ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
AZARGA 10 mg/ml + 5 mg/ml eye drops, suspension
2.
One ml of suspension contains 10 mg brinzolamide and 5 mg timolol (as timolol maleate).
Excipients:
One ml of suspension contains 0.10 mg benzalkonium chloride.
For a full list of excipients, see section 6.1.
3.
Eye drops, suspension (eye drops)
White to off-white uniform suspension, pH 7.2 (approximately).
4.
Decrease of intraocular pressure (IOP) in adult patients with open-angle glaucoma or ocular
hypertension for whom monotherapy provides insufficient IOP reduction. (see section 5.1).
Use in adults, including the elderly
The dose is one drop of AZARGA in the conjunctival sac of the affected eye(s) twice daily.
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 adverse reactions.
If more than one topical ophthalmic medicinal product is being used, the medicines must be
administered at least 5 minutes apart.
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) twice daily.
When substituting another ophthalmic antiglaucoma agent with AZARGA, the other agent should be
discontinued and AZARGA should be started the following day.
Paediatric patients
AZARGA is not recommended for use in children below 18 years due to a lack of data on safety and
efficacy.
2
Use in hepatic and renal impairment
No studies have been conducted with AZARGA or with timolol 5 mg/ml eye drops in patients with
hepatic or renal impairment. No dosage adjustment is necessary in patients with hepatic impairment or
in patients with mild to moderate renal impairment.
AZARGA 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, AZARGA is therefore contraindicated in
patients with severe renal impairment (see section 4.3).
Method of administration
For ocular use.
Instruct patients to shake the bottle well before use.
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. Instruct patients to keep the
bottle tightly closed when not in use.
•
Hypersensitivity to the active substances, or to any of the excipients.
•
Bronchial asthma, a history of bronchial asthma, or severe chronic obstructive pulmonary
disease.
•
Sinus bradycardia, second or third degree atrioventricular block, overt cardiac failure, or
cardiogenic shock.
•
Severe allergic rhinitis and bronchial hyperreactivity; hypersensitivity to other beta-blockers.
•
Hyperchloraemic acidosis (see section 4.2).
•
Severe renal impairment.
•
Hypersensitivity to sulphonamides (see section 4.4).
Systemic effects
Like other topically applied ophthalmic agents, brinzolamide and timolol are absorbed systemically.
Due to the beta-adrenergic component, timolol, the same types of cardiovascular and pulmonary
adverse reactions as seen with systemic beta-adrenergic blocking agents may occur. Cardiac failure
should be adequately controlled before beginning therapy with timolol. Patients with a history of
severe cardiac disease should be watched for signs of cardiac failure and have their pulse rates
checked. Respiratory reactions and cardiac reactions, including death due to bronchospasm in patients
with asthma and, rarely, death in association with cardiac failure, have been reported following
administration of timolol maleate. Beta-adrenergic blocking agents should be administered with
caution in patients subject to spontaneous hypoglycaemia or to patients with labile insulin-dependent
diabetes as beta-adrenergic blocking agents may mask the signs and symptoms of acute
hypoglycaemia. They may also mask the signs of hyperthyroidism and cause worsening of Prinzmetal
angina, severe peripheral and central circulatory disorders and hypotension.
AZARGA contains brinzolamide, a sulphonamide. The same types of undesirable effects that are
attributable to sulphonamides may occur with topical administration. Acid-base disturbances have
been reported with oral carbonic anhydrase inhibitors. If signs of serious reactions or hypersensitivity
occur, discontinue the use of this medicinal product.
There is potential for an additive effect on the known systemic effects of carbonic anhydrase inhibition
in patients receiving an oral carbonic anhydrase inhibitor and AZARGA. The concomitant
administration of AZARGA and oral carbonic anhydrase inhibitors has not been studied and is not
recommended (see section 4.5).
3
Anaphylactic reactions
While taking beta-adrenergic blocking agents, patients with a history of atopy or a history of severe
anaphylactic reaction to a variety of allergens may be unresponsive to the usual doses of adrenaline
used to treat anaphylactic reactions.
Concomitant therapy
Timolol may interact with other medicinal products (see section 4.5).
The effect on intraocular pressure or the known effects of systemic beta blockade may be potentiated
when AZARGA is given to patients already receiving an oral beta-adrenergic blocking agent. The use
of two local beta-adrenergic blocking agents or two local carbonic anhydrase inhibitors is not
recommended.
