Tizoptan

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

Composition:

Active substances: bimatoprost, timolol maleate;

1 ml of solution contains: bimatoprost — 0.3 mg, timolol maleate — 6.83 mg, equivalent to timolol — 5 mg;

Excipients: benzalkonium chloride; citric acid monohydrate; sodium hydrogen phosphate heptahydrate; sodium chloride; hydrochloric acid; sodium hydroxide; water for injections.

Pharmaceutical form. Eye drops, solution.

Main physicochemical properties: clear, colorless or slightly yellow solution.

Pharmacotherapeutic group. Agents used in ophthalmology. Anti-glaucoma and miotic agents. Timolol, combinations. Beta-adrenergic blockers.

ATC code S01E D51.

Pharmacological Properties

Pharmacodynamics

Tizoptan is a combination medicinal product containing bimatoprost and timolol maleate, which reduce elevated intraocular pressure (IOP) through a combined effect, providing a significantly greater reduction than either component used alone.

Bimatoprost belongs to the synthetic prostamide class and is structurally similar to prostaglandin F2α (PGF2α); however, bimatoprost does not act on any of the known prostaglandin receptor types. The mechanism of IOP reduction by bimatoprost involves increased outflow of aqueous humor through both the trabecular meshwork and the uveoscleral pathways of the eye.

Timolol is a non-selective beta-adrenergic receptor blocker that lacks intrinsic sympathomimetic and membrane-stabilizing activity.

Reduction in IOP occurs due to decreased production of aqueous humor. The exact mechanism of action of timolod is not fully established, but it may be related to inhibition of cyclic adenosine monophosphate (cAMP) synthesis induced by endogenous stimulation of beta-adrenergic receptors.

The combination product Tizoptan provides a hypotensive effect comparable to that achieved with combination therapy using bimatoprost (once daily) and timolol (twice daily) administered separately.

Pharmacokinetics

Systemic absorption of the combination product Tizoptan is minimal and does not differ from that observed during combination therapy with each individual component administered separately.

Bimatoprost

In in vitro studies, bimatoprost penetrated well into the cornea and sclera. The mean corneal permeability coefficient was 3.24 × 10^–6 cm/sec. Bimatoprost penetrates scleral tissues more effectively than corneal tissues. After topical administration of bimatoprost eye drops, systemic exposure is very low, with no accumulation. Following instillation of one drop of 0.03% bimatoprost solution into both eyes of healthy subjects once daily for 2 weeks, maximum plasma concentration was reached within 10 minutes after administration, and within 1.5 hours, plasma levels dropped below the limit of quantification (0.025 ng/mL). On days 7 and 14 of treatment, mean C_max and area under the concentration–time curve (AUC_0–24h) values for bimatoprost were similar, at approximately 0.08 ng/mL and 0.09 ng·h/mL, respectively, indicating that steady-state concentrations are achieved within the first week of topical administration.

Blood concentrations of bimatoprost observed during a 12-month study were comparable to those measured in healthy subjects. No significant systemic accumulation of the substance was observed during long-term use. The C-1 carboxylic acid metabolite (AGN 191522) was generally not detected in blood during these studies.

Bimatoprost is moderately distributed into tissues, with a systemic volume of distribution in humans at steady state of 0.67 L/kg. Bimatoprost is primarily distributed into plasma.

Plasma protein binding of bimatoprost is approximately 88% across concentrations ranging from 1 to 250 ng/mL. Bimatoprost is practically not metabolized in the human eye and, after topical administration, enters the systemic circulation almost entirely unchanged. Subsequently, bimatoprost undergoes glucuronidation, oxidation, N-deethylation, and deamidation, forming several metabolites. Glucuronide conjugates of bimatoprost are the most prevalent metabolites excreted via the kidneys and gastrointestinal tract. Hydrolysis of bimatoprost to its free acid is not required for its hypotensive activity.

