Fotil®

Composition:

Active substances: pilocarpine hydrochloride; timolol ;

1 ml of eye drops contains 20 mg of pilocarpine hydrochloride; 5 mg of timolol maleate calculated as timolol;

1 ml contains 36 drops;

1 drop contains 0.14 mg of timolol and 0.56 mg of pilocarpine hydrochloride;

Excipients: benzalkonium chloride; citric acid monohydrate; sodium citrate; hypromellose; water for injections.

Pharmaceutical form. Eye drops.

Main physicochemical properties: clear, colourless solution.

Pharmacotherapeutic group. Medicinal products used in ophthalmology. Antiglaucoma and miotic agents. Pilocarpine, combinations. ATC Code S01E B51.

Pharmacological properties.

Pharmacodynamics.

Pilocarpine is a parasympathomimetic agent which, like acetylcholine, stimulates muscarinic receptors. When applied locally to the eye, pilocarpine causes a reduction in intraocular pressure, miosis, and spasm of accommodation. The reduction in intraocular pressure is believed to result from contraction of the ciliary muscle and smooth muscles of the iris, which increases the angle of the anterior chamber and alters the configuration of the trabecular meshwork, thus facilitating the outflow of aqueous humour. Pilocarpine has long been used as a miotic to constrict the pupil and reduce intraocular pressure in almost all forms of glaucoma.

The L-isomer of timolol in Fotil® is a β-blocker that effectively blocks the binding of sympathomimetic neurotransmitters to β-1 and β-2 adrenergic receptors. Timolol has no significant sympathomimetic activity or local membrane-stabilizing effect. Timolol is also used in the treatment of elevated arterial blood pressure and angina pectoris, but its primary indication is glaucoma. The reduction in intraocular pressure occurs due to decreased production of aqueous humour. The drug penetrates locally into the target tissue of the eye, specifically the ciliary body, where aqueous humour is produced. It is unknown whether it affects blood vessels of the anterior segment of the eye in any other way, but evidence suggests that with reduced intraocular pressure, blood flow in the retina improves. Like many other β-blockers, timolol exerts a prolonged post-receptor effect; the adrenergic receptor cannot mediate the agonist effect even after timolol has undergone its degradation phase.

Fotil® eye drops do not cause dependence. Due to the low dose, withdrawal syndrome observed during systemic β-blocker therapy does not occur after discontinuation of Fotil® eye drops.

Elevated intraocular pressure is the main risk factor in the pathogenesis of glaucomatous visual field defects. When pilocarpine and timolol are combined in a single preparation, an enhanced effect in reducing intraocular pressure is expected, as these agents have different mechanisms of action and affect different tissues. Timolol prolongs the residence time of pilocarpine in the eye by delaying its elimination. Fotil® eye drops reduce both elevated and normal intraocular pressure in various forms of glaucoma and ocular hypertension. They contain a compound that causes miosis and can therefore also be used to reduce intraocular pressure in angle-closure glaucoma.

Paediatric patients.

There are only limited data on the use of timolol (0.25%, 0.5%, 1 drop twice daily) in children for treatment courses up to 12 weeks. One small, double-blind, randomized, published clinical study was conducted in 105 children (n=71 on timolol) aged from 12 days to 5 years, which provides some evidence that timolol is effective in short-term treatment of primary congenital and primary juvenile glaucoma.

Pharmacokinetics.

After application to the surface of the eye, pilocarpine rapidly penetrates through the cornea. Accommodation spasm and miosis begin within 10 minutes after instillation, with maximum effect reached within one hour. Miosis and reduced intraocular pressure last for several hours, while accommodation spasm usually disappears within 2 hours. Pilocarpine is hydrolysed in several tissues, such as blood and liver, but only minimally in the eye. The plasma half-life is less than half an hour. The substance is eliminated from the anterior segment of the eye primarily with the flow of aqueous humour.

Timolol is a lipophilic substance and is well absorbed in the eye. It is also absorbed into the bloodstream through the conjunctiva, nasal mucosa, and gastrointestinal tract. Maximum effect in the eye is achieved 3–4 hours after instillation and may last up to 24 hours. In the eye, timolol binds to the surface of cells in various tissues, particularly pigment cells of the endothelium, iris, and ciliary processes. It is eliminated from the eye with the flow of aqueous humour. The half-life from ocular tissues is approximately 8 hours. Timolol is metabolized in the liver and converted into inactive metabolites, which are primarily excreted via the kidneys. After oral administration, the first-pass metabolism in the liver is the most significant. Bioavailability is approximately 50%. Plasma protein binding is moderate (60%). The volume of distribution averages 2.1 L/kg. The plasma half-life is approximately 4 hours.

