Combigan eye drops with internal pressure reduction (5ml)

Dosage form Bottle x 5ml
Specifications Brimonidina, Timolol
Ingredient Glocom glaucoma

Ingredient

Composition informationContent
Brimonidina2mg/ml
Timolol5mg/ml

Uses

indications

Combigan eye drops are indicated in the following cases:

Reducing the internal pressure (IOP) in patients with chronic open -angle glaucoma or adequate glaucoma response to local used beta blockers.

Pharmacology

Pharmacological - Treatment Group: The form of combination in the scientific label between Glaucoma and Dong Tu Treatment Preparations - Beta Timolol blockers.

Code ATC: S01ED 51.

Mechanism of action

Combigan consists of 2 active ingredients: Brimonidin Tartrat and Timolol Maleat. These two components reduce the increase in internal pressure (IOP) with the additional mechanism of additional effects and the combined effect, leading to further reduction of internal incubation than when using one of these two components.

Combigan has a quick acting. Brimonidin Tartrat is an Adrenergic Alpha receptor owner - 2 selected 1000 times for the Andrenalin Alpha 2 receptor compared to Adrenalin Alpha receptor - 1. This selection leads to not dilating the pupil and does not shrink circuits in micro -circuits related to retinal transplant in humans. Brimonidin Tartrat is thought to reduce internal pressure (IOP) by inhibiting the water flow flowing in and increasing the aura flow released through grape - enhanced veins.

Timolol is a Adrenergic Beta and Beta receptor blockers, which are not selective, without a significant intrinsic sympathetic nerve, which weakens the heart muscle directly, or the local anesthetic effect (stabilizes the membrane). Timolol reduces intraocular pressure by reducing the formation of aquaculture. The exact mechanism of this effect has not been clearly defined but may be due to inhibition of an increase in amp amp due to beta - endogenous adrenergic stimulation.

pharmacokinetics

Combigantm

The concentration of brimonidine and timolol in plasma has been determined in a diagonal study that compares a single therapy with Combigantm treatment in healthy people. There is no statistical difference in area under the concentration - time (AUC) curve (AUC) for Brimonidine or Timolol between Combigantm and the corresponding therapy.

The highest concentration value in plasma (average cmax for Brimonidine and Timolol after using Combigantm is 0.0327 ng/ ml for brimonidine and 0.406 ng/ mL for Timolol.

brimonidin

After using 0.2% small eye solution in humans, low plasma brimonidine concentrations. Brimonidine is not strongly metabolized in the human eye and the attachment to plasma proteins is about 29%.

The semi -cancellation time on the average of the whole week of the whole body is about 3 hours after using the place in humans. After drinking in humans, Brimonidin is well absorbed and quickly eliminated.

Most of the dose (about 74% of the dose) is excreted in the form of chemicals in the urine within 5 days, a small amount of doses excreted in the form of initial drugs in the urine.

In Vitro studies using animal and human liver liver, showing that the metabolism is largely performed by Aldehyd Oxidase and Cytochcrom P450. Therefore, the body elimination seems to be mainly through the metabolism in the liver. Brimonidine is strongly attached to melanin and can recover in the eye tissue without any unfavorable effect. Brimonidine accumulation does not occur without melanin.

Brimonidine is not metabolized at a high level in the human eye.

timolol

After using 0.5% small eye solution in people who had cataract surgery, the peak concentration of Timolol was 898 ng/ ml in a hydroelectric after 1 hour. Part of this dose is absorbed in the body and is strongly metabolized in the liver.

Timolol's apparent sale time in plasma is 4 hours. Timolol is partially metabolized in the liver, Timolol and its metabolites are excreted through the kidneys. Timolol is not strongly attached to plasma proteins.

Before taking Combigan eye drops with internal pressure reduction (5ml)

How to use

Small into the eyes of the sick person.

Dosage

recommended dose in adults (including the elderly)

The recommended dose is a small drop of Combigan into the eyes 2 times/ day about 12 hours apart. If you use more than one eye drops, different drugs must be at least 5 minutes apart.

Like any eye drops, to reduce the body's ability to absorb the whole body, it should be pressed into the tear pocket in the middle of the eye (bitter point) for 1 minute. This should be done immediately after each drop.

Used in kidney failure and liver failure

Combigan ™ has not been studied in patients with liver failure or renal failure. So be cautious when used for these patients.

Use in children and teenagers

Do not use Combigan ™ for babies (see the contraindications and how to overdose).

Safety and effectiveness of Combigan ™ in children and teenagers have not been determined, so do not recommend this drug for children and teenagers.

