Fixaprost®

INSTRUCTIONS for medical use of the medicinal product Fixaprost® (Fixaprost®)

Composition:

Active substances: latanoprost, timolol;

1 ml of solution contains 50 mcg of latanoprost and timolol maleate equivalent to 5 mg of timolol;

Excipients: polyoxyl 40 hydrogenated castor oil; sorbitol (E 420), carbomer, macrogol 4000, disodium edetate, sodium hydroxide, water for injections.

Pharmaceutical form. Eye drops, solution.

Main physicochemical properties: yellowish opalescent solution, practically free from particles.

Pharmacotherapeutic group. Medicinal products used in ophthalmology. Beta-blocking agents. Timolol, combinations. ATC code S01ED51.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Xalacom® contains two components: latanoprost and timolol maleate. Each of these two components has its own mechanism of reducing elevated intraocular pressure (IOP), and their combined use results in an additive IOP-lowering effect compared to each component used alone.

Lataprost, a prostaglandin F2α analogue, is a selective prostaglandin FP receptor agonist that reduces IOP by increasing the outflow of aqueous humour. The primary mechanism of action is enhanced uveoscleral outflow. Additionally, some increase in outflow facility (reduced resistance to trabecular outflow) has been reported in humans. Latanoprost does not significantly affect aqueous humour production, the blood-ocular barrier, or intraocular blood flow. Long-term treatment with latanoprost in eyes of monkeys that underwent extracapsular lens extraction did not affect retinal blood vessels, as demonstrated by fluorescein angiography. Latanoprost did not cause fluorescein leakage in the posterior segment of the human eye in pseudophakic patients during short-term treatment.

Timolol is a beta-1 and beta-2 (non-selective) adrenergic receptor blocker with no significant intrinsic sympathomimetic activity, direct myocardial depressant effect, or membrane-stabilizing effect. Timolol reduces IOP by decreasing aqueous humour production in the ciliary epithelium.

The exact mechanism of action is not fully established, but it is likely due to inhibition of cyclic adenosine monophosphate (cAMP) elevation caused by endogenous beta-adrenergic stimulation. It is not known whether timolol significantly affects the permeability of the blood-ocular barrier to plasma proteins. In rabbit studies, timolol did not affect regional ocular blood flow after long-term treatment.

Pharmacodynamic effect

Clinical efficacy

In dose-finding studies, the reference combination product latanoprost/timolol containing a preservative caused significantly greater reductions in mean diurnal IOP compared to latanoprost and timolol administered once daily as monotherapy. In two well-controlled, double-masked, six-month clinical studies, the IOP-lowering effect of the reference combination product latanoprost/timolol containing a preservative was compared with monotherapy using latanoprost and timolol in patients with IOP values of 25 mm Hg or higher. After 2–4 weeks of prior treatment with timolol (mean reduction in IOP of 5 mm Hg from baseline), after 6 months of treatment, additional mean diurnal IOP reductions from baseline were 3.1, 2.0, and 0.6 mm Hg, respectively, in patients treated with the reference combination product latanoprost/timolol containing a preservative, latanoprost, and timolol (twice daily). The IOP-lowering effect of the reference combination product latanoprost/timolol containing a preservative was maintained during subsequent 6-month open-label extension studies.

Available data suggest that evening administration of the drug may be more effective in reducing IOP than morning administration. However, when considering recommendations for dosing in the morning or evening, the patient's lifestyle and likely compliance should be taken into account.

It should be noted that if the combination product is insufficiently effective, separate administration of timolol twice daily and latanoprost once daily may be effective, as confirmed during studies.

The effect of the reference combination product latanoprost/timolol containing a preservative begins within 1 hour, and maximum effect is achieved within 6–8 hours. Adequate IOP-lowering effect persists for up to 24 hours after dose administration with long-term treatment.

