Instructions Normatin eye drops 0.5% dropper bottle 5 ml
Composition
active ingredient: timolol;
1 ml of solution contains timolol (in the form of timolol maleate) 5 mg;
Excipients: disodium phosphate dodecahydrate; sodium dihydrogen phosphate monohydrate; sodium chloride; disodium edetate; benzalkonium chloride; sodium hydroxide; water for injections.
Dosage form
Eye drops, solution.
Main physicochemical properties: colorless or almost colorless transparent solution.
Pharmacotherapeutic group
Antiglaucoma and miotic agents. Beta-adrenergic blockers. ATX code S01E D01.
Pharmacological properties
Pharmacodynamics
The active substance of the drug is the L-isomer of timolol maleate. Timolol is a non-selective beta-blocker used to reduce blood and intraocular pressure, as well as in the treatment of angina pectoris. L-timolol has a high affinity for β-1 and β-2 receptors. The effect of reducing intraocular pressure is based on a decrease in the formation of intraocular fluid. Timolol is administered topically into the eye. It does not have a significant effect on the outflow of intraocular fluid. It is not known whether timolol affects the blood vessels of the anterior segment of the eye, but with a decrease in intraocular pressure, an improvement in retinal blood flow has been observed. Like many other beta-blockers, timolol has a long post-receptor effect; the adrenergic receptor cannot mediate the effect of the agonist, since timolol is already dissociated.
Timolol has no intrinsic sympathomimetic activity and no significant membrane-stabilizing activity. It does not affect pupil size or accommodation. The effectiveness of timolol in the treatment of open-angle glaucoma and ocular hypertension has been confirmed. Timolol can be successfully used in many types of secondary glaucoma. It is well tolerated and does not cause addiction. Probably due to the small dose, the withdrawal syndrome that should be expected with systemic beta-blocker treatment was not observed when timolol treatment was discontinued.
Pediatric patients.
There are very limited data on the use of timolol (0.25%, 0.5%; 1 drop twice daily) in paediatric patients for treatment periods of up to 12 weeks. In a clinical study conducted in 105 children aged 12 days to 5 years, timolol was shown to be somewhat effective in the short-term treatment of primary congenital or primary juvenile glaucoma.
Pharmacokinetics
Timolol is a lipid-soluble substance and is therefore well absorbed into the eye. In addition, it can enter the systemic circulation through the conjunctiva and nasal mucosa, as well as the digestive tract. Intraocular pressure is reduced due to local action. The maximum effect in the eye is achieved 3–4 hours after instillation, and the effect can last for 24 hours.
In the eye, timolol binds to cell surfaces in many tissues, particularly the pigment cells of the iris endothelium and the ciliary processes. It is excreted from the eye with the outflow of aqueous humor. The expected half-life from ocular tissues is about 8 hours.
Timolol is metabolized in the liver to inactive metabolites, which are excreted mainly by the kidneys. After an oral dose, presystemic metabolism in the liver is significant, about 50%. Binding to plasma proteins is moderate (60%). The volume of distribution averages more than 2 l/kg, passes through the blood-brain barrier. The half-life from plasma is about 4 hours.
Pediatric patients.
It has been confirmed that in adults, 80% of timolol eye drops pass through the nasolacrimal canal, where they are rapidly absorbed into the systemic circulation through the nasal mucosa, conjunctiva, nasolacrimal duct, oropharynx, and digestive tract.
In children, the concentration of timolol in the blood plasma is higher than in adults. In newborns, the metabolism is not sufficiently developed, which may lead to an increase in its half-life. According to some reports, the level of timolol in the blood plasma in children who received it at a concentration of 0.25% is significantly higher than in adults after application at a concentration of 0.5%. In young children, an increased risk of adverse reactions such as bronchospasm and bradycardia is expected.
Indication
For the treatment of open-angle glaucoma, increased intraocular pressure, glaucoma after cataract surgery, in some cases - secondary glaucoma. For the treatment of angle-closure glaucoma, provided that miotics are used concomitantly.
The medicine should be used only as prescribed by an ophthalmologist or as a continuation of treatment initiated by such a specialist.
