Ducressa eye drops solution bottle 5 ml

Instructions for Ducress eye drops solution bottle 5 ml

Composition

active ingredients: levofloxacin, dexamethasone;

1 ml of eye drop solution contains dexamethasone (as dexamethasone sodium phosphate) 1 mg and levofloxacin (as levofloxacin hemihydrate) 5 mg;

Excipients: sodium dihydrogen phosphate, monohydrate; sodium hydrogen phosphate, dodecahydrate; sodium citrate; benzalkonium chloride (50% solution); sodium hydroxide / hydrochloric acid diluted; water for injections.

1 drop (about 30 μl) contains about 0.03 mg of dexamethasone and 0.150 mg of levofloxacin.

Dosage form

Eye drops, solution.

Main physical and chemical properties: transparent solution of greenish-yellow color, free from particles; pH 7.0–7.4; osmolality 270–330 mOsm/kg. Individual drops appear transparent and colorless.

Pharmacotherapeutic group

Ophthalmic agents. Anti-inflammatory and antibacterial agents in combination. Corticosteroids and antibacterial agents in combination. Dexamethasone and antibacterial agents.

ATX code S01C A01.

Pharmacological properties

Pharmacodynamics

Levofloxacin

Mechanism of action

Levofloxacin, the active L-isomer of ofloxacin, is an antibacterial agent of the fluoroquinolone group that inhibits the activity of bacterial type II topoisomerases - DNA gyrase and topoisomerase IV. The action of levofloxacin in gram-negative bacteria is directed mainly at DNA gyrase, and in gram-positive bacteria - at topoisomerase IV. The spectrum of activity against pathogens of eye diseases includes aerobic gram-positive microorganisms (e.g. S. aureus MSSA, S. pyogenes, S. pneumoniae, Streptococcus viridans group), aerobic gram-negative bacteria (e.g. E. coli, H. influenzae, M. catarrhalis, isolates of the P. aeruginosa group), other organisms (e.g. Chlamydia trachomatis).

Mechanisms of resistance emergence

There are two main mechanisms by which bacteria develop resistance to levofloxacin: a decrease in the concentration of the drug inside the bacterial cell and a change in the set of enzymes against which the drug acts. Such changes occur as a result of mutations in the chromosomal genes encoding DNA gyrase (gyrA and gyrB) and topoisomerase IV (parC and parE; grlA and grlB in Staphylococcus aureus). Resistance due to a decrease in the concentration of the drug inside the bacterial cell is caused by changes in the outer membrane porins (OmpF), which reduce the possibility of penetration of fluoroquinolones into gram-negative bacteria, or efflux pumps. Efflux resistance has been described in pneumococci (PmrA), staphylococci (NorA), anaerobic and gram-negative bacteria. In addition, plasmid-mediated resistance to quinolones (determined by the qnr gene) has been reported in Klebsiella pneumoniae and E. coli.

Cross-resistance

Cross-resistance between fluoroquinolones is possible. A single mutation does not confer clinical resistance, but multiple mutations usually confer clinical resistance to all drugs in the fluoroquinolone class. Alterations in outer membrane porins and efflux systems can have broad substrate specificity, be directed against multiple classes of antibacterial agents, and lead to the emergence of multiple resistance.

Criteria for interpreting susceptibility test results

There are no interpretation criteria.

Dexamethasone

Mechanism of action

Corticosteroids such as dexamethasone exert their anti-inflammatory effects by inhibiting vascular endothelial cell adhesion molecules, cyclooxygenase I or II, and cytokine expression. This results in decreased expression of inflammatory mediators and inhibition of leukocyte adhesion to vascular endothelium, thereby preventing leukocyte entry into inflamed ocular tissues. Dexamethasone has a pronounced anti-inflammatory effect with reduced mineralocorticoid effects compared with some other steroids and is one of the most potent anti-inflammatory agents.

Clinical efficacy

Efficacy data were obtained from 395 patients who received DUCRESSA® and 393 patients who received the comparator after cataract surgery. After 14 days of treatment, the proportion of patients without signs of inflammation (primary endpoint) in the DUCRESSA® and dexamethasone group compared with the tobramycin + dexamethasone group was 95.19% and 94.91%, respectively. The difference between these two proportions was 0.0028 (95% CI: [-0.0275; 0.0331]), indicating no difference in efficacy between the study and comparator regimens. No cases of endophthalmitis were reported in either group. Signs of anterior chamber inflammation in the DUCRESSA® eye drops group were absent in 73.16% on day 4 and in 85.57% of patients on day 8 after surgery. In the tobramycin + dexamethasone group, signs of anterior chamber inflammation were absent in 76.84% on day 4 and in 86.77% of patients on day 8. Conjunctival hyperemia disappeared already on day 4 in 85.75% of patients in the DUCRESSA® group compared to 82.19% in the tobramycin + dexamethasone group, respectively. The safety profile was similar in both groups.

