Dorzolamide 20mg/ml eye drops

United Kingdom - English - MHRA (Medicines & Healthcare Products Regulatory Agency)

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Active ingredient:
Dorzolamide hydrochloride
Available from:
Mylan
ATC code:
S01EC03
INN (International Name):
Dorzolamide hydrochloride
Dosage:
20mg/1ml
Pharmaceutical form:
Eye drops
Administration route:
Ocular
Class:
No Controlled Drug Status
Prescription type:
Valid as a prescribable product
Product summary:
BNF: 11060000; GTIN: 5016695003306
Authorization number:
PL 04569/1035

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Package leaflet: Information for the patient

Dorzolamide 20 mg/ml Eye drops, solution

Dorzolamide

Read all of this leaflet carefully before you start using this medicine because it contains important

information for you.

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 only. Do not pass it on to others. It may harm them, even

if their signs of illness are the same as yours.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects

not listed in this leaflet. See section 4.

What is in this leaflet

What Dorzolamide is and what it is used for

What you need to know before you use Dorzolamide

How to use Dorzolamide

Possible side effects

How to store Dorzolamide

Contents of the pack and other information

1.

What Dorzolamide is and what it is used for

Dorzolamide is supplied as a sterile eye drop solution. Dorzolamide contains dorzolamide, a sulfonamide-

related compound, as the active ingredient.

Dorzolamide belongs to a group of medicines called ophthalmic carbonic anhydrase inhibitors which reduce

high pressure in the eye.

Dorzolamide is used to lower raised pressure in the eye and to treat glaucoma (open-angle glaucoma, pseudo-

exfoliative glaucoma). Dorzolamide can be used alone or in addition to other medicines which lower the

pressure in the eye (so-called beta-blockers).

2.

What you need to know before you use Dorzolamide

Do not use Dorzolamide

if you are allergic to dorzolamide or any of the other ingredients of this medicine (listed in section 6)

if you have severe kidney problems.

- if you have a disturbance in the pH (acid/alkali balance) of your blood.

Warnings and precautions

Talk to your doctor or pharmacist before using Dorzolamide if:

if you have, or have had, liver problems in the past

if you have been told you have a corneal defect

if you have had any allergies to any sulfonamide like medicines e.g. co-trimoxazole

if you have had, or are about to have, eye surgery

if you have suffered an eye injury or very low pressure in the eye (hypotony)

- if you have a prior history of kidney stones

- if you are taking another carbonic anhydrase inhibitor by mouth e.g acetazolamide

if you wear contact lenses (see the section ‘Dorzolamide contains the preservative benzalkonium

chloride’)

During treatment

You should contact your doctor immediately if you develop any eye irritation or any new eye problems such

as redness of the eye or swelling of the surface layer of the eye or eyelids.

Stop using Dorzolamide and contact your doctor immediately if you suspect that Dorzolamide is causing an

allergic reaction (for example, skin rash or itching, or inflammation of the eye).

Children and adolescents

Dorzolamide should only be used in children and adolescents if the benefits outweigh the risks. Your

doctor will be able to advise you.

Other medicines and Dorzolamide

Tell your doctor or pharmacist if you are taking or using, or have recently taken or used, or might take or

use any other medicines., including medicines obtained without a prescription.

In particular you should tell your doctor if you are taking another carbonic anhydrase inhibitor by mouth

such as acetazolamide.

Pregnancy, breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your

doctor or pharmacist for advice before using this medicine. Dorzolamide should not be used during

pregnancy unless your doctor still recommends it.

Dorzolamide should not be used while breast-feeding.

Driving and using machines

Dorzolamide may cause dizziness and visual disturbances in some patients. Do not drive or use any tools or

machines until the symptoms have cleared.

Dorzolamide

contains the preservative benzalkonium chloride

Benzalkonium chloride may cause eye irritation

Benzalkonium chloride is known to discolour soft contact lenses

Avoid contact with soft contact lenses

Remove contact lenses prior to application and wait until 15 minutes before reinsertion.

3.

HOW TO USE DORZOLAMIDE

Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or

pharmacist if you are not sure.

The appropriate dosage and duration of treatment will be established by your doctor.

When Dorzolamide is used alone, the recommended dose is one drop in the affected eye(s) three times a day,

for example in the morning, in the afternoon and in the evening.

If your doctor has recommended you use Dorzolamide with a beta-blocker eye drop (other medicines which

lower the pressure of the eye), then the recommended dose is one drop of Dorzolamide in the affected eye(s)

two times a day, for example in the morning and in the evening.

If you use Dorzolamide with another eye drop, leave at least 10 minutes between putting in Dorzolamide

and the other medicine.

If you are about to start using Dorzolamide to replace another eye drop medicine, used to lower eye pressure,

you should stop using the other medicine after taking the proper dosing on one day, and start Dorzolamide

on the next day.

