Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
In clinical trials, the most common adverse reactions were blurred vision, eye irritation and eye pain, occurring in approximately 2% to 7% of patients.

Tabulated summary of adverse reactions
The following adverse reactions have been reported during clinical studies and post- marketing surveillance with AZARGA and the individual components brinzolamide and timolol. They 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 <1/1 000), 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.

System Organ Classification         MedDRA Preferred Term (v. 18.0)
Infections and infestations         Not known: nasopharyngitis3, pharyngitis3, sinusitis3, rhinitis3

Blood and lymphatic system          Uncommon: white blood cell count decreased1 disorders                           Not known: decreased red blood cell count3, increased blood chloride3

Immune system disorders             Not known: anaphylaxis2, anaphylactic shock1, systemic allergic reactions including angioedema, 2 localised and generalised rash2, hypersensitivity1,
urticaria2, pruritus2

Metabolism and nutrition            Not known: hypoglycaemia2 disorders

Psychiatric disorders               Rare: insomnia1
Not known: hallucinations2, depression1, memory loss2, apathy3, depressed mood3, decreased libido3,
nightmare2,3, nervousness3

Nervous system disorders      Common: dysgeusia1

Not known: cerebral ischaemia2, cerebrovascular accident2, syncope2, increases in the signs and symptoms of myasthenia gravis2, somnolence3, motor dysfunction3, amnesia3, memory impairment3,
paraesthesia2,3, tremor3, hypoaesthesia3, ageusia3,
dizziness1, headache1
Eye disorders                 Common: punctate keratitis1, blurred vision1, eye pain1, eye irritation1
Uncommon: keratitis1,2,3, dry eye1, vital dye staining cornea present1, eye discharge1, eye pruritus1, foreign body sensation in eyes1, ocular hyperaemia1,
conjunctival hyperaemia1

Rare: corneal erosion1, anterior chamber flare1,
photophobia1, lacrimation increased1, scleral hyperaemia1, erythema of eyelid1, eyelid margin crusting1

Not known: increased optic nerve cup/disc ratio3,
choroidal detachment following filtration surgery2
(see section 4.4 Special warnings and precautions for use), keratopathy3, corneal epithelium defect3,
corneal epithelium disorder3, increased intraocular pressure3, eye deposit3, corneal staining3, corneal oedema3, decreased corneal sensitivity2,
conjunctivitis3, meibomianitis3, diplopia2, 3, glare3,
photopsia3, reduced visual acuity3, visual impairment1, pterygium3, ocular discomfort3,
keratoconjunctivitis sicca3, hypoaesthesia of the eye3,
scleral pigmentation3, subconjunctival cyst3, visual disturbance3, eye swelling3, eye allergy3, madarosis3,
eyelid disorder3, eyelid oedema1, ptosis2
Ear and labyrinth disorders   Not known: vertigo3, tinnitus3

Cardiac disorders             Common: heart rate decreased1

Not known: cardiac arrest2, cardiac failure2,
congestive heart failure2, atrioventricular block2,
cardio-respiratory distress3, angina pectoris3,
bradycardia2,3, irregular heart rate3, arrhythmia2,3,
palpitations2,3, tachycardia3, increased heart rate3,
chest pain2, oedema2
Vascular disorders            Uncommon: decreased blood pressure1
Not known: hypotension2, hypertension3, blood pressure increased1, Raynaud's phenomenon2, cold hands and feet2
Respiratory, thoracic and          Uncommon: cough1 mediastinal disorders
Rare: oropharyngeal pain1, rhinorrhoea1
Not known: bronchospasm2 (predominantly in patients with pre-existing bronchospastic disease),
dyspnoea1, asthma3, epistaxis1, bronchial hyperactivity3, throat irritation3, nasal congestion3,
upper respiratory tract congestion3, postnasal drip3,
sneezing3, nasal dryness3
Gastrointestinal disorders     Not known: vomiting2,3, abdominal pain upper1, abdominal pain2, diarrhoea1, dry mouth1, nausea1,
oesophagitis3, dyspepsia2,3, abdominal discomfort3,
stomach discomfort3, frequent bowel movements3,
gastrointestinal disorder3, oral hypoaesthesia3, oral paraesthesia3, flatulence3
Hepatobiliary disorders        Not known: abnormal liver function test3 Skin and subcutaneous tissue   Not known: Stevens-Johnson syndrome (SJS)/toxic disorders                      epidermal necrolysis (TEN) (see section 4.4), urticaria3, maculo-papular rash3, generalised pruritus3, skin tightness3, dermatitis3, alopecia1,
psoriasiform rash or exacerbation of psoriasis2, rash1,
erythema1
Musculoskeletal and connective Not known: myalgia1, muscle spasms3, arthralgia3, tissue disorders               back pain3, pain in extremity3
Renal and urinary disorders    Uncommon: blood urine present1
Not known: renal pain3, pollakiuria3
Reproductive system and        Not known: erectile dysfunction3, sexual dysfunction2, breast disorders               decreased libido2

General disorders and              Uncommon: malaise1,3 administration site conditions     Not known: chest pain1, pain3, fatigue1, asthenia2,3, chest discomfort3, feeling jittery3, irritability3,
peripheral oedema3, medication residue3

Investigations                     Uncommon: blood potassium increase1, blood lactate dehydrogenase increased1
1 adverse reactions observed for AZARGA
2 additional adverse reactions observed with timolol monotherapy
3 additional adverse reactions observed with brinzolamide monotherapy 

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.

Timolol is absorbed into the systemic circulation. This may cause similar adverse reactions as seen with systemic beta-blocking medicinal products. Listed adverse reactions include reactions seen within the class of ophthalmic beta-blockers. Additional adverse reactions associated with the use of the individual components that may potentially occur with AZARGA are included in the table above. The incidence of systemic adverse reactions after topical ophthalmic administration is lower than for systemic administration. To reduce the systemic absorption, see section 4.2.

Paediatric population
AZARGA is not recommended for use in children and adolescents below 18 years due to a lack of data on safety and efficacy.

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.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il/