The mean maximum concentration of total radioactivity in blood, measured after intravenous administration of radiolabeled bimatoprost at a dose of 3.12 μg/kg to 6 healthy volunteers, was 14.5 ng-eq/mL. Total radioactivity was eliminated rapidly, with a short elimination half-life of 1.74 hours. Intact bimatoprost concentration in blood peaked at 12.2 ng/mL and declined rapidly, with an elimination half-life of approximately 45 minutes. Total systemic clearance of unchanged bimatoprost was 1.50 L/h/kg.

Approximately 67% of the administered dose was excreted in urine, with only a minor fraction excreted unchanged. About 25% of the dose was eliminated via the gastrointestinal tract, of which 15–40% was excreted unchanged.

In subjects aged 18–44 years (mean age 28.5 years) and elderly patients aged 65–80 years (mean age 71 years), no significant systemic accumulation of bimatoprost was observed after twice-daily administration for 7 days. Bimatoprost rapidly entered the bloodstream in both age groups, and in most patients, concentrations fell below the limit of quantification within 1.5 hours. Systemic exposure was higher in elderly subjects compared to younger patients, both after single (124%) and multiple doses (213%). The mean AUC_0–24h was 0.0634 ng·h/mL in elderly patients, which was statistically significantly higher than in younger subjects (0.0218 ng·h/mL), indicating an age-related effect. However, this difference is not considered clinically significant, as bimatoprost demonstrates comparable efficacy and safety in both younger and elderly patients.

Timolol

Timolol is weakly bound to plasma proteins (~60%).

Systemic effects of timolol in humans following oral administration are well characterized. After oral intake, timolol is rapidly and almost completely absorbed (~90%). Its plasma concentration can be detected within 30 minutes, with peak levels occurring approximately 1–2 hours post-dose. The elimination half-life of timolol from plasma is about 4 hours. This half-life does not differ significantly in patients with moderate renal impairment.

Timolol is partially metabolized in the liver and excreted by the kidneys along with its metabolites. After oral administration, it undergoes moderate first-pass metabolism (~50%), and only a small amount of unchanged drug is excreted in urine along with metabolites.

In patients undergoing cataract surgery, peak concentration of timolol in aqueous humor was 898 ng/mL one hour after instillation of 0.5% ophthalmic solution. A small amount of the drug enters the systemic circulation. The elimination half-life of timolol from plasma is approximately 4–6 hours.

Mean pharmacokinetic parameters and associated variability for bimatoprost were very similar between monotherapy and combination therapy, indicating no significant "drug–drug" interaction for bimatoprost.

The mean C_max of timolol was lower (by 29%) with the combination product compared to timolol monotherapy (p < 0.05). Considering systemic adverse effects associated with timolol, this reduction may represent an advantage of combination therapy in terms of overall safety. No significant differences were observed in AUC_0–24h or elimination half-life of timolol between the combination product and monotherapy. Results from two pivotal phase III safety and efficacy trials showed that bimatoprost blood concentrations measured in patients with glaucoma or ocular hypertension were similar to those observed in healthy subjects, and no significant systemic accumulation of the drug was observed over 12 months.

Clinical characteristics.

Indications.

For reduction of intraocular pressure (IOP) in patients with open-angle glaucoma and ocular hypertension when monotherapy with beta-adrenergic blocking agents or topical prostaglandin analogs has been insufficiently effective.

Contraindications.

• Hypersensitivity to timolol, bimatoprost, or any of the excipients contained in the medicinal product.
• Increased airway reactivity syndrome, including bronchial asthma in the acute stage and history of previous episodes, severe chronic obstructive bronchopulmonary diseases.
• Sinus bradycardia, sinoatrial node dysfunction syndrome, sinoatrial block, second- and third-degree atrioventricular block not controlled by a cardiac pacemaker, clinically significant heart failure, cardiogenic shock.

Interaction with other medicinal products and other forms of interaction.

Interaction studies have not been conducted.

Beta-adrenergic blocking agents. Patients receiving systemic beta-adrenergic blockers (e.g., orally or intravenously) and Tizoptan should be under close monitoring due to the potential for additive beta-blocking effects on systemic and intraocular pressure.