Contraindication
Hypersensitivity to the active substance and/or to any of the excipients of the medicinal product. Sinus bradycardia. Sick sinus syndrome. Sinoatrial block. Atrioventricular block of the 2nd or 3rd degree not controlled by a pacemaker. Severe heart failure. Cardiogenic shock. Reactive airway disease, including bronchial asthma or a history of bronchial asthma. Severe chronic obstructive pulmonary disease.
Interaction with other medicinal products and other types of interactions
No specific drug interaction studies have been conducted with timolol eye drops.
Timolol eye drops can be used with other antiglaucoma medications.
Oral calcium antagonists (calcium channel blockers), beta-blockers, antiarrhythmics (including amiodarone), digitalis glycosides, parasympathomimetics, guanethidine.
Concomitant use of timolol with such agents increases the risk of arterial hypotension and/or severe bradycardia.
Systemic alpha-blockers, reserpine, group I antiarrhythmics (e.g. quinidine), clonidine.
Concomitant use of timolol with such agents may exacerbate adverse reactions. In the case of concomitant use of these agents, patients should be monitored.
CYP 2D6 inhibitors (e.g. quinidine, fluoxetine, paroxetine).
Potential systemic beta-blockade (e.g., decreased heart rate, depression) has been reported with concomitant use of timolol with such agents.
Barbiturates, painkillers, ergot alkaloids.
Concomitant use of timolol with such agents may increase adverse reactions from the central nervous system.
Adrenaline (epinephrine).
Mydriasis has been reported with concomitant use of timolol with adrenaline (epinephrine).
Application features
Before starting the use of the drug, the patient's health status should be assessed (see the "Contraindications" section).
Since the response to beta-blockers may vary, it is recommended that the patient's intraocular pressure be measured 2-4 weeks after starting the drug. Regular ophthalmological examinations should be performed thereafter, as in some cases the response to timolol may change with prolonged use.
Risk of systemic adverse reactions.
Like other topically applied ophthalmic agents, timolol is absorbed systemically. Due to the beta-adrenergic component, the same cardiovascular, pulmonary and other adverse reactions as with systemic beta-blockers may occur. The incidence of systemic adverse reactions following topical ophthalmic administration is lower than with systemic administration.
Interaction with other beta-blockers.
The effect on intraocular pressure or other effects of systemic beta-blockers may be potentiated when timolol is used in patients already receiving an oral beta-blocker. In case of concomitant use, the response of such patients should be carefully monitored. The use of 2 topical beta-blockers is not recommended (see section 4.5).
Risk of heart disorders.
The use of beta-blockers in patients with cardiovascular disease (e.g. coronary artery disease, vasospastic (spontaneous) angina and heart failure) and hypotension should be seriously considered, with consideration of treatment with other active substances. Patients with cardiovascular disease should be monitored for worsening of their condition and any adverse reactions when using the medicinal product.
The drug should be used with caution only in patients with first-degree heart block.
Risk of vascular disorders.
The drug should be used with caution in patients with severe peripheral or circulatory disorders (i.e. severe Raynaud's disease or Raynaud's syndrome).
Risk of respiratory disorders.
Respiratory adverse reactions, including fatal outcomes, due to bronchospasm have been reported in patients with asthma following the use of some ophthalmic beta-blockers. The drug should be used with caution in patients with mild/moderate chronic obstructive pulmonary disease (COPD) and only if the potential benefit outweighs the potential risk.
Risk of anaphylactic reactions.
When using beta-blockers, patients with a history of atopy or a history of severe anaphylactic reactions to a variety of allergens may react to repeated exposure to such allergens and may not respond to the usual dose of epinephrine (adrenaline) used to treat anaphylactic reactions.
Anesthesia during surgical interventions.
Ophthalmic beta-blockers may block the systemic effects of beta-agonists, such as adrenaline. If the drug is used, the anaesthetist should be informed.
Use in patients with hypoglycemia/diabetes.
The drug should be used with caution in patients prone to spontaneous hypoglycemia or in patients with labile diabetes, since beta-blockers may mask the symptoms of acute hypoglycemia.
Risk of hyperthyroidism (overactive thyroid gland).
Beta-blockers may mask the symptoms of hyperthyroidism.
Use in patients with myasthenia gravis.
When using timolol eye drops, worsening of the general condition of such patients has been reported.
Ophthalmic beta-blockers may cause dry eyes. The drug should be used with caution in patients with corneal diseases.
