Rozakom

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

Composition:

Active substances: dorzolamide (in the form of dorzolamide hydrochloride) and timolol (in the form of timolol maleate);

1 ml of solution contains dorzolamide 20 mg (in the form of dorzolamide hydrochloride) and timolol 5 mg (in the form of timolol maleate);

Excipients: mannite (E 421), sodium citrate, hydroxyethylcellulose, benzalkonium chloride, sodium hydroxide, water for injections.

Pharmaceutical form. Eye drops, solution.

Main physicochemical properties: slightly opalescent, almost colorless, slightly viscous solution. Color: must not exceed standard B9. Opalescence: must not exceed reference suspension I.

Pharmacotherapeutic group. Agents used in ophthalmology. Anti-glaucoma preparations and miotics. Beta-adrenergic blockers.

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 aqueous humor, but through different mechanisms of action.

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

Timolol maleate is a non-selective beta-adrenergic receptor blocker. The precise 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. Additionally, timolol may enhance fluid outflow.

The combined action of both components results in a greater reduction of intraocular pressure than monotherapy with either agent alone.

When applied topically, Rozak reduces elevated intraocular pressure regardless of whether it is associated with glaucoma. Elevated intraocular pressure plays a significant role in the pathogenesis of optic nerve damage and visual field loss in glaucoma. Rozak lowers intraocular pressure without causing the typical side effects associated with miotic agents, such as night blindness, accommodative spasm, or pupillary constriction.

Pharmacokinetics

Dorzolamide hydrochloride

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

Timolol maleate

Following topical ocular administration, timolol is systemically absorbed. Systemic exposure to timolol has been 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, it was 0.35 ng/mL.

Clinical Characteristics.

Indications.

Indicated 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.

Rozakom is contraindicated in patients with:

• reactive respiratory diseases, including bronchial asthma or history of bronchial asthma, or severe chronic obstructive pulmonary disease (COPD);
• 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 (CrCl) <30 mL/min) or hyperchloremic acidosis;

hypersensitivity to either or both active substances or to any of the excipients of the product, as well as during pregnancy and breastfeeding.

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

Interaction with other medicinal products and other forms of interaction.

Specific studies on the interaction between Rozakom and other medicinal products have not been conducted.

In clinical studies, this medicinal product was used concomitantly with the following systemically acting medicinal products without signs (without confirmation) of adverse drug interactions: angiotensin-converting enzyme (ACE) inhibitors, calcium channel blockers, diuretics, nonsteroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid, 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 reducing catecholamine production, or beta-adrenergic blockers, antiarrhythmics (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 Rozakom as monotherapy has minimal or no effect on pupil size, mydriasis 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 system reactions

Like other topically applied ophthalmic medicinal products, timolol is systemically absorbed. Since timolol is a beta-blocker, systemic side effects affecting the cardiovascular and respiratory systems, which may occur with systemic administration of such agents, are possible. The incidence of systemic side effects after topical application of ophthalmic medicinal products is lower than with systemic administration. For measures to reduce systemic absorption, see section "Dosage and administration".

Cardiac disorders

Patients with cardiovascular disorders (e.g., ischemic heart disease, vasospastic angina/Prinzmetal's angina, and heart failure) and hypotension should be carefully evaluated before initiating treatment with beta-blockers, and alternative active substances should be considered. Patients with cardiovascular disorders should be monitored for signs of worsening of these conditions and for adverse reactions.

Due to the negative effect on impulse conduction time, beta-blockers should be administered with caution to 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

Cases of respiratory side effects, including fatal outcomes due to bronchospasm, have been reported in patients with asthma following the use of certain ophthalmic beta-blockers.

Rozakom 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 has not been studied in patients with hepatic function impairment; therefore, it should be prescribed 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 administration of sulfonamide-containing drugs may occur with topical use, 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 ophthalmic solutions have been reported during the use of 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 when taking beta-blockers and may not respond to the usual dose of adrenaline.

Concomitant therapy

The effect on intraocular pressure or the known systemic effects of beta-blockers may be enhanced when timolol is used in patients already receiving systemic beta-blockers. These 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 concomitant use of dorzolamide and oral carbonic anhydrase inhibitors is not recommended.

