Betoptic® s

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BETOPTIC® S (BETOPTIC®S)

Composition:

Active ingredient: betaxolol hydrochloride;

1 ml of suspension contains 2.8 mg of betaxolol hydrochloride, equivalent to 2.5 mg of betaxolol;

Excipients: mannitol (E 421), polystyrene sulfonic acid, carbomer 974P, edetate disodium, benzalkonium chloride, N-lauroyl sarcosine, boric acid, sodium hydroxide and/or hydrochloric acid concentrated (for pH adjustment), purified water.

Pharmaceutical form. Eye drops.

Main physicochemical characteristics: white to almost white suspension.

Pharmacotherapeutic group. Agents used in ophthalmology. Anti-glaucoma preparations and miotics. Beta-adrenergic blockers.
ATC code: S01ED02.

Pharmacological properties.

Pharmacodynamics.

Betaxolol is a cardioselective beta-1-adrenergic receptor blocker that does not exert significant membrane-stabilizing (local anesthetic) or intrinsic sympathomimetic activity.

Elevated intraocular pressure is the major risk factor for the development of glaucomatous visual field loss. The higher the intraocular pressure, the greater the likelihood of optic nerve damage and visual field loss. After ocular instillation, betaxolol is capable of reducing both elevated and normal intraocular pressure, regardless of whether it is associated with glaucoma or not. The mechanism of its hypotensive effect is related to a reduction in aqueous humor production, as demonstrated by tonography and fluorophotometry. Betaxolol begins to act within 30 minutes, and the maximum effect is usually achieved within 2 hours after topical administration. A single dose provides reduction of intraocular pressure for up to 12 hours.

BETOPTIC® S suspension (0.25% betaxolol) provides reduction of intraocular pressure equivalent to that demonstrated by BETOPTIC® S solution (0.5% betaxolol).

The vasorelaxant effect of betaxolol on peripheral blood vessels has been demonstrated in an in vivo study in dogs. Additionally, the vasorelaxant effect of betaxolol and its ability to block calcium channels have been demonstrated in several in vitro studies using ocular and non-ocular vascular models in rats, guinea pigs, rabbits, dogs, pigs, and cows. The neuroprotective effect of betaxolol has been demonstrated in experiments both in vivo and in vitro on rabbit retina, rat cortical cultures, and chick retinal cultures.

Data from controlled clinical trials in patients with chronic open-angle glaucoma and ocular hypertension indicate that treatment with betaxolol provides a longer-lasting beneficial effect on visual field compared to treatment with timolol, a non-selective beta-blocker. Moreover, betaxolol administration was not associated with any negative impact on optic nerve blood supply. Betaxolol maintains or improves ocular blood flow/perfusion.

When applied topically as ophthalmic drops, betaxolol has minimal or no effect on pupil constriction and exerts minimal influence on pulmonary and cardiovascular function. Ophthalmic betaxolol has not shown significant effects on lung function, as assessed by measurements of forced expiratory volume in one second, vital lung capacity, and their ratio. No signs of cardiovascular beta-adrenergic blockade were observed during the study.

Orally administered beta-adrenergic blockers reduce cardiac output in healthy volunteers and in patients with heart disease. In patients with severe myocardial dysfunction, beta-adrenergic receptor antagonists may suppress the sympathetic stimulation necessary to maintain adequate cardiac function.

Results of clinical trials indicate that BETOPTIC® S suspension was tolerated significantly better than BETOPTIC® S solution.

The polar nature of betaxolol may cause ocular discomfort. In BETOPTIC® S, betaxolol molecules are ionically bound to amberlite resin. After instillation, betaxolol molecules are transferred by sodium ions into the tear film. This transfer process occurs over several minutes and enhances ocular comfort during BETOPTIC® S use.

Preclinical safety data

Lifetime studies with oral betaxolol administered at doses of 6, 20, or 60 mg/kg/day in mice and 3, 12, or 48 mg/kg/day in rats showed no evidence of carcinogenic potential.

Various in vitro and in vivo studies in bacterial and mammalian cells did not reveal any mutagenic effect of betaxolol.

