Dorzitim

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

Composition:

Active substances: dorzolamide, timolol;

1 ml of solution contains 20 mg dorzolamide in the form of 22.26 mg dorzolamide hydrochloride and 5 mg timolol in the form of 6.830 mg timolol maleate;

Excipients: benzalkonium chloride, mannitol (E 421), sodium citrate dihydrate, hydroxyethylcellulose, 1 M sodium hydroxide solution, water for injections.

Pharmaceutical form. Eye drops, solution.

Main physicochemical properties: almost colorless, slightly viscous, opalescent solution.

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 reduced secretion of aqueous humor due to slowed formation of bicarbonate ions, which in turn results in decreased 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 outflow of fluid.

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

After topical administration, the medicinal product Dorzitem\textregistered reduces intraocular pressure regardless of whether the elevation is associated with glaucoma. Elevated intraocular pressure plays a significant role in the pathogenesis of optic nerve damage and visual field loss in glaucoma.

The medicinal product Dorzitem\textregistered reduces intraocular pressure without inducing the typical side effects associated with miotic agents, such as night blindness, accommodative spasm, or pupillary constriction.

Pharmacodynamic effects

Clinical effects

Clinical data are available from studies of up to 15 months' duration comparing the effect on intraocular pressure reduction of the medicinal product administered twice daily (with specific morning and evening doses) versus 0.5% timolol and 2.0% dorzolamide used separately and in combination, in patients with glaucoma or ocular hypertension for whom combination therapy was considered appropriate and necessary in these studies. Both untreated patients and patients inadequately controlled on timolol monotherapy were included. Most patients had been receiving treatment with a topical beta-blocker as monotherapy prior to study entry. In the analysis of combined studies, the effect of the medicinal product administered twice daily on lowering intraocular pressure was greater than that of monotherapy with 2% dorzolamide administered three times daily or 0.5% timolol administered twice daily. The effect of the medicinal product administered twice daily on reducing intraocular pressure was equivalent to that of combined therapy with dorzolamide and timolol administered twice daily. The effect of the medicinal product administered twice daily on reducing intraocular pressure was demonstrated at various time points throughout the day, and this effect was maintained during long-term administration.

Pediatric patients

Information is available from a 3-month controlled study primarily designed to investigate and confirm the safety of using 2% dorzolamide hydrochloride ophthalmic solution in children under 6 years of age. In this study, 30 patients aged 2 to 6 years, whose intraocular pressure was not adequately controlled with dorzolamide or timolol monotherapy, received the medicinal product in the open-label phase of the study. Efficacy in these patients has not been established. In this small group, 19 patients who completed the treatment period generally tolerated the medicinal product administered twice daily, while 11 patients discontinued treatment due to surgical intervention, change of medication, or other reasons.

Pharmacokinetics.

Dorzolamide hydrochloride. After topical administration, 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 drug in plasma. Dorzolamide is metabolized to a single N-desethyl metabolite, which is less potent in inhibiting carbonic anhydrase type II compared to the parent compound and also inhibits carbonic anhydrase type I, a less active isoenzyme. The 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 unchanged and as metabolite. After discontinuation of the medicinal product, dorzolamide is eliminated nonlinearly from erythrocytes, characterized by an initial 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 chronic topical ophthalmic use, steady state was achieved within 13 weeks. At steady state, virtually no free active substance or metabolite was detectable in plasma; inhibition of carbonic anhydrase in erythrocytes was less than that expected to be required for pharmacological effects on kidney or respiratory function. Similar pharmacokinetic results were obtained after chronic topical administration of dorzolamide hydrochloride. However, in some elderly patients with impaired renal function (creatinine clearance (CrCl) defined as 30–60 mL/min), higher concentrations of the metabolite in erythrocytes (RBCs) were observed, although significant differences in carbonic anhydrase inhibition and clinically significant systemic adverse reactions were not directly linked to this finding.

Timolol maleate. After topical ocular administration, timolol is systemically absorbed. Systemic exposure to timolol was measured after topical administration of 0.5% ophthalmic solution twice daily. 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.

Elevated intraocular pressure in patients with open-angle glaucoma or pseudoexfoliative glaucoma when topical use of beta-blockers alone is insufficient.

Contraindications.

The medicinal product is contraindicated in patients with:

• 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, severe heart failure, cardiogenic shock;
• severe renal function impairment (creatinine clearance less than 30 mL/min) or hyperchloremic acidosis;
• hypersensitivity to one 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 of Dorzithem® with other medicinal products have not been conducted.