The base avoids eye infections or eye drops, not to let the drip tip touch any surface.

Note: The above dose is for reference only. Specific dosage depends on the condition and level of progression of the disease. For a suitable dose, you need to consult a doctor or medical specialist.What do

do when using overdose? The bradycardia has been reported related to the use of higher doses than the recommended dose. If overdose occurs, symptomatic treatment and support, should maintain airy airway.

There has been an overdose report due to unintentional Timolol eye solution, which leads to the same body effect as seen with beta - adrenergic blockers using the whole body such as dizziness, headache, shortness, slow heart rate, hypotension, bronchospasm and cardiac arrest.

brimonidin

In the case of Brimonidin used as part of congenital medical treatment for glaucoma, brimonidine overdose symptoms such as hypotension, slow heart rate, reduced body temperature and apnea are recorded in some infants being treated with Brimonidine.

There have been reports on oral overdose of other types of alpha -2 hosts causing symptoms such as hypotension, weakness, vomiting, sleep, drowsiness, slow heart rate, arrhythmia, pupils, apnea, reducing tone, reducing body temperature, respiratory failure and seizures.

timolol

Symptoms of overdose of the whole body such as: slow heart rate, hypotension, bronchospasm, headache, dizziness and cardiac arrest. In vitro hemocyst, using 14C Timolol added to human plasma or total blood shows that Timolol is easily separated from these fluids. However, a study in patients with renal failure shows that Timolol is not easy to separate.

If an overdose occurs, symptomatic treatment and supportive treatment occur.

What to do when you forget a dose? However, if close to the next dose, skip the forgotten dose and take the next dose at the time as planned. Do not drink twice as prescribed.

Side Effects

When using Combigan eye drops, you may experience unwanted effects (ADR).

Based on clinical data for 12 months, the most commonly reported side effects are conjunctival conjunctiva (about 15% of patients) and the burning sensation in the eye (about 11% of patients). Most of these cases are mild and the stop rate of drugs is only 3.4% for conjunctival congestion and 0.5% for a burning sensation in the eye.

The following side effects have been recorded in clinical trials with Combigan ™:

Eye disorders

Very common (> 1/10): congestion congestion, burning sensation in the eye.

Common (> 1/100,

Uncommon (> 1/1000,

Mental disorders:

Common (> 1/100,

Nervous system disorders:

Common (> 1/100,

Less (> 1/1/ 1000, Heart disorders:

Less (> 1/1,

circuit disorders:

Common (> 1/100,

Respiratory, chest and mediastinum disorders:

Less (> 1/1/ 1000,

Gastrointestinal disorders:

Common (> 1/100,

Uncommon (> 1/1 1/1,

Skin and subcutaneous disorders:

Common (> 1/100,

Uncommon (> 1/1000,

Mental disorders and in place use:

Common (> 1/100,

Testing:

Common (> 1/100, 10/10): LFT abnormalities.

immune system disorders:

Less (> 1/1,

Additional side effects

Additional side effects have been recorded with one of the components and also likely to occur with Combigan.

brimonidin

Eye disorders: Eye nail inflammation - eyelash infection (Early vascular inflammation), irisitis, pupils.

immune system disorders: hypersensitivity, skin reaction (including erythema, face edema, itching, rash), vasodilation.

Mind disorders: Insomnia.

Heart disorders: Brushing chest/ arrhythmia (including bradycardia and tachycardia)

circuit disorders: hypotension, fainting.

Respiratory, chest and mediastinum disorders: upper respiratory symptoms, shortness of breath.

Gastrointestinal disorders: digestive symptoms.

Systemic disorders and on -site use: Systemic allergic reaction.

timolol

Eye disorders: Reduce the sensitivity of cornea, songs, eyelid prolapse, peeling of darkness (after filtration surgery), refractive changes (due to stop use of pupils in some cases), folliculum points, keratitis, pemphigus fake disease.

Mental disorders: insomnia, nightmares, decreased libido, behavior change and mental disorders including anxiety, confusion, loss of orientation, hallucinations, memory loss, restlessness.

Nervous system disorders: Memory loss, increased signs and symptoms of severe, abnormalities, ischemia in the brain, stroke.

Disorders of ears and mesmerizing: tinnitus.

Heart disorders: heart blockage, cardiac arrest, arrhythmia, slow heartbeat, atrial block, heart failure, chest pain, edema, pulmonary edema, angina, worsening.

Vascular disorders: Hypotension, stroke, limping, raynaud, hands and feet.

