Timodrops d®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TIMO DROPS D® (TIMODROPS D)

Composition:

Active substances: dorzolamide, timolol;

1 ml of solution contains dorzolamide hydrochloride equivalent to dorzolamide 20 mg and timolol maleate equivalent to timolol 5 mg;

Excipients: benzalkonium chloride, mannitol, sodium citrate, hydroxyethylcellulose, sodium hydroxide (for pH adjustment), water for injections.

Pharmaceutical form. Eye drops, solution.

Main physicochemical properties: transparent, colorless or almost colorless, slightly viscous solution, practically free from particles.

Pharmacotherapeutic group. Agents used in ophthalmology. Antiglaucoma preparations and miotics. Beta-adrenergic receptor blockers. Timolol, combinations.

ATC code S01ED51.

Pharmacological properties.

Pharmacodynamics.

The medicinal product contains two active substances: dorzolamide hydrochloride and timolol maleate. Each of these components reduces elevated intraocular pressure by decreasing the secretion of intraocular fluid, but their mechanisms of action differ.

Dorzolamide hydrochloride is a potent inhibitor of carbonic anhydrase type II. Inhibition of carbonic anhydrase in the ciliary body reduces the secretion of intraocular fluid by slowing the formation of bicarbonate ions, which in turn leads to a reduction in the transport of sodium and fluid.

Timolol maleate is a non-selective beta-adrenergic receptor blocker. The exact mechanism by which timolol reduces intraocular pressure is not fully understood. Fluorometric and tonographic studies indicate that the effect of timolol is due to reduced secretion of aqueous humor. In addition, timolol may enhance outflow of fluid.

The combined action of the two components results in a greater reduction in intraocular pressure than therapy with either agent alone.

After administration, Timodrops D® reduces intraocular pressure regardless of whether its elevation is associated with glaucoma, without causing the typical side effects of miotic agents such as night blindness, accommodative spasm, or pupillary constriction.

Pharmacokinetics.

Dorzolamide hydrochloride. After topical application, dorzolamide penetrates into the systemic circulation. With prolonged use, dorzolamide accumulates in erythrocytes due to binding to carbonic anhydrase type II, maintaining very low concentrations of free active substance in plasma. Dorzolamide is metabolized to a single N-desethylated metabolite, which inhibits carbonic anhydrase type II less potently than the parent compound, but also inhibits the less active isoenzyme CA-I. The metabolite also accumulates in erythrocytes, where it binds primarily to carbonic anhydrase type I. Approximately 33% of dorzolamide is protein-bound in plasma. Dorzolamide is excreted in urine in unchanged form and as metabolite. After discontinuation of treatment, dorzolamide is eliminated nonlinearly from erythrocytes, initially resulting in a rapid decline in concentration followed by a slow elimination phase with a half-life of approximately 4 months.

When dorzolamide was administered orally to simulate maximum systemic exposure following long-term topical ophthalmic use, steady state was reached within 13 weeks. At steady state, there was practically no free active substance or metabolite in plasma; inhibition of carbonic anhydrase in erythrocytes was less than that expected to be necessary for pharmacological effects on renal or respiratory function. Similar pharmacokinetic results were obtained after continuous topical application of dorzolamide hydrochloride. However, in some elderly patients with impaired renal function (creatinine clearance defined as 30–60 mL/min), higher concentrations of the metabolite in erythrocytes were observed, although significant differences in carbonic anhydrase inhibition and clinically significant systemic adverse effects were not directly associated with this finding.

Timolol maleate. After topical ocular administration, timolol is systemically absorbed. Systemic exposure to timolol was measured after topical administration of a 0.5% ophthalmic solution twice daily. The maximum plasma concentration after the morning dose was 0.46 ng/mL, and after the evening dose was 0.35 ng/mL.

Clinical characteristics.

Indications. For the treatment of elevated intraocular pressure in patients with open-angle glaucoma or pseudoexfoliative glaucoma when topical use of beta-blockers alone is insufficient.

Contraindications.

