Azarga - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Unwanted Effects Shelf Life and Storage Other Information

Active ingredients: Brinzolamide, Timolol

AZARGA 10 mg / ml + 5 mg / ml eye drops, suspension

Why is Azarga used? What is it for?

AZARGA contains two active ingredients, brinzolamie and timolol, which work together to reduce the pressure in the eye.

AZARGA is used to treat high pressure in the eye, also called glaucoma or ocular hypertension, in patients over 18 years of age and whose high pressure in the eye cannot be effectively controlled by one medicine alone.

Contraindications When Azarga should not be used

Do not use AZARGA

  • if you are allergic to brinzolamide, to medicines called sulphonamides (for example medicines used to treat diabetes and infections and also diuretics (tablets to promote diuresis), to timolol, beta-blockers (medicines used to lower blood pressure or to treat heart disease) or any of the other ingredients of this medicine (listed in section 6)
  • if you have or have had in the past respiratory problems such as asthma, severe chronic obstructive bronchitis (severe lung disease which can cause wheezing, difficulty in breathing and / or long lasting cough) or other types of breathing problems.
  • in case of severe hay fever
  • if you have slow heart beats, heart failure or heart rhythm disturbances (irregular heartbeat).
  • if you have too much acidity in your blood (a condition called hyperchloraemic acidosis).
  • if you have severe kidney problems.

Precautions for use What you need to know before taking Azarga

Put AZARGA drops only in the eyes.

Talk to your doctor or pharmacist before using AZARGA if you suffer from, or have suffered in the past from

  • coronary heart disease (symptoms may include chest pain or tightness, wheezing or choking), heart failure, low blood pressure.
  • changes in heart rate such as slow heart rate.
  • trouble breathing, asthma or chronic obstructive pulmonary disease.
  • poor circulation disease (such as Raynauld's disease or Raynauld's syndrome)
  • diabetes, as timolol can mask the signs and symptoms of low blood sugar
  • overactive thyroid gland, as timolol can mask the signs and symptoms of thyroid disease
  • muscle weakness (myasthenia gravis)
  • Before an operation, tell your doctor that you are using AZARGA, as timolol may change the effects of some medicines used during anesthesia.
  • if you have a history of atopy (a tendency to develop an allergic reaction) and severe allergic reactions, you may be more likely to develop an allergic reaction with the use of AZARGA and adrenaline treatment may not be effective enough to treat the reaction If you have any other treatment, please tell your doctor or nurse that you are taking AZARGA.
  • if you have liver problems.
  • if you have dry eyes or corneal problems.
  • if you have kidney problems.

Children and adolescents

AZARGA is not recommended for children and adolescents under 18 years of age.

Interactions Which drugs or foods may change the effect of Azarga

Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines.

AZARGA may interact with other medicines you are taking, including other eye drops to treat glaucoma. Tell your doctor if you are taking or intend to take medicines to lower blood pressure, such as parasympathomimetics and guanethidine or other heart medicines including quinidine (used to treat heart problems and some types of malaria), amiodarone or other medicines to treat heart rhythm disturbances and glycosides for heart failure.

Also tell your doctor if you are taking or intend to take medicines to treat diabetes, or to treat stomach ulcers or antifungals, antiviral medicines or antibiotics or antidepressants known as fluoxetine and paroxetine.

If you are taking another carbonic anhydrase inhibitor (acetazolamide or dorzolamide), please tell your doctor.

Warnings It is important to know that:

Pregnancy and breastfeeding

You should not use AZARGA if you are pregnant or conceive unless your doctor considers it necessary. Talk to your doctor before using AZARGA.

Do not use AZARGA while breastfeeding, timolol may be excreted in breast milk. Ask your doctor for advice before using any medicine while breastfeeding.

Driving and using machines

Do not drive or operate machinery until your vision is clear. Your vision may be blurred for some time immediately after using AZARGA.

One of the active ingredients may decrease the ability to perform operations that require mental attention and / or physical coordination. If you experience this symptom, be careful when driving vehicles or using machines.

AZARGA contains benzalkonium chloride

AZARGA contains a preservative (benzalkonium chloride) which may discolor soft contact lenses and may cause eye irritation. Therefore, do not wear contact lenses while taking AZARGA. Wait 15 minutes after using AZARGA before putting your contact lenses back in.

Dose, Method and Time of Administration How to use Azarga: Posology

Always use this medicine exactly as your doctor or pharmacist has told you. If in doubt, consult your doctor or pharmacist.

If you are changing the eye drops previously used for the treatment of glaucoma with AZARGA, you should stop using the other medicine and start using AZARGA the following day. If in doubt, consult your doctor or pharmacist.

The following is useful for limiting the amount of medicine that goes into the blood after applying the eye drops:

  • Keep the eyelid closed and at the same time apply gentle pressure with a finger on the inner corner of the eye near the nose for at least 2 minutes.

The recommended dose is one drop in the affected eye (s), twice a day.

