DORZOLAMIDE BGR 20 mg/ml Eye Drops Solution Bottle 5ml

Eye drops in solution.

Slightly viscous and opalescent solution, almost colourless.

Dorzolamide...................................................................................................................................................20 mg

As dorzolamide hydrochloride.......................................................................................22,26 mg

For 1 ml of eye drops in solution.

Excipient with known effect: 75 micrograms/ml of benzalkonium chloride.

Excipients:

DORZOLAMIDE BGR is indicated:

• In combination with a beta-blocker eye drop antiglaucoma treatment,

• As monotherapy in patients not responding to beta-blockers or in patients for whom beta-blockers are contraindicated.

In the treatment of elevated intraocular pressure in patients with:

• Ocular hypertension,

• Open-angle glaucoma,

• Pseudoexfoliative glaucoma.

Dosage

As monotherapy, the dose is one drop of dorzolamide in the conjunctival sac of the affected eye(s), three times a day.

In combination with an ophthalmic beta-blocker, the dose is one drop of dorzolamide in the conjunctival sac of the affected eye(s), twice a day.

When replacing another antiglaucoma treatment with dorzolamide, discontinue the other medicinal product after the last dose of the day at the appropriate dose, then start dorzolamide the following day.

When several eye drops are used concomitantly, the medicinal products must be administered at least 10 minutes apart.

Patients should be advised to wash their hands before use and to avoid contact of the bottle tip with the eye or surrounding areas.

Patients should also be informed that ophthalmic solutions, if improperly handled, may become contaminated by common bacteria known to cause eye infections. Use of contaminated solutions may cause serious eye damage and subsequent loss of vision.

Systemic absorption is reduced by nasolacrimal occlusion or closure of the eyelids for 2 minutes. This technique may reduce systemic adverse effects and increase local efficacy.

Paediatric population

In the paediatric population, limited clinical data are available following administration of dorzolamide three times a day (for more information on dosage in children see section Pharmacodynamics).

Method of administration

1. Before using this eye drop solution for the first time, make sure the safety strip on the front of the bottle is not torn. A gap between the bottle and the cap is normal when the bottle is not opened.

2. Wash your hands first, then tear off the safety strip to break the tamper seal.

3. To open the bottle, unscrew the cap by turning it as indicated by the arrows on the top of the cap. Do not pull the cap directly upwards. Pulling the cap directly upwards would prevent your bottle from working normally.

4. Tilt your head back and gently pull the lower eyelid down to form a pocket between your eyelid and your eye.

5. Turn the bottle upside down and gently press the dropper with your thumb or index finger until a single drop falls into the eye as indicated by your doctor. DO NOT TOUCH THE EYE OR EYELID WITH THE TIP OF THE BOTTLE.

6. After first opening, if dispensing drops is difficult, replace the cap on the bottle and screw it on (do not screw it on too tightly), then remove the cap by unscrewing it in the other direction as indicated by the arrows on the top of the cap.

7. Repeat steps 4 & 5 for the other eye if your doctor has prescribed it.

8. Screw the cap back on by turning it until it is firmly in contact with the bottle. For proper closure, the arrow on the left side of the cap must be aligned with the arrow on the left side of the bottle label. Do not screw it on too tightly, as this could damage the bottle and the cap.

9. The tip is designed to deliver a single drop; therefore, do NOT enlarge the hole in the tip.

10. When you can no longer extract drops, a little eye drop solution will still remain in the DORZOLAMIDE BGR bottle. This should not worry you, as an additional quantity of DORZOLAMIDE BGR has been added to allow you to have the sufficient number of drops of DORZOLAMIDE BGR as prescribed by your doctor. Do not try to extract the excess eye drop solution from the bottle.

Hypersensitivity to the active substance or to any of the excipients listed in section Composition.

Dorzolamide has not been studied in patients with severe renal impairment (creatinine clearance < 30 ml/min) or hyperchloraemic acidosis. Dorzolamide and its metabolites are excreted mainly by the kidney; dorzolamide is therefore contraindicated in such patients.

Dorzolamide has not been studied in patients with hepatic impairment and should therefore be used with caution in such patients.

The treatment of patients with acute angle-closure glaucoma requires therapeutic interventions in addition to ocular hypotensive agents. Dorzolamide has not been studied in patients with acute angle-closure glaucoma.

Dorzolamide contains a sulfonamide group, which is also present in sulfonamides, and although administered topically, it passes into the systemic circulation. Therefore, the same types of adverse effects as those observed with sulfonamides may occur with topical administration, including severe reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. In the event of serious reactions or hypersensitivity, this medicine must be discontinued.