• Reactive respiratory diseases, including bronchial asthma or history of bronchial asthma, or severe chronic obstructive pulmonary disease;
• Sinus bradycardia, sick sinus syndrome, sinoatrial block, second- or third-degree atrioventricular block not controlled by a pacemaker, overt heart failure, cardiogenic shock;
• Severe renal impairment (creatinine clearance < 30 mL/min) or hyperchloremic acidosis;
• Hypersensitivity to any component of the medicinal product;
• Pregnancy and lactation period.

The above-mentioned contraindications are based on data regarding individual active components and are not specific to the combination.

Interaction with other medicinal products and other forms of interaction.

Specific interaction studies between Timodrops D® and other medicinal products have not been conducted.

In clinical studies, this drug was administered concomitantly with the following systemically acting medicinal products without evidence (unconfirmed) of adverse drug interactions: angiotensin-converting enzyme (ACE) inhibitors, calcium channel blockers, diuretics, nonsteroidal anti-inflammatory drugs, including aspirin, and hormones (e.g., estrogen, insulin, thyroxine).

There is a risk of additive effects causing arterial hypotension and/or marked bradycardia when ophthalmic beta-blocker solutions are used concomitantly with oral calcium channel blockers, agents that reduce catecholamine production, or beta-adrenergic blockers, antiarrhythmic drugs (including amiodarone), digitalis glycosides, parasympathomimetics, guanethidine, narcotics, and monoamine oxidase inhibitors (MAOIs).

Potentiation of systemic beta-blockade (e.g., reduced heart rate, depression) has been reported during combined therapy with CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) and timolol.

Although Timodrops D® itself (as monotherapy) has little or no effect on pupil size, miosis has occasionally been reported with concomitant use of ophthalmic beta-blockers and adrenaline (epinephrine).

Beta-blockers may enhance the hypoglycemic effect of antidiabetic agents.

Oral beta-adrenergic blockers may provoke rebound arterial hypertension upon discontinuation of clonidine.

Special precautions for use

Cardiovascular and respiratory reactions

Like other topically applied ophthalmic medicinal products, timolol is systemically absorbed. Since timolol is a beta-blocker, adverse reactions affecting the cardiovascular and respiratory systems, similar to those observed with systemic administration of such agents, may occur. The frequency of systemic adverse reactions after topical application of ophthalmic medicinal products is lower than with systemic administration. For information on reducing systemic absorption, see section "Dosage and administration".

Cardiac disorders

The use of beta-blockers should be carefully considered in patients with cardiovascular disorders (e.g., ischemic heart disease, vasospastic angina/Prinzmetal's angina, and cardiac failure) and in patients with arterial hypotension. Alternative active substances should be considered. Patients with cardiovascular disorders should be closely monitored for signs of worsening of their condition or adverse reactions.

Due to the negative effect on impulse conduction time, beta-blockers should be administered with caution in patients with first-degree heart block.

Vascular disorders

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

Respiratory disorders

Respiratory reactions, including fatal cases due to bronchospasm, have been reported in asthmatic patients following the use of certain ophthalmic beta-blockers.

Timodrops D**®** 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.

Hepatic function impairment

The use of this medicinal product in patients with impaired liver function has not been studied, and therefore it should be used with caution in such patients.

Immunological and hypersensitivity reactions

Like other topically applied ophthalmic medicinal products, this medicinal product may be systemically absorbed. Dorzolamide, like sulfonamides, contains a sulfonamide group. Therefore, adverse reactions associated with systemic use of sulfonamide-containing drugs may occur with topical application, including severe reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. If signs of serious reactions or hypersensitivity occur, the use of the medicinal product should be discontinued.

Local ocular adverse reactions similar to those observed with dorzolamide hydrochloride eye drops have been reported during treatment with this medicinal product. If such reactions occur, discontinuation of the medicinal product should be considered. Patients with atopy or a history of severe anaphylactic reactions to multiple allergens may be more sensitive to re-exposure to allergens during anaphylactic reactions while taking beta-blockers and may not respond to usual doses of adrenaline.

Concomitant therapy

The effect on intraocular pressure or known systemic effects of beta-blockers may be potentiated when timolol is used in patients already receiving systemic beta-blockers. Such patients should be carefully monitored for treatment response. The use of two topical beta-adrenergic blockers is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

The combination of dorzolamide and oral carbonic anhydrase inhibitors is not recommended.