Children

The European Medicines Agency has waived the obligation to submit the results of studies on the safety and efficacy of DUCRESSA® for the prevention and treatment of inflammation and the prevention of infections associated with cataract surgery in all subsets of the paediatric population (for information on use in children, see section 4.2).

Pharmacokinetics

Instillation of DUCRESSA® into the eyes results in the absorption of both active ingredients into the eye tissue and, to a much lesser extent, into the systemic circulation.

After instillation of the drug into the eyes of rabbits, the plasma concentration of levofloxacin increases with increasing dose after single or multiple administration. Low levels of dexamethasone sodium phosphate are detected in plasma. In fact, dexamethasone sodium phosphate is rapidly metabolized in vivo to dexamethasone, which is the active metabolite. The content of dexamethasone in the blood serum increases with dose, and after repeated administrations of the drug, a slight accumulation of both levofloxacin and dexamethasone is observed. The levels of levofloxacin and dexamethasone in the tissues of the eye (aqueous humor, cornea and conjunctiva) after single and repeated instillations are higher than the maximum concentration in plasma. In particular, after 28 days of treatment, the level of levofloxacin and dexamethasone in the tissues of the eye is 50-100 times and 3-4 times higher, respectively, than the Cmax level in the blood plasma. 125 patients undergoing cataract surgery were randomly assigned to 3 treatment groups: levofloxacin, dexamethasone, and DUCRESSA®. One drop of each drug was instilled 90 and 60 minutes before limbal paracentesis. The mean observed levofloxacin concentration was 711.899 ng/mL (95% CI: 595.538; 828.260) in the DUCRESSA® group compared to 777.307 ng/mL (95% CI: 617.220; 937.394) with levofloxacin alone. Levofloxacin concentrations in aqueous humor are significantly higher than the minimum inhibitory concentrations for ocular pathogens within the range of activity of levofloxacin.

When DUCRESSA® was administered, dexamethasone concentrations reached 11.774 ng/mL (95% CI: 9.812, 13.736) compared to 16.483 ng/mL (95% CI: 13.736, 18.838) when dexamethasone was administered alone. Both levofloxacin and dexamethasone are excreted in the urine.

Indication

The drug DUCRESSA®, eye drops, solution, is intended for the prevention and treatment of inflammation and the prevention of infections associated with cataract surgery in adults.

The need for official guidance on the appropriate use of antibacterial agents should be considered.

Contraindication

- Hypersensitivity to the active substances: levofloxacin (or other quinolones) and dexamethasone (or other steroids) - or to any of the excipients.

- Herpes simplex, keratitis, chickenpox, cowpox and other viral diseases of the cornea and conjunctiva.

- Mycobacterial infections of the eye, caused in particular by acid-fast bacteria such as Mycobacterium tuberculosis, Mycobacterium leprae or Mycobacterium avium.

- Fungal diseases of eye structures.

- Untreated purulent eye infection.

- Corneal perforation.

Interaction with other medicinal products and other types of interactions

Interaction studies have not been conducted.

Since the maximum plasma concentrations of levofloxacin and dexamethasone after ocular administration are at least 1000 times lower than those reported after standard oral doses, interactions with other systemic drugs are unlikely to be of clinical significance.

Concomitant use of probenecid, cimetidine, or cyclosporine with levofloxacin changed some pharmacokinetic parameters of levofloxacin, but not to a clinically significant level.

CYP3A4 inhibitors (including ritonavir and cobicistat) may decrease the clearance of dexamethasone, leading to increased exposure. This combination should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid side effects, in which case patients should be monitored for systemic corticosteroid effects.

Application features

Eye effects

DUCRESSA® is for ophthalmic use only. DUCRESSA® should not be administered subconjunctivally. The solution should not be administered directly into the anterior chamber of the eye.

Prolonged use may result in antibiotic resistance as a result of overgrowth of non-susceptible organisms, including fungi. If infection develops, treatment should be discontinued and alternative therapy instituted. In all cases where clinical judgment warrants, the patient should be examined using, for example, slit-lamp biomicroscopy and, where appropriate, fluorescent staining.