Treatment with oral carbonic anhydrase inhibitors has been associated with urolithiasis resulting from acid-base disturbances, particularly in patients with a history of renal calculi. Although no acid-base disturbances have been observed with dorzolamide, urolithiasis has rarely been reported. Because dorzolamide is a carbonic anhydrase inhibitor that is absorbed systemically, patients with a history of renal calculi may have a higher risk of urolithiasis when treated with dorzolamide.

If allergic reactions (for example conjunctivitis and eyelid reactions) are observed, discontinuation of treatment should be considered.

There is a possibility of additive systemic effects of known carbonic anhydrase inhibition in patients receiving an oral carbonic anhydrase inhibitor concomitantly with dorzolamide. Concomitant administration of dorzolamide and an oral carbonic anhydrase inhibitor is not recommended.

Corneal oedema and irreversible corneal decompensation have been reported in patients with pre-existing chronic corneal abnormalities and/or a history of intraocular surgery while being treated with DORZOLAMIDE BGR. Topical dorzolamide should be used with caution in such patients.

Choroidal detachments concurrent with ocular hypotony have been reported after filtration surgery with the administration of therapies that decrease aqueous humour secretion.

DORZOLAMIDE BGR contains a preservative, benzalkonium chloride, which may cause eye irritation. Contact lenses must be removed before instilling the eye drops and it is necessary to wait at least 15 minutes before reinserting them. Benzalkonium chloride is known to discolour soft contact lenses. Benzalkonium chloride is known to cause eye irritation and symptoms of dry eye syndrome, and may affect the tear film and the surface of the cornea. Should be used with caution in patients with dry eye and those at risk of corneal damage. Patients should be monitored in case of prolonged use.

Paediatric population

Dorzolamide has not been studied in patients with a gestational age of less than 36 weeks and aged less than one week. Due to the risk of metabolic acidosis, the benefit-risk ratio must be carefully considered before administering dorzolamide to patients with significant renal tubular immaturity.

No specific drug interaction studies have been performed with dorzolamide.

In clinical studies, dorzolamide has been used concomitantly without apparent adverse interactions with the following medicines: timolol ophthalmic solution, betaxolol ophthalmic solution, and systemic medicines including angiotensin-converting enzyme inhibitors, calcium channel blockers, diuretics, non-steroidal anti-inflammatory drugs including aspirin, and hormones (for example oestrogens, insulin, thyroxine).

The combination of dorzolamide with miotics and adrenergic agonists has not been fully evaluated in the treatment of glaucoma.

Pregnancy

Dorzolamide must not be used during pregnancy.

There are no data or limited data on the use of dorzolamide in pregnant women. In rabbits, dorzolamide administered at maternotoxic doses produced teratogenic effects (see section Preclinical safety).

Breast-feeding

It is not known whether dorzolamide or its metabolites are excreted in human milk. Available pharmacodynamic and toxicological data in animals have shown excretion of dorzolamide and its metabolites in milk. A decision whether to discontinue breast-feeding or to discontinue dorzolamide therapy should take into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. A risk to the newborn or infant cannot be excluded.

Fertility

Animal data do not suggest an effect of dorzolamide treatment on male and female fertility. Human data are insufficient.

The effects on the ability to drive and use machines have not been studied. Undesirable effects such as dizziness and visual disturbances may impair the ability to drive a car and operate machinery.

Dorzolamide has been evaluated in controlled and uncontrolled clinical studies in more than 1 400 subjects. In long-term studies involving 1 108 patients treated with dorzolamide as monotherapy or in combination with an ophthalmic beta-blocker, the most frequent cause of discontinuation of treatment with dorzolamide was drug-related ocular adverse reactions (approximately 3% of patients), mainly conjunctivitis and eyelid reactions.

The following adverse reactions have been reported either during clinical studies or since dorzolamide was marketed:

Very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare
(≥ 1/10 000, < 1/1000) and frequency not known (cannot be estimated from the available data).

Nervous system disorders:

Common : headache.

Rare : dizziness, paraesthesia.

Eye disorders:

Very common : burning and stinging.

Common : superficial punctate keratitis, lacrimation, conjunctivitis, eyelid inflammation, ocular itching, eyelid irritation, blurred vision.

Uncommon : iridocyclitis.

Rare : irritation including redness, pain, crusting eyelid lesions, transient myopia (which resolved upon discontinuation of treatment), corneal oedema, ocular hypotony, choroidal detachment following filtration surgery.

Not known : sensation of foreign body in the eye, photophobia.