Discontinuation of treatment

As with systemic beta-blockers, ophthalmic timolol should be withdrawn gradually in patients with ischemic heart disease (IHD) if discontinuation of the medicinal product is necessary.

Additional effects of beta-blockers

Hypoglycemia/diabetes

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

Beta-blockers may also mask signs of hyperthyroidism. Abrupt withdrawal of beta-blockers may lead to worsening of symptoms.

Corneal disorders

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

Anesthesia during surgery

Ophthalmic beta-blockers may block the systemic effects of beta-agonists, such as adrenaline. The anesthesiologist should be informed that the patient is receiving timolol.

Beta-blocker treatment may exacerbate symptoms in myasthenia gravis.

Additional effects of carbonic anhydrase inhibition

Treatment with oral carbonic anhydrase inhibitors has been associated with the development of urolithiasis due to disturbances in acid-base balance, particularly in patients with a history of nephrolithiasis. Although acid-base disturbances have not been observed with this medicinal product, rare cases of urolithiasis have been reported. Since carbonic anhydrase inhibitors are systemically absorbed even after topical use, patients with a history of nephrolithiasis have an increased risk of developing urolithiasis when using Timodrops D**®**.

Other special considerations

Treatment of patients with acute angle-closure glaucoma requires additional therapeutic measures beyond intraocular pressure-lowering agents. The use of this medicinal product in patients with acute angle-closure glaucoma has not been studied.

Corneal edema and irreversible corneal decompensation have been reported during dorzolamide use in patients with pre-existing chronic corneal disorders and/or a history of intraocular surgery. Corneal edema is highly likely in patients with a low number of endothelial cells. Precautions should be taken when prescribing Timodrops D**®** to such patients.

Choroidal detachment has been reported following filtration procedures when aqueous suppressants (e.g., timolol, acetazolamide) were prescribed.

As with other antiglaucoma agents, reduced responsiveness to ophthalmic timolol maleate has been observed in some patients after prolonged treatment. However, in clinical studies involving 164 patients monitored for at least three years, no significant difference in mean intraocular pressure was observed after initial pressure stabilization.

Use of contact lenses

This medicinal product contains the preservative benzalkonium chloride, which may cause eye irritation. Contact lenses should be removed before instilling the drops and at least 15 minutes should elapse before reinserting them. Benzalkonium chloride is known to discolor soft contact lenses.

Use during pregnancy or breastfeeding

Pregnancy

This medicinal product should not be used during pregnancy.

Dorzolamide. There are no clinical data on the effects of dorzolamide during pregnancy. In rabbits, dorzolamide showed teratogenic effects during pregnancy.

Timolol. There are insufficient data on the use of timolol during pregnancy. Timolol should not be administered during pregnancy unless clearly necessary. For information on reducing systemic absorption, see section "Dosage and administration".

Epidemiological studies have not provided evidence of an increased risk of intrauterine growth retardation with oral beta-blockers used during pregnancy. However, newborns exposed to beta-blockers before delivery may exhibit signs of beta-blockade (e.g., bradycardia, hypotension, respiratory distress syndrome, and hypoglycemia). If this medicinal product is used before delivery, newborns should be closely monitored during the first days of life.

Breastfeeding

It is unknown whether dorzolamide is excreted in human breast milk. In rats receiving dorzolamide, reduced weight gain in offspring was observed. Beta-blockers are excreted in breast milk. However, when timolol eye drops are used at therapeutic doses, it is unlikely that sufficient amounts will be present in breast milk to cause clinical signs of beta-blockade in the infant.

For information on reducing systemic absorption, see section "Dosage and administration".

If treatment with this medicinal product is necessary, breastfeeding is not recommended.

Ability to affect reaction speed when driving or operating machinery. No specific studies on the effect of this medicinal product on reaction speed have been conducted.

Adverse reactions such as blurred vision may negatively affect the ability of some patients to drive or operate machinery.

Method of Administration and Dosage

If Timodrops D**®** is used as monotherapy, instill 1 drop into the conjunctival sac of the affected eye(s) twice daily.

When used in combination with other ophthalmic drops, an interval of at least 10 minutes should be maintained between instillation of Timodrops D**®** and the other medicinal product. Ophthalmic ointments should be applied last.