Clinical efficacy and safety

The efficacy of the preservative-free ophthalmic solution Xalacom® was evaluated in a 3-month randomized, masked study comparing it with the reference product latanoprost/timolol 50 mcg/5 mg per mL containing a preservative in 242 patients with ocular hypertension or open-angle glaucoma who had documented inadequate control on monotherapy. Prior to the start of the study, patients were treated and stabilized using either the reference product or generic products (fixed combination ophthalmic solution of latanoprost/timolol 50 mcg/5 mg per mL containing a preservative) for at least 2 months.

The primary efficacy endpoint was the change from baseline in mean intraocular pressure (IOP) on day 84.

On day 84, the mean change in IOP from baseline was –0.49 mm Hg with Xalacom® and was comparable to that observed with the reference product latanoprost/timolol 50 mcg/5 mg per mL containing a preservative.

CI = confidence interval; mITT = modified intent-to-treat; N = number of patients in the treatment group; n = number of patients with data; SE = standard error; SD = standard deviation

In this 3-month study, no ocular adverse effects of the medicinal product Fixaprost**®** were identified other than those already adequately documented for the reference drug latanoprost/timolol. Treatment with Fixaprost**®** was associated with fewer subjective symptoms upon instillation on Day 84 (irritation/burning/stinging: 20.5% vs. 41.8%, p < 0.001; itching: 4.9% vs. 13.9%, p = 0.010), as well as fewer subjective symptoms during the day regardless of instillation (irritation/burning/stinging: 7.4% vs. 12.7%, p = 0.094; itching: 1.6% vs. 13.6%, p < 0.001), compared to the reference product.

Several systemic adverse reactions, already well known for timolol but not observed in clinical trials with the preservative-containing reference combination product latanoprost/timolol (see section "Adverse Reactions"), occurred at a frequency of "uncommon": dysgeusia, arrhythmia, and fatigue.

Pharmacokinetics.

Latanoprost.

Absorption.

Latanoprost is an isopropyl ester of the active substance; thus, it is a prodrug that is inactive per se but becomes biologically active after hydrolysis by esterases in the cornea to form latanoprost acid. It is well absorbed through the cornea, and all of the drug reaching the aqueous humor is hydrolyzed during passage through the cornea.

Distribution. Studies in humans indicate that maximum concentration in the aqueous humor, approximately 15–30 ng/mL, is reached about 2 hours after topical administration of latanoprost. After topical application in monkeys, latanoprost distributes predominantly to the anterior segment, conjunctiva, and eyelids.

Plasma clearance of latanoprost acid is 0.4 L/h/kg; the volume of distribution is small, approximately 0.16 L/kg, resulting in a short plasma half-life of 17 minutes. After topical ocular administration, systemic bioavailability of latanoprost acid is 45%. Latanoprost acid is 87% bound to plasma proteins.

Metabolism and Elimination. Metabolism of latanoprost acid in the eye is negligible. The main metabolism occurs in the liver. The primary metabolites, 1,2-dinor and 1,2,3,4-tetranor, which showed no significant biological activity in animal studies, are excreted primarily in the urine.

Timolol.

Absorption and Distribution. Maximum concentration of timolol in the aqueous humor of the eye is reached approximately 1 hour after topical administration of eye drops. A portion of the dose is absorbed into the systemic circulation; maximum plasma concentration of 1 ng/mL is achieved within 10–20 minutes after topical administration of 1 drop in each eye once daily (300 µg/day).

Metabolism. The plasma half-life of timolol is approximately 6 hours. Timolol is extensively metabolized in the liver.

Elimination. Metabolites, along with some unchanged timolol, are excreted in the urine.

Pharmacokinetic/Pharmacodynamic Interaction. No pharmacokinetic interactions between latanoprost and timolol were observed, although approximately a 2-fold increase in the concentration of latanoprost acid in the aqueous humor of the eye was observed 1–4 hours after administration of the combination product latanoprost/timolol compared to monotherapy.

Clinical characteristics.

Indications.