Antihypertensive/cardiac glycosides. There is a possibility of additive effects that may lead to arterial hypotension and/or marked bradycardia when ophthalmic solutions containing beta-adrenergic blockers are used concomitantly with calcium channel blockers, antiarrhythmics (including amiodarone), digitalis glycosides, parasympathomimetics, guanethidine, and other antihypertensive agents.

Mydriatic agents. Although timolol has minimal or no effect on pupil size, there have been occasional reports of mydriasis when timolol is used concomitantly with mydriatic agents such as adrenaline (epinephrine).

CYP2D6 inhibitors. Cases of enhanced systemic beta-blockade (e.g., reduced heart rate, depression) have been reported during combined treatment with CYP2D6 inhibitors (e.g., quinidine, selective serotonin reuptake inhibitors) and timolol.

If Tizoptan is used with other ophthalmic medicinal products, a 5-minute interval should be maintained between instillation of each product. In addition, any ophthalmic ointment or gel should be administered last.

Special precautions for use.

The medicinal product should be prescribed with caution to patients:

• with acute eye inflammation (e.g., uveitis), due to the possibility of exacerbating inflammation;
• at risk of macular edema (after intraocular surgery, retinal vein occlusion, ocular inflammatory diseases, and diabetic retinopathy), including cystoid macular edema;

Eye disorders. Prior to initiating treatment, patients should be informed about possible eyelash growth, darkening of the eyelids or periorbital area, and increased pigmentation of the iris (brown color), as such reactions have been observed during treatment with bimatoprost. Increased iris pigmentation may become permanent even after discontinuation of the drug and may result in a difference in eye color if only one eye has been treated. After 12 months of treatment with Tizoptan, the incidence of iris pigmentation was 0.2%. After 12 months of treatment with bimatoprost ophthalmic solution alone, the incidence was 1.5% and did not increase after 3 years of treatment. The pigmentation change is explained by increased melanin content in melanocytes, not by an increase in the number of melanocytes. The long-term effects of increased iris pigmentation are unknown. Changes in iris color observed with ophthalmic use of bimatoprost may be subtle and develop over several months or years. Treatment does not affect iris nevi or freckles. Periocular tissue pigmentation has been reported to be reversible in some patients.

Macular edema, including cystoid macular edema, has been reported with the use of bimatoprost. Therefore, Tizoptan should be used with caution in aphakic patients, pseudophakic patients with posterior capsule rupture, or patients with risk factors for macular edema (e.g., intraocular surgery, retinal vein occlusion, ocular inflammatory disease, diabetic retinopathy).

Excipients. The preservative benzalkonium chloride contained in Tizoptan may cause eye irritation.

Patients wearing soft contact lenses should be advised to remove the lenses before instillation of the medication and may reinsert them 15 minutes after administration.

Benzalkonium chloride may discolor soft contact lenses. Contact between the medicinal product and soft contact lenses should be avoided.

Benzalkonium chloride has been reported to cause punctate keratopathy and/or toxic ulcerative keratopathy. Therefore, patients with dry eye syndrome or corneal damage who are frequently or long-term treated with Tizoptan should be monitored.

Skin. Since eyelash growth may occur in areas where the drug repeatedly contacts the skin surface, it is important to apply Tizoptan strictly according to instructions, avoiding runoff of excess solution down the cheek or onto other skin areas.

Other. Clinical studies with 0.03% ophthalmic bimatoprost solution indicate that frequent administration of more than one dose per day in patients with glaucoma or ocular hypertension may reduce the hypotensive effect. When bimatoprost is used concomitantly with other prostaglandin analogs, intraocular pressure (IOP) changes should be monitored.

The use of the drug has not been studied in patients with ocular inflammatory diseases, neovascular, inflammatory, or angle-closure glaucoma, congenital glaucoma, or narrow-angle glaucoma. The drug should be used with caution in patients with active intraocular inflammation (e.g., uveitis), as inflammation may worsen.