Prolonged use of topical ophthalmic corticosteroids may lead to ocular hypertension/glaucoma, but this is unlikely when DUCRESSA® is used for the recommended treatment period (7 days). In any case, frequent monitoring of intraocular pressure is recommended. The likelihood of corticosteroid-induced elevation of intraocular pressure is increased in patients with risk factors (e.g., diabetes mellitus).

Visual disturbances may occur with systemic and topical corticosteroids. If a patient presents with symptoms such as blurred vision or other visual disturbances, they should be referred to an ophthalmologist for evaluation of possible causes, which may include complications following cataract surgery, development of glaucoma, or rare conditions such as central serous chorioretinopathy (CSCR), which have been reported with systemic and topical corticosteroids.

Topical ophthalmic corticosteroids may slow the healing of corneal wounds. Topical ocular nonsteroidal anti-inflammatory drugs (NSAIDs) are also known to slow or delay healing. Concomitant use of topical NSAIDs and ocular steroids may increase the likelihood of healing problems.

It is known that in diseases that cause thinning of the cornea or sclera, perforations may occur when topical corticosteroids are used.

Systemic effects

Fluoroquinolones have been associated with hypersensitivity reactions even after a single dose. If an allergic reaction to levofloxacin occurs, the drug should be discontinued.

Tendon inflammation and rupture have been reported with systemic fluoroquinolone therapy, including levofloxacin, particularly in elderly patients and those receiving concomitant corticosteroids. Therefore, caution should be exercised and DUCRESSA therapy should be discontinued at the first sign of tendon inflammation (see section 4.8).

Cushing's syndrome and/or adrenal suppression associated with systemic absorption of ocular dexamethasone may occur in susceptible patients, including children and patients receiving CYP3A4 inhibitors (including ritonavir and cobicistat), after intensive or prolonged continuous therapy. In these cases, treatment should be gradually discontinued.

Impact on the immune system

Prolonged use may also result in the development of secondary ocular bacterial, viral, or fungal infections (usually occurring within 2 weeks of initiation of treatment) due to suppression of the immune response or delayed healing. In addition, topical ocular corticosteroids may promote, worsen, or mask the signs and symptoms of ocular infections caused by opportunistic pathogens. With short-term treatment with corticosteroids, such as DUCRESSA®, the occurrence of these conditions is limited.

Excipients

Benzalkonium chloride

Benzalkonium chloride has been reported to cause eye irritation, dry eyes, and may affect the tear film and corneal surface. It should be used with caution in patients with dry eyes and in patients whose corneas may be damaged. Patients should be monitored during prolonged use.

After cataract surgery, patients should not wear contact lenses during the entire period of DUCRESSA® therapy.

Use during pregnancy or breastfeeding

Pregnancy

There are no or limited amount of data from the use of dexamethasone and levofloxacin in pregnant women.

Since relevant systemic effects of corticosteroids following ocular administration cannot be excluded, treatment with DUCRESSA® is not recommended during pregnancy, especially during the first three months, and should only be undertaken after careful risk/benefit assessment.

Breastfeeding

Systemic corticosteroids and levofloxacin are excreted in human milk. There is no information on whether significant amounts of dexamethasone are excreted in human milk and whether it could have a clinical effect on the infant. A risk to the breastfed child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from DUCRESSA® therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

Systemic administration of corticosteroids may alter male and female fertility by affecting hypothalamic and pituitary hormone secretion and testicular and ovarian gametogenesis. It is unknown whether dexamethasone reduces human fertility following ocular administration.

Levofloxacin did not cause impaired fertility in rats at exposures significantly in excess of the maximum human exposure following ocular administration.

Ability to influence reaction speed when driving vehicles or other mechanisms

As with any eye drops, temporary blurred vision or other visual disturbances may affect the ability to drive or use machines. If blurred vision occurs, the patient should wait until the vision clears before driving or operating machinery.

Method of administration and doses

Dosage

Apply 1 drop into the conjunctiva of the eye after surgery every 6 hours. Duration of treatment – 7 days. Do not stop treatment prematurely.

If one dose is missed, treatment should be continued with the next dose as scheduled.

It is recommended that the patient be re-evaluated to assess the need for continued corticosteroid eye drops as monotherapy after one week of treatment with DUCRESSA® eye drops. The duration of this treatment may depend on the presence of risk factors and the results of surgery and should be determined by the physician based on the results of slit-lamp microscopy and the severity of the clinical picture. Further treatment with steroid eye drops should not exceed 2 weeks. However, care should be taken to ensure that treatment is not discontinued prematurely.

Elderly patients

No dose adjustment is necessary for elderly patients.

Renal/hepatic failure

DUCRESSA® has not been studied in patients with renal/hepatic impairment and should be used with caution in such patients.