Do not change the dosage of this medicine without talking to your doctor. If you must stop treatment, contact

your doctor immediately.

Do not allow the tip of the container to touch your eye or areas around your eye. It may become contaminated

with bacteria that can cause eye infections that may lead to serious damage of the eye, or even loss of vision.

To avoid possible contamination of the container, keep the tip of the container away from contact with any

surface.

Instructions for use:

It is recommended that you wash your hands before putting in your eye drops.

It may be easier to apply your eye drops in front of a mirror.

1. Before using the medication for the first time, be sure that the tamper-proof seal on the bottle neck is

unbroken. A gap between the bottle and the cap is normal for an unopened bottle. Then break the seal.

2. Take off the cap of the bottle.

3. Tilt your head back and gently pull your lower eyelid down to form a small pocket between your eyelid

and your eye.

4. Invert the bottle, and squeeze it until a single drop is dispensed into the eye as directed by your doctor.

DO NOT TOUCH YOUR EYE OR EYELID WITH THE DROPPER TIP.

5. Repeat steps 3 & 4 with the other eye if instructed to do so by your doctor.

6. Put the cap back on and close the bottle straight after you have used it.

If you use more Dorzolamide than you should

If you put too many drops in your eye or swallow any of the contents, you should contact your doctor

immediately.

If you forget to use Dorzolamide

It is important to use Dorzolamide as prescribed by your doctor.

If you miss a dose, use it as soon as possible. However, if it is almost time for the next dose, skip the missed

dose and go back to your regular dosing schedule.

Do not use a double dose to make up for a forgotten dose.

If you stop using Dorzolamide

Dorzolamide should be used every day to work properly. If you must stop treatment, contact your doctor

immediately.

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

4.

Possible side effects

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

Stop using Dorzolamide immediately and go straight away to hospital or seek medical advice from

your doctor if you get any of the following side effects:

Common (may affect up to 1 in 10 people):

Damage to the front layer of the eye, which may cause eye pain, redness of the eye and blurred

vision , with possible sensitivity to light, or a feeling that something is in the eye, (superficial

punctate keratitis)

Uncommon (may affect up to 1 in 100 people):

Swelling of the iris (the coloured part of the eye) which may cause blurred vision and seeing dark

spots that appear to float across the eye or possible flashing lights (iridocyclitis)

Rare (may affect up to 1 in 1000 people):

Allergic reactions that may appear as a very itchy or sudden rash, sudden swelling of the eye,

eyelid, lips, tongue, face, hands or throat which may cause difficulty breathing and wheezing.

Excessive painful redness of the skin, large blisters, skin peeling off in sheets, bleeding of the lips,

eyes, genitals or mouth accompanied by fever (this may indicate Stevens-Johnson syndrome or

toxic epidermal necrolysis)

Sudden loss of vision, accompanied by pain and sometimes feeling and being sick which may

occur after eye surgery (choroidal detachment)

A large decrease in the pressure of the eye, which can lead to eye problems such as loss of vision

or the vision may become distorted

Other side effects include:

Very common (may affect more than 1 in 10 people):

Burning and stinging sensations of the eyes

Common (may affect up to 1 in 10 people):

Headache

Increased tear production

Inflammation or infection of the eye

Inflammation or crusting of the eyelid

Itching of the eye

Eyelid irritation

Blurred vision (without other side effects)

Feeling sick

Bitter taste sensation

Weakness or feeling tired

Rare (may affect up to 1 in 1000 people):

Dizziness

Tingling of hands and/or feet

Irritation of the eyes which may cause redness and eye pain

Difficulty in focussing on distant objects (myopia) which normally resolves when treatment is

stopped

Swelling of the front layer of the eye which you may notice as blurred vision possibly with

appearance of halos around objects (corneal oedema)

Nosebleeds

Irritated throat

Dry mouth

Itchy and scaly skin, sometimes with burning and stinging, which may also occur in the skin

surrounding the eye and maybe a sign of an allergic reaction in the skin

Kidney stones

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

Shortness of breath

Foreign body sensation (feeling that there is something in your eye)

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side

effects not listed in this leaflet. You can also report side effects directly via the Yellow Card Scheme

at: www.mhra.gov.uk/yellowcard

By reporting side effects you can help provide more information on the safety of this medicine.

5.

How to store Dorzolamide

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 label and the carton after “EXP”:

The expiry date refers to the last day of that month.

Keep the bottle in the outer carton in order to protect from light. Store below 30°C.

Dorzolamide should be used within 28 days after the bottle is first opened. Therefore, you must throw away

the bottle 4 weeks after you first opened it, even if some solution is left. To help you remember, write down

the date that you opened it in the space on the carton.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw

away medicines you no longer use. These measures will help protect the environment.