Ocular effects
There is limited experience with AZARGA in the treatment of patients with pseudoexfoliative
glaucoma or pigmentary glaucoma. Caution should be utilised in treating these patients and close
monitoring of IOP is recommended.
AZARGA has not been studied in patients with narrow-angle glaucoma and its use is not
recommended in these patients.
Oral carbonic anhydrase inhibitors may impair the ability to perform tasks requiring mental alertness
and/or physical coordination in elderly patients. AZARGA is absorbed systemically and therefore this
may occur with topical administration.
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 AZARGA contains
benzalkonium chloride, close monitoring is required with frequent or prolonged use
AZARGA contains benzalkonium chloride which 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 AZARGA and wait 15 minutes after instillation of the
dose before reinsertion.
No interaction studies have been performed with AZARGA.
AZARGA contains brinzolamide, 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 AZARGA.
The cytochrome P-450 isozymes responsible for metabolism of brinzolamide include CYP3A4 (main),
CYP2A6, CYP2B6, 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
There is a potential for additive effects resulting in hypotension and/or marked bradycardia when eye
drops with timolol are administered concomitantly with oral calcium channel blockers, guanethidine or
beta-blocking agents, antiarrhythmics, digitalis glycosides or parasympathomimetics.
The hypertensive reaction to sudden withdrawal of clonidine can be potentiated when taking
beta-blockers.
Potentiated systemic beta-blockade (e.g. decreased heart rate) has been reported during combined
treatment with CYP2D6 inhibitors (e.g. quinidine, cimetidine) and timolol.
Beta-blockers may increase the hypoglycaemic effect of antidiabetic agents. Beta-blockers can mask
the signs and symptoms of hypoglycaemia (see section 4.4).
Pregnancy
There are no adequate data from the use of brinzolamide in pregnant women. Studies in animals have
shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.
Well-controlled epidemiological studies with systemic use of beta-blockers did not indicate
malformative effects, but some pharmacological effects such as bradycardia have been observed in
foetuses or neonates. Data on a limited number of exposed pregnancies indicate no adverse effects of
timolol in eye drops on pregnancy or on the health of the foetus/newborn child but bradycardia and
arrhythmia have been reported in one case in the foetus of a woman treated with timolol eye drops. To
date, no other relevant epidemiological data are available.
AZARGA should not be used during pregnancy unless clearly necessary.
Lactation
It is not known whether brinzolamide is excreted in human breast milk. Animal studies have shown
excretion of brinzolamide in breast milk. Timolol does appear in human breast milk. However, at
therapeutic doses of AZARGA, no effects on the breastfed newborns/infants are anticipated.
AZARGA can be used during breast-feeding.
As with any eye drops, temporary blurred vision or other visual disturbances may affect the ability to
drive or use machines. 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 of elderly patients to perform tasks requiring
mental alertness and/or physical coordination (see section 4.4).
Summary of the safety profile
In two clinical trials of 6 and 12 months duration involving 394 patients treated with AZARGA, the
most frequently reported adverse reaction was transient blurred vision upon instillation (3.6%), lasting
from a few seconds to a few minutes.
Tabulated summary of adverse reactions
The following adverse reactions 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), or
very rare (<1/10,000). Within each frequency grouping, undesirable effects are presented in order of
decreasing seriousness.
5
System Organ Classification
MedDRA Preferred Term
Psychiatric disorders
Uncommon
: insomnia
Nervous system disorders
Common
: dysgeusia
Eye disorders
Common
: blurred vision, eye pain, eye irritation, foreign
body sensation in eyes
Uncommon
: corneal erosion, punctate keratitis, dry eye,
eye discharge, eye pruritus, ocular hyperaemia, blepharitis,
allergic conjunctivitis, corneal disorder, anterior chamber
flare, conjunctival hyperaemia, eyelid margin crusting,
astenopia, abnormal sensation in eye, eyelids pruritus,
allergic blepharitis, erythema of eyelid
Vascular disorders
Uncommon
: decreased blood pressure
Respiratory, thoracic and
mediastinal disorders
Uncommon
: chronic obstructive pulmonary disease,
pharyngolaryngeal pain, rhinorrhoea, cough
Skin and subcutaneous tissue
disorders
Uncommon
: hair disorder, lichen planus
Description of selected adverse reactions
Dysgeusia (bitter or unusual taste in the mouth following instillation) was a frequently reported
systemic adverse reaction associated with the use of AZARGA during clinical trials. It is likely to be
caused by passage of the eye drops in the nasopharynx via the nasolacrimal canal and is attributable to
brinzolamide. Nasolacrimal occlusion or gently closing the eyelid after instillation may help reduce
the occurrence of this effect (see section 4.2).