In clinical studies, this 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 leading to arterial hypotension and/or marked bradycardia when ophthalmic beta-blocker solutions are used concomitantly with oral calcium channel blockers, drugs that reduce catecholamine production, or beta-adrenoblockers, antiarrhythmic agents (including amiodarone), digitalis glycosides, parasympathomimetics, guanethidine, narcotics, and monoamine oxidase inhibitors (MAO inhibitors).

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 Dorzithem® itself (as monotherapy) has minimal 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 effects of antidiabetic medicinal products.

Oral beta-adrenoblockers may provoke rebound arterial hypertension upon withdrawal of clonidine.

Special precautions for use.

Cardiovascular and respiratory reactions

Like other topically applied ophthalmic agents, timolol is systemically absorbed. Since timolol is a beta-blocker, adverse reactions affecting the cardiovascular and respiratory systems, as seen with systemic administration of such agents, may occur. The frequency of systemic adverse reactions following topical administration of ophthalmic agents is lower than with systemic administration. For measures to reduce systemic absorption, see section "Directions for use and dosage".

Cardiac disorders. Beta-blockers should be used with caution in patients with cardiovascular disorders (e.g., ischemic heart disease, vasospastic angina/Prinzmetal's angina, and heart failure) and arterial hypotension. The benefit-risk ratio should be carefully assessed, and alternative active substances considered. Patients with cardiovascular disorders should be monitored for signs of worsening of their condition and for the occurrence of 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 disorders (i.e., severe forms of Raynaud's disease or Raynaud's syndrome) should be treated with caution.

Respiratory disorders. Reactions affecting the respiratory system, including fatal outcomes due to bronchospasm, have been reported in patients with asthma following administration of some ophthalmic beta-blockers.

The medicinal product DorzitimÒ 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 used with caution in such patients.

Immunological and hypersensitivity reactions. Like other topically applied ophthalmic medicinal products, this product may be systemically absorbed. Dorzolamide, like sulfonamides, contains a sulfonamide group. Therefore, adverse reactions observed 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 medicinal product should be discontinued.

Local ocular adverse reactions similar to those observed with dorzolamide hydrochloride eye drops have been reported during use of this medicinal product. If such reactions occur, discontinuation of the product should be considered.

Patients with atopy or a history of severe anaphylactic reactions to multiple allergens may be more sensitive to repeated allergen exposure during anaphylactic reactions when taking beta-blockers and may not respond to usual doses of adrenaline.

Concomitant therapy. The effect on intraocular pressure or the known systemic effects of beta-blockers may be potentiated when timolol is used in patients already receiving systemic beta-blockers. Such patients should be closely 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 therapy. 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 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 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.

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 disturbances in acid-base balance, particularly in patients with a history of nephrolithiasis. Although disturbances in acid-base balance have not been observed with this medicinal product, rare cases of urolithiasis have been reported. Since carbonic anhydrase inhibitors are systemically absorbed following topical administration, patients with a history of nephrolithiasis may have an increased risk of developing urolithiasis when using DorzitimÒ.

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 has not been studied in patients with acute angle-closure glaucoma.

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. Corneal edema is highly likely in patients with a low number of endothelial cells. Precautions should be taken when using DorzitimÒ in such patients.

Ciliary detachment has been reported following filtration procedures with concomitant use of aqueous suppressants (e.g., timolol, acetazolamide).

As with other antiglaucoma agents, reduced responsiveness to ophthalmic timolol maleate has been reported after prolonged treatment in some patients. However, in studies where patients were monitored for at least 3 years, no significant difference in mean intraocular pressure was observed after initial pressure stabilization.

Use of contact lenses

The medicinal product contains benzalkonium chloride, which may cause eye irritation. Contact lenses should be removed before instillation of the medicinal product and reinserted at least 15 minutes after administration. Benzalkonium chloride is known to discolor soft contact lenses.

Use during pregnancy or breastfeeding.

Pregnancy

The medicinal product should not be used during pregnancy.

Dorzolamide

There are no clinical data on the effect of DorzitimÒ on pregnancy. Dorzolamide has shown teratogenic effects in rabbits during pregnancy.

Timolol

There are insufficient data on the use of timolol during pregnancy. Timolol should not be used during pregnancy unless clearly necessary. For measures to reduce systemic absorption, see section "Directions for use and dosage".