6.

Contents of the pack and other information

What Dorzolamide contains

The active substance is dorzolamide. Each ml contains 20 mg dorzolamide (as dorzolamide

hydrochloride).

The other ingredients are benzalkonium chloride (as a preservative) (see section 2), mannitol,

hydroxyethylcellulose, sodium citrate, sodium hydroxide for pH adjustment and water for injection.

What Dorzolamide looks like and contents of the pack

Dorzolamide is a sterile, pH, buffered, colourless, slightly viscous solution in a white plastic bottle with a

sealed dropper tip and a two-piece tamper proof cap assembly. Each bottle contains 5 mL of the eye drop

solution.

Dorzolamide is available in packs containing 1 bottle, 3 bottles or 6 bottles.

Not all pack sizes may be marketed.

Marketing Authorisation Holder:

Mylan, Potters Bar, Hertfordshire, EN6 1TL, United Kingdom

Manufacturers:

Pharmathen S.A., Dervenakion 6, Pallini 15331, Attiki, Greece.

Famar SA – 63 Agiou Dimitriou Street, Alimos, Athens, 174-56 Greece

Mc Dermott Laboratories Limited t/a Gerard Laboratories – 35 Baldoyle Industrial Estate, Grange Road,

Dublin 13, Ireland

Generics (UK) – Station Close, Potters Bar, Hertfordshire, EN6 1AG, United Kingdom

This leaflet was last revised in February 2017

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Object 1

Dorzolamide/Timolol 20 mg/ml + 5 mg/ml Eye

drops, Solution

Summary of Product Characteristics Updated 22-Sep-2017 | Generics UK T/A Mylan

1. Name of the medicinal product

Dorzolamide/Timolol 20 mg/ml + 5 mg/ml Eye drops, Solution

2. Qualitative and quantitative composition

Each ml contains 20 mg dorzolamide (as dorzolamide hydrochloride) and 5 mg timolol (as timolol

maleate).

Excipients with known effect:

Each ml of eye drops solution contains 0.15 mg benzalkonium chloride.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Eye drops, solution.

Clear, slightly viscous, colourless aqueous solution.

4. Clinical particulars

4.1 Therapeutic indications

Dorzolamide/Timolol is indicated in the treatment of elevated intra-ocular pressure (IOP) in patients with

open-angle glaucoma or pseudo-exfoliative glaucoma when topical beta-blocker monotherapy is not

sufficient.

4.2 Posology and method of administration

Posology

The dose is one drop of Dorzolamide/Timolol in the conjunctival sac of the affected eye(s) two times

daily.

If another topical ophthalmic medicinal product is being used, the other agent should be administered at

least ten minutes apart.

When using nasolacrimal occlusion or closing the eyelids for 2 minutes, the systemic absorption is

reduced. This may result in a decrease in systemic side effects and an increase in local activity.

Paediatric population:

Efficacy in paediatric patients has not been established.

Safety in paediatric patients below the age of two years has not been established. (for information

regarding safety in paediatric patients ≥2 and < 6 years of age, see section 5.1).

Method of administration

For ocular use.

Patients should be instructed to wash their hands before use and avoid allowing the tip of the dispensing

container to contact the eye or surrounding structures.

In order to secure correct dosage - the dropper tip should not be enlarged.

Patients should also be instructed that ocular solutions, if handled improperly, can become contaminated

by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of

vision may result from using contaminated solutions.

Patients should be informed of the correct handling of the ophthalmic [Dorzolamide/Timolol].

Usage instructions:

1. The tamper-proof seal on the bottle neck must be unbroken before the product is being used for the first

time. A gap between the bottle and the cap is normal for an unopened bottle.

2. The cap of the bottle should be taken off.

3. The patient's head must be tilted back and the lower eyelid must be pulled gently down to form a small

pocket between the eyelid and the eye.

4. The bottle should be inverted and squeezed until a single drop is dispensed into the eye. THE EYE OR

EYELID MUST NOT BE TOUCHED WITH THE DROPPER TIP.

5. Steps 3 & 4 should be repeated with the other eye if it is necessary.

6. The cap must be put back on and the bottle must be closed straight after it has been used.

4.3 Contraindications

Dorzolamide/Timolol is contra-indicated in patients with:

hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

reactive airway disease, including bronchial asthma or 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 a pace-maker, overt cardiac failure, cardiogenic shock

severe renal impairment (creatinine clearance < 30 ml/min) or hyperchloraemic acidosis

The above are based on the components and are not unique to the combination.

