Oftan® timolol

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT OFTAN® TIMOLOL (OFTAN® TIMOLOL)

Composition:
Timolol maleate
Active substance: 1 ml of eye drops contains: timolol maleate 6.84 mg, equivalent to 5.0 mg of timolol.
Excipients: sodium dihydrogen phosphate dihydrate; sodium hydrogen phosphate dodecahydrate; benzalkonium chloride; sodium hydroxide; water for injections.

Pharmaceutical form:
Eye drops.

Main physicochemical properties:
Clear, colorless solution.

Pharmacotherapeutic group:
Antiglaucoma and miotic agents. Beta-adrenergic blockers.
ATC Code: S01ED01.

Pharmacological properties

Pharmacodynamics:
The active substance of Of tan® Timolol eye drops is the L-isomer of timolol maleate. Timolol maleate is a non-selective beta-adrenergic blocker 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 intraocular pressure-lowering effect of Of tan® Timolol eye drops is based on reduced production of aqueous humor. The drug is administered locally into the eye. Timolol does not significantly affect the outflow of aqueous humor. It is unknown whether the drug affects blood vessels of the anterior segment of the eye, but improved retinal blood flow has been reported with reduction in intraocular pressure.

Like many other beta-blockers, timolol has a prolonged post-receptor effect: the adrenergic receptor cannot mediate agonist effects even after timolol has dissociated. Timolol has no intrinsic sympathomimetic activity and minimal membrane-stabilizing activity. Of tan® Timolol does not affect pupil size or accommodation.

Of tan® Timolol has been proven effective in the treatment of open-angle glaucoma and ocular hypertension. The drug can also be successfully used in many forms of secondary glaucoma. Of tan® Timolol is well tolerated and does not cause drug dependence. Due to the low dose, withdrawal syndrome, which may occur with systemic beta-blocker therapy, has not been observed upon discontinuation of Of tan® Timolol treatment.

Pediatric patients:
There are only very limited data on the use of timolol (0.25%, 0.5%; one 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 for primary congenital or primary juvenile glaucoma.

Pharmacokinetics:
Timolol is a lipophilic substance and thus is well absorbed into the eye. The drug may also enter the systemic circulation via the conjunctiva and nasal mucosa, as well as the gastrointestinal tract. Intraocular pressure reduction is due to local action. Maximum ocular effect occurs 3–4 hours after instillation and 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. The drug is eliminated from the eye with aqueous humor outflow. The expected half-life in 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, pre-systemic metabolism in the liver is significant, approximately 50%. Plasma protein binding is moderate (60%). The volume of distribution averages over 2 L/kg, and the substance crosses the blood-brain barrier. The plasma half-life is approximately 4 hours.

Pediatric patients:
As confirmed by data obtained in adults, about 80% of each drop passes through the nasolacrimal duct, where it is rapidly absorbed into the systemic circulation via the nasal mucosa, conjunctiva, nasolacrimal duct, oropharynx, and gastrointestinal tract. Plasma concentrations of the drug are higher in children than in adults. In neonates, metabolism is underdeveloped, which may lead to prolonged elimination half-life. Limited data indicate that plasma timolol levels in children receiving 0.25% solution are significantly higher than in adults receiving 0.5% solution. Young children are expected to have an increased risk of adverse reactions such as bronchospasm and bradycardia.

Clinical characteristics

Indications:
Treatment of open-angle glaucoma, elevated intraocular pressure, postoperative glaucoma following cataract surgery, and in selected cases, secondary glaucoma. Treatment of closed-angle glaucoma when used concomitantly with miotics.

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

Contraindications:
Hypersensitivity to the active substance or to any of the excipients.
Sinus bradycardia, sick sinus syndrome, sinoatrial block, second- or third-degree atrioventricular block not controlled by a pacemaker, overt 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 interaction studies between Of tan® Timolol and other medicinal products have been conducted. Of tan® Timolol eye drops may be used concomitantly with other antiglaucoma agents.

The reduction in blood pressure and/or marked bradycardia may be potentiated when ophthalmic beta-blocker solution is used concomitantly with oral calcium antagonists (calcium channel blockers), beta-adrenergic blockers, antiarrhythmics (including amiodarone), digitalis glycosides, parasympathomimetics, or guanethidine.

Additionally, patients receiving systemic alpha-blocking agents, reserpine, antiarrhythmics of class I (e.g., quinidine), or clonidine should be monitored for possible exacerbation of adverse reactions.

Concomitant use of CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) with timolol has been associated with potential systemic beta-blockade (e.g., reduced heart rate, depression).

Concurrent therapy with barbiturates, analgesics, or ergot alkaloids may enhance central nervous system adverse reactions.

Miosis has occasionally been reported due to concomitant use of ophthalmic beta-blockers and adrenaline (epinephrine).

Special precautions for use:

Prior to initiating treatment, the patient's health status should be evaluated (see section "Contraindications"). Since response to beta-blockers may vary, intraocular pressure should be measured 2–4 weeks after starting treatment. Thereafter, regular ophthalmological examinations are recommended, as response to timolol maleate may change during prolonged use.

