Skip to Content

BRINZOLAMIDE SANDOZ 10 MG/ML EYE DROPS SUSPENSION

Active substance(s): BRINZOLAMIDE / BRINZOLAMIDE / BRINZOLAMIDE

View full screen / Print PDF » Download PDF ⇩

PDF Transcript

SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Brinzolamide Sandoz 10 mg/ml eye drops, suspension

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each ml of suspension contains 10 mg brinzolamide (0.33 mg brinzolamide per
drop).
Excipient (s) with known effect
Each ml of suspension contains 0.10 mg benzalkonium chloride.
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Eye drops, suspension.
White to off-white suspension, pH 7.1 – 7.9 and osmolality 270 – 320 m Osm/kg.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Brinzolamide is indicated to decrease elevated intraocular pressure in:


ocular hypertension



open-angle glaucoma

as monotherapy in adult patients unresponsive to beta-blockers or in adult patients in
whom beta-blockers are contraindicated, or as adjunctive therapy to beta-blockers or
prostaglandin analogues (see also section 5.1).

4.2

Posology and method of administration
Posology
When used as monotherapy or adjunctive therapy, the dose is one drop of
Brinzolamide in the conjunctival sac of the affected eye(s) twice daily. Some
patients may have a better response with one drop three times a day.
Special populations
Elderly population
No dose adjustment in elderly patients is necessary.
Hepatic and renal impairment

Brinzolamide has not been studied in patients with hepatic impairment and is
therefore not recommended in such patients.
Brinzolamide has not been studied in patients with severe renal impairment
(creatinine clearance < 30 ml/min) or in patients with hyperchloraemic
acidosis. Since brinzolamide and its main metabolite are excreted
predominantly by the kidney, Brinzolamide is therefore contraindicated in such
patients (see also section 4.3).
Paediatric population
The safety and efficacy of Brinzolamide in infants, children and adolescents
aged 0 to 17 years has not been established. Currently available data are
described in sections 4.8 and 5.1. Brinzolamide is not recommended for use in
infants, children and adolescents.
Method of administration
For ocular use.
Nasolacrimal occlusion or gently closing the eyelid after instillation is
recommended. This may reduce the systemic absorption of medicinal products
administered via the ocular route and result in a decrease in systemic side
effects.
Instruct the patient to shake the bottle well before use. After the cap is removed,
if tamper evident snap collar is loose, remove before using the product.
To prevent contamination of the dropper tip and suspension, care must be taken
not to touch the eyelids, surrounding areas or other surfaces with the dropper
tip of the bottle. Instruct patients to keep the bottle tightly closed when not in
use.
When substituting another ophthalmic antiglaucoma agent with Brinzolamide,
discontinue the other agent and start the following day with Brinzolamide.
If more than one topical ophthalmic medicinal product is being used, the
medicines must be administered at least 5 minutes apart. Eye ointments
should be administered last.
If a dose is missed, treatment should be continued with the next dose as
planned. The dose should not exceed one drop in the affected eye(s) three
times daily.
4.3

4.4

Contraindications
• Hypersensitivity to the active substance or any of the excipients listed in
section 6.1.
• Known hypersensitivity to sulphonamides (see also section 4.4).
• Severe renal impairment.
• Hyperchloraemic acidosis.
Special warnings and precautions for use
Systemic effects
Brinzolamide is a sulphonamide inhibitor of carbonic anhydrase and, although
administered topically, is absorbed systemically. The same types of adverse
reactions that are attributable to sulphonamides may occur with topical
administration. If signs of serious reactions or hypersensitivity occur,
discontinue the use of this preparation.
Acid-base disturbances have been reported with oral carbonic anhydrase
inhibitors. Use with caution in patients with risk of renal impairment because of the