4.4 Special warnings and precautions for use

Cardiovascular/respiratory reactions

Like other topically applied ophthalmic agents, dorzolamide/timolol is absorbed systemically. Due to

beta-adrenergic component, timolol, the same types of cardiovascular, pulmonary and other adverse

reactions seen with systemic beta-adrenergic blocking agents may occur. Incidence of systemic ADRs

after topical ophthalmic administration is lower than for systemic administration. To reduce the systemic

absorption, see section 4.2.

Cardiac disorders:

In patients with cardiovascular diseases (e.g. coronary heart disease, Prinzmetal's angina and cardiac

failure) and hypotension therapy with beta-blockers should be critically assessed and the therapy with

other active substances should be considered. Patients with cardiovascular diseases should be watched for

signs of deterioration of these diseases and of adverse reactions.

Due to its negative effect on conduction time, beta-blockers should only be given with caution to patients

with first degree heart block.

Vascular disorders:

Patients with severe peripheral circulatory disturbance/disorders (i.e. severe forms of Raynaud's disease

or Raynaud's syndrome) should be treated with caution.

Respiratory disorders:

Respiratory reactions, including death due to bronchospasm in patients with asthma have been reported

following administration of some ophthalmic beta-blockers.

Dorzolamide/Timolol should be used with caution, in patients with mild/moderate chronic obstructive

pulmonary disease (COPD) and only if the potential benefit outweights the potential risk.

Hepatic impairment

Dorzolamide/timolol has not been studied in patients with hepatic impairment and therefore should be

used with caution in such patients.

Immunology and hypersensitivity

As with other topically-applied ophthalmic agents, this drug may be absorbed systemically. The

dorzolamide component is a sulphonamide. Therefore the same types of adverse reactions found with

systemic administration of sulphonamides may occur with topical administration, including severe

reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. If signs of serious reactions

or hypersensitivity occur, discontinue use of this preparation.

Local ocular adverse effects, similar to those observed with dorzolamide hydrochloride eye drops, have

been seen with dorzolamide/. If such reactions occur, discontinuation of Dorzolamide/Timolol should be

considered.

Anaphylactic reactions:

While taking beta-blockers, patients with a history of atopy or a history of severe anaphylactic reaction to

a variety of allergens may be more reactive to repeated challenge with such allergens and may be

unresponsive to the usual doses of adrenaline used to treat anaphylactic reactions.

Concomitant therapy

The following concomitant medication is not recommended:

− dorzolamide and oral carbonic anhydrase inhibitors

− topical beta-adrenergic blocking agents.

Other beta-blocking agents:

The effect on intra-ocular pressure or the known effects of systemic beta-blockade may be potentiated

when timolol is given to patients already receiving a systemic beta-blocking agent. The response of these

patients should be closely observed. The use of two topical beta-adrenergic blocking agents is not

recommended (see section 4.5)

Withdrawal of therapy

As with systemic beta-blockers, if discontinuation of ophthalmic timolol is needed in patients with

coronary heart disease, therapy should be withdrawn gradually.

Additional effects of beta-blockade

Hypoglycaemia/diabetes:

Beta-blockers should be administered with caution in patients subject to spontaneous hypoglycaemia or to

patients with labile diabetes, as beta-blockers may mask the signs and symptoms of acute hypoglycaemia.

Beta-blockers may also mask the signs of hyperthyroidism.

Abrupt withdrawal of beta-blocker therapy may precipitate a worsening of symptoms.

Corneal diseases:

Ophthalmic beta-blockers may induce dryness of eyes. Patients with corneal diseases should be treated

with caution.

Surgical anaesthesia:

Beta-blocking ophthalmological preparations may block systemic beta-agonist effects e.g. of adrenaline.

The anaesthesiologist should be informed when the patient is receiving timolol.

Therapy with beta-blockers may aggravate symptoms of myasthenia gravis.

Additional effects of carbonic anhydrase inhibition

Therapy with oral carbonic anhydrase inhibitors has been associated with urolithiasis as a result of acid-

base disturbances, especially in patients with a prior history of renal calculi. Although no acid-base

disturbances have been observed with dorzolamide/timolol, urolithiasis has been reported infrequently.

Because Dorzolamide/Timolol contains a topical carbonic anhydrase inhibitor that is absorbed

systemically, patients with a prior history of renal calculi may be at increased risk of urolithiasis while

using Dorzolamide/Timolol.

Other

The management of patients with acute angle-closure glaucoma requires therapeutic interventions in

addition to ocular hypotensive agents. dorzolamide/timolol has not been studied in patients with acute

angle-closure glaucoma.

Corneal oedema and irreversible corneal decompensation have been reported in patients with pre-existing

chronic corneal defects and/or a history of intra-ocular surgery while using dorzolamide. There is an

increased potential for developing corneal oedema in patients with low endothelial cell counts. Topical

dorzolamide should be used with caution in such patients.