A significant reduction in intraocular pressure after a single instillation of Fotil® eye drops is observed within 1 hour. The maximum effect usually lasts for 3 hours.

Paediatric patients

As confirmed in studies on adult patients, approximately 80% of the drug passes through the nasolacrimal system, where it can be rapidly absorbed into the bloodstream via the nasal mucosa, conjunctiva, nasolacrimal ducts, oropharynx, and intestines, or through the skin due to excessive tearing.

Since children have a smaller blood volume than adults, higher concentrations of Fotil® should be considered. Furthermore, in newborns, metabolic enzyme pathways are underdeveloped, which may lead to prolonged half-life and increased incidence of adverse effects.

Limited data indicate that plasma levels of timolol in children, especially infants, exceeding 0.25% significantly exceed those in adults exceeding 0.5% and are believed to increase the risk of adverse effects such as bronchospasm and bradycardia.

Clinical characteristics.

Indications.

Treatment of open-angle, closed-angle, aphakic, and secondary glaucoma. As part of combination therapy for glaucoma, reduction of intraocular pressure after ophthalmic surgery, treatment of glaucoma after cataract extraction, and reduction of elevated intraocular pressure in patients for whom monotherapy is insufficient.

Recommended for use only under medical prescription.

Contraindications.

Hypersensitivity to the active substances or to any excipient of the product. Beta-blockers (timolol) are contraindicated in patients with second- or third-degree atrioventricular block without a cardiac pacemaker, sinus bradycardia, sick sinus syndrome, sinoatrial block, severe heart failure, cardiogenic shock, reactive airway disease including severe bronchial asthma or history of severe bronchial asthma, and severe chronic obstructive pulmonary disease.

Cholinergic agents (pilocarpine) are contraindicated in acute iritis and in conditions where miosis should be avoided.

Interaction with other medicinal products and other forms of interaction.

Specific interaction studies between Fotil® and other drugs have not been conducted.

There is a possibility of additive effects leading to hypotension and/or marked bradycardia when ophthalmic β-blocker drops are used concomitantly with oral calcium channel blockers, β-adrenergic blockers, antiarrhythmic agents (including amiodarone), digitalis glycosides, parasympathomimetics, or guanethidine. Additionally, systemic α-blockers or drugs that reduce catecholamine levels, such as reserpine, may cause additive effects, namely hypotension, bradycardia, atrioventricular conduction disturbances, left ventricular dysfunction, dizziness, and syncope. Intravenous administration should be particularly avoided. Due to the risk of worsening adverse effects, antiarrhythmic agents of class I (e.g., lidocaine, quinidine) and clonidine should be used with particular caution. The unfavourable effect of the drug on the central nervous system may be enhanced by concomitant use of barbiturates, analgesics, or ergot alkaloids. Potentiated systemic β-blockade (e.g., reduced heart rate, depression) has been reported during combined therapy with CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) and timolol. Rare cases of mydriasis development have been described due to concomitant use of ophthalmic β-blockers and adrenaline (epinephrine).

Special precautions for use.

Before initiating treatment, the patient's health status should be evaluated (see section "Contraindications"). Since the effect of treatment, especially with β-blockers, may vary, intraocular pressure should be checked 2–4 weeks after starting treatment with Fotil® eye drops. As with other glaucoma medications, the effect of treatment with eye drops may diminish with prolonged use (over several years).

As with other topical ophthalmic agents, the active substances of the product are systemically absorbed. Despite the very low dose, topical ocular application may cause adverse reactions similar to those occurring with systemic use of β-blockers and parasympathomimetics. Due to the presence of the β-adrenergic component, timolol may cause the same types of cardiovascular and pulmonary adverse reactions as systemic β-blockers. Systemic adverse effects occur less frequently with topical ophthalmic use than with systemic administration. To reduce systemic absorption, see section "Dosage and administration".