AZARGA contains brinzolamide which 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
attributable to oral carbonic anhydrase inhibitors may occur with topical administration.
AZARGA contains brinzolamide and timolol (as timolol maleate). Additional adverse reactions
associated with the use of the individual components observed in clinical trials and postmarketing
experience that may potentially occur with AZARGA include:
6
Brinzolamide 10 mg/ml
Timolol 5 mg/ml
System Organ Classification
MedDRA Preferred Term
Infections and infestations
nasopharyngitis, pharyngitis,
sinusitis, rhinitis
Blood and lymphatic system
disorders
decreased red blood cell count,
increased blood chloride
Immune system disorders:
hypersensitivity
Metabolism and nutrition disorders
hypoglycaemia
Psychiatric disorders
apathy, depression, depressed
mood, decreased libido,
nightmare, nervousness
depression
Nervous system disorders
somnolence, motor dysfunction,
amnesia, memory impairment,
dizziness, paraesthesia, tremor,
headache, hypoaesthesia, ageusia
cerebral ischaemia,
cerebrovascular
accident, syncope,
myasthenia gravis,
paresthesia, headache,
dizziness
Eye disorders
keratitis, keratopathy, increased
optic nerve cup/disc ratio, corneal
epithelium defect, corneal
epithelium disorder, increased
intraocular pressure, eye deposit,
corneal staining, corneal oedema,
conjunctivitis, meibomianitis,
diplopia, glare, photophobia,
photopsia, reduced visual acuity,
pterygium, ocular discomfort,
keratoconjunctivitis sicca,
hypoaesthesia of the eye, scleral
pigmentation, subconjunctival
cyst, increased lacrimation, visual
disturbance, eye swelling, eye
allergy, madarosis, eyelid
disorder, eyelid oedema
conjunctivitis,
diplopia, eyelid ptosis,
keratitis, visual
disturbance
Ear and labyrinth disorders
tinnitus, vertigo
Cardiac disorders
cardio-respiratory distress, angina
pectoris, bradycardia, irregular
heart rate, arrhythmia,
palpitations, tachycardia,
increased heart rate
cardiac arrest, cardiac
failure, arrhythmia,
atrioventricular block,
bradycardia,
palpitations
Vascular disorders
increased blood pressure,
hypertension
hypotension
Respiratory, thoracic and
mediastinal disorders
dyspnoea, asthma, bronchial
hyperactivity, epistaxis, throat
irritation, nasal congestion, upper
respiratory tract congestion,
postnasal drip, sneezing, nasal
dryness
respiratory failure,
bronchospasm,
dyspnoea, nasal
congestion
7
Gastrointestinal disorders
dry mouth, oesophagitis,
vomiting, diarrhoea, nausea,
dyspepsia, upper abdominal pain,
abdominal discomfort, stomach
discomfort, frequent bowel
movements, gastrointestinal
disorder, oral hypoaesthesia, oral
paraesthesia, flatulence
diarrhoea, nausea
Hepato-biliary disorders
abnormal liver function test
Skin and subcutaneous tissue
disorders
urticaria, maculo-papular rash,
rash, generalised pruritus,
alopecia, skin tightness,
dermatitis, erythema
alopecia, rash
Musculoskeletal and connective
tissue disorders
back pain, muscle spasms,
myalgia, arthralgia, pain in
extremity
Renal and urinary disorders
renal pain, pollakiuria
Reproductive system and breast
disorders
erectile dysfunction
General disorders and
administrative site conditions
pain, asthenia, chest discomfort,
fatigue, feeling abnormal, feeling
jittery, irritability, chest pain,
peripheral oedema, malaise,
medication residue
asthenia, chest pain
Injury, poisoning and procedural
complications
foreign body in eye
Paediatric population
AZARGA is not recommended for use in children below 18 years due to a lack of data on safety and
efficacy.
No case of overdose has been reported.
If overdose with AZARGA eye drops occurs, treatment should be symptomatic and supportive.
Electrolyte imbalance, development of an acidotic state, and possibly central nervous system effects
may occur. Serum electrolyte levels (particularly potassium) and blood pH levels should be monitored.
Studies have shown that timolol does not dialyse readily.
5.