Choroidal detachment

Choroidal detachment has been reported with administration of aqueous suppressant therapy (e.g. timolol,

acetazolamide) after filtration procedures.

As with the use of other antiglaucoma drugs, diminished responsiveness to ophthalmic timolol maleate

after prolonged therapy has been reported in some patients. However, in clinical studies in which 164

patients have been followed for at least three years, no significant difference in mean intra-ocular pressure

has been observed after initial stabilisation.

Contact lens use

Dorzolamide/Timolol contains the preservative benzalkonium chloride, which may cause eye irritation.

Benzalkonium chloride is known to discolour soft contact lenses. Remove contact lenses prior to

application and wait at least 15 minutes before reinsertion.

Paediatric population

See section 5.1.

4.5 Interaction with other medicinal products and other forms of interaction

No specific drug interaction studies have been performed with dorzolamide/timolol.

In clinical studies, dorzolamide/timolol on was used concomitantly with the following systemic

medications without evidence of adverse interactions: ACE-inhibitors, calcium channel blockers,

diuretics, non-steroidal anti-inflammatory drugs including aspirin, and hormones (e.g. oestrogen, insulin,

thyroxine).

There is a potential for additive effects resulting in hypotension and/or marked bradycardia when

ophthalmic beta-blockers solution is administered concomitantly with oral calcium channel blockers,

catecholamine-depleting medicines or beta-adrenergic blocking agents, antiarrhythmics (including

amiodarone), digitalis glycosides, parasympathomimetics, guanethidine.

Potentiated systemic beta-blockade (e.g., decreased heart rate, depression) has been reported during

combined treatment with CYP2D6 inhibitors (e.g. quinidine, fluoxetine, paroxetine) and timolol.

The dorzolamide component of Dorzolamide/Timolol is a carbonic anhydrase inhibitor and although

administered topically, is absorbed systemically. In clinical studies, dorzolamide hydrochloride

ophthalmic solution was not associated with acid-base disturbances. However, these disturbances have

been reported with oral carbonic anhydrase inhibitors and have in some instances, resulted in drug

interactions (e.g., toxicity associated with high-dose salicylate therapy). Therefore, the potential for such

drug interactions should be considered in patients receiving Dorzolamide/Timolol.

Although dorzolamide/timolol alone has little or no effect on pupil size, mydriasis resulting from

concomitant use of ophthalmic beta-blockers and adrenaline (epinephrine) has been reported

occasionally.

Beta-blockers may increase the hypoglycaemic effect of antidiabetic agents.

Oral beta-adrenergic blocking agents may exacerbate the rebound hypertension which can follow the

withdrawal of clonidine.

4.6 Fertility, pregnancy and lactation

Pregnancy

Dorzolamide/Timolol should not be used during pregnancy.

Dorzolamide

No adequate clinical data in exposed pregnancies are available. In rabbits, dorzolamide produced

teratogenic effects at maternotoxic doses (see Section 5.3).

Timolol

There are no adequate data for the use of timolol in pregnant women. Timolol should not be used during

pregnancy unless clearly necessary.

To reduce systemic absorption, see section 4.2.

Epidemiological studies have not revealed malformative effects but show a risk for intra uterine growth

retardation when beta-blockers are administered by the oral route. In addition, signs and symptoms of

beta-blockade (e.g. bradycardia, hypotension, respiratory distress and hypoglycaemia) have been

observed in the neonate when beta-blockers have been administered until delivery. If

Dorzolamide/Timolol is administered until delivery, the neonate should be carefully monitored during the

first days of life.

Breast-feeding

It is not known whether dorzolamide is excreted in human milk. In lactating rats receiving dorzolamide,

decreases in the body weight gain of offspring were observed. Beta-blockers are excreted in breast milk.

However, at therapeutic doses of timolol in eye drops it is not likely that sufficient amounts would be

present in breast milk to produce clinical symptoms of beta-blockade in the infant. To reduce the systemic

absorption, see section 4.2.

If treatment with Dorzolamide/Timolol is required, thenbreast-feeding is not recommended.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. Possible side

effects such as blurred vision may affect some patients' ability to drive and/or operate machinery.

4.8 Undesirable effects

In clinical studies no adverse experiences specific to dorzolamide/timolol have been observed; adverse

experiences have been limited to those that were reported previously with dorzolamide hydrochloride

and/or timolol maleate. In general, common adverse experiences were mild and did not cause

discontinuation.

During clinical studies, 1,035 patients were treated with Dorzolamide/Timolol eye drops solution.

Approximately 2.4% of all patients discontinued therapy with dorzolamide/timolol because of local

ocular adverse reactions, approximately 1.2 % of all patients discontinued because of local adverse

reactions suggestive of allergy or hypersensitivity (such as lid inflammation and conjunctivitis).