Cardiac disorders

Frequency not known : palpitations, tachycardia.

Vascular disorders

Frequency not known : hypertension.

Respiratory, thoracic and mediastinal disorders:

Rare : epistaxis.

Not known : dyspnoea.

Gastrointestinal disorders:

Common : nausea, bitter taste.

Rare : irritation of the throat, dryness of the mouth.

Skin and subcutaneous tissue disorders:

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

Renal and urinary disorders:

Rare : urinary lithiasis.

General disorders and administration site conditions:

Common : asthenia/fatigue.

Rare : hypersensitivity: signs and symptoms of local reactions (palpebral reactions) and of systemic allergic reactions, including angioedema, urticaria and pruritus, rash, shortness of breath, rarely bronchospasm.

Investigations:

No clinically significant fluid or electrolyte disorders have been associated with dorzolamide.

Paediatric population 

See section Pharmacodynamics.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reaction via the national reporting system: National Agency for the Safety of Medicines and Health Products (ANSM) and the network of Regional Centres of Pharmacovigilance - Website:
https://signalement.social-sante.gouv.fr/.

There is only a limited amount of data available in humans concerning overdose by accidental or intentional ingestion of dorzolamide hydrochloride.

Symptoms

The following effects have been reported following oral ingestion: drowsiness; with topical application: nausea, dizziness, headache, fatigue, abnormal dreams and dysphagia.

Treatment

Treatment should be symptomatic and supportive. Fluid and electrolyte imbalance, development of acidosis and possible effects on the central nervous system may occur. Serum electrolyte levels (in particular potassium) and blood pH should be monitored.

Pharmacotherapeutic class: Antiglaucoma preparations and miotics, Carbonic anhydrase inhibitors, dorzolamide, ATC code: S01EC03.

Mechanism of action

Carbonic anhydrase (CA) is an enzyme found in many tissues, including the eye. In humans, carbonic anhydrase exists as many isoenzymes, the most active being carbonic anhydrase II (CA II), found mainly in red blood cells (RBC) but also in other tissues.

Inhibition of carbonic anhydrase in the ciliary processes of the eye decreases aqueous humour secretion. The result is a reduction in intraocular pressure (IOP).

DORZOLAMIDE BGR contains dorzolamide hydrochloride, a potent inhibitor of carbonic anhydrase II in humans. After topical administration, dorzolamide reduces elevated intraocular pressure, whether or not associated with glaucoma. Elevated intraocular pressure is a major risk factor in the pathogenesis of optic nerve damage and visual field loss. Dorzolamide does not cause pupillary constriction and reduces intraocular pressure without side effects such as night blindness and accommodation spasm. Dorzolamide has little or no effect on heart rate and blood pressure.

Ophthalmic beta-blockers also reduce IOP by decreasing aqueous humour secretion through a different mechanism of action. Studies have shown that when dorzolamide is added to an ophthalmic beta-blocker, an additional reduction in IOP is observed; this finding is consistent with the known additive effects of beta-blockers and orally administered carbonic anhydrase inhibitors.

Clinical efficacy and safety

In adults

In patients with glaucoma or ocular hypertension, the efficacy of dorzolamide administered three times daily as monotherapy (baseline IOP ≥ 23 mmHg) or twice daily as an adjunct to ophthalmic beta-blockers (baseline IOP ≥ 22 mmHg) has been demonstrated in large-scale clinical studies lasting up to one year.

The IOP-lowering effect of dorzolamide as monotherapy or in combination has been demonstrated throughout the day, and this effect persists during long-term administration. Long-term monotherapy efficacy was similar to that of betaxolol and slightly lower than that of timolol. In combination with ophthalmic beta-blockers, dorzolamide produced an additional IOP reduction similar to that observed with pilocarpine 2% four times daily.

Paediatric population

A multicentre, double-blind, active-controlled clinical study, lasting 3 months, was conducted in 184 children (including 122 receiving dorzolamide) aged from one week to under 6 years, with glaucoma or elevated intraocular pressure (baseline IOP ≥ 22 mmHg), to evaluate the safety of topically administered dorzolamide 3 times daily. In both groups, approximately half of the patients had a diagnosis of congenital glaucoma; the other most frequent aetiologies were Sturge-Weber syndrome, mesenchymal iridocorneal dysgenesis or aphakia. The distribution by age and by treatment during the monotherapy phase was as follows:

	Dorzolamide 2%	Timolol
Age cohort < 2 years	N = 56 Age range: 1 to 23 months	Timolol LP 0,25 % N = 27 Age range: 0,25 to 22 months
Age cohort ≥ 2 years and < 6 years	N = 66 Age range: 2 to 6 years	Timolol 0,50 % N = 35 Age range: 2 to 6 years

For both age cohorts, approximately 70 patients received treatment for at least 61 days and approximately 50 patients received between 81 and 100 days of treatment.