5.1
Pharmacodynamic properties
Pharmacotherapeutic group: Antiglaucoma preparation and miotics
ATC code: S01ED51
Mechanism of action
AZARGA contains two active substances: brinzolamide and timolol maleate. These two components
decrease elevated IOP primarily by reducing aqueous humour secretion, but do so by different
mechanisms of action. The combined effect of these two active substances results in additional IOP
reduction compared to either compound alone.
8
Brinzolamide is a potent inhibitor of human carbonic anhydrase II (CA-II), the predominant
iso-enzyme in the eye. 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.
Timolol is a non-selective adrenergic-blocking agent that has no intrinsic sympathomimetic, direct
myocardial depressant or membrane-stabilising activity. Tonography and fluorophotometry studies in
man suggest that its predominant action is related to reduced aqueous humour formation and a slight
increase in outflow facility.
Pharmacodynamic effects
Clinical effects:
In a twelve-month, controlled clinical trial in patients with open-angle glaucoma or ocular
hypertension who, in the investigator’s opinion could benefit from a combination therapy, and who
had baseline mean IOP of 25 to 27 mmHg, the mean IOP-lowering effect of AZARGA dosed twice
daily was 7 to 9 mmHg. The non-inferiority of AZARGA as compared to dorzolamide
20 mg/ml + timolol 5 mg/ml in the mean IOP reduction was demonstrated across all time-points at all
visits.
In a six-month, controlled clinical study in patients with open-angle glaucoma or ocular hypertension
and baseline mean IOP of 25 to 27 mmHg, the mean IOP-lowering effect of AZARGA dosed twice
daily was 7 to 9 mmHg, and was up to 3 mmHg greater than that of brinzolamide 10 mg/ml dosed
twice daily and up to 2 mmHg greater than that of timolol 5 mg/ml dosed twice daily. A statistically
superior reduction in mean IOP was observed compared to both brinzolamide and timolol at all
time-points and visits throughout the study.
In three controlled clinical trials, the ocular discomfort upon instillation of AZARGA was significantly
lower than that of dorzolamide 20 mg/ml + timolol 5 mg/ml.
5.2
Pharmacokinetic properties
Absorption
Following topical ocular administration, brinzolamide and timolol are absorbed through the cornea
and into the systemic circulation. In a pharmacokinetic study, healthy subjects received oral
brinzolamide (1 mg) twice daily for 2 weeks to shorten the time to reach steady-state prior to starting
AZARGA administration. Following twice daily dosing of AZARGA for 13 weeks, red blood cell
(RBC) concentrations of brinzolamide averaged 18.8 ± 3.29 µM, 18.1 ± 2.68 µM and 18.4 ± 3.01 µM
at weeks 4, 10 and 15, respectively, indicating that steady-state RBC concentrations of brinzolamide
were maintained
At steady state, following administration of AZARGA, the mean plasma C
max
and AUC
0-12h
of timolol
were 27% and 28% lower (C
max
: 0.824 ± 0.453 ng/ml; AUC
0-12h
: 4.71 ± 4.29 ng·h/ml), respectively, in
comparison to the administration of timolol 5 mg/ml (C
max
: 1.13 ± 0.494 ng/ml;
AUC
0-12h
: 6.58 ± 3.18 ng·h/ml). The lower systemic exposure to timolol following AZARGA
administration is not clinically relevant. Following administration of AZARGA, mean C
max
of timolol
was reached at 0.79 ± 0.45 hours.
Distribution
Plasma protein binding of brinzolamide is moderate (about 60%). Brinzolamide is sequestered in
RBCs due to its high affinity binding to CA-II and to a lesser extent to CA-I. Its active N-desethyl
metabolite also accumulates in RBCs where it binds primarily to CA-I. The affinity of brinzolamide
and metabolite to RBC and tissue CA results in low plasma concentrations.
Ocular tissue distribution data in rabbits showed that timolol can be measured in aqueous humour up
to 48 hours after administration of AZARGA. At steady-state, timolol is detected in human plasma for
up to 12 hours after administration of AZARGA.
9
Metabolism
The metabolic pathways for the metabolism of brinzolamide involve N-dealkylation, O-dealkylation
and oxidation of its N-propyl side chain. N-desethyl brinzolamide is a major metabolite of
brinzolamide formed in humans, which also binds to CA-I in the presence of brinzolamide and
accumulates in RBCs.
In vitro
studies show that the metabolism of brinzolamide mainly involves
CYP3A4 as well as at least four other isozymes (CYP2A6, CYP2B6, CYP2C8 and CYP2C9).