As with topical application of other ophthalmic medications, systemic absorption of the active ingredients of Tizoptan (bimatoprost and timolol) is possible, although enhanced systemic absorption of individual active ingredients has not been observed. Due to the presence of the beta-adrenergic component timolol, adverse reactions typical of systemic beta-blockers may occur.

Cardiovascular disorders. Tizoptan should be used with caution in patients with cardiovascular diseases (e.g., ischemic heart disease, Prinzmetal’s angina, heart failure) who are receiving antihypertensive therapy with beta-blockers. Such patients should undergo thorough evaluation. Consideration should be given to alternative therapies. Patients with cardiovascular diseases should be monitored for signs of worsening conditions and adverse reactions.

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

Vascular disorders. The drug should be used with caution in patients with severe peripheral circulatory disorders (severe forms of Raynaud’s disease/syndrome).

Respiratory disorders. Respiratory disorders, including fatal bronchospasm in asthmatic patients, have been reported after the use of some ophthalmic beta-blockers.

Tizoptan may be prescribed to patients with chronic obstructive pulmonary disease of mild to moderate severity only if the expected benefit outweighs the potential risk to the patient.

Anaphylactic reactions. In patients with atopic disorders or severe anaphylactic reactions to a wide range of allergens, the usual doses of epinephrine (adrenaline) used to treat anaphylactic reactions may be ineffective when beta-adrenergic blockers are administered.

Endocrine disorders. Beta-adrenergic receptor blocking agents should be used with caution in patients prone to spontaneous episodes of hypoglycemia or in patients with diabetes mellitus (especially unstable diabetes), as beta-blockers may mask signs and symptoms of acute hypoglycemia.

Hyperthyroidism. Beta-adrenergic blockers may also mask signs of hyperthyroidism.

Corneal disorders. Ophthalmic beta-adrenergic receptor blockers may cause dry eyes; therefore, they should be prescribed with caution to patients with corneal disorders.

Retinal detachment. Retinal detachment has been reported with aqueous suppressant therapy (e.g., timolol, acetazolamide) following filtration procedures.

Other beta-adrenergic blockers. The effect on IOP or known systemic beta-blocking effects may be enhanced when timolol is administered to patients already receiving systemic beta-blocking agents. Such patients should be closely monitored. Concomitant use of two locally acting beta-adrenergic blocking agents is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Surgical anesthesia. Ophthalmic beta-blocking agents may block the effects of systemic beta-agonists, such as adrenaline. The anesthesiologist should be informed if the patient is receiving timolol.

Liver. In patients with mild liver disease or initial elevation of liver enzymes—alanine aminotransferase (ALT), aspartate aminotransferase (AST), and/or total bilirubin—bimatoprost did not affect liver function during a study period of over 24 months.

Hepatic adverse reactions with ocular use of timolol are unknown.

Use during pregnancy or breastfeeding.

Pregnancy.

Adequate data on the use of the fixed combination bimatoprost/timolol in pregnant women are lacking. Tizoptan should be used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus. To minimize systemic absorption, see section "Dosage and administration."

Bimatoprost.

There are insufficient clinical data on use in pregnant women. Animal studies have shown reproductive toxicity at high doses.

Timolol.

Epidemiological studies have not shown congenital malformations, but have indicated a risk of intrauterine growth retardation with systemic beta-blocker use. Additionally, newborns exposed to beta-blockers before delivery have shown signs of beta-blockade (e.g., bradycardia, hypotension, respiratory depression, and hypoglycemia). If Tizoptan is used before delivery, newborns should be monitored during the first days of life. Animal studies have shown that timolol's reproductive toxicity occurs at doses significantly higher than those used clinically.

Breastfeeding.

Tizoptan should not be administered to women who are breastfeeding.

Timolol.

Beta-blockers pass into breast milk. Although with therapeutic doses of timolol eye drops, the presence of significant amounts in breast milk that could cause clinical symptoms of beta-blockade in newborns is unlikely.