Studies on the effects of betaxolol on reproductive function, as well as teratological, perinatal, and postnatal studies conducted in rats and rabbits following oral administration of betaxolol hydrochloride, demonstrated evidence of post-implantation loss in rats and rabbits at doses exceeding 12 mg/kg and 128 mg/kg, respectively.

Betaxolol hydrochloride did not show teratogenic effects, nor were any other adverse effects on reproductive function observed at subtoxic doses.

Pharmacokinetics.

Betaxolol has high lipophilicity, resulting in a high degree of corneal penetration and high drug concentrations in ocular tissues. Plasma levels of betaxolol after topical administration are low. In clinical pharmacokinetic studies, plasma concentrations were below the limit of quantification (2 ng/mL). Betaxolol is well absorbed after oral administration, has low first-pass losses, and a relatively long elimination half-life of approximately 16–22 hours. Betaxolol is primarily excreted by the kidneys and to a lesser extent in feces. The main metabolites are two forms of carboxylic acid and unchanged betaxolol, which are excreted in urine (approximately 16% of the administered dose).

Betaxolol begins to act within 30 minutes, and the maximum effect is usually achieved within 2 hours after topical administration. A single dose provides reduction of intraocular pressure for up to 12 hours.

Clinical characteristics.

Indications.

Reduction of intraocular pressure in patients with chronic open-angle glaucoma or ocular hypertension (either as monotherapy or in combination with other medicinal products).

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients of the medicinal product.
• Sinus bradycardia, sick sinus syndrome, sinoatrial node dysfunction, second- or third-degree atrioventricular block, absence of a functioning pacemaker. Severe heart failure or cardiogenic shock.
• Reactive respiratory disorders, including severe bronchial asthma or history of severe bronchial asthma, severe chronic obstructive pulmonary disease.

Interaction with other medicinal products and other forms of interaction.

Specific studies on betaxolol interactions with other medicinal products have not been conducted.

• There is a potential for additive effects leading to arterial hypotension and/or marked bradycardia when ophthalmic solutions containing beta-blockers are used concomitantly with oral calcium channel blockers, beta-adrenergic blocking agents, antiarrhythmic agents (including amiodarone), cardiac glycosides, parasympathomimetics, or guanethidine.
• Beta-blockers may reduce sensitivity to epinephrine used in the treatment of anaphylactic reactions. Caution should be exercised when prescribing to patients with atopy or a history of anaphylaxis.
• In rare cases, mydriasis has been reported during concomitant use of ophthalmic beta-blockers and epinephrine (adrenaline).
• If several ophthalmic medicinal products are used simultaneously, at least 5 minutes should be waited between their applications. Ophthalmic ointments should be applied last.
• Since betaxolol is an adrenergic receptor blocker, it should be administered with caution to patients who are concurrently receiving adrenergic psychotropic agents, due to the risk of enhanced effects.

Special precautions for use.

For ophthalmic use only.

After the first opening of the bottle, remove the tamper-evident ring designed to control the first opening.

The frequency of adverse reactions with local ocular administration is lower than with systemic administration. For information on reducing systemic absorption, see section "Dosage and administration".

Corneal disease

Dry eye may occur during topical ocular administration of beta-blockers. Beta-blockers should be used with caution in patients with corneal diseases.

Other beta-blockers

When betaxolol is administered to patients already receiving systemic beta-blocking agents, the effect on intraocular pressure may be enhanced, or known systemic beta-blocking effects may occur. Patients in this category should be closely monitored. Concomitant use of two locally acting beta-adrenergic agents is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

When using BETOPTIC® S eye drops to reduce intraocular pressure in patients with angle-closure glaucoma, it should only be used in combination with miotic agents.

Choroidal detachment

Choroidal detachment has been reported after filtration surgery in patients treated with medicinal products that suppress aqueous humor production (e.g., timolol, acetazolamide).

Surgical anesthesia

Beta-blocking anesthetic agents may block the effects of systemic beta-agonists such as epinephrine. Anesthesiologists should be informed if the patient is taking betaxolol.

Nasolacrimal occlusion or keeping the eyelids closed for 2 minutes after instillation can reduce systemic absorption of the drug. This may reduce systemic effects and increase local effects of the medication.