possible risk of metabolic acidosis (see section 4.2).
Brinzolamide has not been studied in pre-term infants (less than 36 weeks
gestational age) or those less than 1 week of age. Patients with significant renal
tubular immaturity or abnormalities should only receive brinzolamide after
careful consideration of the risk benefit balance because of the possible risk of
metabolic acidosis.
Oral carbonic anhydrase inhibitors may impair the ability to perform tasks
requiring mental alertness and/or physical coordination . Brinzolamide is
absorbed systemically and therefore this may occur with topical administration.
Concomitant therapy
There is a potential for an additive effect on the known systemic effects of
carbonic anhydrase inhibition in patients receiving an oral carbonic anhydrase
inhibitor and Brinzolamide. The concomitant administration of Brinzolamide
and oral carbonic anhydrase inhibitors has not been studied and is not
recommended (see also section 4.5).
Brinzolamide was primarily evaluated in concomitant administration with
timolol during adjunctive glaucoma therapy. Additionally the IOP-reducing
effect of Brinzolamide as adjunctive therapy to the prostaglandin analogue
travoprost has been studied. No long term data are available on the use of
Brinzolamide as adjunctive therapy to travoprost(see also section 5.1).
There is limited experience with brinzolamide in the treatment of patients with
pseudoexfoliative glaucoma or pigmentary glaucoma. Caution should be used
in treating these patients and close monitoring of intraocular pressure (IOP) is
recommended. Brinzolamide has not been studied in patients with narrow-angle
glaucoma and its use is not recommended in these patients.
The possible role of brinzolamide on corneal endothelial function has not been
investigated in patients with compromised corneas (particularly in patients with
low endothelial cell count). Specifically, patients wearing contact lenses have
not been studied and careful monitoring of these patients when using
brinzolamide is recommended, since carbonic anhydrase inhibitors may affect
corneal hydration and wearing contact lenses might increase the risk for the
cornea. Careful monitoring of patients with compromised corneas such as
patients with diabetes mellitus or corneal dystrophies is recommended.
Benzalkonium chloride, which is commonly used as a preservative in
ophthalmic products, has been reported to cause punctate keratopathy and/or
toxic ulcerative keratopathy. Since Brinzolamide contains benzalkonium
chloride, close monitoring is required with frequent or prolonged use in dry eye
patients, or in conditions where the cornea is compromised.
Brinzolamide has not been studied in patients wearing contact lenses.
Brinzolamide contains benzalkonium chloridewhich may cause eye irritation
and is known to discolour soft contact lenses. Contact with soft contact lenses is
to be avoided. Patients must be instructed to remove contact lenses prior to the
application of Brinzolamide and wait at least 15 minutes after instillation of the
dose before reinsertion.
Potential rebound effects following cessation of treatment with Brinzolamide
have not been studied; the IOP-lowering effect is expected to last for 5-7 days.
Paediatric population
The safety and efficacy of Brinzolamide in infants, children and adolescents
aged 0 to 17 years has not been established and its use is not recommended in

infants, children or adolescents.
4.5

Interaction with other medicinal products and other forms of interaction
Specific interaction studies with other medicinal products have not been performed
with Brinzolamide. In clinical studies, brinzolamide was used concomitantly with
prostaglandin analogues and timolol ophthalmic preparations without evidence of
adverse interactions. Association between brinzolamide and miotics or adrenergic
agonists has not been evaluated during adjunctive glaucoma therapy.
Brinzolamide is a carbonic anhydrase inhibitor and, although administered topically,
is absorbed systemically. Acid-base disturbances have been reported with oral
carbonic anhydrase inhibitors. The potential for interactions must be considered in
patients receiving Brinzolamide.
The cytochrome P-450 isozymes responsible for metabolism of brinzolamide include
CYP3A4 (main), CYP2A6, CYP2C8 and CYP2C9. It is expected that inhibitors of
CYP3A4 such as ketoconazole, itraconazole, clotrimazole, ritonavir and
troleandomycin will inhibit the metabolism of brinzolamide by CYP3A4. Caution is
advised if CYP3A4 inhibitors are given concomitantly. However, accumulation of
brinzolamide is unlikely as renal elimination is the major route. Brinzolamide is not
an inhibitor of cytochrome P-450 isozymes.

4.6

Fertility, pregnancy and lactation
Pregnancy
There are no or limited amount of data from the use of ophthalmic brinzolamide
in pregnant women. Studies in animals have shown reproductive toxicity
following systemic administration (see also section 5.3). Brinzolamide is not
recommended during pregnancy and in women of childbearing potential not
using contraception.
Breastfeeding
It is un known whether brinzolamide/metabolites are excreted in human milk
following topical ocular administration. Animal studies have shown the
excretion of minimal levels of brinzolamide in breast milk following oral
administration.
A risk to the newborns/infants cannot be excluded. A decision must be made
whether to discontinue breastfeeding or to discontinue/abstain from Brinzolamide
therapy taking into account the benefit of breast-feeding for the child and the
benefit of therapy for the woman.
Fertility
Animal studies with brinzolamide demonstrated no effect on fertility. Studies
have not been performed to evaluate the effect of topical ocular administration
of brinzolamide on human fertility.

