Prospect: information for the user

COMBIGAN 2 mg/ml + 5 mg/ml eye drops in solution.

Brimonidine tartrate and timolol

1. What is COMBIGAN and for what it is used

2. What you need to know before starting to use COMBIGAN

3. How to use COMBIGAN

4. Possible adverse effects

5. Storage of COMBIGAN

6. Contents of the package and additional information

COMBIGANis an eye drop used for the control of glaucoma. It contains two medications (brimonidine and timolol) that both reduce elevated eye pressure. Brimonidine belongs to a group of medications called alpha-2 adrenergic receptor agonists. Timolol belongs to a group of medications called beta-blockers.

COMBIGANis prescribed to reduce elevated eye pressure inside the eye when the use of beta-blocker eye drops is not sufficient.

Your eye contains a clear watery liquid that nourishes the inside of the eye. Continuously, liquid is eliminated from the eye and new liquid is generated to replace it. If the liquid cannot exit the eye quickly enough, eye pressure increases and could, over time, damage your vision.COMBIGANacts by reducing the production of liquid and increasing the amount of liquid that exits. This reduces eye pressure while new liquid continues to be generated.

No useCOMBIGANeye drops in solution:

• If you areallergic(hypersensitive) tobrimonidine tartrate, timolol, beta-blockersor to any of theother components ofthis medication (listed in section 6). The symptoms of an allergic reaction may include swelling of the face, lips, and throat, hissing, feeling of weakness, difficulty breathing, itching or redness around the eye.

• If you have or have had respiratory problems such asasthma, severe chronic obstructive bronchitis(a serious lung disease that can cause wheezing, difficulty breathing, and/or constant coughing)

• If you have heart problems such asslow heart rate, heart failure, heart rhythm disorders(unless controlled with a pacemaker) If you are taking monoamine oxidase (MAO) inhibitors or some other antidepressant medications

If you believe any of these points apply to you, do not useCOMBIGANuntil you have consulted with your doctor again.

Warnings and Precautions

Consult your doctor before starting to useCOMBIGAN,

• if you have or have had
• • coronary heart disease (symptoms may include chest pain or pressure, difficulty breathing, or asphyxia), heart failure, low blood pressure
  • heart rhythm disorders, such as low heart rate
  • peripheral circulatory disease (such as Raynaud's disease or Raynaud's syndrome)
  • diabetes, as timolol may mask the signs and symptoms of low blood sugar hyperthyroidism, as timolol may mask the signs and symptoms.
  • kidney or liver problems
  • adrenal gland tumor
  • eye surgery to reduce eye pressure

• if you suffer or have suffered from any allergy (e.g. hay fever, eczema) or severe allergic reaction be aware that you may need to increase the dose of adrenaline you normally use to control a severe reaction.
• inform your doctor that you are using COMBIGAN, before undergoing surgery, as timolol may change the effects of some medications used during anesthesia.

Children and Adolescents

COMBIGANshould not be used in children under 2 years or generally in children between 2 and 17 years.

Other Medications and COMBIGAN

COMBIGAN may affect or be affected by other medications you are taking, including other eye drops for glaucoma treatment.

Inform your doctor or pharmacist if you are taking, have taken recently, or may need to take any other medication, including medications for any other condition, even if not related to your eye problem, and even those acquired without a prescription.

There are a series of medications that may interfere with COMBIGAN, so it is very important to tell your doctor if you are taking:

• Pain relievers
• Medications to help you sleep or for anxiety
• Medications to treat high blood pressure (hypertension)
• Medications to treat heart rhythm disorders (e.g. abnormal heartbeat) such as beta-blockers, digoxin, or quinidine (used to treat heart problems and some types of malaria)
• Medications to treat diabetes or high blood sugar
• Medications for depression such as fluoxetine and paroxetine
• Other eye drops used to reduce high eye pressure (glaucoma)
• Medications to treat severe allergic reactions
• Medications that affect some of the hormones in your body, such as adrenaline and dopamine
• Medications that affect the muscles of your blood vessels
• Medications to treat stomach burning or ulcers

If you change the dose of any of the medications you take or if you consume alcohol regularly, you must tell your doctor.

If you are to undergo anesthesia, you must tell your doctor or dentist that you are using COMBIGAN.

Pregnancy and Breastfeeding

If you are pregnant or breastfeeding, or if you think you may be pregnant or intend to become pregnant, consult your doctor or pharmacist before using this medication.Do not use COMBIGANif you are pregnant unless your doctor considers it necessary.

Do not useCOMBIGANif you are breastfeeding. Timolol may pass into breast milk. Consult your doctor before using any medication during breastfeeding.

Driving and Operating Machinery

COMBIGANmay cause drowsiness, fatigue, or blurred vision in some patients.Do not drive or operate tools or machinery until the symptoms have disappeared. If you notice any problem, talk to your doctor.