Fixaprosta**®** is indicated to reduce intraocular pressure (IOP) in adult patients (including elderly people) with open-angle glaucoma and ocular hypertension who are insufficiently responsive to beta-adrenergic blockers or topical prostaglandin analogs.

Contraindications.

Fixaprosta**®** is contraindicated in patients with:

• respiratory tract hyperreactivity syndrome, including bronchial asthma or history of bronchial asthma, severe chronic obstructive pulmonary disease;
• sinus bradycardia, sick sinus syndrome, sinoatrial block, second- or third-degree atrioventricular block not controlled by a pacemaker, severe heart failure, cardiogenic shock;
• hypersensitivity to the active substance or any of the excipients of the medicinal product.

Interaction with other medicinal products and other forms of interactions.

Specific studies on interactions between Fixaprosta**®** and other medicinal products have not been conducted.

Paradoxical increase in intraocular pressure has been reported after concomitant topical ocular administration of two prostaglandin analogs. Therefore, concomitant use of two or more prostaglandins, prostaglandin analogs, or prostaglandin derivatives is not recommended.

There is a risk of additive effects leading to arterial hypotension and/or marked bradycardia when ophthalmic beta-blocker solutions are used concomitantly with orally administered medicinal products such as calcium channel blockers, beta-adrenergic blockers, antiarrhythmic agents (including amiodarone), digitalis glycosides, parasympathomimetics, and guanethidine.

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

The effect on intraocular pressure or known systemic beta-blocking effects may be enhanced when Fixaprosta**®** is administered to patients already receiving oral beta-adrenergic blockers; therefore, the use of two or more topical beta-adrenergic blockers is not recommended.

There have been isolated reports of mydriasis occurring with concomitant use of ophthalmic beta-adrenergic blockers and adrenaline (epinephrine).

With beta-blockers, the hypertensive response to abrupt withdrawal of clonidine may be enhanced.

Beta-adrenergic blockers may enhance the hypoglycemic effect of antidiabetic agents and may also mask signs and symptoms of hypoglycemia (see section "Special precautions for use").

Special precautions for use.

Systemic effects.

Like other topically acting ophthalmic agents, Fiksaprosta**®** may be absorbed into the systemic circulation. Since timolol is a beta-blocker, adverse reactions affecting the cardiovascular, respiratory, and other systems associated with systemic use of such agents may occur. The frequency of systemic adverse reactions after topical administration of ophthalmic agents is lower than with systemic administration. For methods to reduce systemic absorption, see section "Dosage and administration".

Cardiac disorders.

Beta-blockers should be used with caution in patients with cardiovascular diseases (e.g., ischemic heart disease, vasospastic angina / Prinzmetal's angina, heart failure) and hypotension. The patient's condition should be carefully assessed, and alternative treatment with a different mechanism of action should be considered. Patients with cardiovascular disorders should be monitored for signs of worsening of these conditions and adverse reactions.

Beta-blockers should be prescribed cautiously in patients with first-degree atrioventricular block due to their negative effect on impulse conduction velocity.

Cardiac reactions and, rarely, fatal outcomes related to cardiac disorders have been reported following timolol administration.

Vascular disorders.

Fiksaprosta**®** should be used with caution in patients with severe peripheral circulatory disorders (e.g., severe forms of Raynaud's disease/syndrome).

Respiratory disorders.

Respiratory adverse reactions (including fatal cases due to bronchospasm) have been reported in asthmatic patients treated with ophthalmic beta-blockers. Fiksaprosta**®** should be used cautiously in patients with mild to moderate chronic obstructive pulmonary disease only if the expected benefit outweighs the potential risk.

Hypoglycemia/diabetes.

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

Hyperthyroidism.

Beta-blockers may mask the symptoms of hyperthyroidism.

Corneal disorders.

Ophthalmic beta-blockers may cause dry eye. The drug should be used with caution in patients with corneal diseases.

Other beta-blockers.