Respiratory, chest and mediastinum disorders: bronchospasm (mainly in patients with bronchospasm before), shortness of breath, cough, respiratory failure, nasal congestion, upper respiratory tract infection.

Gastrointestinal disorders: indigestion, abdominal pain, anorexia, vomiting, taste disorders.

Skin and tissue disorders: hair loss, psoriasis or worse psoriasis, skin rash.

musculoskeletal disorders, connective tissue and bone: Lupus erythematosus, muscle pain.

Kidney and urinary disorders: Reduce sexual desire, Peyronie disease, posterior abdominal fibrosis, sexual dysfunction.

Systemic disorders and local condition: edema, chest pain.

immune system disorders (also known as hypersensitivity or immune disorders): allergic reactions include anaphylaxis, angioedema, body rash and localized, itching, urticaria, systemic lupus erythematosus.

Chemical and nutrition disorders (also known as endocrine disorders): Hypoglycemia (in diabetes patients).

After -sales experience

The following side effects have been reported since Combigan ™ was sold on the market. Because these reactions are voluntarily reported from an unknown scale population, unpredictable frequency:

eye disorders: blurred vision.

vascular disorders: hypotension.

Skin and tissue disorders: Red face.

Instructions on how to handle ADR

When experiencing side effects of the drug, it is necessary to stop using and notify the doctor or go to the nearest medical facility for timely treatment.

Warnings

Before using Combigan 5ml medicine, you need to read the instructions carefully and refer to the information below.

contraindicated

Combigan eye drops contraindicated in the following cases:

Respiratory diseases regenerated including bronchial asthma or a history of bronchial asthma, chronic obstructive pulmonary disease.

Sinus slow heart rate, sinus node impairment syndrome, atrial sinus button block, atrial atrial block of degree 2 or degree 3 are not controlled by a pacemaker (pace - maker), heart failure, heart shock.

Used in infants and young children (children under 2 years old, see the dose section (used in children and teenagers).

Patients who are treating monoamin oxidase inhibitors (IMAO).

Patients taking antidepressants affect noradrenergic transmission (e.g. 3 -round antidepressants and mianserin).

Hypersensitivity to active ingredients or any excipients of the drug: benzalkonium chloride, sodium phosphate monobasic monohydrate, sodium phosphate dibasic heptahydrate, hydrochloric acid or sodium hydroxid to adjust pH, pure water.

Be cautious when using

like other eye medications used on the spot, active ingredients (Brimonidin tartrat and Timolol) in Combigan ™ can be absorbed in the body. Not yet recorded the increase in the body absorption of individual active ingredients.

Some patients have eye allergic reactions (allergic conjunctivitis and allergic lash inflammation) with Combigan ™ in clinical trials. Allergic conjunctivitis is recorded in 5.2% of patients. The onset is typical from 3 to 9 months, resulting in the entire stop rate of 3.1%.

Allergic lash inflammation is less reported (

Due to the active component of Beta - Adrenergic is Timolol's of the same form of cardiovascular and respiratory reactions that have been occurred when it is encountered when using body beta blockers.

Be careful when treating patients with severe or unstable cardiovascular disease and uncontrolled (eg coronary artery disease, prinzmetal and heart failure) and hypotension.

Need to fully check the heart failure before starting treatment. Patients with a history of severe heart disease must be checked for signs of heart failure and pulse. Due to the adverse effect on the transmission time, beta blockers should only be used with caution for patients with heart blocks 1. The heart and respiratory reactions, including death from bronchospasm in patients with asthma and rare cases related to heart failure have been recorded after taking Timolol Maleat.

Beta blockers for eyes can reduce the tachycardia and increase the risk of hypotension when used in combination with anesthesia. Anesthesia must notify if the patient is using Combigan ™. In general, patients with chronic or medium clogged pulmonary disease should not be used for beta blockers, including Combigan ™; However, if Combigan ™ is thought to be necessary in these patients, caution should be used.

Beta blockers can also cover the signs of hyperthyroidism and worsen Prinzmetal angina, peripheral and central circulatory disorders and hypotension. Beta blockers for eyes can cause dry eyes. Be careful when treating patients with corneal disease.

Should be cautious when used simultaneously with beta - adrenergic blockers used body due to the ability to work plus the body block. Need to closely monitor the response of these patients. It is not recommended to use two beta - adrenergic blockers on the spot.

Be cautious when using Combigan ™ in patients with metabolic acidosis and chrome -preferred cell tumors. Beta - Adregegic blockers should be used carefully in patients with spontaneous hypoglycemia or patients with diabetes (especially those with unstable diabetes), because beta blockers can cover the signs and symptoms of acute hypoglycemia. Signs and symptoms of acute hypoglycemia may be hidden, especially tachycardia, brushing chest drums and sweating.