Method of administration

For ophthalmic use.

1 drop of the drug is instilled into the lateral commissure of the eyelids, simultaneously pressing on the medial commissure to prevent the drops from leaking.

Patients should be instructed to wash their hands before instilling the drug and to avoid contact of the tip of the bottle with the eyes or surrounding tissues, as this may result in eye injury.

Patients should also be instructed that eye solutions, if used improperly, can be contaminated with common bacteria that cause eye infections. The use of contaminated solutions can cause serious eye damage and subsequent vision loss.

Occlusion of the nasolacrimal duct by compression of the lacrimal ducts may reduce systemic absorption.

When concomitantly treated with other eye drops, instillation should be carried out at 15-minute intervals.

Children

The safety and efficacy of DUCRESSA® in children (under 18 years of age) have not been established. Data are not available.

DUCRESSA® is not recommended for use in children (under 18 years of age).

Overdose

The total amount of levofloxacin and dexamethasone sodium phosphate in a vial of DUCRESSA® is too small to cause toxic effects following accidental oral ingestion.

In case of local overdose, treatment should be discontinued. In case of prolonged irritation, the eye(s) should be flushed with sterile water.

Symptoms caused by accidental oral ingestion are unknown. The physician may consider gastric lavage or induction of vomiting.

Adverse reactions

Summary of safety profile

438 patients were treated with DUCRESSA® in clinical trials. No serious adverse reactions were observed. The most commonly reported non-serious adverse reactions were eye irritation, ocular hypertension, and headache.

Tabulated list of adverse reactions

The following adverse reactions have been reported in clinical trials in patients undergoing cataract surgery (within each frequency grouping, adverse reactions are presented in order of decreasing frequency).

The frequency of possible adverse reactions listed below is determined according to the following categories:

Very common ≥ 1/10

Common ≥ 1/100 to

Uncommon ³ l/l000 to

Single ³ 1/10000 to

Rare £1/10000

Table 1

DUCRESSA® (levofloxacin/dexamethasone combination)

Adverse reactions that have been observed with either ophthalmic active substance (levofloxacin or dexamethasone) and that may occur with DUCRESSA® are listed in Tables 2 and 3.

Table 2

Levofloxacin

Table 3

Dexamethasone

Description of selected adverse reactions

Increased intraocular pressure

Increased intraocular pressure (IOP) and development of glaucoma are possible. Prolonged use of corticosteroids may lead to hypertension/glaucoma (especially in patients with a previous steroid-induced increase in IOP or with pre-existing high IOP or glaucoma). Children and elderly patients may be particularly susceptible to steroid-induced IOP elevation (see section 4.4). Patients with diabetes mellitus are also more likely to develop subcapsular cataracts after prolonged steroid use.

Adverse reactions after surgery

Visual disturbances (e.g. corneal oedema, eye irritation, abnormal eye sensation, increased lacrimation, asthenopia, corneal disorder, dry eye, eye pain, eye discomfort, uveitis, blurred vision, visual acuity reduced, conjunctivitis) and nausea have been reported in clinical studies. These reactions are generally mild and transient and are considered to be related to the cataract surgery itself.

Possible corneal adverse reactions

In diseases that cause thinning of the cornea, topical steroid use may in some cases lead to corneal perforation (see section "Special warnings and precautions for use").

In some patients with significantly damaged corneas, cases of corneal calcification have been very rarely reported in association with the use of phosphate-containing eye drops.

Additional adverse reactions that have been observed with long-term use of levofloxacin and may potentially occur with DUCRESSA®:

Tendon ruptures of the shoulder, hand, Achilles, or other tendons requiring surgery or resulting in long-term disability have been reported in patients receiving systemic fluoroquinolones. Studies and post-marketing experience with systemic quinolones suggest that the risk of these ruptures may be increased by concomitant use of corticosteroids, particularly in patients with geriatric conditions. There is also an increased risk of tendon ruptures under high load, including the Achilles tendon (see section 4.4).

It is important to report suspected adverse reactions after the drug has been authorised. This allows for continuous monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.

Expiration date

2 years.

Discard 28 days after first opening.

Storage conditions

Store in original packaging at a temperature not exceeding 25 ° C. Keep out of the reach of children.

Packaging

5 ml in a bottle with a dropper tip and cap. 1 bottle in a cardboard box.

Vacation category

According to the recipe.

Producer

Santen Oy

Location of the manufacturer and address of its place of business

Kelloportinkatu 1, Tampere, 33100, Finland / Kelloportinkatu 1, Tampere, 33100, Finland