The effect on IOP or other known systemic effects of beta-blockers may be enhanced when timolol is administered to patients already receiving systemic beta-blockers. Close monitoring of clinical efficacy is required in such patients. Concomitant use of two or more locally acting beta-adrenergic blockers is not recommended (see section "Interaction with other medicinal products and other forms of interactions").

Concomitant therapy.

Timolol may interact with other drugs (see section "Interaction with other medicinal products and other forms of interactions").

Other prostaglandin analogs.

Concomitant use of two or more prostaglandins, prostaglandin analogs, or prostaglandin derivatives is not recommended (see section "Interaction with other medicinal products and other forms of interactions").

Anaphylactic reactions.

Patients with a history of atopy or severe anaphylactic reactions to various allergens may exhibit increased sensitivity upon repeated exposure to such allergens when treated with beta-blockers. In case of anaphylactic reactions, they may not respond to usual doses of adrenaline used for treatment of such reactions.

Choroidal detachment.

Choroidal detachment has been reported after filtration surgery and with the use of aqueous humor suppressants (e.g., timolol, acetazolamide).

Anesthesia for surgical procedures.

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

Changes in iris pigmentation.

Lataprost may cause a gradual change in eye color due to increased brown pigment in the iris. Similar to the experience with latanoprost ophthalmic solution, increased pigmentation of the iris was observed in 16–20% of all patients treated with the combined reference product latanoprost/timolol containing a preservative for up to one year (data based on photographs).

This effect is predominantly observed in patients with mixed iris color, e.g., green-brown, yellow-brown, or blue/grey-brown, and is due to increased melanin content in the stromal melanocytes of the iris. Typically, brown pigmentation around the pupil spreads concentrically toward the periphery of the affected eye, although the entire iris or parts thereof may become more brownish. In patients with uniformly blue, grey, green, or brown eyes, iris pigmentation changes were very rare during two years of treatment in clinical trials with latanoprost.

Changes in iris color develop slowly and may remain unnoticed for several months to years and have not been associated with any symptoms or pathological changes.

After discontinuation of treatment, further progression of brown iris pigmentation was not observed; however, the existing color change may be permanent.

No changes in iris nevi or freckles have been reported under therapy.

No pigment accumulation in the trabecular meshwork or any other part of the anterior chamber of the eye has been observed; however, patients should undergo regular examinations and, if clinically indicated, discontinue treatment in case of increased iris pigmentation.

At the beginning of treatment, patients should be informed about the possibility of eye color changes. Treatment of only one eye may lead to permanent heterochromia.

Changes in eyelids and eyelashes.

Skin darkening of the eyelids has been reported with latanoprost use, which is usually reversible.

Latanoprost may gradually alter the eyelashes and vellus hair around the treated eye, including increased length, thickness, pigmentation, and number of eyelashes or vellus hair, as well as misdirected growth of eyelashes. Changes in eyelashes are reversible and resolve after discontinuation of the drug.

Glaucoma.

There are no documented data on the use of latanoprost in inflammatory, neovascular, or chronic angle-closure glaucoma, open-angle glaucoma in pseudophakic patients, or pigmentary glaucoma. Latanoprost has no or minimal effect on the pupil, but there are no data on its use during acute attacks of angle-closure glaucoma. Therefore, Fiksaprosta**®** should be used with caution in these conditions.

Herpetic keratitis.

Latanoprost should be used with caution in patients with a history of herpetic keratitis. The drug should be avoided in patients with active herpes simplex virus keratitis and in those with recurrent herpetic keratitis, especially if associated with prostaglandin analogs.

Macular edema.

Cases of macular edema, including cystoid macular edema, have been reported during treatment with latanoprost.

This edema occurred primarily in aphakic patients, pseudophakic patients with posterior lens capsule rupture or anterior chamber lens, and patients with existing risk factors for macular edema. Fiksaprosta**®** should be used with caution in such patients.

Excipients.

Fiksaprosta**®** contains polyoxyl 40 hydrogenated castor oil, which may cause skin reactions. Currently, there are no adequate safety data available for this excipient.