Like other topically applied ophthalmic drugs, dorzolamide/timolol is absorbed into the systemic

circulation. This may cause similar undesirable effects as seen with systemic beta-blocking agents.

Incidence of systemic ADRs after topical ophthalmic administration is lower than for systemic

administration. Listed adverse reactions include reactions seen within the class of ophthalmic beta-

blockers

The following adverse reactions have been reported with dorzolamide/timolol or one of its components

either during clinical trials or during post-marketing experience:

[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) and Not known (cannot be estimated from the available data)].

Immune system disorders:

Dorzolamide/Timolol ophthalmic solution

Rare: signs and symptoms of systemic allergic reactions, including angioedema, urticaria, pruritus, rash,

anaphylaxis

Timolol maleate ophthalmic solution

Rare: signs and symptoms of systemic allergic reactions including angioedema, urticaria, localised and

generalised rash, anaphylactic reaction, systemic lupus erythematosus

Not known**: pruritus

Metabolism and nutrition disorders:

Timolol maleate ophthalmic solution:

Not known**: hypoglycaemia

Psychiatric disorders:

Timolol maleate ophthalmic solution

Uncommon: depression*

Rare: insomnia*, nightmares*, memory loss.

Nervous system disorders:

Dorzolamide/Timolol ophthalmic solution

Very common: dysgeusia

Dorzolamide hydrochloride ophthalmic solution

Common: headache*

Rare: dizziness*, paraesthesia*

Timolol maleate ophthalmic solution

Common: headache*

Uncommon: dizziness*, syncope*

Rare: paraesthesia*, increase in signs and symptoms of myasthenia gravis, cerebrovascular accident*,

cerebal ischaemia

Eye disorders:

Dorzolamide/Timolol ophthalmic solution

Very common: burning and stinging

Common: conjunctival injection, blurred vision, corneal erosion, ocular itching, tearing

Not known: foreign body sensation in eye

Dorzolamide hydrochloride ophthalmic solution

Common: eyelid inflammation*, eyelid irritation*

Uncommon: iridocyclitis*

Rare: irritation including redness*, pain*, eyelid crusting*, transient myopia (which resolved upon

discontinuation of therapy), corneal oedema*, ocular hypotony*, choroidal detachment (following

filtration surgery)*

Not known: foreign body sensation in eye

Timolol maleate ophthalmic solution

Common: signs and symptoms of ocular irritation (e.g. burning, stinging, itching, tearing, redness)

including blepharitis*, keratitis*, decreased corneal sensitivity, and dry eyes*

Uncommon: visual disturbances including refractive changes (due to withdrawal of miotic therapy in

some cases)*

Rare: ptosis, diplopia, choroidal detachment following filtration surgery (see section 4.4)*

Not known**: itching, tearing, redness, blurred vision, corneal erosion

Ear and labyrinth disorders:

Timolol maleate ophthalmic solution

Rare: tinnitus*

Cardiac disorders:

Timolol maleate ophthalmic solution

Uncommon: bradycardia* *

Rare: chest pain*, palpitations*, oedema*, arrhythmia*, congestive heart failure*, cardiac arrest*, heart

block

Not known**: atrioventricular block, cardiac failure

Vascular disorders:

Timolol maleate ophthalmic solution

Rare: hypotension*, claudication, Raynaud's phenomenon*, cold hands and feet*

Respiratory, thoracic and mediastinal disorders:

Dorzolamide/Timolol ophthalmic solution

Common: sinusitis

Rare: shortness of breath, respiratory failure, rhinitis, rarely bronchospasm

Dorzolamide hydrochloride ophthalmic solution

Rare: epistaxis*

Not known: dyspnea

Timolol maleate ophthalmic solution

Uncommon: dyspnoea*

Rare: bronchospasm (predominantly in patients with pre-existing bronchospastic disease)*, respiratory

failure, cough*

Gastrointestinal disorders:

Dorzolamide hydrochloride ophthalmic solution

Common: nausea*

Rare: throat irritation, dry mouth*

Timolol maleate ophthalmic solution

Uncommon: nausea*, dyspepsia*

Rare: diarrhoea, dry mouth*

Now known**: abdominal pain, vomiting

Skin and subcutaneous tissue disorders:

Dorzolamide/Timolol ophthalmic solution

Rare: contact dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis

Dorzolamide hydrochloride ophthalmic solution

Rare: rash*

Timolol maleate ophthalmic solution

Rare: alopecia*, psoriasiform rash or exacerbation of psoriasis*

Now known**: skin rash

Musculoskeletal and connective tissue disorders:

Timolol maleate ophthalmic solution:

Now known**: myalgia

Renal and urinary disorders:

Dorzolamide/Timolol ophthalmic solution

Uncommon: urolithiasis

Reproductive system and breast disorders:

Timolol maleate ophthalmic solution

Rare: peyronie's disease* , decreased libido

Now known**: sexual dysfunction

General disorders and administration site condition:

Dorzolamide hydrochloride ophthalmic solution

Common: asthenia/fatigue*

Timolol maleate ophthalmic solution

Uncommon: asthenia/fatigue*

*These adverse reactions were also observed with dorzolamide/timolol during post-marketing experience.