Bimatoprost.

It is unknown whether bimatoprost passes into human breast milk, but animal studies have shown the presence of bimatoprost in animal milk.

Fertility.

There are no data on the effect of the medicinal product on human fertility.

Ability to affect reaction speed when driving or operating machinery.

Tizoptan has a minor influence on the ability to drive or operate machinery. As with other ophthalmic medications, if transient blurred vision occurs after instillation, patients should wait until vision clears before driving or operating machinery.

Method of Administration and Dosage

Tizoptan is intended for topical ocular administration.

Instill 1 drop into the conjunctival sac of the affected eye once daily in the morning.

If a dose is missed, resume treatment the following day. Do not exceed the recommended dose: one instillation per day.

As with other ophthalmic drops, to minimize potential systemic absorption, it is recommended to gently press the finger against the inner corner of the lower eyelid near the nose (punctal occlusion) for at least 1 minute immediately after instillation.

To prevent eye injury and contamination of the eye drops, avoid contact between the dropper tip and the eye or surrounding tissues.

Use in elderly patients

Dosage adjustment is not required.

Children

The safety and efficacy of Tizoptan in children have not been established.

The drug should not be administered to patients under 18 years of age.

Overdose

There have been no reports of overdose with Tizoptan.

Treatment. In case of overdose, symptomatic and supportive therapy should be applied. Following accidental oral ingestion, no signs of toxic effects from bimatoprost were observed at doses up to 100 mg/kg/day, which is 36 times higher than the bimatoprost dose contained in one bottle, potentially ingested by a 10 kg child. Overdose of timolol may cause symptoms such as bradycardia, arterial hypotension, bronchospasm, headache, dizziness, dyspnea, and cardiac arrest. In cases of renal failure, timolol is not effectively eliminated by hemodialysis.

Adverse reactions.

The adverse reactions listed below were considered to be related to the administration 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), or not known (frequency cannot be estimated based on available data).

The following adverse reactions may occur with the use of the medicinal product Tizoptan (within each group, reactions are listed in decreasing order of severity).

Additional adverse reactions listed below were observed during the use of the active substances bimatoprost and timolol and may occur during the use of the medicinal product Tizoptan.

Bimatoprost

As with other ophthalmic medicinal products for local use, bimatoprost/timolol enters the systemic circulation. Absorption of timolol may cause the same adverse reactions as those seen with systemic beta-blockers. The incidence of systemic adverse reactions to the medicinal product after local ocular administration is lower than with systemic administration. For measures to reduce systemic absorption, see section "Dosage and administration".

Timolol

Side effects of eye drops containing phosphates

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

Reporting suspected adverse reactions

Reporting suspected adverse reactions after drug registration is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of drug efficacy via the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Do not use after the expiry date stated on the packaging.

Shelf life after first opening of the bottle — 28 days.

Storage conditions.

Store at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

3 ml in a bottle with a dropper cap and closure; 1 in a box.

Prescription status.

Prescription only.

Manufacturer.

SENTISS PHARMA PVT. LTD., India / SENTISS PHARMA PVT. LTD., India.

Manufacturer's address and location of operations.

Village Khera Nihla, Tehsil Nalagarh, Distt. Solan, Himachal Pradesh, 174 101, India /
Village Khera Nihla, Tehsil Nalagarh, Distt. Solan, Himachal Pradesh, 174 101, India.

Marketing Authorization Holder.

SENTISS PHARMA PVT. LTD., India / SENTISS PHARMA PVT. LTD., India.

Phone numbers and email address of the marketing authorization holder's pharmacovigilance contact person (for reporting all cases of suspected adverse reactions and lack of drug efficacy, available 24/7): 0681291858 (mobile), 0445850460 (tel/fax), [email protected].

Address of the marketing authorization holder.

212/D-1, Ashirwad Commercial Complex, Green Park, New Delhi, 110016, India /
212/D-1, Ashirwad Commercial Complex, Green Park, New Delhi, 110016, India.