General

• As with other ophthalmic medicinal products for topical use, betaxolol is absorbed systemically. Due to the presence of a beta-adrenergic component, the same adverse reactions affecting the cardiovascular and respiratory systems, as well as other adverse reactions, may occur with betaxolol as with systemic beta-adrenergic receptor blockers.

Cardiac disorders

• Patients with cardiovascular diseases (e.g., coronary artery disease, Prinzmetal's angina, heart failure) or arterial hypotension should be carefully evaluated for the necessity of beta-blocker therapy, and alternative treatments should be considered. Patients with cardiovascular diseases should be monitored for signs of worsening condition and adverse reactions. Due to the adverse effects of beta-blockers on conduction time, they should be used with caution and only in patients with first-degree heart block.

Vascular disorders

• Treatment should be administered with caution in patients with severe peripheral circulatory disorders (i.e., severe forms of Raynaud's disease or Raynaud's syndrome).

Respiratory disorders

• There have been reports of respiratory reactions, including fatal cases due to bronchospasm in asthmatic patients, following administration of certain beta-blockers. This medication should be used with caution in patients with mild to moderate bronchial asthma, a history of mild to moderate bronchial asthma, or mild to moderate chronic obstructive pulmonary disease (COPD).

Hypoglycemia/diabetes

• Beta-adrenoblockers should be used with caution in patients prone to spontaneous hypoglycemia or in patients with labile diabetes, as beta-blockers may mask the signs and symptoms of acute hypoglycemia.

Hyperthyroidism

• Beta-adrenoblockers may also mask signs of hyperthyroidism.

Muscle weakness

• Beta-adrenoblockers may exacerbate muscle weakness associated with certain symptoms of myasthenia (e.g., diplopia, ptosis, and generalized weakness).
• Anaphylactic reactions

Patients with a history of atopy or severe anaphylactic reactions to various allergens may exhibit increased reactivity upon re-exposure to these allergens while on beta-blockers. They may also fail to respond to usual doses of epinephrine used to treat anaphylactic reactions.

• Contact lenses

BETOPTIC® S contains benzalkonium chloride, which may cause eye irritation and is known to discolor soft contact lenses. Contact with soft contact lenses should be avoided. Patients should be advised to remove contact lenses before instilling BETOPTIC® S eye drops and to wait 15 minutes before reinserting contact lenses.

Use during pregnancy or breastfeeding.

Reproductive function

There are no data available on the effect of this medicinal product on human reproductive function.

Pregnancy

There are insufficient data on the use of betaxolol in pregnant women. For information on reducing systemic absorption, see section "Dosage and administration".

Epidemiological studies have not shown a negative effect on fetal development; however, oral administration of beta-blockers has been associated with a risk of intrauterine growth retardation. In addition, newborns exposed to beta-blockers before delivery have shown signs and symptoms of beta-blockade (e.g., bradycardia, hypotension, respiratory distress, and hypoglycemia).

Betaxolol should not be used during pregnancy except in cases of acute necessity. However, if BETOPTIC® S was administered before delivery, careful monitoring of the newborn is required during the first days after birth.

Breastfeeding period

Beta-blockers are excreted in breast milk and may cause serious adverse effects in breastfed infants. However, when therapeutic doses of betaxolol are administered as eye drops, it is unlikely that sufficient amounts will reach breast milk to cause clinical symptoms of beta-blockade in the infant. For information on reducing systemic absorption, see section "Dosage and administration".

Ability to influence reaction speed when driving or operating machinery.

BETOPTIC® S has no or negligible effect on the ability to drive or operate machinery. Transient blurred vision or other visual disturbances may adversely affect the ability to drive or operate machinery. If blurred vision occurs after instillation, patients should wait until vision clears before driving or operating machinery.

Method of Administration and Dosage

For ophthalmic use.

Dosage

Use in adults, including elderly patients

The recommended dose is 1 drop of BETOPTIC® S into the conjunctival sac of the affected eye(s) twice daily. In some patients, several weeks of treatment with BETOPTIC® S may be required to achieve a stable hypotensive effect. Close monitoring is recommended for patients with glaucoma.

If intraocular pressure is not adequately controlled with the recommended doses, concomitant therapy with other anti-glaucoma agents may be used.