Use during pregnancy or breastfeeding.

Pregnancy.

Fiksaprosta**®** is not recommended during pregnancy.

Lataprost.

There are insufficient data on the use of latanoprost in pregnant women. Animal studies have shown reproductive toxicity. The potential risk in humans is unknown.

Timolol.

There are insufficient data on the use of timolol in pregnant women. Timolol should not be used during pregnancy unless clearly necessary. To reduce systemic absorption, see section "Dosage and administration".

Epidemiological studies have not shown teratogenic effects but have demonstrated a risk of intrauterine growth retardation with oral use of beta-blockers. Signs and symptoms of beta-adrenergic blockade (e.g., bradycardia, hypotension, respiratory distress syndrome, and hypoglycemia) have been observed in infants born to mothers who received beta-blockers before delivery. If Fiksaprosta**®** is used before delivery, the newborn should be closely monitored during the first days of life.

Breastfeeding period.

Fiksaprosta**®** is not recommended for use in breastfeeding women.

Timolol.

Beta-blockers are excreted in breast milk. However, even with therapeutic doses of timolol administered as eye drops, it is highly unlikely that its concentration in milk would be sufficient to cause clinical symptoms in infants. For methods to reduce systemic absorption, see section "Dosage and administration".

Lataprost.

Lataprost and its metabolites may be excreted in breast milk.

Reproductive function.

Animal studies have shown no effect of latanoprost and timolol on reproductive function in males and females.

Ability to affect reaction speed when driving or operating machinery.

The medicinal product has a minor influence on the ability to drive or operate machinery.

Instillation of eye drops may cause transient blurred vision. Patients should wait until these symptoms resolve before driving or operating machinery.

Method of Administration and Dosage

For ophthalmic use.

Dosage

Adults (including elderly patients)

The recommended dose is 1 drop in the affected eye(s) once daily.

If a dose is missed, treatment should be continued with the next dose as planned. The maximum daily dose should not exceed 1 drop in the affected eye(s) once daily.

Administration Instructions

As with any eye drops, to minimize potential systemic absorption, it is recommended to press the lacrimal sac at the medial canthus of the eye (lacrimal duct occlusion) for 2 minutes immediately after instilling each drop.

Contact lenses should be removed before instillation of eye drops. They may be reinserted 15 minutes after administration.

When using multiple topically acting ophthalmic agents, the medications should be administered at least 5 minutes apart.

The single-dose container contains sufficient solution for treatment of both eyes and is intended for single use only.

This medicinal product is a sterile, preservative-free solution. The solution from the individual single-dose container must be used immediately after opening. Since sterility cannot be maintained after opening the single-dose container, the container with any residual solution must be discarded immediately after use.

Patients should:

• avoid contact between the dropper tip and the eye or eyelid;
• use the eye drop solution immediately after first opening the single-dose container and discard the container with any remaining medication after use;
• store unused single-dose containers in the sachet until use.

Method of Administration

1. Wash your hands and assume a comfortable sitting or standing position.
2. Open the sachet containing 5 single-dose containers. Record the date of first opening of the sachet.
3. Detach one single-dose container from the strip.

1. Remove the top part of the single-dose container as shown in the picture. Do not touch the tip after opening the container.

1. Gently pull down the lower eyelid of the affected eye with a finger.
2. Position the tip of the single-dose container close to the eye, but without touching it.
3. Squeeze the single-dose container gently to instill only one drop into the eye, then release the lower eyelid.

1. Press the inner corner of the affected eye near the nose with a finger. Close the eye and keep the finger pressed for 2 minutes to reduce potential systemic absorption. This should be done immediately after instilling each drop.

1. Repeat for the other eye if prescribed by a physician. Each single-dose container contains sufficient solution for administration in both eyes.
2. Discard the single-dose container after use. Do not store for future use! Since sterility cannot be maintained after opening a single-dose container, a new container must be opened for each administration.
3. Unused single-dose containers should be returned to the sachet. The sachet, from which containers have been opened, should be returned to the cardboard box. Repeat these steps until all containers in the sachet are used or the expiry date is reached. Containers from an opened sachet must be used within 1 month of opening.