Epidemiological studies have not shown evidence of intrauterine growth retardation associated with oral beta-blocker use during pregnancy. However, newborns exposed to beta-blockers before delivery have shown signs of beta-blockade (e.g., bradycardia, hypotension, respiratory distress syndrome, and hypoglycemia). If this product is used before delivery, newborns should be closely monitored during the first days after birth.

Breastfeeding period

It is unknown whether dorzolamide is excreted in human breast milk. In rats administered dorzolamide, reduced weight gain in offspring was observed. Beta-blockers are excreted in breast milk. However, when ophthalmic timolol is used at therapeutic doses, it is unlikely that sufficient amounts will be present in breast milk to cause clinical symptoms of beta-blockade in the infant. For information on reducing systemic absorption, see section "Directions for use and dosage".

If use of the product is necessary, breastfeeding is not recommended.

Ability to influence reaction speed when driving or operating machinery.

Studies on the effect of the medicinal product on the ability to drive or operate machinery have not been conducted. However, adverse reactions such as blurred vision may negatively affect the ability of some patients to drive or operate machinery.

Method of Administration and Dosage

The medicinal product Dorzitim® is administered as 1 drop into the conjunctival sac of the affected eye(s) twice daily.

If another topical ophthalmic agent is used simultaneously, the interval between instillation of Dorzitim® and the other medicinal product should be at least 10 minutes.

Patients should wash their hands before administering the medicinal product and avoid contact of the dropper tip with the surface of the eye or eyelids.

Patients should be advised that ophthalmic solutions may become contaminated with common bacteria, known to cause ocular infections, if not properly handled. Use of contaminated solutions may lead to serious eye injury and subsequent loss of vision.

Applying nasolacrimal occlusion or closing the eyelids for 2 minutes after instillation reduces systemic absorption. This may result in reduced systemic adverse effects and enhanced local effect.

Instructions for Use of the Polyethylene Dropper Bottle:

1. Before first use of the medicinal product, ensure that the cap is undamaged.
2. To open the bottle, unscrew the cap by turning it counterclockwise.
3. Tilt the head backward and pull the lower eyelid downward to create a space between the eyelid and the eye.

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4. Turn the bottle upside down and gently squeeze with the thumb and index finger on the bottle walls until one drop falls into the space between the eyelid and the eye.

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DO NOT TOUCH THE SURFACE OF THE EYE OR EYELIDS WITH THE BOTTLE TIP.

Improper use may result in contamination of the bottle, leading to serious infectious eye damage and subsequent vision loss.

5. Repeat steps 3 and 4 for both eyes, if prescribed by the physician.
6. Close the bottle with the cap and screw it tightly. Do not overtighten, as this may damage the bottle or cap.

Children

The efficacy of Dorzitim® in children has not been established.

The safety of Dorzitim® in children under 2 years of age has not been established (see section "Pharmacodynamics" for information on safety in children aged ≥2 and <6 years).

Overdose

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

Symptoms: There have been reports of accidental overdose with ophthalmic timolol maleate solution, which may lead to systemic effects such as dizziness, headache, dyspnea, bradycardia, bronchospasm, and cardiac arrest—similar to those observed with systemic beta-adrenergic blockers. The most common expected symptoms following dorzolamide overdose include electrolyte imbalance, development of acidosis, and possible effects on the central nervous system.

Limited data exist 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: 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

Available data from clinical trials indicate that the adverse reactions observed with the drug are consistent with those previously reported for dorzolamide hydrochloride and/or timolol maleate.

Like other ophthalmic agents administered locally, timolol is absorbed into the systemic circulation. This absorption can lead to systemic adverse effects similar to those seen with systemic beta-blockers. The incidence of systemic adverse reactions following topical ophthalmic administration is lower than with systemic administration.

The adverse reactions listed below have been reported during clinical trials or post-marketing experience with the drug or one of its components.

Frequency: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), frequency not known (cannot be estimated from available data).

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

** Additional adverse reactions have been observed with ophthalmic beta-blockers and may likely occur with the use of Dorzitim.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicinal product registration is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions.

Shelf life. 2 years.

After opening the bottle, the storage period should not exceed 4 weeks.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging.

5 ml in a polyethylene bottle with a dropper and tamper-evident seal, 1 bottle per carton.

Prescription status.

Prescription only.

Manufacturer.

JSC "KYIV VITAMIN PLANT" (manufactured from bulk product by Rafarm S.A., Greece).

Manufacturer's address and place of business.

38 Kopilivska Street, Kyiv, 04073, Ukraine.

Web-site: www.vitamin.com.ua