Concomitant use with other β-blockers

When timolol is prescribed to a patient already taking β-blockers, its effect on intraocular pressure or known systemic β-blocking effects may be enhanced. Patients should be closely monitored. The use of two locally applied β-adrenergic blockers is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Cardiac disorders

Treatment with β-blockers in patients with cardiovascular disorders (e.g., coronary heart disease, Prinzmetal's angina, heart failure) and hypotension should be critically evaluated; alternative active substances should be considered. Sympathetic nervous system stimulation may play a significant role in maintaining circulation in patients with reduced myocardial contractility, and its suppression via β-adrenergic receptor blockade may lead to uncompensated heart failure. Patients with cardiovascular disorders should be monitored for signs of worsening conditions and adverse reactions. If any signs or symptoms of heart failure occur, Fotil® or Fotil® Forte should be discontinued immediately.

β-blockers should be used with caution in patients with first-degree heart block due to their negative effect on conduction time.

Vascular disorders

Patients with severe peripheral circulatory disorders (i.e., severe forms of Raynaud's disease or Raynaud's syndrome) should be treated with caution.

If any signs or symptoms of worsening cerebral blood flow occur during treatment with Fotil® or Fotil® Forte, alternative treatment should be considered.

Respiratory disorders

Respiratory reactions, including fatal outcomes due to bronchospasm, have been observed in asthmatic patients after administration of some ophthalmic β-blockers.

Fotil® or Fotil® Forte should be used with caution in patients with mild to moderate chronic obstructive pulmonary disease (COPD) and only when potential benefit outweighs potential risk.

Timolol may suppress bronchodilation caused by endogenous or exogenous catecholamines.

Anaphylactic reactions

Patients with a history of atopy or severe anaphylactic reactions to various allergens may have exaggerated responses to re-exposure to such allergens while taking β-blockers and may not respond to the usual dose of adrenaline used to treat anaphylactic reactions.

Surgical anaesthesia

Medicinal products containing β-blockers should be used with caution in patients scheduled for surgery under general anaesthesia. Gradual discontinuation of the drug before surgery is recommended to avoid suppression of cardiac reflexes regulated by β-adrenergic action, thus reducing the risk of hypotension and cardiac arrest during anaesthesia. Ophthalmic β-blockers may block the action of systemic β-agonists, such as adrenaline. The anaesthesiologist should be informed if the patient is taking timolol.

Hypoglycaemia/diabetes

β-blockers should be used with caution in patients prone to spontaneous hypoglycaemia or with labile diabetes, as β-blockers may mask signs and symptoms of acute hypoglycaemia.

Hyperthyroidism

β-blockers may mask signs of hyperthyroidism.

Myasthenia

Products containing timolol should be prescribed with caution to patients with a history of myasthenia gravis.

Retinal damage.

Miotics should not be instilled into eyes with compromised retinal integrity.

Corneal disorders

Ophthalmic beta-blockers may cause dry eyes. Treatment should be prescribed with caution to patients with corneal disorders.

Choroidal detachment (vascular layer of the eye)

Choroidal detachment has been reported with the use of drugs that suppress aqueous humour production (e.g., timolol, acetazolamide) after filtering surgeries.

Benzalkonium chloride

Fotil® eye drops contain the preservative benzalkonium chloride, which has been reported to cause eye irritation, dry eye symptoms, and may affect the tear film and corneal surface. It should be used with caution in patients with dry eye disease and in patients whose cornea may be compromised. Patients should be monitored during prolonged use.

Benzalkonium chloride may be absorbed by soft contact lenses and may alter the colour of contact lenses. If contact lenses are worn during treatment with Fotil®, they should be removed before using this product and reinserted 15 minutes after instillation.

Paediatric patients

Timolol solutions should generally be used with caution in young patients with glaucoma (see also section "Pharmacological properties"). It is important to inform parents about possible adverse effects so they can discontinue treatment immediately if necessary. Observable signs include cough and wheezing. Due to the possible risk of dyspnoea (difficulty breathing) and Cheyne-Stokes respiration, the product should be used with great caution in newborns, infants, and young children. A portable apnoea monitoring device may also be beneficial for newborns receiving timolol.

Use during pregnancy or breastfeeding.

Pregnancy

Fotil® and Fotil® Forte should not be used during pregnancy except when absolutely necessary. To reduce systemic absorption, see section "Dosage and administration". Timolol crosses the placenta.

There are no adequate data on the use of timolol in pregnant women. Epidemiological studies have not shown an effect on fetal malformations, but have indicated a risk of intrauterine growth retardation with oral use of β-blockers. Additionally, signs and symptoms of β-blockade (e.g., bradycardia, hypotension, respiratory distress, and hypoglycaemia) have been observed in newborns when β-blockers were administered before delivery. If Fotil® and Fotil® Forte were used before delivery, the newborn should be under close medical supervision during the first days of life.