Discontinuation of treatment

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

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 the 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 surgical procedures

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 therapy 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 acid-base imbalances, particularly in patients with a history of nephrolithiasis. Although acid-base imbalances have not been observed with the use of this medicinal product, rare cases of urolithiasis have been reported. Since carbonic anhydrase inhibitors are systemically absorbed after topical administration, patients with a history of nephrolithiasis may have an increased risk of developing urolithiasis when treated with Rozakom.

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 with dorzolamide use in patients with pre-existing chronic corneal disorders and/or a history of intraocular surgery. There is a high likelihood of corneal edema in patients with a low number of endothelial cells. Precautions should be taken when using Rozakom in such patients.

Ciliary body 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 reported in some patients after prolonged treatment. However, in clinical studies involving 164 patients followed 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 a 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.

It is unknown whether dorzolamide is excreted in breast milk. Timolol is excreted in breast milk; therefore, breastfeeding should be discontinued during treatment.

Ability to affect reaction speed when driving vehicles or operating machinery.

No studies on the effect of the medicinal product on the ability to drive vehicles or operate machinery have been conducted. Possible adverse reactions such as blurred vision may negatively affect the ability of some patients to drive or operate machinery.

Dosage and Administration

If Rozakom is used as monotherapy, instill 1 drop into the affected eye(s) twice daily.

If multiple topical ophthalmic agents are used, they should be administered with an interval of at least 10 minutes between each.

During administration of the medication, avoid contact between the dropper tip and the surface of the eye or surrounding skin. Otherwise, microorganisms may enter the solution and cause eye infection(s). Use of a contaminated solution may lead to serious eye injury, up to and including loss of vision.

Instructions for using eye drops:

1. Before first use, ensure the bottle is sealed with the original tamper-evident band.
2. To open the bottle, tear the band and unscrew the cap counterclockwise.
3. Tilt the head backward and gently pull down the lower eyelid to create a small pocket between the eyelid and the eyeball.
4. Invert the bottle and gently squeeze until one drop of the medication falls into the eye. A light pressure on the bottle’s sides is sufficient to dispense one drop. DO NOT enlarge the dropper opening. DO NOT TOUCH THE TIP OF THE DROPPER TO THE EYE, EYELIDS, OR OTHER SURFACES.
5. After instilling Rozakom solution into the eye, press gently with a finger on the inner corner of the eye near the nose, or close the eyelids for 2 minutes to reduce systemic absorption. This may help reduce systemic side effects and enhance local activity.
6. If the physician has prescribed the medication for the second eye, repeat steps 3, 4, and 5.
7. After instillation, securely replace the cap on the bottle.

Children

Not applicable.

Overdose

There are no data on overdose in humans following accidental or intentional ingestion of Rozakom.

Symptoms

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

Limited data are available on dorzolamide hydrochloride overdose in humans following accidental or intentional ingestion. 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 is symptomatic and supportive. Serum electrolyte levels (particularly potassium) and blood pH should be monitored. Studies have shown that timolol is not completely removed by dialysis.

Adverse reactions.

In clinical studies of the drug Rozacom, the adverse reactions observed were consistent with those previously reported with the use of dorzolamide hydrochloride and/or timolol maleate.

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

The adverse reactions listed below have been reported during clinical studies or post-marketing surveillance with Rozacom or one of its components.

Frequency: very common (≥ 1/10), common (from ≥ 1/100 to < 1/10), uncommon (from ≥ 1/1,000 to < 1/100), rare (from ≥ 1/10,000 to < 1/1,000), frequency not known (cannot be estimated from available data).

Immune system disorders

Rozacom

Timolol maleate ophthalmic solution

Rare

Symptoms of allergic reactions, including angioneurotic edema, urticaria, localized and generalized rash, anaphylactic reaction.

Frequency not known**

Itching.

Metabolism and nutrition disorders

Timolol maleate ophthalmic solution

Frequency not known**

Hypoglycemia

Psychiatric disorders

Timolol maleate ophthalmic solution

Uncommon

Depression*.

Rare

Insomnia*, nightmares*, memory loss.

Not known

Hallucinations

Nervous system disorders

Dorzolamide hydrochloride ophthalmic solution

Common

Headache*.

Rare

Dizziness*, paresthesia* (skin sensory disturbances).

Timolol maleate ophthalmic solution

Common

Headache*.

Uncommon

Dizziness*, syncope*.