Only use AZARGA in both eyes if your doctor tells you to. Use the medicine for the length of time recommended by your doctor.

How to use it

  • Get the bottle and a mirror.
  • Wash your hands.
  • Shake well before use.
  • Unscrew the bottle cap. After removing the cap, if the safety ring has come loose remove it before using the product.
  • Take the bottle, turn it upside down and hold it between your thumb and forefinger.
  • You tilt your head back. Pull the lower lid down with a clean finger, so that a "pocket" is formed between the lid and the eye. The drop will go there (figure 1).
  • Keep the tip of the bottle close to your eye. Use the mirror if it helps.
  • Do not touch your eye or eyelid, surrounding areas or other surfaces with the bottle tip. It could infect the eye drops.
  • Gently squeeze the base of the bottle to release one drop of AZARGA at a time.
  • Do not press the bottle hard: it is designed to work with light pressure on the bottom (figure 2).
  • After using AZARGA, press the corner of your eye near your nose with your finger for 2 minutes (figure 3). This helps prevent AZARGA from spreading to the rest of the body.
  • If you need to put the drops in both eyes, repeat the steps for the other eye.
  • Screw the cap back on immediately after use.
  • Finish one bottle before opening the next one.

If a drop misses your eye, try again.

If you are using other eye drops or eye ointments, allow at least 5 minutes between instillation of each medicine. Ophthalmic ointments should be given last.

If you forget to take AZARGA, carry on with the next dose as scheduled. Do not take a double dose to make up for a forgotten dose. Do not use more than one drop in the affected eye (s), twice a day.

If you stop taking AZARGA without talking to your doctor, your intraocular pressure will not be controlled with possible loss of vision.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

Overdose What to do if you have taken too much Azarga

If you take more AZARGA than you should, immediately wash your eye with lukewarm water. Do not use the drops until it is time for your next dose.

You may experience decreased heart rate, decreased blood pressure, heart failure, difficulty in breathing and your nervous system may be affected.

Side Effects What are the side effects of Azarga

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Stop using this medicine and contact your doctor immediately if you develop a rash, severe skin reactions, or intense red or itchy eye. These could be signs of an allergic reaction (frequency is not known).

You can usually continue to use the drops, unless the effects are severe. If you are worried, talk to your doctor or pharmacist. Do not stop using AZARGA without first talking to your doctor.

Common side effects (may affect up to 1 in 10 users)

  • Effects in the eye: blurred vision, signs and symptoms of eye irritation (eg burning, irritation, itching, tearing, redness), eye pain.
  • General side effects: taste disturbance

Uncommon side effects (may affect up to 1 in 100 users)

  • Effects in the eye: corneal erosion (damage to the anterior surface of the eyeball), intraocular inflammation, sensitivity to light, abnormal eye sensitivity, ocular discharge, dry eye, tired eyes, eyelid crusting.
  • General side effects: low blood pressure, cough, difficulty sleeping (insomnia).

Not known (frequency cannot be estimated from the available data)

  • Effects in the eye: disturbance in vision, damage to the optic nerve, increased eye pressure, deposits on the ocular surface, corneal disturbances, reduced eye sensitivity, inflammation or infection of the conjunctiva, abnormal, double or reduced vision, increased ocular pigmentation, growth on the surface of the eye, increased tearing, eye swelling, sensitivity to light, decreased growth or number of eyelashes, drooping of the upper eyelids (the eye stays half closed), inflammation of the eyelids and eyelid glands, inflammation of the cornea and detachment of the layer under the retina that contains the blood vessels following filtering surgery which can cause visual disturbances, decreased corneal sensitivity.
  • Heart and circulation: changes in rhythm or heart rate, slow heart rate, palpitations, a type of heart rhythm disorder, chest pain, decreased heart function, heart attack, increased blood pressure, decreased blood supply to the brain, stroke , edema (fluid buildup), congestive heart failure (heart disease with shortness of breath and swelling of the feet and legs due to fluid buildup), swelling of the extremities, low blood pressure, change in the color of the fingers and feet and occasionally other areas of the body (Raynaud's phenomenon), cold hands and feet.
  • Respiratory: constriction of the airways in the lungs (predominantly in patients with pre-existing illness), shortness of breath or difficulty in breathing, cold symptoms, chest congestion, nasal passages infection, sneezing, stuffy nose, dry nose, runny nose, bleeding nose, asthma, throat irritation.
  • Nervous system and general disorders: depression, nightmares, memory loss, headache, nervousness, irritability, fatigue, tremor, abnormal sensation, fainting, dizziness, sleepiness, generalized or severe weakness, unusual sensations such as pins and needles.
  • Gastric: nausea, vomiting, diarrhea, intestinal gas or abdominal pain, inflammation of the throat, feeling of dry or abnormal mouth, indigestion, stomach pain
  • Blood: blood tests showing abnormal liver function values, increased blood chlorine levels, decreased blood count of red blood cells
  • Allergy: increased allergy symptoms, generalized allergic reactions including swelling under the skin which can occur in areas such as the face and limbs and which can obstruct the airways causing difficulty in swallowing or breathing, hives, localized and generalized rash , itching, severe sudden life-threatening allergic reactions.
  • Ear: ringing in the ears, feeling of dizziness or vertigo
  • Skin: rash, redness or inflammation of the skin, decreased or abnormal skin sensitivity, hair loss, silvery-white skin rash (psorasiform rash) or worsening of psoriasis.
  • Muscle: generalized back, joint or muscle pain not caused by exercise, muscle spasms, pain in extremity, muscle weakness / weakness, increased signs and symptoms of myasthenia gravis (muscle disorder).
  • Kidneys: back pain-like kidney pain in the lower back, frequent urination
  • Reproduction: sexual dysfunction, decreased libido, male sexual difficulty.
  • Metabolism: low blood sugar levels