Contact between the dropper tip and the surface of the eye or surrounding skin should be avoided, otherwise microorganisms may enter the eye drops, potentially causing eye infection(s). Use of a contaminated solution may lead to severe eye damage and loss of vision.

Application of nasolacrimal occlusion or closure of eyelids for 2 minutes reduces systemic absorption. This, in turn, helps reduce systemic adverse effects and increases local activity.

• Wash hands before instillation.
• Take the dropper bottle and unscrew the protective cap.
• If, after removing the cap, the safety ring around the dropper is loose and rotates freely, remove it before instillation.
• Hold the bottle with the dropper pointing downward between the index and middle fingers.
• Tilt the head backward. Pull down the eyelid with a clean finger to create a "pocket" between the eyelid and the eye, into which the drop should be directed (Fig. 1).
• Bring the tip of the bottle close to the eye. This may be done while looking in a mirror.
• Do not touch the dropper tip to the eye, eyelid, surrounding areas, or any other surfaces to avoid contaminating the remaining solution in the bottle.
• Gently press the bottom of the bottle to release one drop (Fig. 2).
• After instillation of Timodrops D**®**, press with a finger at the inner corner of the eye near the nose for 2–3 minutes (Fig. 3). This helps prevent the drug from draining into the nose and systemic circulation, especially in newborns and young children.
• If instilling drops into both eyes, wash hands before instilling into the second eye to prevent spreading infection from one eye to the other.
• Immediately after use, tightly replace the cap on the bottle.

If a drop misses the eye, repeat the instillation.

Do not use the medicinal product in any way other than as recommended by the physician.

Children. Since clinical data on the use of Timodrops D**®** ophthalmic solution in children are limited, its use in children is not recommended.

Overdose

There are no data on overdose in humans following accidental or intentional ingestion of Timodrops D**®**.

Symptoms

There have been reports of accidental overdose with ophthalmic timolol maleate solution, which may result in systemic effects similar to those observed with systemic beta-blockers overdose, including dizziness, headache, dyspnea, bradycardia, bronchospasm, and cardiac arrest. The most common expected signs and symptoms of dorzolamide overdose include electrolyte imbalance, development of acidosis, and effects on the central nervous system.

There is limited information on overdose in humans following accidental or intentional ingestion of dorzolamide hydrochloride. Drowsiness has been reported after oral intake. With topical use, nausea, dizziness, headache, weakness, unusual dreams, and dysphagia (difficulty swallowing) have been reported.

Treatment

Treatment should be symptomatic and supportive. Serum electrolyte levels (especially potassium) and blood pH should be monitored. Studies have shown that timolol is not completely removed by dialysis.

Adverse Reactions

The adverse reactions observed with the use of Timodrops D® were consistent with those previously reported with dorzolamide hydrochloride and/or timolol maleate.

In clinical studies, approximately 2.4% of all patients discontinued treatment due to the occurrence of local ocular adverse reactions, and approximately 1.2% of all patients discontinued treatment due to local adverse reactions indicative of allergy or hypersensitivity (specifically, eyelid inflammation and conjunctivitis).

Like other topically administered ophthalmic drugs, timolol is absorbed into the systemic circulation. This may cause adverse effects similar to those seen with systemic beta-blockers. The frequency of systemic adverse reactions after topical ophthalmic administration is lower than with systemic administration.

The adverse reactions listed below are classified by frequency 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), and not known (cannot be estimated from available data). Within each frequency group, adverse reactions are listed in order of decreasing severity.

Immune system disorders

Timodrops D®

Rare: symptoms of systemic allergic reactions, including angioedema, urticaria, pruritus, rash, anaphylactic reaction

Timolol maleate

Rare: symptoms of allergic reactions, including angioedema, urticaria, localized and generalized rash, anaphylactic reaction

Not known**: pruritus

Metabolism and nutrition disorders

Timolol maleate

Not known**: hypoglycemia

Psychiatric disorders

Timolol maleate

Uncommon: depression*

Rare: insomnia*, nightmares*, memory loss

Not known: hallucinations

Nervous system disorders

Dorzolamide hydrochloride

Common: headache*

Rare: dizziness*, paresthesia* (skin sensory disturbances)

