Normatin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NORMATIN (NORMATIN)

Composition:

Active substance: timolol;

1 ml of solution contains timolol maleate 6.83 mg, equivalent to timolol 5 mg;

Excipients: sodium dihydrogen phosphate monohydrate, anhydrous sodium hydrogen phosphate, benzalkonium chloride, sodium hydroxide, water for injections.

Pharmaceutical form. Eye drops, solution.

Main physicochemical properties: clear liquid, colorless to light yellow, with a very faint characteristic odor.

Pharmacotherapeutic group.
Antiglaucoma and miotic agents. Beta-adrenoreceptor blockers. ATC code S01ED01.

Pharmacological properties.

Pharmacodynamics.

The active substance of the medicinal product is the L-isomer of timolol maleate. Timolol is a non-selective beta-adrenoblocker used to reduce blood pressure and intraocular pressure, as well as in the treatment of angina pectoris. L-timolol has high affinity for β-1 and β-2 receptors. The effect of reducing intraocular pressure is based on decreased production of aqueous humor. Timolol is administered locally to the eye. It does not significantly affect the outflow of aqueous humor. It is not known whether timolol affects blood vessels of the anterior segment of the eye, but improved retinal blood flow has been observed with reduction of intraocular pressure. Like many other beta-adrenoblockers, timolol has a prolonged post-receptor effect; adrenergic receptors cannot mediate the agonist effect once timolol has dissociated.

Timolol has no intrinsic sympathomimetic activity and minimal membrane-stabilizing activity. It does not affect pupil size or accommodation. The efficacy of timolol has been confirmed in the treatment of open-angle glaucoma and ocular hypertension. Timolol can be successfully used in many forms of secondary glaucoma. It is well tolerated and does not cause dependence. Likely due to the low dose, withdrawal syndrome, which would be expected with systemic beta-adrenoblocker therapy, has not been observed upon discontinuation of timolol treatment.

Pediatric patients

There are only very limited data on the use of timolol (0.25%, 0.5%; 1 drop twice daily) in pediatric patients for treatment periods up to 12 weeks. In a clinical study involving 105 children aged from 12 days to 5 years, timolol demonstrated some efficacy in short-term treatment of primary congenital or primary juvenile glaucoma.

Pharmacokinetics.

Timolol is a lipophilic substance and therefore is well absorbed into the eye. Additionally, it may enter the systemic circulation via the conjunctiva and nasal mucosa, as well as the gastrointestinal tract. Intraocular pressure is reduced due to local action. Maximum ocular effect is achieved within 3–4 hours after instillation, and the effect may last up to 24 hours.

In the eye, timolol binds to cell surfaces in various tissues, particularly to pigment cells of the iris endothelium and ciliary processes. It is eliminated from the eye via aqueous humor outflow. The expected half-life from ocular tissues is approximately 8 hours.

Timolol is metabolized in the liver to inactive metabolites, which are primarily excreted by the kidneys. After oral administration, presystemic metabolism in the liver is substantial, approximately 50%. Plasma protein binding is moderate (60%). The volume of distribution averages more than 2 L/kg, and timolol crosses the blood-brain barrier. The plasma half-life is approximately 4 hours.

Pediatric patients

It has been confirmed that in adults, 80% of timolol eye drops pass through the nasolacrimal duct, where they are rapidly absorbed into the systemic circulation via the nasal mucosa, conjunctiva, nasolacrimal duct, oropharynx, and gastrointestinal tract.

In children, plasma concentrations of timolol are higher than in adults. In neonates, metabolism is underdeveloped, which may lead to an increased half-life of timolol. According to some data, plasma levels of timolol in children receiving the 0.25% concentration significantly exceed levels in adults after administration of the 0.5% concentration. In young children, an increased risk of adverse reactions such as bronchospasm and bradycardia is expected.

Clinical characteristics.

Indications.

• For the treatment of open-angle glaucoma, elevated intraocular pressure, postoperative glaucoma following cataract surgery, and in selected cases – secondary glaucoma.
• For the treatment of closed-angle glaucoma provided that miotics are concurrently administered.

The medicinal product should be used only upon prescription by an ophthalmologist or as continuation of treatment initiated by such a specialist.

Contraindications.

• Hypersensitivity to the active substance and/or to any of the excipients of the medicinal product.
• Sinus bradycardia.
• Sinoatrial node dysfunction (sick sinus syndrome).
• Sinoatrial block.
• Second- or third-degree atrioventricular block not controlled by a pacemaker.
• Severe heart failure.
• Cardiogenic shock.
• Reactive airway disease, including bronchial asthma or history of bronchial asthma.
• Severe chronic obstructive pulmonary disease.