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This also applies to any side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

Expiry and Retention

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the bottle and carton after EXP. The expiry date refers to the last day of the month.

This medicinal product does not require any special storage conditions.

To prevent infections, discard the bottle 4 weeks after first opening and use a new bottle. Write the opening date in the space provided on the bottle and carton label.

Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

Deadline "> Other information

What AZARGA contains

  • The active ingredients are brinzolamide and timolol. One ml of suspension contains 10 mg of brinzolamide and 5 mg of timolol (as maleate).
  • The other ingredients are benzalkonium chloride (see section 2 "AZARGA contains benzalkonium chloride"), carbopol 974P, disodium edetate, mannitol (E421), purified water, sodium chloride, tyloxapol, hydrochloric acid and / or sodium hydroxide. Small amounts of hydrochloric acid and / or sodium hydroxide are added to maintain normal acidity levels (pH levels).

What AZARGA looks like and contents of the pack

AZARGA is a liquid (white to off-white uniform suspension) supplied in a pack containing a 5 ml plastic bottle with a screw cap or in a pack containing three 5 ml bottles.

Not all pack sizes may be marketed.

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

Further information on Azarga can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT - 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION - 03.0 PHARMACEUTICAL FORM - 04.0 CLINICAL PARTICULARS - 04.1 Therapeutic indications - 04.2 Posology and method of administration - 04.3 Contraindications - 04.4 Special warnings and appropriate precautions for use - 04.5 Interactions with other medicinal products and other forms of interaction - 04.6 Pregnancy and lactation - 04.7 Effects on the ability to drive and use machines - 04.8 Undesirable effects - 04.9 Overdose - 05.0 PHARMACOLOGICAL PROPERTIES - 05.1 "Pharmacodynamic properties - 05.2 Pharmacokinetic properties" - 05.3 Preclinical safety data - 06.0 PHARMACEUTICAL PARTICULARS - 06.1 Excipients - 06.2 Incompatibility "- 06.3 Shelf life" - 06.4 Special precautions for storage - 06.5 Nature of the primary packaging and contents of the package - 06.6 Instructions for use and handling - 07.0 AUTHORIZATION HOLDER ALL "PLACING ON THE MARKET - 08.0 MARKETING AUTHORIZATION NUMBER - 09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION - 10.0 DATE OF REVISION OF THE TEXT - 11.0 FOR RADIO DRUGS, COMPLETE DATA ON INTERNAL RADIATION DOSIMETRY - 12.0 INSTRUCTIONS FOR RADIOPHONES ON EXTEMPORARY PREPARATION AND QUALITY CONTROL -

01.0 NAME OF THE MEDICINAL PRODUCT -

AZARGA 10 MG / ML + 5 MG / ML EYE DROPS, SUSPENSION

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION -

One ml of suspension contains 10 mg of brinzolamide and 5 mg of timolol (as timolol maleate).

Excipient (s) with known effect:

One ml of suspension contains 0.10 mg of benzalkonium chloride.

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM -

Eye drops, suspension (eye drops).

White to off-white uniform suspension, pH 7.2 (approximately).

04.0 CLINICAL INFORMATION -

04.1 Therapeutic indications -

Reduction of intraocular pressure (IOP) in adult patients with open angle glaucoma or ocular hypertension for whom monotherapy produces insufficient IOP reduction (see section 5.1).

04.2 Posology and method of administration -

Dosage

Use in adults, including the elderly

The dose is one drop of AZARGA in the conjunctival sac of the affected eye (s) twice a day.

Systemic absorption is reduced by occluding the nasolacrimal duct or lowering the eyelid for 2 minutes. In this way the reduction of systemic side effects and the increase of local activity can be achieved (see section 4.4).

If you miss a dose, continue treatment with the next dose as scheduled. The dose should not exceed one drop twice a day per affected eye.

When AZARGA is used as a substitute for another antiglaucoma medicine, the other medicine should be stopped and AZARGA therapy started the next day.