Timolol is metabolised by two pathways. One route yields an ethanolamine side chain on the
thiadiazole ring and the other giving an ethanolic side chain on the morpholine nitrogen and a second
similar side chain with a carbonyl group adjacent to the nitrogen. Timolol metabolism is mediated
primarily by CYP2D6.
Excretion
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-desethyl-brinzolamide are the
predominant components found in the urine along with trace levels (<1%) of the N-desmethoxypropyl
and O-desmethyl metabolites.
Timolol and its metabolites are primarily excreted by the kidneys. Approximately 20% of a timolol
dose is excreted in the urine unchanged and the remainder excreted in urine as metabolites. The
plasma t
1/2
of timolol is 4.8 hours after administration of AZARGA.
5.3
Preclinical safety data
Brinzolamide
Non-clinical data reveal no special hazard for humans with brinzolamide 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
(214 times the recommended daily clinical dose of 28 µg/kg/day) 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 (642 times the recommended daily clinical 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.
Timolol
Non-clinical data reveal no special hazard for humans with timolol based on conventional studies of
safety pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential. Reproduction
toxicity studies with timolol showed delayed foetal ossification in rats with no adverse effects on
postnatal development (at 50 mg/kg/day or 3500 times the daily clinical dose of 14 μg/kg/day) and
increased foetal resorptions in rabbits (at 90 mg/kg/day or 6400 times the daily clinical dose).
10
6.
6.1 List of excipients
Benzalkonium chloride
Mannitol (E421)
Carbopol 974P
Tyloxapol
Disodium edetate
Sodium chloride
Hydrochloric acid and/or sodium hydroxide (for pH adjustment)
Purified water
6.2
Incompatibilities
Not applicable.
6.3
Shelf life
2 years
4 weeks after first opening
6.4
Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5
Nature and contents of container
5 ml round opaque low density polyethylene bottles with a dispensing plug and white polypropylene
screw cap (DROP-TAINER) containing 5 ml suspension.
Cartons containing 1 or 3 bottles. Not all pack sizes may be marketed.
6.6
Special precautions for disposal
No special requirements.
7.
Alcon Laboratories (UK) Ltd.
Pentagon Park
Boundary Way
Hemel Hempstead
Herts HP2 7UD
United Kingdom
11
8.
EU/1/08/482/001-002
9.
Date of first Authorisation: 25
th
November 2008
Detailed information on this medicine is available on the European Medicines Agency (EMEA)
website: http://www.emea.europa.eu
12
ANNEX II
A
MANUFACTURING AUTHORISATION HOLDERS
RESPONSIBLE FOR BATCH RELEASE
B
CONDITIONS OF THE MARKETING AUTHORISATION
13
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
S.A. Alcon-Couvreur N.V.,
Rijksweg 14,
B-2870 Puurs,
Belgium.
or
Alcon Cusí, S.A.,
Camil Fabra 58,
08320 El Masnou,
Barcelona,
Spain
The printed package leaflet of the medicinal product must state the name and address of the
manufacturer responsible for the release of the concerned batch.
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to medical prescription
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version in version
4.0 dated 21 June 2007 presented in Module 1.8.1. of the Marketing Authorisation Application, is in
place and functioning before and whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 01 dated 30 September 2007 (with effective date
16 May 2008) of the Risk Management Plan (RMP) presented in Module 1.8.2. of the Marketing
Authorisation Application and any subsequent updates of the RMP agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the
updated RMP should be submitted at the same time as the next Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted
•
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
•
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
14
•
At the request of the EMEA
15
ANNEX III
LABELLING AND PACKAGE LEAFLET
16
A. LABELLING
17
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON FOR SINGLE BOTTLE 5 ml + CARTON FOR 3 x 5 ml BOTTLES
1.
AZARGA 10 mg/ml + 5 mg/ml eye drops, suspension
Brinzolamide/Timolol
2.
STATEMENT OF ACTIVE SUBSTANCE
1 ml of suspension contains 10 mg brinzolamide and 5 mg timolol (as timolol maleate)
3.
LIST OF EXCIPIENTS
Contains: benzalkonium chloride, mannitol (E421), carbopol 974P, tyloxapol, disodium edetate,
sodium chloride, hydrochloric acid and/or sodium hydroxide (to adjust pH), purified water.
See the package leaflet for further information.
4.
Eye drops, suspension
1 x 5 ml
3 x 5 ml
5.
METHOD AND ROUTE OF ADMINISTRATION
Ocular use.
Shake well before use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
Discard 4 weeks after first opening.
Opened:
18
9.
SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Alcon Laboratories (UK) Ltd.