**Additional adverse reactions have been seen with ophthalmic beta-blockers and may potentially occur

with [Dorzolamide/Timolol].

Laboratory findings

Dorzolamide/timolol was not associated with clinically meaningful electrolyte disturbances in clinical

studies.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows

continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are

asked to report any suspected adverse reactions via the Yellow Card Scheme at:

www.mhra.gov.uk/yellowcard

4.9 Overdose

No data are available in humans in regard to overdosage by accidental or deliberate ingestion of

dorzolamide/timolol.

SymptomsThere have been reports of inadvertent overdosage with timolol maleate ophthalmic solution

resulting in systemic effects similar to those seen with systemic beta-adrenergic blocking agents such as

dizziness, headache, shortness of breath, bradycardia, bronchospasm, and cardiac arrest. The most

common signs and symptoms to be expected with overdosage of dorzolamide are electrolyte imbalance,

development of an acidotic state, and possibly central nervous system effects.

Only limited information is available with regard to human overdosage by accidental or deliberate

ingestion of dorzolamide hydrochloride. With oral ingestion, somnolence has been reported. With topical

application the following have been reported: nausea, dizziness, headache, fatigue, abnormal dreams, and

dysphagia.

Treatment

Treatment should be symptomatic and supportive. Serum electrolyte levels (particularly potassium) and

blood pH levels should be monitored. Studies have shown that timolol does not dialyse readily.

5. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antiglaucoma preparations and miotics, beta-blocking agents, ATC code:

S01E D51

ATC code: S01E D51

Mechanism of action

Dorzolamide/Timolol is comprised of two components: dorzolamide hydrochloride and timolol maleate.

Each of these two components decreases elevated intra-ocular pressure by reducing aqueous humor

secretion, but does so by a different mechanism of action.

Dorzolamide hydrochloride is a potent inhibitor of human carbonic anhydrase II. 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

maleate is a non-selective beta-adrenergic receptor blocking agent. The precise mechanism of action of

timolol maleate in lowering intra-ocular pressure is not clearly established at this time, although a

fluorescein study and tonography studies indicate that the predominant action may be related to reduced

aqueous formation. However, in some studies a slight increase in outflow facility was also observed. The

combined effect of these two agents results in additional intra-ocular pressure reduction compared to

either component administered alone.

Following topical administration, dorzolamide/timolol reduces elevated intra-ocular pressure, whether or

not associated with glaucoma. Elevated intra-ocular pressure is a major risk factor in the pathogenesis of

optic nerve damage and glaucomatous visual field loss.

Dorzolamide/timolol reduces intra-ocular pressure without the common side effects of miotics such as

night blindness, accommodative spasm and pupillary constriction.

Pharmacodynamic effects

Clinical effects

Adult patients

Clinical studies of up to 15 months duration were conducted to compare the IOP-lowering effect of

Dorzolamide/Timolol eye drops solution b.i.d. (dosed morning and bedtime) to individually- and

concomitantly-administered 0.5 % timolol and 2.0 % dorzolamide in patients with glaucoma or ocular

hypertension for whom concomitant therapy was considered appropriate in the trials. This included both

untreated patients and patients inadequately controlled with timolol monotherapy. The majority of

patients were treated with topical beta-blocker monotherapy prior to study enrolment. In an analysis of

the combined studies, the IOP-lowering effect of Dorzolamide/Timolol eye drops solution b.i.d. was

greater than that of monotherapy with either 2% dorzolamide t.i.d. or 0.5% timolol b.i.d. The IOP-

lowering effect of Dorzolamide/Timolol eye drops solution b.i.d. was equivalent to that of concomitant

therapy with dorzolamide b.i.d. and timolol b.i.d. The IOP-lowering effect of Dorzolamide/Timolol eye

drops solution b.i.d. was demonstrated when measured at various time points throughout the day and this

effect was maintained during long-term administration.

Paediatric population

A three months controlled study, with the primary objective of documenting the safety of 2%

dorzolamide hydrochloride ophthalmic solution in children under the age of 6 years has been conducted.

In this study, 30 patients under six and greater than or equal to two years of age whose IOP was not

adequately controlled with monotherapy by dorzolamide or timolol received Dorzolamide/Timolol eye

drops solution in an open label phase. Efficacy in those patients has not been established. In this small

group of patients, twice daily administration of Dorzolamide/Timolol was generally well tolerated with

19 patients completing the treatment period and 11 patients discontinuing for surgery, a change in

medication, or other reasons.