Special populations

Pediatric population

The safety and efficacy of AZARGA in children and adolescents aged 0 to 18 years have not yet been established.

No data are available.

Hepatic and renal impairment

Studies with AZARGA or eye drops containing timolol 5 mg / ml have not been conducted in patients with hepatic or renal impairment. No dosage adjustment is required in patients with hepatic impairment or in patients with renal impairment.

AZARGA has not been studied in patients with severe renal impairment (creatinine clearance hyperchloraemic acidosis (see section 4.3). Since brinzolamide and its major metabolite are predominantly excreted by the kidney, AZARGA is contraindicated in patients with severe renal impairment (see paragraph 4.3).

AZARGA should be used with caution in patients with severe hepatic impairment (see section 4.4).

Method of administration

For ophthalmic use.

Patients should be advised to shake the bottle well before use. After removing the cap, if the safety ring has come loose remove it before using the product.

To prevent contamination of the dropper bottle tip and solution, care should 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.

In case of concomitant use of more than one topical ophthalmic medicinal product, the medicinal products should be administered with an interval of at least 5 minutes.

Ophthalmic ointments should be administered last.

04.3 Contraindications -

• Hypersensitivity to the active substances or to any of the excipients.

• Hypersensitivity to other beta-blockers

• Hypersensitivity to sulfonamides (see section 4.4.)

• Reactive airway disease, including bronchial asthma and a "history of bronchial asthma, severe chronic obstructive pulmonary disease."

• Sinus bradycardia, sick sinus syndrome, sino-atrial block, second or third degree atrioventricular block not controlled with pace-maker. Manifest heart failure or cardiogenic shock.

• Severe allergic rhinitis

• Hyperchloraemic acidosis (see section 4.2).

• severe renal impairment.

04.4 Special warnings and appropriate precautions for use -

Systemic effects

• Brinzolamide and timolol are absorbed systemically. Due to the beta-adrenergic component of timolol, the same types of cardiovascular, pulmonary and other adverse reactions seen with beta substances can occur.-adrenergic blockers administered systemically. The incidence of systemic adverse reactions after topical ophthalmic administration is lower than that seen after systemic administration. To reduce systemic absorption see section 4.2.

• Hypersensitivity reactions common to all sulfonamide derivatives may occur in patients treated with AZARGA, as the medicinal product is absorbed systemically.

Cardiac pathologies

In patients with cardiovascular disease (e.g. coronary heart disease, Prinzmetal's angina and heart failure) and hypotension, beta-blocker therapy should be critically evaluated and therapy with other active substances should be considered. Signs of worsening of these diseases and unwanted reactions should be monitored in patients with cardiovascular disease.

Due to the negative effect on conduction time, beta-blockers should be administered with caution to patients with first degree heart block.

Vascular disorders

Patients with severe peripheral circulatory disturbances / disorders (e.g. severe forms of Raynauld's disease or Raynauld's syndrome) should be treated with caution.

Hyperthyroidism

Beta blockers can also mask the signs of hyperthyroidism.

Muscle weakness

Beta-adrenergic blocking medicinal products have been reported to increase muscle weakness related to some symptoms of myasthenia (e.g. diplopia, ptosis and generalized weakness).

Respiratory pathologies

Respiratory reactions, including death due to bronchospasm in patients with asthma, have been reported following administration of some ophthalmic beta-blockers.

In patients with mild to moderate chronic obstructive pulmonary disease AZARGA should be used with caution and only if the potential benefit outweighs the potential risk.

Hypoglycemia / diabetes

Beta-blockers should be administered with caution in patients with spontaneous hypoglycaemia or in patients with labile diabetes, as beta-blockers may mask the signs and symptoms of acute hypoglycaemia.

Disorders of acid / base balance

AZARGA contains brinzolamide, a sulfonamide. The same types of adverse reactions that are attributable to sulphonamides can occur with topical administration. Acid / base disturbances have been reported with oral use of carbonic anhydrase inhibitors. This medicinal product should be used with caution in patients at risk of renal impairment due to the possible risk of metabolic acidosis. Discontinue use of this medicine, if signs of severe reactions or hypersensitivity are observed.

Mental alertness

Oral carbonic anhydrase inhibitors may impair the ability to perform tasks that require mental alertness or physical coordination. AZARGA is absorbed systemically and therefore this can occur following topical administration.

Anaphylactic reactions

While taking beta-blockers, patients with a history of atopy or severe anaphylactic reaction to a plurality of allergens may be more reactive to repeated contact with such allergens and may not respond to the usual doses of adrenaline used to treat anaphylactic reactions.

Detachment of choroid

Choroid detachment has been reported following administration of therapy for the reduction of aqueous humor production (e.g. timolol, acetazolamide) after filtration procedures.

Surgical anesthesia

Beta-blocking ophthalmological preparations may block the systemic beta-agonist effects of eg adrenaline. The anesthesiologist should be informed when the patient is taking timolol.