Pentagon Park
Boundary Way
Hemel Hempstead
Herts HP2 7UD
United Kingdom
12. MARKETING AUTHORISATION NUMBERS
EU/1/08/482/001 1 x 5 ml
EU/1/08/482/002 3 x 5 ml
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16 INFORMATION IN BRAILLE
azarga
19
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
BOTTLE LABEL
1.
AZARGA 10 mg/ml + 5 mg/ml eye drops
Brinzolamide/Timolol
Ocular use
2.
METHOD OF ADMINISTRATION
Read the package leaflet before use.
3.
EXPIRY DATE
EXP
Discard 4 weeks after first opening.
Opened:
4.
BATCH NUMBER
Lot
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
5 ml
6
OTHER
20
PACKAGE LEAFLET
21
PACKAGE LEAFLET: INFORMATION FOR THE USER
AZARGA 10 mg/ml + 5 mg/ml eye drops, suspension
Brinzolamide/Timolol
Read all of this leaflet carefully
before you start using this medicine.
-
Keep this leaflet.
You may need to read it again.
-
If you have any further questions, ask your doctor or pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them even if
their symptoms are the same as yours.
-
If any of the side effects gets serious,
or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
1. What AZARGA is and what it is used for
2. Before you use AZARGA
3. How to use AZARGA
4. Possible side effects
5. How to store AZARGA
6. Furtherinformation
1. WHAT AZARGA IS AND WHAT IT IS USED FOR
AZARGA is used to treat high pressure in the eye.
This pressure can lead to an illness called
glaucoma.
AZARGA
is a combination of treatments for glaucoma.
It contains two active substances which work together to reduce pressure within the eye.
2. BEFORE YOU USE AZARGA
Do not use AZARGA
−
if you are allergic to
any of the ingredients of AZARGA. For a full list of ingredients please see
section 6.
−
if you have respiratory problems
such as asthma, bronchitis or other types of breathing
problems.
−
if you have a slow heart beat, heart failure or disorders of heart rhythm.
−
if you have too much acidity in your blood
(a condition called hyperchloraemic acidosis).
−
if you have severe kidney problems.
Take special care with AZARGA
•
if you have angina (chest pains), circulation problems or low blood pressure. AZARGA
may make any of these worse. If you are concerned about any changes in these symptoms, tell
your doctor as soon as possible.
•
if you get any severe allergic reaction
while you are using AZARGA
,
whatever the cause,
adrenaline treatment may not be as effective. So, when receiving any other treatment please
tell the health professional that you are taking AZARGA.
•
if you have diabetes. AZARGA
can mask the symptoms of low blood sugar (hypoglycaemia)
such as shakiness and dizziness, so you need to use it with care.
22
•
if you have liver problems.
Talk to your doctor.
•
if you have dry eyes or cornea problems.
Talk to your doctor.
•
AZARGA is not recommended for children under 18 years.
Using other medicines
AZARGA
can affect or be affected by other medicines you are taking, including other eye drops for
the treatment of glaucoma. Tell your doctor if you are taking or intend to take medicines to lower
blood pressure, heart medicines, medicines to treat diabetes, medicines to treat gastric ulcers, or
antifungal, antiviral or antibiotic medicines.
Please tell your doctor or pharmacist if you are taking or have recently taken any other
medicines,
including medicines obtained without a prescription.
Pregnancy and breast-feeding
You should not use AZARGA if you are pregnant or might get pregnant.
Talk to your doctor
before you use AZARGA.
If you are breast-feeding,
you can use AZARGA.
Ask your doctor for advice
before taking any medicine.
Driving and using machines
Do not drive or use machines
until your vision is clear. You may find that your vision is blurred for a
time just after using AZARGA.
One of the active ingredients may impair the ability of elderly patients to perform tasks requiring
mental alertness and/or physical coordination. If affected take care when driving or using machines.
Important information about some of the ingredients of AZARGA
There is a preservative in AZARGA (benzalkonium chloride) that can discolour soft lenses and may
cause eye irritation.
Therefore, do not wear contact lenses
whilst using AZARGA. Wait 15 minutes
after using AZARGA before putting your lenses back in.
3.
HOW TO USE AZARGA
Always use AZARGA exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure.
The usual dose is
Adults:
One drop in the affected eye or eyes, twice a day
-morning and night.
Only use AZARGA in both eyes if your doctor told you to. Take it for as long as your doctor told you
to.
1
2
3
23
•
Get the AZARGA bottle and a mirror.