Be cautious when using Combigan ™ in patients with congestion vasculitis, need to be cautious when treating patients with severe peripheral circulatory disorders (i.e. Raynaud phenomenon).

While taking beta blockers, patients with a history of allergies or a history of anaphylactic reactions with many allergens that can react more strongly when exposed to repeated allergens. These patients may not respond to adrenalin doses often used to treat anaphylactic reaction.

As well as beta blockers, if the stop treatment is needed in patients with heart disease due to coronary artery, should withdraw the treatment slowly to avoid arrhythmia, myocardial infarction or sudden death.

There have been reports on the black bong after filtration procedure when using water inhibitors (such as Timolol, Acetazolamid). Benzalkonium chloride preservatives in Combigan ™ can cause eye irritation. It is necessary to guide patients with soft contact lenses (water -loving) contact lenses before use and wait at least 15 minutes after Combigan ™ before bringing the glass back. Benzalkonium chloride has been known to be absorbed and changed the color of soft contact lenses. Avoid contact with soft contact lenses. It is necessary to guide patients to avoid the head of the vial to touch the eyes or the surrounding structure to avoid eye damage and eye drops.

Combigan ™ has not been studied in patients with closed angle glaucoma.

Combigan ™ has not been studied in children under 18 years old. However, in a 3 -month study, phase 3 in children (from 2 - 7 years old) with Glaucoma is not fully controlled with beta blockers, the use of small eye solutions Brimonidin Tartrat has led to a high and intense drowsiness in children aged 2 and older, especially children weighing Slow hypersensitivity reaction in the eye has been reported with 0.2%0.2%Brimonidin Tartrat eye solution, some cases are reported related to intraocular pressure increased.

Combigan eye drops have not been studied in patients with liver or kidney failure; Be careful when treating these patients.

The ability to drive and operate machinery

as well as with other similar drugs, Combigantm can cause fatigue and/ or drowsiness in some patients. Combigan ™ can cause fuzzy vision, visual disorders, fatigue and/ or drowsiness are conditions that can impair driving capabilities or operating machinery. Patients participating in activities such as driving and operating machinery should be warned of the ability to reduce mental alertness. Patients should wait until these symptoms before driving or using machines.

Pregnancy

There are no adequate and well -controlled studies with combicantm in pregnant women. Because animal reproductive studies do not always be predicted in humans, only Combigan ™ should be used during pregnancy if the benefits may be available to mothers who are higher than the risk that may occur for fetuses.

brimonidin tartrat

There is no enough clinical data when used for pregnant women. Animal studies show that toxicity about reproduction when using high doses toxic to mother objects.

timolol

studies on epidemiology have not detected malformations but have shown the risk of growth in the uterus when the beta blockers are taken orally.

In addition, signs and symptoms of beta blockers (for example, slow heart rate, hypotension, acute respiratory failure and hypoglycemia) have been recorded in infants when beta blockers are used until birth. If Combigan ™ is used until birth, must monitor babies carefully throughout the first days of life. Animal studies with Timolol have shown to toxicity of reproduction in significantly higher doses than when used in clinical practices.

Do not use Combigan ™ during pregnancy unless really necessary.

breastfeeding period

Timolol is excreted in human milk. It is not clear whether brimonidin is excreted in human milk, but it is excreted in the milk of breastfeeding mice. Because of the ability to have a serious adverse reaction due to Timolol or Brimonidin tartrat in breastfeeding, it is necessary to decide to stop breastfeeding or stop taking the drug, taking into account the importance of the mother.

Do not use Combigantm in women who are breastfeeding.

used in children

There is no complete and well -controlled study for Combigantm in children (under 18 years old). In a 3 -month study, phase 3 in children (from 2-7 years old) with Glaucoma was not fully controlled by beta blockers, there was a high proportion of drowsiness (55%) when using 0.2% Brimoniclin Tartrat eye solution as supplementary treatment for beta blockers used on the spot. Intense drowsiness in 8% of children and leads to stopping treatment in 13% of children. The rate of drowsiness decreased with age increased, at least in the 7 -year -old group (25%), but more affected by weight, occurring more often in children weight smaller than or equal to 20 kg (63%) than those with a weight> 20 kg (25%).