Like other topically applied ophthalmic agents, timolol is systemically absorbed. Due to its beta-adrenergic component, timolol may cause cardiovascular, pulmonary, and other adverse reactions similar to those observed with systemic beta-blockers. The frequency of systemic adverse reactions after topical ophthalmic administration is lower than with systemic administration.

Other beta-blockers:
The effect on intraocular pressure or known 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. The use of two topical beta-adrenergic blockers is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Cardiac disorders:
Beta-blocker therapy should be carefully evaluated and the need for alternative agents considered in patients with cardiovascular disorders (e.g., ischemic heart disease, Prinzmetal's angina, heart failure) or hypotension. Patients with cardiovascular disorders should be monitored for worsening of their condition and any adverse reactions. Due to the negative effect on impulse conduction, beta-blockers should be used with caution only in patients with first-degree heart block.

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

Respiratory disorders:
Adverse respiratory reactions, including fatal bronchospasm in asthmatic patients, have been reported after the use of some ophthalmic beta-blockers. Of tan® Timolol should be used with caution in patients with mild to moderate chronic obstructive pulmonary disease (COPD) and only if the expected benefit outweighs the potential risk.

Anaphylactic reactions:
Patients with a history of atopy or severe anaphylactic reactions to various allergens may exhibit an exaggerated response to re-exposure to such allergens and may not respond to the usual dose of adrenaline used to treat anaphylactic reactions while on beta-blockers.

Surgical procedures with anesthesia:
Ophthalmic beta-blockers may block the systemic effects of beta-agonists such as adrenaline. The anesthesiologist should be informed if the patient is receiving timolol.

Hypoglycemia / diabetes mellitus:
Beta-blockers should be used with caution in patients prone to spontaneous hypoglycemia or with labile diabetes mellitus, as beta-blockers may mask symptoms of acute hypoglycemia.

Hyperthyroidism:
Beta-blockers may mask symptoms of hyperthyroidism.

Myasthenia gravis:
Worsening of clinical status has been reported in patients with myasthenia gravis using timolol eye drops.

Corneal disorders:
Ophthalmic beta-blockers may cause dry eyes. Patients with corneal disorders should be treated with caution.

Choroidal detachment:
Choroidal detachment has been reported with the use of ophthalmic suppressive agents (such as timolol, acetazolamide) following filtering procedures.

Benzalkonium chloride:
Benzalkonium chloride may 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 or those with potentially compromised corneal integrity. Patients should be monitored during prolonged use.

Use of contact lenses:
Of tan® Timolol eye drops contain benzalkonium chloride as a preservative, which may deposit on soft contact lenses and alter their color. Contact lenses must be removed before instillation and reinserted no sooner than 15 minutes after administration of the drug.

Use during pregnancy or breastfeeding

Pregnancy:
Timolol crosses the placenta. There is insufficient data on the use of timolol in pregnant women. Of tan® Timolol should not be used during pregnancy unless clearly necessary. Systemic absorption can be reduced (see section "Dosage and administration").

Epidemiological studies have not shown any teratogenic effects but have demonstrated a risk of intrauterine growth retardation with oral use of beta-blockers. Additionally, signs and symptoms of beta-blocker effects (such as bradycardia, hypotension, respiratory distress, and hypoglycemia) have been observed in newborns when beta-blockers were administered before delivery. If Of tan® Timolol was used before delivery, the newborn should be closely monitored during the first days of life.

Breastfeeding:
Beta-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 cause beta-blockade symptoms in newborns. Systemic absorption can be reduced (see section "Dosage and administration").

Ability to influence reaction rate when driving or operating machinery:
When used according to the recommended dosing regimen, Of tan® Timolol does not cause visual impairment or drowsiness and therefore does not negatively affect the ability to drive or operate machinery. However, it may reduce blood pressure, which could lead to syncope or dizziness in some patients. Patients should be informed of this possibility at the beginning of treatment.

Dosage and administration

Dosage for adults:
One drop 1–2 times daily. The recommended dose is one drop in the affected eye 1–2 times daily (morning and evening).

Administration method:
The pressure-lowering effect may be enhanced when Of tan® Timolol is combined with other antiglaucoma agents (prostaglandin analogs, miotics, adrenergic agonists/mimetics, or carbonic anhydrase inhibitors). When switching from another antiglaucoma agent to Of tan® Timolol, the previous agent should be discontinued immediately and treatment with Of tan® Timolol initiated as described above.

Nasolacrimal occlusion or eyelid closure for 2 minutes reduces systemic absorption of the drug, thereby decreasing the likelihood of systemic adverse effects and increasing local activity.

Dosage for children:
The benefit-risk ratio of using timolol in children should be carefully evaluated before prescribing. A thorough examination and medical history review to identify systemic disorders should be performed before initiating timolol in children.