Concomitant therapy

The effect on intra-ocular pressure or known systemic effects of beta-blockers may be potentiated when timolol is administered to patients already receiving a systemic beta-blocking agent. The response of such patients should be carefully monitored. Topical of two beta-adrenergic blocking agents or two carbonic anhydrase inhibitors is not recommended (see section 4.5).

Additive effects on the known systemic effects of carbonic anhydrase inhibitors may occur in patients receiving AZARGA and an oral carbonic anhydrase inhibitor. The concomitant administration of AZARGA and oral carbonic anhydrase inhibitors has not been studied and is not recommended (see section 4.5).

Ocular effects

There is limited experience with AZARGA in the treatment of patients with pseudoexfoliative or pigmentary glaucoma. Care should be taken in treating these patients and closely monitoring the IOP is recommended.

AZARGA has not been studied in patients with narrow angle glaucoma and its use is not recommended in these patients.

Ophthalmic beta-blockers can cause dry eyes. Patients with corneal disease should be treated with caution.

The possible role of brinzolamide on corneal endothelial function of patients with compromised corneas (particularly in patients with low endothelial cell counts) has not been studied. Patients with contact lenses have not been specifically studied and, in these patients , careful monitoring is recommended during use of brinzolamide, as carbonic anhydrase inhibitors can impair corneal hydration and contact lens wear may increase the risk to the cornea. Careful monitoring of patients with corneas is recommended. impaired, as well as patients with diabetes mellitus or corneal dystrophies.

AZARGA can be used while wearing contact lenses under close observation (see under "Benzalkonium chloride")

Benzalkonium chloride

AZARGA contains benzalkonium chloride which can cause eye irritation and is known to discolour soft contact lenses. Contact with soft contact lenses should be avoided. Patients should be advised to remove contact lenses before use. application of AZARGA and wait 15 minutes after instillation of the dose before reinserting them.

Benzalkonium chloride has also been reported to cause punctate keratopathy and / or toxic ulcerative keratopathy. Close monitoring is required with frequent or prolonged use.

Hepatic impairment

AZARGA should be used with caution in patients with severe hepatic impairment.

04.5 Interactions with other medicinal products and other forms of interaction -

No drug 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 the oral use of carbonic anhydrase inhibitors. The possibility of interaction should be considered in patients receiving AZARGA.

The potential for an additive effect on the known systemic effects of carbonic anhydrase inhibition exists in patients treated with oral carbonic anhydrase inhibitors and eye drops containing brinzolamide. Concomitant administration of eye drops containing brinzolamide and oral carbonic anhydrase inhibitors is not recommended.

Cytochrome P isoenzymes-450 responsible for the metabolism of brinzolamide include CYP3A4 (the main one), CYP2A6, CYP2B6, CYP2C8 and CYP2C9. CYP3A4 inhibitors such as ketoconazole, itraconazole, clotrimazole, ritonavir and troleandomycin are expected to inhibit the metabolism of brinzolamide via CYP3A4. Caution should be exercised if CYP3A4 inhibitors are used concurrently. However, since elimination is primarily via the kidney, accumulation of brinzolamide is unlikely. Brinzolamide is not an inhibitor of cytochrome P isoenzymes-450.

Additive effects such as hypotension and / or marked bradycardia may occur when an ophthalmic solution beta-blocker is administered concomitantly with oral calcium channel blockers, beta-adrenergic blocking agents, antiarrhythmics (including amiodarone), digitalis glycosides, parasympathomimetics, guanethidine .

Beta-blockers may reduce the response to adrenaline used to treat anaphylactic reactions. Particular care should be taken in patients with a history of atopy or anaphylaxis (see section 4.4).

The hypertensive reaction to sudden withdrawal of clonidine may be potentiated when taking beta-blocking agents. Caution is advised in concomitant use of this medicinal product with clonidine.

Potentiation of beta has been reported during combined treatment with CYP2D6 inhibitors (e.g. quinidine, fluoxetine, paroxetine) and timolol.-systemic block (eg, decreased heart rate, depression). Caution is advised.

The betas-blockers may potentiate the hypoglycemic effect of antidiabetic agents-blockers may mask the signs and symptoms of hypoglycaemia (see section 4.4).

Mydriasis has occasionally been reported following concomitant use of ophthalmic beta-blockers and adrenaline (epinephrine).

04.6 Pregnancy and breastfeeding -

Pregnancy

There are no adequate data on the ophthalmic use of brinzolamide and timolol in pregnant women. Animal studies with brinzolamide have shown reproductive toxicity following systemic administration, see section 5.3. AZARGA should not be used during pregnancy if not in case of absolute necessity. To reduce systemic absorption see section 4.2.

Epidemiological studies have not shown malformative effects but show a risk of intra-uterine growth retardation when beta-blockers are administered orally. In addition, signs and symptoms of beta-blocker effects (e.g. bradycardia, hypotension, respiratory distress and hypoglycaemia) have been observed in neonates when beta-blockers have been administered up to the time of delivery. If AZARGA is administered until delivery, the neonate should be carefully monitored in the first days of life.

