
• Eye discharge
• Increased lacrimation
• Eyelid erythema
• Abnormal sensation in eye
• Asthenopia
• Vertigo

Others

• Medication residue

Brinzolamide
Central Nervous System Disorders

• Apathy
• Depression
• Depressed mood
• Decreased libido
• Nightmares
• Nervousness
• Motor dysfunction
• Amnesia
• Memory impairment
• Paraesthesia
• Tremor
• Hypoaesthesia
• Feeling abnormal
• Feeling jittery
• Irritability

Cardiovascular Disorders 

• Cardio-respiratory distress
• Angina pectoris
• Palpitations
• Irregular heart rate
• Bradycardia

Respiratory Disorders 

• Nasopharyngitis
• Pharyngitis
• Sinusitis
• Rhinitis
• Rhinorrhoea
• Dyspnoea
• Bronchial hyperactivity
• Pharyngolaryngeal pain
• Cough
• Epistaxis
• Throat irritation
• Upper respiratory tract congestion
• Sneezing
• Asthma
• Chest discomfort
• Chest pain

Gastrointestinal Disorders

• Oesophagitis
• Diarrhoea
• Frequent bowel movements
• Flatulence
• Nausea and vomiting

Hepatobiliary Disorders 

• Abnormal hepatic function test

Genitourinary Disorders

• Erectile dysfunction
• Renal pain
• Pollakiuria

Musculoskeletal Disorders 

• Back pain
• Muscle spasms
• Myalgia
• Arthralgia
• Pain in extremity

Skin and Subcutaneous Tissue Disorders 

• Urticaria
• Rash
  - Maculopapular rash
• Generalised pruritus
• Alopecia
• Skin tightness
• Dermatitis
• Erythema

Immune, Blood and Lymphatic System Disorders 

• Decreased red blood cells
• Increased blood chloride
• Peripheral oedema

Sensory Disorders 

• Ageusia
• Corneal oedema
• Photopsia
• Eye swelling
• Reduced visual acuity
• Pterygium
• Meibomianitis
• Diplopia
• Glare
• Eye hypoaesthesia
• Scleral pigmentation
• Subconjunctival cyst
• Visual disturbances
• Madarosis
• Tinnitus
• Oral hypoaesthesia

Others

• Pain

Brimonidine Tartrate
Central Nervous System Disorders

• Depression
• Dizziness
• Syncope

Cardiovascular Disorders 

• Hypertension
• Bradycardia
• Tachycardia
• Arrhythmia
• Palpitations

Skin and Subcutaneous Tissue Disorders 

• Dermatitis
• Erythema

Immune, Blood and Lymphatic System Disorders 

• Peripheral oedema
• Hypersensitivity

Sensory Disorders 

• Abnormal vision
• Conjunctival blanching
• Face oedema
• Miosis
• Uveitis

• Monoamine oxidase inhibitors
• Antidepressants which affect noradrenergic transmission 
• Tricyclic antidepressants 
• Mianserin
• Central nervous system (CNS) depressants
• Barbiturates
• Opiates
• Sedatives
• Anaesthetics
• Agents which affect the metabolism and uptake of circulating amines 
• Chlorpromazine
• Methylphenidate
• Reserpine
• Serotonin-norepinephrine reuptake inhibitors
• Beta-blockers (ophthalmic and systemic)
• Antihypertensives 
• Cardiac glycosides
• Digoxin
• Systemic agents (irrespective of pharmaceutical form) which may interact with α-adrenergic agonists or interfere with their activity
• Adrenergic receptor agonists 
• Adrenergic receptor antagonists
• Isoprenaline
• Prazosin
• Oral carbonic anhydrase inhibitors
• CYP3A4 inhibitors
• Ketoconazole
• Itraconazole
• Clotrimazole
• Ritonavir
• Troleandomycin

Other interactions

• Alcohol

• Ophthalmic examination
• Intraocular pressure (IOP) (intermittently)

Ocular effects

• Brinzolamide/ brimonidine has not been studied in patients with narrow-angle glaucoma and its use is not recommended in these patients
• The potential effects following cessation of treatment with brinzolamide/ brimonidine have not been studied. While the duration of the IOP-lowering effect for brinzolamide/ brimonidine has not been studied, the IOP-lowering effect of brinzolamide is expected to last for 5-7 days. The IOP-lowering effect of brimonidine may be longer

Benzalkonium chloride

• Brinzolamide/ brimonidine contains benzalkonium chloride which may cause eye irritation and is known to discolour soft contact lenses. Contact with soft contact lenses should be avoided. Patients must be instructed to remove contact lens prior to application of brinzolamide/ brimonidine and wait at least 15 minutes before reinsertion
• Benzalkonium chloride has been reported to cause eye irritation and symptoms of dry eyes and may affect the tear film and corneal surface. It should be used with caution in dry eye patients and in patients whose cornea may be compromised. Patients should be monitored in case of prolonged use

Brinzolamide/ brimonidine tartrate lowers intraocular pressure (IOP) in patients with open-angle glaucoma (OAG) and ocular hypertension (OHT) by suppressing the formation of aqueous humour from the ciliary process in the eye. Although both brinzolamide and brimonidine tartrate lower IOP by suppressing aqueous humour formation, their mechanisms of action are different. Brinzolamide acts by inhibiting the enzyme carbonic anhydrase (CA-II) in the ciliary epithelium that reduces the formation of bicarbonate ions with subsequent reduction in sodium and fluid transport across the ciliary epithelium, resulting in decreased aqueous humour formation. Brimonidine tartrate, an alpha-2 adrenergic agonist, inhibits the enzyme adenylate cyclase and suppresses the cAMP-dependent formation of aqueous humour. Additionally, administration of brimonidine tartrate results in an increase in uveoscleral outflow.

COMBINATION PREPARATIONS

Brinzolamide/ Brimonidine Tartrate

Eye drops (per ml) 10mg/2mg

• Simbrinza (Novartis) originator