5.2 Pharmacokinetic properties

Dorzolamide hydrochloride:

Unlike oral carbonic anhydrase inhibitors, topical administration of dorzolamide hydrochloride allows for

the drug to exert its effects directly in the eye at substantially lower doses and therefore with less systemic

exposure. In clinical trials, this resulted in a reduction in IOP without the acid-base disturbances or

alterations in electrolytes characteristic of oral carbonic anhydrase inhibitors.

When topically applied, dorzolamide reaches the systemic circulation. To assess the potential for systemic

carbonic anhydrase inhibition following topical administration, active substanceand metabolite

concentrations in red blood cells (RBCs) and plasma and carbonic anhydrase inhibition in RBCs were

measured. Dorzolamide accumulates in RBCs during chronic dosing as a result of selective binding to

CA-II while extremely low concentrations of free active substance in plasma are maintained. The parent

active substanceforms a single N-desethyl metabolite that inhibits CA-II less potently than the parent

active substancebut also inhibits a less active isoenzyme (CA-I). The metabolite also accumulates in

RBCs where it binds primarily to CA-I. Dorzolamide binds moderately to plasma proteins (approximately

33%). Dorzolamide is primarily excreted unchanged in the urine; the metabolite is also excreted in urine.

After dosing ends, dorzolamide washes out of RBCs non-linearly, resulting in a rapid decline of active

substance concentration initially, followed by a slower elimination phase with a half-life of about four

months.

When dorzolamide was given orally to simulate the maximum systemic exposure after long term topical

ocular administration, steady state was reached within 13 weeks. At steady state, there was virtually no

free active substanceor metabolite in plasma; CA inhibition in RBCs was less than that anticipated to be

necessary for a pharmacological effect on renal function or respiration. Similar pharmacokinetic results

were observed after chronic, topical administration of dorzolamide hydrochloride. However, some elderly

patients with renal impairment (estimated creatinine clearance 30-60 millilitre/min) had higher metabolite

concentrations in RBCs, but no meaningful differences in carbonic anhydrase inhibition and no clinically

significant systemic side effects were directly attributable to this finding.

Timolol maleate:

In a study of plasma active substance concentration in six subjects, the systemic exposure to timolol was

determined following twice daily topical administration of timolol maleate ophthalmic solution 0.5 %.

The mean peak plasma concentration following morning dosing was 0.46 ng/millilitre and following

afternoon dosing was 0.35 ng/millilitre.

5.3 Preclinical safety data

The ocular and systemic safety profile of the individual components is well established.

Dorzolamide

In rabbits given maternotoxic doses of dorzolamide associated with metabolic acidosis, malformations of

the vertebral bodies were observed.

Timolol

Animal studies have not shown a teratogenic effect.

Furthermore, no adverse ocular effects were seen in animals treated topically with dorzolamide

hydrochloride and timolol maleate ophthalmic solution or with concomitantly-administered dorzolamide

hydrochloride and timolol maleate. In vitro and in vivo studies with each of the components did not reveal

a mutagenic potential. Therefore, no significant risk for human safety is expected with therapeutic doses

of Dorzolamide/Timolol.

6. Pharmaceutical particulars

6.1 List of excipients

Mannitol

Hydroxyethyl cellulose

Sodium citrate (E331)

Sodium hydroxide

Benzalkonium chloride

Water for injections

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

After first opening: 28 days

6.4 Special precautions for storage

This medicinal product does not require any special temperature storage conditions. Store in the original

package in order to protect from light and moisture.

6.5 Nature and contents of container

White opaque medium density polyethylene bottle ophthalmic dispenser with a sealed LDPE dropper tip

and a HDPE screw cap with tamper proof seal in a cardboard box.

Pack size: 1, 3 or 6 or bottles of 5 ml each

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

7. Marketing authorisation holder

Generics [UK] Limited t/a Mylan

Station Close

Potters Bar

Hertfordshire EN6 1TL

8. Marketing authorisation number(s)

PL 04569/1035

9. Date of first authorisation/renewal of the authorisation

18/03/2011

10. Date of revision of the text

February 2017

Company Contact Details

Generics UK T/A Mylan

Address

Building 4, Trident Place, Mosquito Way, Hatfield, Hertfordshire, AL10 9UL

Telephone

+44 (0)1707 853 000

Medical Information Direct Line

+44 (0)1707 853 000

Customer Care direct line

+44 (0)1707 853 000 select option 2

Stock Availability

+44 (0)1707 853 000 select option 2

http://www.mylan.com

+44 (0)1707 261 803

Medical Information e-mail

[email

protected]

Medical Information Fax

+44 (0)1707 261 803

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