•
Wash your hands.
•
Shake well before use.
•
Twist off the bottle cap.
•
Hold the bottle, pointing down, between your thumb and fingers.
•
Tilt your head back. Pull down your eyelid with a clean finger, until there is a ‘pocket’ between
the eyelid and your eye. The drop will go in here (picture 1).
•
Bring the bottle tip close to the eye. Use the mirror if it helps.
•
Do not touch your eye or eyelid, surrounding areas or other surfaces with the dropper.
It
could infect the drops.
•
Gently press on the base of the bottle to release one drop of AZARGA at a time.
•
Do not squeeze the bottle: it is designed so that a gentle press on the bottom is all that it needs
(picture 2).
•
After using AZARGA, press a finger into the corner of your eye, by the nose (picture 3). This
helps to stop AZARGA getting into the rest of the body.
•
If you use drops in both eyes, repeat the steps for your other eye.
•
Close the bottle cap firmly immediately after use.
•
Use up one bottle before opening the next bottle.
If a drop misses your eye,
try again.
If you use more AZARGA than you should,
rinse your eye with warm water. Do not put in any
more drops until it is time for your next regular dose.
If you forget to use AZARGA,
continue with the next dose as planned.
Do not
use a double dose to
make up for the forgotten dose.
Do not
use more than one drop in the affected eye(s) twice daily.
If you stop using AZARGA
without speaking to your doctor, the pressure in your eye will not be
controlled which could lead to loss of sight.
If you are using other eye drops
, wait at least 5 minutes between using AZARGA and the other
drops.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
4. POSSIBLE SIDE EFFECTS
Like all medicines, AZARGA can cause side effects although not everybody gets them.
You can usually carry on taking the drops, unless the effects are serious. If you are worried, talk to
your doctor or pharmacist.
The following side effects have been seen with AZARGA:
Common side effects
(affects 1 to 10 users in 100)
Effects in the eye:
blurred vision, eye irritation, eye pain, abnormal sensation in eyes
General side effects:
bad taste
Uncommon side effects
(affects 1 to 10 users in 1,000)
24
Effects in the eye:
eye surface inflammation with surface damage-inflammation inside the eye-red
eye-itchy eye-eyelid itching-redness-swelling, or crusting-eye discharge-eye allergy-dry eye-tired eyes
General side effects:
chronic lung disease-decreased blood pressure-throat irritation-cough-difficulty
sleeping-skin inflammation-redness or itching-runny nose-hair disorder
Additionally:
AZARGA is a combination of 2 currently marketed medicines.Side effects that have been observed
with the individual medicines which may occur with AZARGA are as follows:
Effects in the eye:
damage to the optic nerve-increased pressure in eye-deposits on the eye surface-
corneal disorder-decreased eye sensation-inflammation or infection of the conjunctiva-abnormal,
double or reduced vision-increased pigmentation of the eye-growth on surface of eye-increased tear
production-eye swelling-sensitivity to light-decreased growth or number of eyelashes-drooping of the
eyelids-inflammation of the eyelid glands
General side effects:
Heart and circulation:
changes in heart rate or rhythm-chest pain-reduced heart function-stopping of
the heart-increased blood pressure-decreased blood flow to the brain-stroke-swelling of the extremities
Respiratory:
shortness of breath or difficulty breathing-cold symptoms-chest congestion-sinus
infection-sneezing-stuffy nose-dry nose-nose bleeds-asthma
Nervous system and general disorders:
depression-difficulty with memory-headache-nervousness-
irritability-tiredness-shaking-feeling abnormal-fainting-dizziness-drowsiness-generalised or severe
weakness
Gastric:
nausea-vomiting-diarrhoea-intestinal gas or abdominal pain-inflammation of the throat-dry or
abnormal sensation in mouth-decreased taste sensation-indigestion-stomach ache
Blood:
abnormal liver function values-increased blood chlorine levels, or decreased red blood cell
count as seen in a blood test
Allergy:
increased allergic symptoms
Ear:
ringing in the ears-sensation of spinning or dizziness
Skin:
itching- rash-abnormal or decreased skin sensation-loss of hair
Muscular:
generalised back, joint, or muscle pain-muscle spasms-pain in extremities-muscle
weakness
Kidney:
kidney pain such as lower back pain-frequent urination
Reproduction:
decreased sex drive-male sexual difficulty
Metabolism:
low blood sugar
If any of these side effects gets serious
or if you notice any side effects not listed,
please tell your
doctor or pharmacist.
25
5.