There are no specific dosage recommendations due to limited clinical data (see section "Pharmacodynamics"). However, if benefits outweigh risks, the lowest daily dose should be used. If intraocular pressure is not adequately controlled, the dose may be increased to two drops in the affected eye. When administered twice daily, a 12-hour interval between doses should be maintained.

Additionally, patients, especially newborns, should be closely observed for 1–2 hours after the first dose in the physician's office, and local and systemic adverse reactions should be carefully monitored before surgical intervention.

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

Administration method:
To minimize adverse reactions, dosing should be limited to one drop. Systemic absorption after topical application of beta-blockers can be reduced by nasolacrimal occlusion and eyelid closure for as long as possible (e.g., 3–5 minutes) (see sections "Special precautions for use" and "Pharmacokinetics").

Duration of treatment:
For temporary treatment in children. Due to limited data, timolol may only be recommended for primary congenital and primary juvenile glaucoma during the transitional period before deciding on surgical intervention or alternative treatment options.

Overdose:
Overdose should be avoided. The total amount of timolol absorbed from one oral tablet is equivalent to that from 30 drops of Of tan® Timolol 5 mg/ml eye drops. However, since the drug is rapidly absorbed through the ocular and nasal mucosa, even a few drops may cause arrhythmia, transient pulse slowing, reduced blood pressure, and bronchospasm.

Treatment of overdose is symptomatic and includes administration of adrenergic agonists (e.g., isoprenaline, dobutamine, and possibly dopamine).

Adverse reactions:
Of tan® Timolol eye drops are generally well tolerated. Like other topically applied ophthalmic drugs, timolol is systemically absorbed and may cause undesirable effects similar to those seen with systemic beta-blockers. The frequency of systemic adverse reactions after topical ophthalmic use is lower than with systemic administration.

The following adverse reactions are typical for the class of ophthalmic beta-blockers.

Eye disorders:
Uncommon (≥ 1/1000 to < 1/100): reduced corneal sensitivity, superficial punctate keratitis.
Rare (≥ 1/10000 to < 1/1000): dry eye syndrome, blepharoconjunctivitis, visual disturbance, diplopia (double vision), ptosis (drooping eyelid).
Very rare (< 1/10000): corneal calcification (associated with use of phosphate-containing eye drops in patients with severely damaged cornea).

Cardiac disorders:
Uncommon (≥ 1/1000 to < 1/100): bradycardia.
Rare (≥ 1/10000 to < 1/1000): heart failure, arrhythmias.

Vascular disorders:
Rare (≥ 1/10000 to < 1/1000): hypotension, reduced peripheral and cerebral perfusion.

Nervous system disorders:
Common (≥ 1/100 to < 1/10): headache.
Rare (≥ 1/10000 to < 1/1000): dizziness.

Respiratory, thoracic and mediastinal disorders:
Uncommon (≥ 1/1000 to < 1/100): dyspnea.
Rare (≥ 1/10000 to < 1/1000): bronchospasm (especially in patients with bronchospastic disorders such as asthma or heart failure), nasal congestion.

Psychiatric disorders:
Uncommon (≥ 1/1000 to < 1/100): depression.
Rare (≥ 1/10000 to < 1/1000): anxiety, nightmares, confusion (mental clouding).

Skin and subcutaneous tissue disorders:
Rare (≥ 1/10000 to < 1/1000): hypersensitivity reactions: rash, urticaria, alopecia.

General disorders and administration site conditions:
Uncommon (≥ 1/1000 to < 1/100): fatigue.
Rare (≥ 1/10000 to < 1/1000): asthenia (general weakness).

In addition to the above, systemic use of beta-blockers administered as eye drops has been associated with the following adverse reactions, which may also occur with Of tan® Timolol eye drops (see below).

Immune system disorders:
Systemic allergic reactions, including angioedema, 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, sharp pain, itching, lacrimation, redness), keratitis, blurred vision, choroidal detachment after filtering surgery (see section "Special precautions for use"), corneal erosion. Very rare cases of corneal deposits have been reported in some patients with severely damaged corneas using phosphate-containing eye drops.

Cardiac disorders:
Chest pain, tachycardia, 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, diarrhea, dry mouth, abdominal pain, vomiting.

Skin and subcutaneous tissue disorders:
Psoriasis-like rash or exacerbation of psoriasis.

Musculoskeletal and connective tissue disorders:
Myalgia (muscle pain).

Reproductive system and breast disorders:
Sexual dysfunction, decreased libido.

Reporting suspected adverse reactions:
Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions.

Shelf life:
3 years. Use within 28 days after opening the bottle.

Storage conditions:
Store at temperatures not exceeding 25°C, in the original packaging to protect from light. Keep out of reach of children.

Packaging:
5 ml in a bottle with dropper. One bottle with dropper in a cardboard box.

Prescription status:
Prescription only.

Manufacturer:
Santen Oy / Santen Oy.

Manufacturer's address:
Kelloportinkatu 1, Tampere, 33100, Finland.