Interaction with other medicinal products and other forms of interaction.

No specific studies on interactions between timolol eye drops and other medicinal products have been conducted.

Timolol in the form of eye drops may be used together with other antiglaucoma medications.

Oral calcium antagonists (calcium channel blockers), beta-blockers, antiarrhythmic agents (including amiodarone), cardiac glycosides, parasympathomimetics, guanethidine.

Concomitant use of timolol with these agents increases the risk of arterial hypotension and/or severe bradycardia.

Systemic alpha-adrenergic blockers, reserpine, antiarrhythmic agents of Class I (e.g., quinidine), clonidine.

Concomitant use of timolol with these agents may exacerbate adverse reactions. Patients should be monitored when these agents are used together.

Inhibitors of CYP2D6 (e.g., quinidine, fluoxetine, paroxetine).

Concomitant use of timolol with these agents has been associated with potential systemic beta-blockade (e.g., reduced heart rate, depression).

Barbiturates, analgesics, ergot alkaloids.

Concomitant use of timolol with these agents may enhance adverse reactions affecting the central nervous system.

Adrenaline (epinephrine).

Concomitant use of timolol with adrenaline (epinephrine) has been reported to cause mydriasis.

Special precautions for use.

Before initiating treatment with the medicinal product, the patient's health status should be evaluated (see section "Contraindications").

Since the response to beta-adrenergic blockers may vary, measurement of intraocular pressure is recommended 2–4 weeks after starting the medicinal product. Thereafter, regular ophthalmic examinations should be performed, as the response to timolol may change during prolonged therapy.

Risk of systemic adverse reactions.

Like other topically administered ophthalmic agents, timolol is systemically absorbed. Due to its beta-adrenergic component, the same cardiovascular, pulmonary, and other adverse reactions as those observed with systemic beta-blockers may occur. The frequency of systemic adverse reactions following topical ophthalmic administration is lower than with systemic administration.

Interaction with other beta-adrenergic blockers.

The effect on intraocular pressure or other systemic effects of beta-blockers may be enhanced when timolol is used in patients already receiving oral beta-blockers. Close monitoring of such patients is required when used concomitantly. Concomitant use of two topical beta-adrenergic blockers is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Cardiac disorders risk.

The use of beta-adrenergic blockers in patients with cardiovascular disorders (e.g., ischemic heart disease, vasospastic [spontaneous] angina, and heart failure) and hypotension should be carefully considered, and alternative therapies should be evaluated. Patients with cardiovascular disorders receiving the medicinal product should be monitored for worsening of their condition and for any adverse reactions.

The medicinal product may be used cautiously only in patients with first-degree heart block.

Vascular disorders risk.

The medicinal product should be used with caution in patients with severe peripheral disorders or circulatory abnormalities (i.e., severe forms of Raynaud’s disease or Raynaud’s syndrome).

Respiratory disorders risk.

Adverse reactions affecting the respiratory system, including fatal outcomes due to bronchospasm, have been reported in patients with asthma following the use of certain ophthalmic beta-adrenergic blockers. The medicinal product should be used with caution in patients with mild to moderate chronic obstructive pulmonary disease (COPD), and only if the potential benefit outweighs the potential risk.

Anaphylactic reactions risk.

Patients with a history of atopy or previous severe anaphylactic reactions to a variety of allergens may exhibit a heightened reaction to repeated allergen exposure while on beta-blockers and may not respond to the usual doses of epinephrine (adrenaline) used to treat anaphylactic reactions.

Anaesthesia during surgical procedures.

Ophthalmic beta-adrenergic blockers may block the systemic effects of beta-agonists such as adrenaline. If the medicinal product is being used, the anaesthesiologist should be informed.

Use in patients with hypoglycaemia/diabetes mellitus.

The medicinal product should be used with caution in patients prone to spontaneous hypoglycaemia or in patients with labile diabetes, as beta-blockers may mask the symptoms of acute hypoglycaemia.

Hyperthyroidism risk.

Beta-blockers may mask the symptoms of hyperthyroidism.

Use in patients with myasthenia gravis.

Worsening of the general condition has been reported in such patients when using timolol eye drops.

Use in patients with corneal disorders.

Ophthalmic beta-adrenergic blockers may cause dry eyes. The medicinal product should be used with caution in patients with corneal disorders.