HOW TO STORE AZARGA
Keep out
of the reach and sight of children.
Do not use AZARGA after the expiry date which is stated on the bottle and the carton after EXP. The
expiry date refers to the last day of that month.
This medicine does not require any special storage conditions.
Throw away the bottle 4 weeks after first opening
to prevent infections, and use a new bottle. Write
down the date of opening on the bottle label and carton label in the space provided.
Medicines should not be disposed of via waste water or household waste. Ask your pharmacist how to
dispose of medicines you no longer require. These measures will help protect the environment.
6.
FURTHER INFORMATION
What AZARGA contains
The active substances
are brinzolamide and timolol. One ml of suspension contains 10 mg of
brinzolamide and 5 mg of timolol.
The other ingredients are
benzalkonium chloride, carbopol 974P, disodium edetate, mannitol
(E421), purified water, sodium chloride, tyloxapol, hydrochloric acid and/or sodium hydroxide.
Tiny amounts of hydrochloric acid and/or sodium hydroxide are added to keep acidity levels (pH
levels) normal.
What AZARGA looks like and the contents of the pack
AZARGA is a liquid (white to off-white uniform suspension) supplied in a pack containing one 5 ml
plastic bottle with a screw cap or in a pack containing three 5 ml bottles. Not all pack sizes may be
marketed.
Marketing Authorisation Holder
Alcon Laboratories (UK) Ltd.
Pentagon Park
Boundary Way
Hemel Hempstead
Herts HP2 7UD
United Kingdom
Manufacturer
S.A. Alcon-Couvreur N.V.
Rijksweg 14
B-2870 Puurs
Belgium
or
Alcon Cusí, S.A.,
Camil Fabra 58,
08320 El Masnou,
Barcelona,
Spain
26
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder.
België/Belgique/Belgien
Luxembourg/Luxemburg
SA Alcon-Couvreur NV
+ 32 (0)3 890 27 11 (België/Belgique/Belgien)
Lietuva
Alcon Pharmaceuticals Ltd. atstovybė
+ 370 5 2 314 756
България
Алкон България ЕООД
+ 359 2 950 15 65
Magyarország
Alcon Hungária Gyógyszerkereskedelmi Kft.
+ 36-1-463-9080
Česká republika
Alcon Pharmaceuticals (Czech Republic) s.r.o
.
+ 420 225 377 333
Nederland
Alcon Nederland BV
+ 31 (0) 183 654321
Danmark
Alcon Danmark A/S
+ 45 3636 3434
Norge
Alcon Norge AS
+ 47 23 25 25 50
Deutschland
Alcon Pharma GmbH
+ 49 (0)761 1304-0
Österreich
Alcon Ophthalmika GmbH
+ 43 (0)1 596 69 70
Ελλάδα
Κύπρος
Άλκον Λαμποράτορις Ελλάς ΑΕΒΕ
+ 30 210 68 78 300 (Ελλάδα)
Polska
Alcon Polska Sp. z o.o.
+ 48 22 820 3450
Eesti
Alcon Eesti
+ 372 6 313 214
Portugal
Alcon Portugal – Produtos e Equipamentos
Oftalmológicos, Lda.
+ 351 214 400 300
España
Alcon Cusí, S.A.
+ 34 93 497 7000
România
S.C. Alcon Romania S.R.L.
: + 40 21 203 93 24
France
Laboratoires Alcon
+ 33 (0)1 47 10 47 10
Slovenija
Alcon d.o.o.
+ 386 1 422 5280
Ireland
Malta
United Kingdom
Alcon Laboratories (UK) Ltd.
+ 44 (0) 1442 34 1234 (United Kingdom)
Slovenská republika
Alcon Pharmaceuticals Ltd – oz
+ 421 2 5441 0378
Ísland
Alcon Danmark A/S
+ 45 3636 3434
Suomi/Finland
Alcon Finland Oy
+358 207 871 600
27
Italia
Alcon Italia S.p.A.
+ 39 02 81803.1
Sverige
Alcon Sverige AB
+ 46 (0)8 634 40 00
E-post: receptionen@alconlabs.com
Latvija
Alcon Pharmaceuticals Ltd
+ 371 7 321 121
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency website:
http://www.ema.europa.eu
28
Source: European Medicines Agency
- Please bookmark this page (add it to your favorites).
- If you wish to link to this page, you can do so by referring to the URL address below this line.
https://theodora.com/drugs/eu/azarga.html
Copyright © 1995-2021 ITA all rights reserved.