If IOP was not adequately controlled by dorzolamide or Timolol LP as monotherapy, treatment was modified with unblinding as follows: 30 patients under 2 years were switched to dual therapy with Timolol LP 0,25 % once daily and dorzolamide 2 % three times daily, 30 patients over 2 years were switched to a fixed combination of dorzolamide 2 % / Timolol 0,5 % twice daily.

Overall, this study did not reveal any additional safety concerns in children: approximately 26 % of patients (20 % of patients on dorzolamide monotherapy) had treatment-related side effects, the majority of which were local, non-serious ocular effects such as eye burning and stinging, eye stinging sensation and eye pain. A small percentage (< 4 %) had corneal oedema or blurred vision. Local reactions also appeared to be as frequent with the comparator product. Since marketing authorisation, cases of metabolic acidosis have been reported in very young patients, particularly those with immaturity or renal impairment.

Paediatric efficacy data suggest that the mean IOP reduction observed in the dorzolamide group was comparable to the mean IOP reduction observed in the Timolol group, although a numerically slightly greater reduction was observed in the Timolol group.

No long-term efficacy study (more than 12 weeks) is available.

In contrast to oral carbonic anhydrase inhibitors, topical administration of dorzolamide hydrochloride allows a direct action of the active substance on the eye at substantially lower doses and therefore with lower systemic exposure. In clinical trials, the consequence was a reduction in IOP without the acid-base and fluid-electrolyte disturbances characteristic of orally administered carbonic anhydrase inhibitors.r oral route.

When applied topically, dorzolamide passes into the systemic circulation. To assess the possibility of systemic carbonic anhydrase inhibition after topical administration, concentrations of the active substance and its metabolites were measured in red blood cells and plasma, as well as carbonic anhydrase inhibition in red blood cells. During chronic administration, dorzolamide accumulates in red blood cells as a result of selective binding to CA-II, while very low concentrations of the free active substance are maintained in plasma. The parent active substance is transformed into an N-desethyl metabolite which inhibits CA-II less potently but also inhibits a less active isoenzyme (CA-I). This metabolite also accumulates in red blood cells where it binds mainly to CA-I. Dorzolamide binds fairly weakly to plasma proteins (approximately 33 %). Dorzolamide is mainly excreted unchanged in the urine; its metabolite is also eliminated in the urine. At the end of treatment, dorzolamide is released from red blood cells in a non-linear manner, resulting in a rapid decrease in the initial concentration of the active substance followed by a slower elimination phase with a half-life of approximately four months.

When dorzolamide was administered orally to simulate maximum systemic exposure following long-term ocular administration, a steady state was reached in 13 weeks. At steady state, there was virtually no free active substance or metabolite in plasma; carbonic anhydrase inhibition in red blood cells was lower than that predicted to be necessary to obtain a pharmacological effect on renal function or respiration. Similar pharmacokinetic results were observed after prolonged topical administration of dorzolamide. Nevertheless, some elderly patients with renal impairment (estimated creatinine clearance of 30-60 ml/min) had higher metabolite concentrations in red blood cells, but no significant difference in carbonic anhydrase inhibition and no clinically significant systemic side effects were directly attributed to these data.

The main findings obtained in animals after oral administration of dorzolamide hydrochloride were related to the pharmacological effects of systemic carbonic anhydrase inhibition. Some of these findings were species-specific and/or a consequence of metabolic acidosis. In rabbits given maternotoxic doses associated with metabolic acidosis, malformations of the vertebral bodies were observed.

In lactating rats, a decrease in body weight was observed in the offspring. No adverse effect on fertility was observed in males and females to whom dorzolamide was administered before and during mating.

In clinical studies, patients showed no signs of metabolic acidosis or serum fluid-electrolyte disturbances, which are indicative of systemic CA inhibition. Therefore, the effects observed in animal studies are not expected in patients receiving therapeutic doses of dorzolamide.

2 years.

After first opening of the bottle: 28 days.

This medicine does not require any particular storage precautions.

No special requirements.

List I

Marketing authorisation (AMM)

CIP 3400930119013 (Fl/5ml).

Price:

4,41 euros (Fl/5ml).

Social Security reimbursement at 65% based on the TFR: 4.41 euros (Fl/5ml) for the indications:

• Indication(s) appearing in the marketing authorisation at the date of publication of this decree

Collection.