4.7

Effects on ability to drive and use machines
Brinzolamide has a minor influence on the ability to drive and use machines.
Temporary blurred vision or other visual disturbances, may affect the ability to
drive or use machines (see also section 4.8). If blurred vision occurs at
instillation, the patient must wait until the vision clears before driving or using
machines.
Oral carbonic anhydrase inhibitors may impair the ability to perform tasks
requiring mental alertness and/or physical coordination (see also section 4.4
and section 4.8).

4.8

Undesirable effects
Summary of the safety profile
In clinical studies involving 2732 patients treated with brinzolamide as
monotherapy or adjunctive therapy to timolol maleate 5 mg/ml, the most
frequently reported treatment-related adverse reactions were: dysgeusia (6.0%)
(bitter or unusual taste, see description below) and temporary blurred vision
(5.4%) upon instillation, lasting from a few seconds to a few minutes (see also
section 4.7).
Tabulated summary of adverse reactions
The following adverse reactions have been reported with brinzolamide 10mg/ml
eye drops, suspension and are classified according to the following convention:
very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to
<1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), or not known
(cannot be estimated from the available data).
Within each frequency grouping, adverse reactions are presented in order of
decreasing seriousness. The adverse reactions were obtained from clinical trials
and post-marketing spontaneous reports.

System Organ Classification
Infections and infestations
Blood and lymphatic system
disorders
Immune system disorders
Metabolism and nutrition disorders
Psychiatric disorders

Nervous system disorders

MedDRA Preferred Term
Uncommon: nasopharyngitis, pharyngitis, sinusitis
Not Known: rhinitis
Uncommon: red blood cell count decreased, blood
chloride increased
Not Known: hypersensitivity
Not Known: decreased appetite
Uncommon: apathy, depression, depressed mood,
libido decreased, nightmare, nervousness
Rare: insomnia
Uncommon: motor dysfunction, amnesia,
dizziness, paraesthesia, headache
Rare: memory impairment, somnolence.
Not Known: tremor, hypoaesthesia, ageusia

Eye disorders

Ear and labyrinth disorders
Cardiac disorders

Respiratory, thoracic and
mediastinal disorders

Gastrointestinal disorders

Hepatobiliary disorders
Skin and subcutaneous tissue
disorders
Musculoskeletal and connective
tissue disorders
Renal and urinary disorders
Reproductive system and breast
disorders

Common: blurred vision, eye irritation, eye pain,
foreign body sensation in eyes, ocular hyperaemia
Uncommon: corneal erosion, keratitis, punctate
keratitis, keratopathy, deposit eye, corneal staining,
corneal epithelium defect, corneal epithelium disorder,
blepharitis, eye pruritus, conjunctivitis, eye swelling,
meibomianitis, glare, photophobia, dry eye allergic
conjunctivitis, pterygium, scleral pigmentation,
asthenopia, ocular discomfort, abnormal sensation in
eye, keratoconjunctivitis sicca, subconjunctival cyst,
conjunctival hyperaemia, eyelids pruritus, eye
discharge, eyelid margin crusting, lacrimation
increased
Rare: corneal oedema, diplopia, visual acuity reduced,
photopsia, hypoaesthesia eye, periorbital oedema,
intraocular pressure increased, optic nerve cup/disc
ratio increased
Not Known: corneal disorder, visual disturbance, eye
allergy, madarosis, eyelid disorder, erythema of eyelid
Rare: tinnitus
Not Known: vertigo
Uncommon: cardio-respiratory distress, bradycardia,
palpitations
Rare: angina pectoris, heart rate irregular
Not Known: arrhythmia, tachycardia, hypertension,
blood pressure increased, blood pressure decreased,
heart rate increased
Uncommon: dyspnoea, epistaxis, oropharyngeal pain
pharyngolaryngeal pain, throat irritation, upper airway
cough syndrome, rhinorrhoea, sneezing
Rare: bronchial hyperreactivity, upper respiratory tract
congestion, sinus congestion, nasal congestion, cough,
nasal dryness
Not Known: asthma
Common: dysgeusia
Uncommon: oesophagitis, diarrhoea, nausea,
vomiting, dyspepsia, upper abdominal pain,
abdominal discomfort, stomach discomfort, flatulence,
frequent bowel movements, gastrointestinal disorder,
hypoaesthesia oral, paraesthesia oral, dry mouth
Not Known: liver function test abnormal
Uncommon: rash, rash maculo-papular, skin tightness
Rare: urticaria, alopecia, pruritus generalized
Not Known: dermatitis, erythema
Uncommon: back pain, muscle spasms, myalgia
Not Known: arthralgia, pain in extremity
Uncommon: renal pain
Not Known: pollakiuria
Uncommon: erectile dysfunction