Choroidal detachment risk.

Choroidal detachment has been reported with the use of ophthalmic suppressants (e.g., timolol, acetazolamide) following filtration procedures.

Use in patients wearing contact lenses.

The medicinal product contains the preservative benzalkonium chloride, which may be deposited on soft contact lenses. Therefore, it should not be administered while wearing contact lenses. Contact lenses must be removed before instilling the drops and may be reinserted no sooner than 15 minutes after administration of the medicinal product.

Benzalkonium chloride may also cause ocular irritation, symptoms of dry eye, and may affect the tear film and corneal surface. The medicinal product should be used with caution in patients with dry eye or in those who may have compromised corneal integrity. Patients should be monitored during prolonged therapy.

Use during pregnancy or breastfeeding.

Pregnancy

Timolol crosses the placenta. There are insufficient data on the use of timolol in pregnant women.

The medicinal product should not be used during pregnancy unless clearly necessary. Information on reducing systemic absorption can be found in the section "Posology and method of administration."

Epidemiological studies have not shown any teratogenic effects but have demonstrated a risk of intrauterine growth retardation with oral beta-blockers. In addition, newborns exposed to beta-blockers before delivery have shown signs and symptoms of beta-blockade (e.g., bradycardia, hypotension, respiratory distress, and hypoglycaemia). If timolou was administered before delivery, the newborn should be closely monitored during the first days of life.

Breastfeeding period

Beta-adrenergic blockers are excreted in breast milk. However, the therapeutic dose of timolol in eye drops is insufficient to result in detectable levels in breast milk or to cause beta-blockade symptoms in the newborn. Information on reducing systemic absorption can be found in the section "Posology and method of administration."

Effect on ability to drive and use machines.

When used according to the recommended dosing regimen, timolol does not negatively affect the ability to drive or operate machinery.

However, adverse reactions such as dizziness, visual disturbances, refractive changes, diplopia (double vision), ptosis (eyelid drooping), frequent episodes of mild transient blurred vision, and fatigue may occur, which could negatively affect the ability of some patients to drive or operate machinery. Patients should be informed of this at the beginning of treatment.

Method of Administration and Dosage

Adults

The medicinal product is intended for topical administration (into the conjunctival sac).

Eye drops should be instilled at a dose of 1 drop into the affected eye 1–2 times daily (in the morning and evening).

Nasolacrimal occlusion or eyelid closure for 2 minutes reduces systemic absorption of the medicinal product. As a result, the likelihood of systemic adverse reactions is decreased and local activity is increased.

Concomitant use with other agents

The intraocular pressure-lowering effect may generally be enhanced when combining this medicinal product with other antiglaucoma agents (prostaglandin analogues, miotics, adrenergic agonists/adrenomimetics, or carbonic anhydrase inhibitors). When switching from another antiglaucoma agent to Normatin, the previous medication should be discontinued immediately and treatment with Normatin initiated as described above.

Children

The benefit-risk ratio of timolol use in children should be carefully assessed before administering the medicinal product. A thorough examination and medical history evaluation should be performed prior to initiating timolol in children to identify any systemic disorders.

There are no specific dosage recommendations due to limited clinical data (see section "Pharmacodynamics"). However, if benefits outweigh risks, the lowest daily dose is recommended.

To minimize the risk of adverse reactions, eye drops should be administered at a dose of 1 drop into the affected eye daily.

If intraocular pressure is not adequately controlled, the dose may be increased to 2 drops into the affected eye daily. When administered twice daily, a 12-hour interval should be maintained between doses.

Additionally, close monitoring of the patient, especially neonates, is required for 1–2 hours after the first dose in a physician’s office, with careful observation for local and systemic adverse reactions prior to surgical intervention.

In pediatric use, a 0.1% concentration of the active substance may be sufficient.

Systemic absorption of topically applied beta-adrenergic blockers after instillation may be reduced by nasolacrimal occlusion and eyelid closure for as long as possible (e.g., 3–5 minutes) (see sections "Special Instructions" and "Pharmacokinetics").

The medicinal product should be used only for temporary treatment of children.

Children.

Due to limited data, timolol may be recommended only for primary congenital glaucoma and primary juvenile glaucoma during the transitional period before a decision on surgical intervention or alternative treatment options.

Overdose.

Symptoms

Overdose should be avoided. The amount of timolol received from administering 30 drops of this medicinal product equals the total amount of timolol absorbed after oral intake of 1 timolol tablet. However, since timol0l is rapidly absorbed through the nasal and ocular mucosa, even a few drops may cause arrhythmia, transient slowing of pulse rate, decreased arterial blood pressure, and bronchospasm.