Feeding time

It is not known whether ophthalmic brinzolamide is excreted in human breast milk. Studies in animals have shown excretion of brinzolamide in breast milk following oral administration, see section 5.3.

Beta-blockers are excreted in breast milk. However, at therapeutic doses of timolol in eye drops, it is unlikely that sufficient amounts are present in breast milk to produce clinical symptoms of beta-blockers in the infant. To reduce systemic absorption, see section 4.2.

However, a risk to infants cannot be excluded. The decision to discontinue breastfeeding or AZARGA therapy should be made taking into account the benefit of breastfeeding for the baby and the benefit of therapy for the woman.

Fertility

Pre-clinical data show no effect of brinzolamide or timolol on male or female fertility. No effects on male or female fertility are expected with the use of AZARGA.

04.7 Effects on ability to drive and use machines -

AZARGA has negligible influence on the ability to drive and use machines.

Transient blurred vision, as well as other disturbances in vision, may impair the ability to drive or use machines. If blurred vision occurs at the time of instillation, the patient should wait until vision clears before driving or using. machinery.

Carbonic anhydrase inhibitors may impair the ability to perform operations that require mental attention and / or physical coordination (see section 4.4).

04.8 Undesirable effects -

Summary of the safety profile

In clinical studies, the most common adverse reactions were blurred vision, eye irritation and eye pain, which occurred in approximately 2% to 7% of patients.

Table 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 / 1,000 to 1 / 10,000 to

System and organ classification MedDRA Preferred Term Infections and infestations Not known: nasopharyngitis³, pharyngitis³, sinusitis³, rhinitis³ Disorders of the blood and lymphatic system Not known: red blood cell count decreased3, blood chloride increased³ Disorders of the immune system Not known: anaphylaxis², systemic allergic reactions including angioedema², localized and generalized rash², hypersensitivity¹, urticaria², pruritus² Metabolism and nutrition disorders Not known: hypoglycemia² Psychiatric disorders Uncommon: insomnia¹ Not known: depression¹, memory loss², apathy³, depressed mood³, decreased libido³, nightmares2,3, nervousness³ Nervous system disorders common: dysgeusia¹ Not known: cerebral ischaemia², cerebrovascular accident², syncope², increased signs and symptoms of myasthenia gravis², somnolence³, motor dysfunction³, amnesia³, memory impairment³, paraesthesia2,3, tremor³, hypoesthesia³, ageusia³, dizziness¹, headache¹ Eye disorders common: blurred vision¹, eye pain¹, eye irritation¹ Uncommon: corneal erosion¹, punctate keratitis¹, photophobia¹, dry eye¹, ocular discharge¹, ocular pruritus¹, foreign body sensation in the eye¹, ocular hyperaemia¹, hyperaemia of the sclera¹, lacrimation increased¹, anterior chamber Tyndall effect¹, conjunctival hyperaemia¹, eyelid erythema¹ Not known: increased fovea / optic nerve disc ratio³, choroid detachment following filter surgery² (see section 4.4 Special warnings and precautions for use), keratitis², ³, keratopathy³, corneal epithelial defect³, corneal epithelial disease³, increased pressure incraoculare³, ocular deposit³, corneal staining³, corneal edema³, decreased corneal sensitivity², conjunctivitis³, meibomite³, diplopia², 3, glare³, photopsia³, reduced visual acuity³, visual impairment1, pterygium³, ocular discomfort³, keratoconjunctivitis sic sclera pigmentation³, subconjunctival cyst³, visual disturbance³, eye swelling³, eye allergy³, madarosis³, eyelid disorder³, eyelid edema¹, ptosis² Ear and labyrinth disorders Not known: vertigo³, tinnitus³ Cardiac pathologies Not known: cardiac arrest², heart 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, edema² Vascular pathologies Uncommon: reduced blood pressure¹ Not known: hypotension², hypertension³, blood pressure increased¹, Raynaud's phenomenon², cold hands and feet² Respiratory, thoracic and mediastinal disorders Uncommon: cough¹ Not known: bronchospasm² (predominantly in patients with pre-existing bronchospastic disease), dyspnoea¹, asthma³, epistaxis¹, bronchial hyperreactivity³, throat irritation³, nasal congestion³, upper respiratory tract congestion³, retronasal loss³, sneezing³, nasal dryness³ Gastrointestinal disorders Not known: vomiting2,3, upper abdominal pain¹, abdominal pain², diarrhea¹, dry mouth¹, nausea¹, oesophagitis³, dyspepsia2,3, abdominal discomfort³, stomach discomfort³, frequent bowel movements³, gastrointestinal disease³, oral hypoesthesia³, oral paraesthesia³, flatulence³ Hepatobiliary disorders Not known: liver function test abnormal³ Skin and subcutaneous tissue disorders Not known: urticaria³, maculo-papular rash³, generalized pruritus³, skin tightness³, dermatitis³, alopecia¹, psoriasiform rash or exacerbation of psoriasis², rash¹, erythema¹ Musculoskeletal and connective tissue disorders Not known: myalgia¹ muscle spasms³, arthralgia³, back pain³, pain in extremity³ Renal and urinary disorders Not known: kidney pain³, pollakiuria³ Diseases of the reproductive system and breast Not known: erectile dysfunction³, sexual dysfunction², decreased libido² General disorders and administration site conditions Not known: chest pain¹, pain³, fatigue¹, asthenia², ³, malaise³, chest discomfort³, feeling strange³, feeling nervous³, irritability³, peripheral edema³, drug residue³ Diagnostic tests Uncommon: blood potassium increased¹, blood lactic dehydrogenase increased¹