Timolol maleate, ophthalmic solution

Common: headache*

Uncommon: dizziness*, syncope*

Rare: paresthesia*, exacerbation of signs and symptoms of myasthenia gravis, decreased libido (sex drive)*, hemorrhagic stroke*, cerebral ischemia, disturbances of cerebral circulation

Eye disorders

Timodrops D®

Very common: burning and stinging

Common: conjunctival injection, blurred vision, corneal erosion, ocular pruritus, lacrimation

Not known: foreign body sensation

Dorzolamide hydrochloride

Common: eyelid inflammation*, eyelid irritation*

Uncommon: iridocyclitis*

Rare: eye irritation, including redness*, eye pain*, eyelid scaling*, transient myopia (resolving upon discontinuation of treatment), corneal edema*, decreased intraocular pressure*, retinal detachment (with subsequent filtering surgery)*

Timolol maleate

Common: ocular irritation symptoms, including blepharitis*, keratitis*, decreased corneal sensitivity, dry eyes*

Uncommon: visual disturbances, including refractive changes (in some cases due to discontinuation of miotics)*

Rare: ptosis, diplopia, retinal detachment with subsequent filtering surgery* (see section "Special precautions")

Not known**: pruritus, lacrimation, redness, blurred vision, corneal erosion

Ear and labyrinth disorders

Timolol maleate

Rare: tinnitus*

Cardiac disorders

Timolol maleate

Uncommon: bradycardia*

Rare: chest pain*, arrhythmia*, congestive heart failure*, cardiac arrest*, heart block

Not known**: atrioventricular block, heart failure, increased heart rate

Dorzolamide hydrochloride

Not known: tachycardia

Vascular disorders

Timolol maleate

Rare: hypotension*, claudication, Raynaud's phenomenon*, cold sensation in hands and feet*

Dorzolamide hydrochloride

Not known: hypertension

Respiratory, thoracic and mediastinal disorders

Timodrops D®

Rare: sinusitis, dyspnea, respiratory failure, rhinitis, bronchospasm

Dorzolamide hydrochloride

Rare: epistaxis*

Not known: dyspnea

Timolol maleate

Uncommon: difficulty breathing (dyspnea)*

Rare: bronchospasm (predominantly in patients with pre-existing bronchospastic disease)*, respiratory failure, cough*

Gastrointestinal disorders

Timodrops D®

Very common: dysgeusia (altered taste)

Dorzolamide hydrochloride

Common: nausea*

Uncommon: dyspepsia*

Rare: throat irritation, dry mouth*

Timolol maleate

Rare: diarrhea, dry mouth*

Not known**: dysgeusia (altered taste), abdominal pain, vomiting

Skin and subcutaneous tissue disorders

Timodrops D®

Rare: contact dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis

Dorzolamide hydrochloride

Rare: rash*

Timolol maleate

Rare: alopecia*, psoriatic rash or exacerbation of psoriasis

Not known**: skin rash

Musculoskeletal and connective tissue disorders

Timolol maleate

Rare: systemic lupus erythematosus

Not known**: myalgia

Renal and urinary disorders

Timodrops D®

Uncommon: urolithiasis

Reproductive system and breast disorders

Timolol maleate

Rare: Peyronie's disease*, decreased libido (sex drive)

Not known**: sexual dysfunction

General disorders and administration site conditions

Dorzolamide hydrochloride

Common: asthenia/weakness*

Timolol maleate, ophthalmic solution

Uncommon: asthenia/weakness*

* These adverse reactions were also observed during post-marketing surveillance.

** Additional adverse reactions have been reported with ophthalmic beta-blockers and may possibly occur with the use of Timodrops D**®**.

Reporting of adverse reactions after marketing authorization is of great importance. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 24 months. After opening, store for no more than 28 days.

Storage conditions. Store at temperatures not exceeding 25°C, protected from light and out of reach of children.

Packaging. 5 ml in a dropper bottle; 1 or 3 dropper bottles per cardboard box.

Prescription status. Prescription only.

Manufacturer. Micro Labs Limited.

Manufacturer's address and location of business activity.
Plot No. 113-116, Phase IV, KIADB, Bommansandra Industrial Area, Jigani Link Road, Anekal Taluk, Bangalore 560 099, India.