Treatment

In case of overdose, symptomatic therapy should be administered. Adrenergic agonists (e.g., isoprenaline, dobutamine, dopamine) should be used.

Adverse Reactions

Timolol is generally well tolerated. Like other ophthalmic medicinal products administered locally, timolol is absorbed into the systemic circulation. This may cause adverse reactions similar to those observed with systemic beta-adrenergic blockers.

The incidence of systemic adverse reactions after local ophthalmic administration is lower than with systemic administration.

The adverse reactions listed below include those typical of the class of ophthalmic beta-adrenergic blockers.

Frequency of reactions is defined as follows: 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), not known (frequency cannot be estimated from the available data).

Eye disorders:

uncommon — corneal hypoesthesia, superficial punctate keratitis; rare — dry eye syndrome, blepharoconjunctivitis, visual disturbances including refractive changes (due to discontinuation of miotics in some cases), diplopia (double vision), ptosis (eyelid drooping); very rare — corneal calcification (associated with the use of phosphate-containing eye drops in some patients with significantly damaged corneas).

Cardiac disorders:

uncommon — bradycardia; rare — heart failure, arrhythmias.

Vascular disorders:

rare — arterial hypotension, decreased peripheral and cerebral blood perfusion.

Nervous system disorders:

common — headache; rare — dizziness.

Respiratory, thoracic and mediastinal disorders:

uncommon — dyspnea; rare — bronchospasm (especially in patients with bronchospastic conditions such as asthma or heart failure), nasal congestion.

Psychiatric disorders:

uncommon — depression; rare — anxiety, nightmares, confusion (mental clouding).

Skin and subcutaneous tissue disorders:

rare — hypersensitivity reactions: rash, urticaria, alopecia.

General disorders:

uncommon — fatigue; rare — asthenia (general weakness).

In addition to the above, adverse reactions associated with beta-adrenergic blockers during systemic administration may occur when using timolol eye drops.

Immune system disorders:

systemic allergic reactions, including angioneurotic edema, pruritus, anaphylactic reaction.

Metabolism and nutrition disorders:

hypoglycemia.

Psychiatric disorders:

insomnia, memory loss, hallucinations.

Nervous system disorders:

loss of consciousness, stroke, cerebral ischemia, worsening of signs and symptoms of myasthenia gravis, paresthesia.

Eye disorders:

signs and symptoms of eye irritation (e.g., burning, stinging, itching, lacrimation, redness), keratitis, blurred vision, choroidal detachment following filtration surgery (see "Special precautions for use"), corneal erosion.

Very rare cases of corneal deposits have been reported in some patients with significantly damaged corneas associated with the use of phosphate-containing eye drops.

Cardiac disorders:

chest pain, palpitations, edema, congestive heart failure, atrioventricular block, cardiac arrest.

Vascular disorders:

Raynaud's phenomenon.

Respiratory, thoracic and mediastinal disorders:

cough.

Gastrointestinal disorders:

dysgeusia (taste disturbance), nausea, dyspepsia (digestive disturbance), diarrhea, dry mouth, abdominal pain, vomiting.

Skin and subcutaneous tissue disorders:

psoriasiform rashes or exacerbation of psoriasis.

Musculoskeletal and connective tissue disorders:

myalgia (muscle pain).

Reproductive system and breast disorders:

sexual dysfunction, decreased libido.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after medicinal product authorization is important. It allows continuous monitoring of the benefit-risk ratio of the medicinal product. Healthcare professionals should report any suspected adverse reactions via the national pharmacovigilance system.

Shelf life.

2 years.

After first opening the bottle, the product may be used for up to 1 month only.

Storage conditions.

Store at temperatures not exceeding 25 °C. Keep out of reach of children.

Packaging.

5 mL solution in a plastic dropper bottle with a screw cap.

1 dropper bottle in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

«E.I.P.I.Co.», Egypt /
«E.I.P.I.Co.», Egypt.

Manufacturer's address and place of business.

Tenth of Ramadan City, First Industrial Area B1, P.O. box: 149 Tenth, Egypt /
Tenth of Ramadan City, First Industrial Area B1, P.O. box: 149 Tenth, Egypt.

Marketing Authorization Holder.

WORLD MEDICINE, LLC, Ukraine /
WORLD MEDICINE, LLC, Ukraine.