Risk of chorionic detachment (the vascular membrane of the eye).
Chorionic detachment has been reported with the use of ophthalmic suppressants (e.g., timolol, acetazolamide) following filtration procedures.
Use in patients who wear contact lenses.
The medicine contains the preservative benzalkonium chloride, which can be deposited on soft contact lenses, so it should not be used while wearing contact lenses. Before instilling the drops, the lenses must be removed and put back on no earlier than 15 minutes after using the medicine.
Benzalkonium chloride may also cause eye irritation, especially in cases of dry eyes or corneal damage. If you experience unusual eye sensitivity, burning or pain in your eyes, you should consult a doctor.
Ability to influence reaction speed when driving vehicles or other mechanisms
With the correct dosage regimen, timolol does not have a negative effect on the ability to drive vehicles or other mechanisms.
However, adverse reactions such as dizziness, visual disturbances, refractive changes, diplopia (double vision), ptosis (drooping eyelid), frequent cases of mild transient blurred vision, and fatigue are possible, which may adversely affect the ability of some patients to drive or use machines. The patient should be informed of this at the beginning of treatment.
Use during pregnancy or breastfeeding
Pregnancy.
Timolol crosses the placenta. There are no adequate data from the use of timolol in pregnant women.
The drug should not be used during pregnancy unless clearly necessary. To reduce systemic absorption, see section "Method of administration and dosage".
Epidemiological studies have not revealed any malformative effects, but have demonstrated a risk of intrauterine growth retardation with oral beta-blockers. In addition, signs and symptoms of beta-blocking effects (e.g. bradycardia, hypotension, respiratory distress and hypoglycaemia) have been observed in neonates when beta-blockers were used antepartum. If timolol is used antepartum, the neonate should be closely monitored during the first days of life.
Breastfeeding period.
Beta-blockers are found in breast milk. However, the therapeutic dose of timolol in eye drops is not sufficient to be detected in breast milk and to cause symptoms of beta-blockade in the newborn. Regarding reduced systemic absorption, see section "Method of administration and dosage".
Method of administration and doses
Adults.
The medicine is intended for topical use (in the conjunctival sac).
Eye drops should be instilled 1 drop into the affected eye 1–2 times a day (morning and evening).
Nasolacrimal occlusion or eyelid closure for 2 minutes reduces systemic absorption of the drug. As a result, the likelihood of systemic adverse reactions decreases and local activity increases.
Simultaneous use with other agents.
The effect of lowering intraocular pressure can usually be enhanced when the drug is combined with other antiglaucoma drugs (prostaglandin analogues, miotics, adrenergic agonists/adrenomimetics or carbonic anhydrase inhibitors). When switching from another antiglaucoma drug to Normatin, the previous drug should be immediately discontinued and Normatin should be started as described above.
Children.
The benefit/risk ratio of timolol use in children should be carefully assessed before using the drug. A careful examination and history should be taken before starting timolol use in children to determine the presence of systemic disorders.
No specific dosage recommendations are available as clinical data are limited (see section 5.1). However, if the benefits outweigh the risks, the lowest daily dose is recommended.
To limit the development of adverse reactions, eye drops should be instilled 1 drop into the affected eye per day.
If intraocular pressure is not adequately controlled, an increase in dose to 2 drops in the affected eye(s) per day may be considered. When used twice daily, an interval of 12 hours should be maintained between applications.
In addition, patients, especially neonates, should be closely observed after the first dose for 1–2 hours in the physician's office and closely monitored for local and systemic adverse reactions prior to surgery.
When used in pediatrics, an active ingredient concentration of 0.1% may be sufficient.
Systemic absorption of topical beta-blockers after instillation can be reduced by nasolacrimal occlusion and eyelid closure for as long as possible (e.g. 3-5 minutes) (see sections 4.4 and 5.2).
The medicine should only be used for temporary treatment of children.
Due to limited data, timolol can only be recommended in primary congenital and primary juvenile glaucoma during the transitional period before a decision is made about surgery or other treatment options.
Overdose
Symptoms
Overdose should be avoided. The amount of timolol obtained from the use of 30 drops of this medicinal product is equal to the total amount of timolol absorbed from taking 1 timolol tablet orally. However, since timolol is rapidly absorbed through the mucous membrane of the nose and eye, even a few drops can cause arrhythmia, transient slowing of the pulse rate, a decrease in blood pressure and bronchospasm.