1 adverse reactions observed for Azarga

2 additional adverse reactions observed with timolol alone

3 additional adverse reactions observed with brinzolamide alone

Description of selected adverse reactions

Dysgeusia (bitter or unusual taste in the mouth following instillation) was a frequently systemically occurring adverse reaction associated with the use of AZARGA during clinical trials. This is probably due to the passage of the eye drops into the nasopharynx through the nasolacrimal canal and is attributable to brinzolamide. Nasolacrimal occlusion or slight closure of the eyelid after instillation may help reduce the occurrence of this effect (see section 4.2).

AZARGA contains brinzolamide, 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 are possible with topical administration.

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

Pediatric population

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

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. in Appendix V.

04.9 Overdose -

In the event of accidental ingestion, symptoms of beta blocker overdose may include bradycardia, hypotension, heart failure and bronchospasm.

In the event of an overdose with AZARGA eye drops, treatment should be symptomatic and supportive. Due to brinzolamide, electrolyte imbalance, development of a state of acidosis and possible effects on the central nervous system can occur. Serum electrolyte levels (particularly potassium) and blood pH levels should be monitored. Studies have shown that timolol does not readily dialyze.

05.0 PHARMACOLOGICAL PROPERTIES -

05.1 "Pharmacodynamic properties -

Pharmacotherapeutic group: ophthalmologicals, antiglaucoma preparations and miotics.

ATC code: S01ED51.

Mechanism of action

AZARGA contains two active ingredients: brinzolamide and timolol maleate. These two components reduce elevated intraocular pressure (IOP) mainly by reducing the secretion of aqueous humor, but through different mechanisms of action. The combined effect of these two active ingredients determines a further reduction of the IOP compared to the single intake of each component.

Brinzolamide is a potent inhibitor of human carbonic anhydrase II (CA-II), the predominant isoenzyme in the eye. The inhibition of carbonic anhydrase at the level of the ciliary processes of the eye decreases the secretion of aqueous humor, presumably due to a slowdown in the formation of bicarbonate ions with a consequent reduction in the transport of sodium and fluid.

Timolol is a non-selective adrenergic blocking agent that does not have intrinsic sympathomimetic activity, direct myocardial depressant activity or membrane stabilizing activity. Studies of tonography and fluorophotometry on humans indicate that its predominant action is related to a reduction in the formation of aqueous humor and a slight increase in the ease of outflow.

Pharmacodynamic effects

Clinical Effects:

In a twelve-month controlled clinical study in patients with open-angle glaucoma or ocular hypertension who, in the investigator's opinion, could benefit from combination therapy and who had a mean baseline intraocular pressure between 25 and 27 mmHg, the mean intraocular pressure lowering effect of AZARGA administered twice daily ranged from 7 to 9 mmHg. Non-inferiority of AZARGA to dorzolamide 20 mg / ml + timolol 5 mg / ml in mean IOP reduction was demonstrated at 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 intraocular pressure between 25 and 27 mmHg, the mean intraocular pressure lowering effect of AZARGA administered twice daily was included between 7 and 9 mmHg and up to 3 mmHg higher than that of brinzolamide 10 mg / ml administered twice daily and up to 2 mmHg higher than that of timolol 5 mg / ml administered twice daily. There was a statistically greater reduction in mean IOP compared to both brinzolamide and timolol at all time points at all visits.

In three controlled clinical trials, ocular discomfort after instillation of AZARGA was significantly less than discomfort felt after instillation of 20 mg / ml of dorzolamide + 5 mg / ml of timolol.

05.2 "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 steady state before starting AZARGA. Following administration of AZARGA twice daily for 13 weeks, the mean red blood cell (RBC) concentrations of brinzolamide were 18.8 ± 3.29 mcM, 18.1 ± 2.68 mcM and 18, 4 ± 3.01 μM at 4, 10 and 15 weeks, respectively, demonstrating that steady-state concentrations of brinzolamide in RBCs were maintained.