After instillation, it is recommended to firmly close the eyelid or perform nasolacrimal occlusion. This reduces systemic absorption of ophthalmic medications, thereby decreasing the likelihood of systemic adverse effects.

When using concomitant topical ophthalmic medications, an interval of 10–15 minutes between administrations should be maintained.

Use in children and adolescents

The efficacy and safety of BETOPTIC® S eye drops have not been established in patients under 18 years of age.

Use in hepatic and renal impairment

BETOPTIC® S has not been studied in these patient populations.

Method of Administration

The bottle should be shaken well before use.

To prevent contamination of the dropper tip and suspension, care should be taken to avoid touching the eyelids, adjacent areas, or other surfaces with the tip of the dropper bottle.

Children.

The efficacy and safety of BETOPTIC® S eye drops have not been established in patients under 18 years of age.

Overdose.

In case of accidental ingestion, symptoms of beta-blocker overdose may include bradycardia, hypotension, heart failure, and bronchospasm.

In the event of BETOPTIC® S overdose, treatment should be symptomatic and supportive.

Adverse Reactions

Summary of safety data

The most common adverse effect observed during clinical studies of BETOPTIC® S was ocular discomfort, occurring in 12% of patients.

The adverse effects listed below were observed during clinical studies of the medicinal product and were classified 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). Within each frequency category, adverse reactions are listed in order of decreasing severity.

The following adverse reactions have been identified based on post-marketing surveillance data. With the available data, it is not possible to estimate their frequency.

Description of the listed adverse reactions

As with other topically acting ophthalmic medicinal products, betaxolol is absorbed into the systemic circulation. This may cause similar adverse effects as those observed with systemic beta-blockers. The incidence of systemic adverse reactions following topical ocular administration is lower than with systemic administration. The listed adverse reactions include those observed within the class of ophthalmic beta-blockers.

Additional adverse reactions observed with ophthalmic beta-blockers and which may occur with the use of BETOPTIC® S eye drops are:

• Immune system disorders: systemic allergic reactions including angioedema, urticaria, localized and generalized rash, pruritus, anaphylactic reaction, toxic epidermal necrolysis.
• Metabolism and nutrition disorders: hypoglycemia.
• Psychiatric disorders: depression, nightmares, memory loss, hallucinations, psychosis, confusion.
• Nervous system disorders: syncope, cerebrovascular disorder, cerebral ischemia, exacerbation of signs and symptoms of myasthenia gravis, paresthesia.
• Ophthalmic disorders: signs and symptoms of ocular irritation (e.g., burning, stinging, itching, tearing, redness), blepharitis, choroidal detachment following filtration surgery (see section "Special precautions for use"), decreased corneal sensitivity, corneal erosion, ptosis, diplopia.
• Cardiac disorders: chest pain, tachycardia, edema, congestive heart failure, atrioventricular block, cardiac arrest, heart failure.
• Vascular disorders: arterial hypotension, Raynaud's phenomenon, cold extremities, worsening of intermittent claudication.
• Respiratory, thoracic and mediastinal disorders: bronchospasm (predominantly in patients with pre-existing bronchospastic disease).
• Gastrointestinal disorders: dyspepsia, diarrhea, abdominal pain, vomiting, dry mouth, glossitis.
• Skin and subcutaneous tissue disorders: psoriasiform rash or exacerbation of psoriasis.
• Musculoskeletal and connective tissue disorders: myalgia.
• Reproductive system and breast disorders: sexual dysfunction, impotence.
• General disorders and administration site conditions: asthenia/fatigue.

Additionally, increased levels of antinuclear antibodies have been observed; clinical significance has not been established.

Shelf life. 2 years.

Storage period after first opening of the bottle – 4 weeks.

Storage conditions.

Keep the bottle in the cardboard box. Store at 8–30 °C. Keep out of the reach of children. Keep the bottle tightly closed.

Packaging. 5 ml in a dropper bottle; 1 bottle per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Alcon Couvreur/

Alcon Couvreur.

Manufacturer's address and place of business.

Rijksweg 14, Puurs-Sint-Amands, 2870, Belgium/

Rijksweg 14, Puurs-Sint-Amands, 2870, Belgium.