Treatment
In case of overdose, symptomatic therapy should be carried out. Adrenergic agonists (e.g. isoprenaline, dobutamine, dopamine) are used.
Adverse reactions
Timolol is generally well tolerated. Like other topically applied ophthalmic drugs, timolol is absorbed into the systemic circulation. This may cause adverse reactions similar to those observed with systemic beta-blockers.
The incidence of systemic adverse reactions after topical ophthalmic use is lower than with systemic use.
The following adverse reactions include those typical of the class of ophthalmic beta-blockers.
The frequency of reactions is defined as follows: very common (≥ 1/10), common (≥ 1/100 to <1/10), uncommon (≥ 1/1000 to <1/100), rare (≥ 1/10,000 to <1/1000), very rare (<1/10,000), not known (frequency cannot be estimated from the available data).
On the part of the organs of vision:
uncommon - decreased corneal sensitivity, superficial punctate keratitis; rare - dry eye syndrome, blepharoconjunctivitis, visual disturbances, including refractive changes (due to withdrawal of miotics in some cases), diplopia (double vision), ptosis (drooping eyelid); very rare - corneal calcification (associated with the use of eye drops containing phosphates in some patients with significantly affected corneas).
From the heart:
infrequently - bradycardia; rarely - heart failure, arrhythmias.
From the vascular side:
rarely - arterial hypotension, decreased peripheral and cerebral blood perfusion.
From the nervous system:
often - headache; rarely - dizziness.
From the respiratory system, chest organs and mediastinum:
infrequently - shortness of breath; rarely - bronchospasm (especially in patients with bronchospastic diseases such as asthma or heart failure), nasal congestion.
From the psyche:
infrequently - depression; rarely - hallucinations, anxiety, nightmares, confusion (clouding of consciousness).
Skin and subcutaneous tissue disorders:
rarely - hypersensitivity reactions: rash, urticaria, alopecia.
General violations:
infrequently - fatigue; rarely - asthenia (general weakness).
In addition to the above, the use of timolol eye drops may cause adverse reactions that are caused by beta-blockers during systemic use.
On the part of the immune system:
systemic allergic reactions, including angioedema, itching, anaphylactic reaction.
From the side of metabolism and nutrition:
hypoglycemia.
From the psyche:
insomnia, memory loss, hallucinations.
From the nervous system:
loss of consciousness, stroke, cerebral ischemia, increased signs and symptoms of myasthenia gravis, paresthesia.
On the part of the organs of vision:
signs and symptoms of eye irritation (e.g., burning, sharp pain, itching, tearing, redness), keratitis, blurred vision, chorionic detachment after filtering surgery (see "Special instructions"), corneal erosion.
From the heart:
chest pain, rapid heartbeat, edema, congestive heart failure, atrioventricular block, cardiac arrest.
From the vascular side:
Raynaud's phenomenon.
From the respiratory system, chest organs and mediastinum:
cough.
From the digestive tract:
dysgeusia (taste disorder), nausea, dyspepsia (digestive disorder), diarrhea, dry mouth, abdominal pain, vomiting.
Skin and subcutaneous tissue disorders:
psoriasis-like rashes or exacerbation of psoriasis.
Musculoskeletal and connective tissue disorders:
myalgia (muscle pain).
From the genitals and mammary gland:
sexual dysfunction, decreased libido.
Reporting of suspected adverse reactions.
Reporting suspected adverse reactions that occur after the registration of a medicinal product is very important. This allows for continuous monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions through the national pharmacovigilance system.
Expiration date
3 years.
After opening the bottle, use the medicine within 28 days.
Storage conditions
Store at a temperature not exceeding 25 °C in a place protected from light and out of the reach of children.
Packaging
5 ml in a dropper bottle; 1 dropper bottle in a cardboard box.
Vacation category
According to the recipe.
Producer
Location of the manufacturer and its business address
15 Temmuz Mahallesi Cami Yolu Caddesi No:50 Gunesli Bagcilar/Istanbul, Turkey/ 15 Temmuz Mahallesi Cami Yolu Caddesi No:50 Gunesli Bagcilar/Istanbul, Turkey.