Children

Not recommended. The safety and efficacy of Fiksaprost**®** in children and adolescents have not been established.

Overdose

There are no data on overdose with Fiksaprost**®** when used according to therapeutic recommendations.

Symptoms

Symptoms of systemic timolol overdose: bradycardia, hypotension, bronchospasm, and possible cardiac arrest.

In addition to eye irritation and conjunctival hyperemia, no other ocular adverse effects of latanoprost have been reported in cases of overdose.

Treatment

In case of overdose, symptomatic and supportive treatment should be administered.

The following information may be helpful in case of accidental ingestion of the medicinal product.

Studies have shown that timolol is slowly eliminated from the stomach. Therefore, gastric lavage may be performed if necessary.

Latanoprost is largely metabolized during the first pass through the liver. Intravenous infusion of the drug at a dose of 3 mcg/kg in healthy volunteers did not cause any symptoms, whereas doses of 5.5–10 mcg/kg caused nausea, abdominal pain, dizziness, increased fatigue, hot flashes, and sweating. These symptoms were mild to moderate in severity and resolved without treatment within 4 hours after the end of infusion.

Adverse reactions

Most adverse reactions associated with latanoprost are ocular. According to data from the extended phase of pivotal clinical trials of the reference combination product latanoprost/timolol containing a preservative, increased pigmentation of the iris was observed in 16–20% of patients, which may be irreversible. In an open-label 5-year safety study of latanoprost, iris pigmentation developed in 33% of patients (see section "Special precautions"). Other ocular adverse reactions are generally transient and occur at the site of administration.

The most serious adverse reactions associated with timolol are systemic and include bradycardia, arrhythmia, congestive heart failure, bronchospasm, and allergic reactions.

As with other ophthalmic medicinal products administered locally, timolol is absorbed into the systemic circulation. This may cause adverse reactions 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 listed adverse reactions include those observed within the class of ophthalmic beta-blockers.

Adverse reactions related to treatment observed in clinical trials with the reference combination product latanoprost/timolol containing a preservative are listed below.

Table 1. Adverse reactions observed in clinical trials of latanoprost/timolol

Data on adverse reactions of individual components of the medicinal product Fixaprost**®** were obtained from clinical studies, spontaneous reports in the post-marketing period, and scientific publications.

Table 2. Adverse reactions of latanoprost

Table 3. Adverse reactions of timolol maleate (ophthalmic use)

Reporting of possible adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continuous monitoring of the risk-benefit balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions. Information regarding adverse reactions should be sent to: [email protected] or by calling (044) 467-57-70 (24/7), 585-04-60.

Shelf life.

2 years.

After opening the sachet, use the single-dose containers within 1 month.

After opening a single-dose container, use immediately and dispose of the single-dose container after use.

Store unused single-dose containers in the sachet to protect them from light.

Storage conditions.

The medicinal product does not require special storage temperature conditions.

Store single-dose containers in the sachet to protect them from light.

Keep out of reach and sight of children.

Packaging.

0.2 mL in a single-dose container; 5 single-dose containers connected together in a strip, in a sachet; 6 or 18 sachets (No. 30 or 90) in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

EXCELVISION / EXCELVISION

Manufacturer's location and address of place of business.

Zone Industrielle de la Lombardiere, 27 rue de la Lombardiere, ANNONAY, 07100, France /
Zone lndustrielle de la Lombardiere, 27 rue de la Lombardiere, ANNONAY, 07100, France

Marketing authorization holder.

Laboratoires Thea / Laboratoires Thea

Address of the marketing authorization holder.

12 rue Louis Bleriot, 63100 CLERMONT-FERRAND CEDEX 2, France /
12 rue Louis Bleriot 63100 CLERMONT-FERRAND CEDEX 2, France