In after -sales surveillance, there was a report on apnea, slow heartbeat, coma, hypotension, body temperature, reduced tone, sleeping, pale, respiratory failure and drowsiness in newborns, young children and children treated with congenital glaucoma or accidental brimonidine or due to unintentional drinking (see the anti -controlled section).

used in the elderly

Do not observe the overall difference in safety and effectiveness between elderly patients and other adult patients.

Drug interaction

There is no study on drug interaction conducted with Combigan ™.

Although studies of specific drug interactive drugs have not been conducted with Combigan ™, it is necessary to consider the theory of auxiliary effects or strengthen the central nervous system inhibitors (alcohol, barbiturates, opium, sedatives or anesthesia).

There is a potential to have auxiliary effects leading to hypotension, and/ or a significant slow heart rate when beta blockers are used simultaneously with oral calcium channel blockers, Guanethidin, or beta blockers, anti -arrhythmic drugs (including amiodaron), digitalis glycosides, other sympathetic medications and lower blood pressure drugs. After using brimonidine, very rare cases of hypotension ( Although Timolol has little effect or does not affect the size of the pupil, occasionally recorded a pupil relaxation when Timolol was used with pupils relaxing drugs like Adrenalin. Beta blockers can increase the effect of hypoglycemia of anti -diabetes drugs. Beta blockers can cover the signs and symptoms of hypoglycemia (see the cautious part when used).

The reaction that causes hypertension when stopping clonidin can suddenly be strengthened while taking beta blockers.

It has been recognized as a strong beta blocker (e.g. slow heart rate, depression) while treating the combination of CYP2D6 inhibitors [for example, Quinidin, selective Serotonin Rhemorror inhibitors (SSRI)] with Timolol, may be due to quinidine inhibiting the transformation of Timolol through the enzyme P450 is CYP2D6. Simultaneous use of a beta blocker with anesthetics can reduce the tachycardia and increase the risk of hypotension (see the cautious part when used), so it is necessary to notify the anesthetic doctor if the patient is using Combigan ™. Be cautious if Combigan ™ is used simultaneously with contrast drugs with iodine or lidocaine using intravenous tract.

cimetidine, hydralazin and alcohol can increase the level of timolol in plasma.

3 -round antidepressants have been reported to reduce the effect of lowering blood pressure of the body. It is unclear whether the simultaneous use of these drugs with Combigan ™ in humans can lead to intervention in reducing internal pressure.

There is no data on Catecholamine levels during the circulation after using Combigan ™, however, be careful in patients who are taking 3 -round antidepressants that can affect the metabolism and collection of amines during circulation, such as chlorpromazine, methylphenidate, reserpine.

Should be cautious when starting to use simultaneously (or dose change) a medication using systemic sugar (regardless of the form of preparation) can interact with α-adrenergic agreed owners or prevent their activity, ie Adrenergic receptor-controllers (such as isoprenalin, Prazosin).

Although studies on specific drug interactions have not been conducted with Combigan ™, it is necessary to consider the theory of extra low -labeled pressure to use with prostamid, prostaglandin, carbonic inhibitors anhydrase and pilocarpin.

Contraindications to the same time with Mao inhibitors (see the contraindications). Patients who are being treated inhibitor must wait 14 days after stopping the drug before starting with Combigan ™.

Need to monitor patients who are taking a beta - adrenergic blocker using the whole body (eg oral or intravenous) and Combigan ™ about the ability to have additional effects on beta blockers, on both body blood pressure and internal pressure

The ability to cause cancer, mutations, decline in fertility

Data on eye and body safety for individual components have been clearly defined. Prelopatic data does not detect any risks, especially for people based on regular studies for individual ingredients of safe pharmacological pharmacology, repetitive dose toxicity, gene toxicity, and studies on cancer. More studies on the toxicity of the eye for the eye when using Combigan ™ do not show any special risk to humans.

brimonidin

Brimonidin Tartrat does not cause any teratogenic effect in animals, but has caused a miscarriage in the rabbit when taking a dose of about 37 times higher than when treating in humans and reducing development after birth in mice when taking a dose of about 134 times higher than when treatment in humans.

timolol

In animal studies, beta blockers have reduced blood flow through the navel, reducing pregnancy growth, slow chemistry and increased pregnancy and postpartum death, but not causing teratogenic.

With Timolol, embryo toxicity (embryo pepper) in rabbits and pregnancy toxicity (slow core) in rats when using high doses for mother objects. Studies on monitoring in mice, rats and rabbits with Timolol oral doses up to 4200 daily dose of Combigan ™ in humans, do not show manifestations of pregnancy deformities.

Storage

Storage below 30 ° C. Keep the vial in the carton box, avoid light.

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