Combigan contains benzalkonium chloride

This medication contains 0.25 mg of benzalkonium chloride in each 5 ml of solution, equivalent to 0.05 mg/ml.

Benzalkonium chloride may be absorbed by soft contact lenses, altering their color. Remove contact lenses before using this medication and wait 15 minutes before reinserting them.

Benzalkonium chloride may cause eye irritation, especially if you have dry eye or other corneal diseases (transparent layer of the front part of the eye). Consult your doctor if you feel a strange sensation, burning, or pain in the eye after using this medication.

COMBIGAN contains phosphates:

This medication contains 52.9 mg of phosphates in each ml of solution, equivalent to 10.58 mg/ml.

If you have severe corneal damage (the transparent layer of the front part of the eye), treatment with phosphates, in rare cases, may cause blurred vision due to calcium accumulation.

Follow exactly the administration instructions of this medication as indicated by your doctor.In case of doubt, consult your doctor or pharmacist again. COMBIGAN should not be used in children under 2 years and its habitual use is not recommended in children and adolescents (between 2 and 17 years).

The recommended dose is one drop ofCOMBIGAN, twice a day, with a 12-hour interval.Do not change the dose or stop applying it without consulting your doctor.

If you useCOMBIGANwith other eye drops, wait at least five minutes between its application and the application of the other eye drops.

Instructions for use

Do not use the container if the safety seal is broken when opening the product for the first time.

Wash your hands before opening the container.Incline your head backward and look up.

1. Gently pull down on the lower eyelid until a small space is formed.
2. Invert the bottle and press it to releaseonedrop into each eye that needs treatment.
3. Release the lower eyelid, and close the eye
4. Keep the eye closed and press with your finger the lacrimal part (where the eye meets the nose) for two minutes. This helps to preventCOMBIGANfrom passing into the rest of the body.

If the drop falls outside the eye, try again.

To help prevent infections, avoid letting the tip of the container touch the eye, or any other surface. Close the container immediately after use.

If you use moreCOMBIGANthan you should

Adults

If you use more COMBIGAN than you should, it is unlikely to cause any harm. Put the next drop at the usual time. If you are concerned, talk to your doctor or pharmacist.

Babies and children

Some cases of overdose have been reported in babies and children treated with brimonidine (one of the components ofCOMBIGAN) as part of the treatment for glaucoma. Drowsiness, flaccidity, low body temperature, pallor, and respiratory difficulties were observed. If this occurs, contact your doctor immediately.

Adults and children

In case of accidental ingestion, contact your doctor.

In case of overdose or accidental ingestion, consult your doctor or pharmacist immediately or call the Toxicology Information Service, phone 91-562 04 20.

If you forgot to useCOMBIGAN,

If you forgot to useCOMBIGAN,use one drop in each eye that needs treatment as soon as you remember, and then return to your regular routine.Do not duplicate the dose to compensate for the missed doses.

If you interrupt the treatment withCOMBIGAN

ForCOMBIGANto work properly, you must use it every day.

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

Like all medications, this medication may cause side effects, although not everyone will experience them.

If you notice any of the following side effects, please contact your doctor immediately:

• Heart failure (i.e., chest pain) or irregular heartbeats
• Increased or decreased heart rate or low blood pressure

The following side effects may be observed with COMBIGAN:

Affecting the eye

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

• Redness of the eyes, burning sensation

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

• Burning or pain in the eye
• Allergic reaction in the eye or surrounding skin
• Small breaks in the surface of the eye (with or without inflammation)
• Swelling, redness of the eyelids
• Irritation of the eye or sensation of a foreign body
• Itching of the eye and eyelid
• White patches or spots on the layer that covers the surface of the eye, through which we see
• Disturbance of vision
• Excessive tearing
• Dryness of the eye
• Sticky eyes

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

• Difficulty seeing clearly
• Swelling or inflammation of the layer that covers the surface of the eye, through which we see
• Tired eyes
• Sensitivity to light
• Pain in the eyelid
• Whitening of the layer that covers the surface of the eye, through which we see
• Swelling or inflamed areas under the surface of the eye
• Flies in front of the eyes

Unknown frequency (frequency cannot be estimated from available data):

• Blurry vision

Affecting the body:

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

• High blood pressure
• Depression
• Drowsiness
• Headache
• Dryness in the mouth
• General weakness

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

• Heart failure
• Irregular heart rhythm
• Sensation of dizziness
• Fainting
• Dryness in the nose
• Alteration of taste
• Nausea

• Diarrhea

Unknown frequency (frequency cannot be estimated from available data):

• Increased or decreased heart rate
• Low blood pressure
• Redness in the face

Some of these effects may be due to an allergic reaction to one of the components of the product.