General disorders and
administration site conditions

Injury, poisoning and procedural
complications

Uncommon: pain, chest discomfort, fatigue, feeling
abnormal,
Rare: chest pain, feeling jittery, asthenia, irritability
Not Known: peripheral oedema, malaise,
Uncommon: foreign body in eye

Description of selected adverse events
Dysgeusia (bitter or unusual taste in the mouth following instillation) was the
most frequently reported systemic adverse reaction associated with the use of
brinzolamide during clinical studies. It is likely caused by passage of the eye
drops in the nasopharynx via the nasolacrimal canal. Nasolacrimal occlusion or
gently closing the eyelid after instillation may help reduce the incidence of this
effect (see also section 4.2).
Brinzolamide is a sulphonamide inhibitor of carbonic anhydrase with systemic
absorption. Gastrointestinal, nervous system, haematological, renal and
metabolic effects are generally associated with systemic carbonic anhydrase
inhibitors. The same type of adverse reactions that are attributable to oral
carbonic anhydrase inhibitors may occur with topical administration.
No unexpected adverse reactions have been observed with brinzolamide when
used as adjunctive therapy to travoprost. The adverse reactions seen with the
adjunctive therapy have been observed with each active substance alone.
Paediatric population
In small short-term clinical trials, approximately 12.5% of paediatric patients
were observed to experience adverse reactions, the majority of which were
local, non-serious ocular reactions such as conjunctival hyperaemia, eye
irritation, eye discharge, and lacrimation increased (see also section 5.1).
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal
product is important. It allows continued monitoring of the benefit/risk balance
of the medicinal product. Healthcare professionals are asked to report any
suspected adverse reactions via the Yellow Card Scheme
(www.mhra.gov.uk/yellowcard).
4.9

Overdose
No case of overdose has been reported.
Treatment should be symptomatic and supportive. Electrolyte imbalance,
development of an acidotic state, and possible nervous system effects may occur.
Serum electrolyte levels (particularly potassium) and blood pH levels must be
monitored.

5

PHARMACOLOGICAL PROPERTIES

5.1

5.2

Pharmacodynamic properties
Pharmacotherapeutic Group: Antiglaucoma preparations and miotics, carbonic
anhydrase inhibitors
ATC code: S01EC04
Mechanism of action
Carbonic anhydrase (CA) is an enzyme found in many tissues of the body,
including the eye. Carbonic anhydrase catalyses the reversible reaction involving
the hydration of carbon dioxide and the dehydration of carbonic acid.
Inhibition of carbonic anhydrase in the ciliary processes of the eye decreases
aqueous humour secretion, presumably by slowing the formation of bicarbonate
ions with subsequent reduction in sodium and fluid transport. The result is a
reduction in intraocular pressure (IOP) which is a major risk factor in the
pathogenesis of optic nerve damage and glaucomatous visual field loss.
Brinzolamide, an inhibitor of carbonic anhydrase II (CA-II), the predominant
iso-enzyme in the eye, with an in vitro IC50 of 3.2 nM and a Ki of 0.13 nM
against CA-II.
Clinical efficacy and safety
The IOP-reducing effect of brinzolamide as adjunctive therapy to the
prostaglandin analogue travoprost was studied. Following a 4 week run-in with
travoprost, patients with an IOP ≥19 mmHg were randomized to receive added
treatment with brinzolamide or timolol. An additional decrease in mean diurnal
IOP of 3.2 to 3.4 mmHg for the brinzolamide group and 3.2 to 4.2 mmHg for the
timolol group were observed. There was an overall higher incidence of nonserious ocular adverse reactions, mainly related to signs of local irritation, in the
brinzolamide/travoprost groups. The events were mild and did not affect the
overall discontinuation rates in the studies (see also section 4.8).
A clinical trial was conducted with brinzolamide in 32 paediatric patients less
than 6 years of age, diagnosed with glaucoma or ocular hypertension. Some
patients were naive to IOP therapy whilst others were on other IOP-lowering
medicinal product(s). Those who had been on previous IOP medicinal product(s)
were not required to discontinue their IOP medicinal product(s) until initiation of
monotherapy with brinzolamide.
Among patients who were naive to IOP therapy (10 patients), the efficacy of
brinzolamide was similar to that seen previously in adults, with mean IOP
reductions from baseline ranging up to 5 mmHg. Among patients who were on
topical IOP-lowering medicinal product(s) (22 patients), mean IOP increased
slightly from baseline in the brinzolamide group.
Pharmacokinetic properties
Following topical ocular administration, brinzolamide is absorbed into the systemic
circulation. Due to its high affinity for CA-II, brinzolamide distributes extensively
into the red blood cells (RBCs) and exhibits a long half-life in whole blood (mean of
approximately 24 weeks). In humans, the metabolite N-desethylbrinzolamide is
formed, which also binds to CA and accumulates in RBCs. This metabolite binds
mainly to CA-I in the presence of brinzolamide. In plasma, both brinzolamide and Ndesethylbrinzolamide concentrations are low and generally below assay quantitation
limits (<7.5 ng/ml).