Breastfeeding

β-blockers pass into breast milk. However, it is unlikely that therapeutic doses of Fotil® and Fotil® Forte will contain sufficient timolol to pass into breast milk and cause clinical symptoms of β-blockade in the infant. Systemic absorption can be reduced (see section "Dosage and administration").

Ability to affect reaction speed when driving or operating machinery.

Miosis usually impairs adaptation to darkness. Patients should be warned about driving at night. Timolol may reduce blood pressure, which in some patients may cause temporary weakness and dizziness. The patient should be informed about this before starting treatment.

Dosage and administration.

Dosage

It is recommended to start treatment with 1 drop in the affected eye twice daily. If this does not achieve the desired result, switch to Fotil® Forte with 1 drop in the affected eye twice daily. Further dose increases usually do not further reduce intraocular pressure.

If intraocular pressure is not maintained at a satisfactory level with the recommended dose of Fotil®, combination therapy with dipivefrin and/or a carbonic anhydrase inhibitor may be considered.

Administration method

Upon starting treatment with Fotil®, other anti-glaucoma medications should be discontinued, or Fotil® eye drops should be instilled the following day.

Systemic absorption is reduced by occlusion of the nasolacrimal duct or by closing the eyelids for 2 minutes. This may reduce systemic adverse effects and enhance local activity.

Children

The safety and efficacy of Fotil® eye drops in children have not been established in adequate and well-controlled studies.

Due to limited data, the use of timolol in children may only be recommended for primary congenital and primary juvenile glaucoma during a transitional period when surgical treatment has been decided upon and in cases of failed surgery while awaiting further treatment.

When considering treatment of paediatric patients with timolol, physicians must carefully evaluate the risks and benefits. A detailed medical history and examination should be performed before administering timolol to determine the presence of systemic disorders.

A specific dosage cannot be recommended due to limited clinical data (see section "Pharmacodynamics"). However, if benefits outweigh risks, the lowest possible concentration of the active substance once daily is recommended. If intraocular pressure cannot be effectively controlled, a cautious increase in dosage to 2 drops once daily in the affected eye should be considered. When administering twice daily, a 12-hour interval is preferred. Additionally, patients, especially newborns, should be closely monitored in the physician's office for 1–2 hours after the first administration to promptly detect ocular and systemic adverse effects until surgery is performed. In paediatric use, a 0.1% concentration of the active substance may be sufficient.

Administration method

To minimize possible adverse reactions, only 1 drop should be instilled at a time. Systemic absorption of locally applied β-blockers can be reduced by occlusion of the nasolacrimal duct or by closing the eyes for the maximum possible time after instillation (e.g., 3–5 minutes) (see sections "Special precautions for use" and "Pharmacokinetics").

Duration of treatment

For temporary treatment of children.

Overdose.

The amount of timolol entering the bloodstream from one orally administered tablet (10 mg) equals approximately 30 drops of Fotil®. However, since the drops are rapidly absorbed through the mucous membranes of the eyes and nose, only a few drops of Fotil® are sufficient to cause arrhythmia, temporary slowing of pulse rate, reduced arterial pressure, bronchospasm, or heart failure. Overdose is treated symptomatically with adrenergic agonists such as isoprenaline, dobutamine, or possibly dopamine.

Adverse reactions.

Most expected adverse reactions of Fotil® can be explained based on their pharmacological action. The most common adverse reactions of Fotil® eye drops are transient burning and stinging sensations.

Fotil® eye drops are generally well tolerated. As with other topically applied ophthalmic agents, timolol is absorbed into the bloodstream and enters systemic circulation. This may cause adverse effects similar to those occurring with systemic use of β-blockers. Systemic adverse effects occur less frequently with topical ophthalmic use than with systemic administration.

Listed adverse reactions include those observed within the class of ophthalmic β-blockers.

Ocular disorders

Common (from ≥1/100 to <1/10)

Pilocarpine: transient burning and stinging sensation in the eye, blurred vision, increased lacrimation, spasm of accommodation, conjunctival hyperaemia, eye pain, itching and eye irritation, headache in the temporal or supraorbital region, reduced visual acuity in poor lighting (due to miosis, especially in patients with cataract), myopia or accommodation disorder, photophobia.