At steady state, following administration of AZARGA, the mean value of Cmax and AUC0-12h in plasma of timolol was 27% and 28% lower, respectively (Cmax: 0.824 ± 0.453 ng / ml; AUC0-12h: 4.71 ± 4.29 ng h / ml), compared to the administration of 5 mg / ml of timolol (Cmax: 1.13 ± 0.494 ng / ml; AUC0-12h: 6.58 ± 3.18 ng h / ml). The lower systemic exposure to timolol following administration of AZARGA is not clinically relevant. Following administration of AZARGA, the mean Cmax value of timolol was reached at 0.79 ± 0.45 hours.

Distribution

Plasma protein binding of brinzolamide is moderate (approximately 60%). Brinzolamide is sequestered in red blood cells due to its high affinity binding to CA-II and to a lesser extent to CA-I. Its metabolite N-Active desethyl-brinzolamide accumulates in red blood cells by binding mainly to CA-I. The affinity of brinzolamide and the metabolite to CA contained in the red blood cell and tissue results in low plasma concentrations.

Distribution data in the ocular tissue of rabbits showed that timolol can be measured in aqueous humor for up to 48 hours after administration of AZARGA. At steady state, timolol is detected in human plasma for up to 12 hours after administration. by AZARGA

Biotransformation

The metabolic pathways of brinzolamide involve N.-dealkylation, O-dealkylation and oxidation of its N side chain-propyl. The N-desethyl-brinzolamide is a major metabolite of brinzolamide which is formed in humans, which can also bind to CA-I in the presence of brinzolamide and accumulate in red blood cells.n vitro showed that the metabolism of brinzolamide mainly involves the CYP3A4 isoenzyme as well as at least four other isoenzymes (CYP2A6, CYP2B6, CYP2C8 and CYP2C9).

Timolol is metabolised in two ways. One pathway produces an ethanolamine side chain on the thiadiazole ring and the other produces an ethanol side chain on the morpholine nitrogen atom and a second similar side chain with a carbonyl group adjacent to the nitrogen. The metabolism of timolol is mainly mediated by the CYP2D6 isoenzyme.

Elimination

Brinzolamide is eliminated primarily via renal excretion (approximately 60%). Approximately 20% of the dose was recovered in the urine as a metabolite. Brinzolamide and N-desethyl-brinzolamide are the major components found in the urine, along with traces (-desmethyl.

Timolol and its metabolites are mainly excreted by the kidneys. Approximately 20% of a dose of timolol is excreted unchanged in the urine and the remainder is excreted in the urine as metabolites. The t1 / 2 of timolol in plasma is 4.8 hours after ocular administration of AZARGA.

05.3 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 up to 6 mg / kg / day (214 times the recommended clinical daily dose of 28 mcg / kg / day) showed no effect on fetal development despite significant toxicity. maternal. Similar studies in rats showed slightly reduced ossification of the skull and sternum of fetuses from mothers administered brinzolamide at doses of 18 mg / kg / day (642 times the recommended clinical daily dose), but not at doses of 6 mg. / kg / day. These results occurred at doses that caused metabolic acidosis with a reduction in maternal body weight growth and fetal weight.

A reduction in the weight of the fetus dose-dependent was observed in pups of mothers who received brinzolamide orally with variable-to-read decreases (approximately 5-6%) with 2 mg / kg / day up to approximately 14% with 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. Reproductive toxicity studies with timolol have shown delayed fetal ossification in rats. with no adverse effects on postnatal development (at 50 mg / kg / day or 3500 times the daily clinical dose of 14 mcg / kg / day) and an increase in fetal resorptions in rabbits (at 90 mg / kg / day or 6400 times the daily clinical dose).

06.0 PHARMACEUTICAL INFORMATION -

06.1 Excipients -

Benzalkonium chloride

Mannitol (E421)

Carbopol 974P

Tyloxapol

Disodium edetate

Sodium chloride

Hydrochloric acid and / or sodium hydroxide (for pH adjustment)

Purified water

06.2 Incompatibility "-

Not relevant.

06.3 Period of validity "-

2 years.

4 weeks after first opening.

06.4 Special precautions for storage -

This medicinal product does not require any special storage conditions.

06.5 Nature of the immediate packaging and contents of the package -

5 ml opaque low density polyethylene round bottles, with dropper and white polypropylene screw cap (DROP-TAINER) containing 5 ml of suspension.

Cartons containing 1 or 3 bottles. Not all pack sizes may be marketed.

06.6 Instructions for use and handling -

No special instructions.

07.0 HOLDER OF THE "MARKETING AUTHORIZATION" -

Alcon Laboratories (UK) Ltd.

Frimley Business Park

Frimley

Camberley

Surrey, GU16 7SR

08.0 MARKETING AUTHORIZATION NUMBER -

EU / 1/08/482 / 001-002

038837011

038837023

09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION -

Date of first authorization: 25 November 2008

Date of most recent renewal: August 26, 2013

10.0 DATE OF REVISION OF THE TEXT -

D.CCE March 2015

11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY -

12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL -

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