Additional adverse reactions have been observed with brimonidine or timolol, and therefore may occur with COMBIGAN.

The following adverse reactions have been observed in addition to brimonidine:

• Inflammation in the eye, small pupils, difficulty sleeping, symptoms similar to those of a cold, difficulty breathing, gastrointestinal symptoms, general allergic reactions, skin reactions including redness, swelling of the face, itching, rash, and dilation of blood vessels

Like any other medication applied to the eyes, COMBIGAN (brimonidine/timolol) is absorbed into the blood. The absorption of timolol, a beta-blocker component of COMBIGAN, may cause adverse reactions similar to those observed with intravenous and/or oral beta-blockers. The incidence of adverse reactions after topical ocular administration is lower than with oral or injected medications.

The following adverse reactions have been observed with the use of beta-blockers to treat eye diseases:

• Generalized allergic reactions, including swelling under the skin (may occur in areas such as the face or extremities, and may obstruct the airway and cause difficulty breathing or swallowing), urticaria (hives), localized or generalized skin rash, itching, sudden allergic reaction that may be life-threatening

• Low blood sugar

• Difficulty sleeping (insomnia), nightmares, memory loss, hallucinations

• Stroke, reduced blood flow to the brain, worsening of myasthenia gravis symptoms (muscular disorder), strange sensations (such as tingling)

• Inflammation in the cornea, detachment of the layer of the retina that contains blood vessels after surgery to filter, which may cause vision disturbances, reduced corneal sensitivity, corneal erosion (damage to the front layer of the eyeball), drooping eyelid (the eye appears half-closed), double vision

• Chest pain, edema (swelling), changes in heart rate or rhythm, some heart rhythm disorder, heart attack, heart failure

• Raynaud's phenomenon, cold hands and feet

• Constriction of the airways of the lung (mainly in patients with a pre-existing disease), difficulty breathing, cough

• Indigestion, abdominal pain, vomiting

• Hair loss, white-silver skin rash (psoriasiform rash) or worsening of psoriasis, skin rash

• Muscle pain not caused by exercise

• Sexual dysfunction, decreased libido

• Muscle weakness/ fatigue

Other adverse effects reported with eye drops containing phosphate:

If you suffer from severe damage to the cornea (the transparent layer at the front of the eye), treatment with phosphates, in very rare cases, may cause blurry vision due to calcium accumulation.

Reporting of adverse effects:

If you experience any type of adverse effect, consult your doctor or pharmacist, even if it is a possible adverse effect that does not appear in this prospectus. You can also report them directly through the Spanish System for the Vigilance of Medicines for Human Use:https://www.notificaRAM.es. By reporting adverse effects, you can contribute to providing more information on the safety of this medication.

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

Store the container in the outer packaging to protect it from light.

Do not use more than one container at the same time.

Do not use this medication after the expiration date that appears on the box and on the container after EXP. The expiration date is the last day of the month indicated.

You must discard the container four weeks after opening it for the first time, even if there are still some drops left.This will help prevent infections.To help you remember, write the date you opened it in the corresponding space on the box.

Medications should not be thrown away through drains or in the trash.Deposit the containers and medications you do not need in the SIGRE collection point at the pharmacy.In case of doubtask your pharmacist how to dispose of the containers and medications you do not need. By doing so, you will help protect the environment.

Composition of COMBIGAN

• The active ingredients are brimonidine tartrate and timolol.
• One milliliter of solution contains 2 milligrams of brimonidine tartrate and maleate of timolol equivalent to 5 milligrams of timolol.
• The other components are: benzalkonium chloride (as a preservative),sodium monobasic phosphate monohydrate, sodium dibasic phosphate heptahydrate, and purified water. Small amounts of hydrochloric acid or sodium hydroxide may be added to adjust the pH (determination of the acidity or alkalinity of the solution).

Appearance of COMBIGAN and contents of the package

COMBIGAN is a clear, slightly yellowish-green solution in a plastic bottle with a screw cap. Each bottle is filled to approximately half and contains 5 ml of solution. There are available boxes containing 1 or 3 bottles. Some bottle sizes may only be marketed.

Holder of the marketing authorization and responsible for manufacturing

Holder of the marketing authorization:

AbbVie Spain, S.L.U.

Avenida de Burgos 91,

28050 Madrid

Spain

Responsible for manufacturing:

Allergan Pharmaceuticals Ireland

Castlebar Road

Westport, Co Mayo

Ireland

This medicine is authorized in the member states of the European Economic Area with the following names:

Last review date of this leaflet: 11/ 2020

The detailed and updated information on this medicine is available on the website of the Spanish Agency for Medicines and Medical Devices (AEMPS)http://www.aemps.gob.es/