Uncommon (from ≥1/1,000 to <1/100):

Timolol: reduced corneal sensitivity, superficial punctate keratitis.

Rare (from ≥1/10,000 to <1/1,000):

Pilocarpine: retinal detachment, vitreous haemorrhage, iris rigidity, iris cysts, iris vessel dilation, eyelid retraction, narrowing of the anterior chamber, reversible lens opacification (with prolonged use of pilocarpine).

Timolol: dry eye syndrome, blepharoconjunctivitis, visual disturbance, diplopia, ptosis.

Cardiac disorders

Uncommon (from ≥1/1,000 to <1/100)

Timolol: bradycardia.

Rare (from ≥1/10,000 to <1/1,000)

Timolol: heart failure, arrhythmias.

Vascular disorders

Uncommon (from ≥1/1,000 to <1/100)

Pilocarpine: hypotension.

Rare (from ≥1/10,000 to <1/1,000)

Timolol: hypotension, reduced peripheral (cold extremities) and cerebral perfusion.

Nervous system disorders

Common (from ≥1/100 to <1/10)

Timolol: headache.

Rare (from 1/10,000 to <1/1,000)

Timolol: dizziness.

Respiratory, thoracic and mediastinal disorders

Uncommon (from ≥1/1,000 to <1/100)

Timolol: dyspnoea.

Rare (from ≥1/10,000 to <1/1,000)

Timolol: bronchospasm (especially in patients with bronchospastic disorders such as asthma or heart failure), nasal congestion.

Psychiatric disorders

Uncommon (from ≥1/1,000 to <1/100)

Timolol: depression.

Rare (from ≥1/10,000 to <1/1,000)

Timolol: anxiety, nightmares, confusion.

Gastrointestinal disorders

Uncommon (from ≥1/1,000 to <1/100)

Pilocarpine: nausea.

Rare (from ≥1/10,000 to <1/1,000)

Pilocarpine: vomiting, increased salivation, diarrhoea.

Skin and subcutaneous tissue disorders

Rare (from ≥1/10,000 to <1/1,000)

Hypersensitivity reactions: rash, urticaria, alopecia.

Pilocarpine: sweating.

General disorders

Uncommon (from 1/1,000 to <1/100)

Timolol: weakness.

Rare (from ≥1/10,000 to <1/1,000)

Timolol: asthenia.

With prolonged use (over years), the glaucomatous eye may become resistant to pilocarpine and timolol.

In addition to the above, it has been reported that β-blockers administered into the eye have the following adverse effects, which may also occur during use of Fotil® or Fotil® Forte eye drops:

Immune system disorders

Systemic allergic reactions, including angioedema, itching, anaphylactic reactions.

Metabolism and nutrition disorders

Hypoglycaemia.

Psychiatric disorders

Insomnia, memory loss, hallucinations.

Nervous system disorders

Syncope, acute cerebrovascular accident, cerebral ischaemia, worsening of signs and symptoms of myasthenia gravis, paraesthesia.

Ocular disorders

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

Cardiac disorders

Chest pain, palpitations, oedema, congestive heart failure, atrioventricular block, cardiac arrest.

Vascular disorders

Raynaud's phenomenon.

Respiratory, thoracic and mediastinal disorders

Cough.

Gastrointestinal disorders

Taste disturbance, nausea, dyspepsia, diarrhoea, dry mouth, abdominal pain, vomiting.

Skin and subcutaneous tissue disorders

Psoriasis-like rash or exacerbation of psoriasis.

Musculoskeletal and connective tissue disorders

Myalgia.

Sexual disorders

Sexual dysfunction, decreased libido.

Reporting suspected adverse reactions to the medicinal product

Reporting of suspected adverse reactions after product authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Physicians are requested to report any suspected adverse reactions.

Shelf life.

3 years.

An opened bottle should be used within 28 days.

Storage conditions.

Store at 2 to 8 °C.

An opened bottle should be stored at a temperature not exceeding 25 °C.

Keep out of reach of children.

Store the bottle in the original outer cardboard box to protect from light.

Incompatibility.

Benzalkonium chloride may deposit on soft contact lenses.

Packaging.

5 ml in a dropper bottle.

1 bottle in a cardboard box with instructions for medical use.

Prescription status.

Prescription only.

Manufacturer. Santen AT/Santen Oy.

Manufacturer's address and place of business.

Kellotorintie 1, Tampere, 33100, Finland/Kelloportinkatu 1, Tampere, 33100, Finland.