Binding to plasma proteins is not extensive (about 60%). Brinzolamide is eliminated
primarily by renal excretion (approximately 60%). About 20% of the dose has been
accounted for in urine as metabolite. Brinzolamide and N-desethylbrinzolamide are
the predominant components in the urine along with trace levels (<1%) of the Ndesmethoxypropyl and O-desmethyl metabolites.
In an oral pharmacokinetic study, healthy volunteers received 1 mg capsules of
brinzolamide twice daily for up to 32 weeks and RBC CA activity was measured to
assess the degree of systemic CA inhibition.
Brinzolamide saturation of RBC CA-II was achieved within 4 weeks (RBC
concentrations of approximately 20 µM). N-Desethylbrinzolamide accumulated in
RBCs to steady state within 20-28 weeks reaching concentrations ranging from 6-30
µM. The inhibition of total RBC CA activity at steady state was approximately 7075%.
Subjects with moderate renal impairment (creatinine clearance of 30-60 ml/minute)
were administered 1 mg of brinzolamide twice daily orally for up to 54 weeks.
Brinzolamide RBC concentration ranged from about 20 to 40 µM by week 4 of
treatment. At steady-state, brinzolamide and its metabolite RBC concentrations
ranged from 22.0 to 46.1 and 17.1 to 88.6 µM, respectively.
N-desethylbrinzolamide RBC concentrations increased and total RBC CA activity
decreased with decreasing creatinine clearance but brinzolamide RBC concentrations
and CA-II activity remained unchanged. In subjects with the highest degree of renal
impairment inhibition of total CA activity was greater although it was inferior to 90%
at steady-state.
In a topical ocular study, at steady-state, brinzolamide RBC concentrations were
similar to those found in the oral study, but levels of N-desethylbrinzolamide were
lower. Carbonic anhydrase activity was approximately 40-70% of predose levels.

5.3

Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional
studies of safety pharmacology, repeated dose toxicity, genotoxicity, and
carcinogenic potential.
Developmental toxicity studies in rabbits with oral doses of brinzolamide of up
to 6 mg/kg/day (125 times the recommended human ophthalmic dose) revealed
no effect on foetal development despite significant maternal toxicity. Similar
studies in rats resulted in slightly reduced ossification of skull and sternebrae of
foetuses of dams receiving brinzolamide at doses of 18 mg/kg/day (375 times
the recommended human ophthalmic dose), but not 6 mg/kg/day. These
findings occurred at doses that caused metabolic acidosis with decreased body
weight gain in dams and decreased foetal weights. Dose-related decreases in
foetal weights were observed in pups of dams receiving brinzolamide orally

ranging from a slight decrease (about 5-6%) at 2 mg/kg/day to nearly 14% at 18
mg/kg/day. During lactation, the no adverse effect level in the offspring was 5
mg/kg/day.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Benzalkonium chloride
Disodium Edetate
Mannitol (E421)
Carbomer (974P)
Tyloxapol
Sodium Chloride
Sodium Hydroxide and/or Hydrochloric Acid (to adjust pH)
Purified Water

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
2 years
After first opening: 4 weeks

6.4

Special precautions for storage
This medicinal product does not require any special storage conditions.

6.5

Nature and contents of container
5 and 10 ml LDPE bottles with LDPE dropper with e PP tamper –proof screw cap
(DROPTAINER).
The following pack sizes are available: outer cartons containing 1 x 5 ml, 3 x 5 ml
and 1 x 10 ml bottles.
Not all pack sizes may be marketed.

6.6

Special precautions for disposal and other handling

Any unused medicinal product or waste material should be disposed in accordance
with local requirements.

7

MARKETING AUTHORISATION HOLDER
Sandoz Limited
Frimley Business Park,
Frimley, Camberley,
Surrey,
GU16 7SR
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 04416/1380

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
24/06/2014

10

DATE OF REVISION OF THE TEXT
01/05/2017

Expand Transcript

Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

Hide