Rare

Paresthesia*, worsening of signs and symptoms of myasthenia gravis, decreased libido (sex drive)*, hemorrhagic stroke*, cerebral ischemia.

Eye disorders

Rozacom

Very common

Burning and stinging.

Common

Conjunctival injection, blurred vision, corneal erosion, eye itching, lacrimation.

Dorzolamide hydrochloride ophthalmic solution

Common

Eyelid inflammation*, eye irritation*.

Uncommon

Iridocyclitis*.

Rare

Eye irritation, including redness*, eye pain*, eyelid scaling*, transient myopia (resolves upon discontinuation of treatment), corneal edema*, reduction in intraocular pressure*, detachment of the uveal tract (with subsequent filtering surgery)*.

Timolol maleate ophthalmic solution

Common

Eye 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, detachment of the uveal tract with subsequent filtering surgery* (see section "Special precautions").

Frequency not known**

Itching, lacrimation, redness, blurred vision, corneal erosion.

Ear and labyrinth disorders

Timolol maleate ophthalmic solution

Rare

Tinnitus*.

Cardiac disorders

Timolol maleate ophthalmic solution

Uncommon

Bradycardia*.

Rare

Chest pain*, palpitations*, arrhythmia*, congestive heart failure*, cardiac arrest*, heart block.

Frequency not known**

Atrioventricular block, heart failure.

Dorzolamide hydrochloride ophthalmic solution

Frequency not known**

Tachycardia.

Vascular disorders

Timolol maleate ophthalmic solution

Rare

Hypotension*, claudication, Raynaud's phenomenon*, cold sensation in hands and feet*.

Dorzolamide hydrochloride ophthalmic solution

Frequency not known**

Hypertension.

Respiratory, thoracic and mediastinal disorders

Rozacom

Rare

Sinusitis.

Rare

Dyspnea, respiratory failure, rhinitis, rarely bronchospasm.

Dorzolamide hydrochloride ophthalmic solution

Rare

Epistaxis*.

Timolol maleate ophthalmic solution

Uncommon

Dyspnea (shortness of breath)*.

Rare

Bronchospasm (predominantly in patients with pre-existing bronchospastic disease)*, respiratory failure, cough*.

Gastrointestinal disorders

Rozacom

Very common

Dysgeusia (altered taste sensation).

Dorzolamide hydrochloride ophthalmic solution

Common

Nausea*.

Uncommon

Nausea*, dyspepsia*.

Rare

Throat irritation, dry mouth*.

Timolol maleate ophthalmic solution

Rare

Diarrhea*, dry mouth*.

Frequency not known**

Dysgeusia (altered taste sensation), abdominal pain, vomiting.

Skin and subcutaneous tissue disorders

Rozacom

Rare

Contact dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Dorzolamide hydrochloride ophthalmic solution

Rare

Rash*.

Timolol maleate ophthalmic solution

Rare

Alopecia*, psoriatic rash or exacerbation of psoriasis.

Not known**

Skin rash.

Musculoskeletal and connective tissue disorders

Timolol maleate ophthalmic solution

Rare

Systemic lupus erythematosus.

Frequency not known**

Myalgia.

Renal and urinary disorders

Rozacom

Uncommon

Urolithiasis.

Reproductive system and breast disorders

Timolol maleate ophthalmic solution

Rare

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

Frequency not known**

Sexual dysfunction.

General disorders and administration site conditions

Dorzolamide hydrochloride ophthalmic solution

Common

Asthenia/weakness*.

Timolol maleate ophthalmic solution

Uncommon

Asthenia/weakness*

* These adverse reactions were also observed during post-marketing surveillance with Rozacom;

** Additional adverse reactions observed with ophthalmic beta-blockers, which may possibly occur with the use of Rozacom.

Shelf life. 2 years. Shelf life after first opening: 4 weeks.

Storage conditions. Store in the original packaging at a temperature below 25°C. Keep out of reach of children. Do not use after the expiry date stated on the packaging.

Packaging. 5 ml in a bottle with dropper and cap; 1 bottle per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Manufacturer responsible for batch release:

Pharmaserv International Betriebsgesellschaft GmbH.

Manufacturer's address and location of business activity.

Ernst-Melchior-Gasse 20, 1020 Vienna, Austria.