Azydrop (Drops) Instructions for Use

Marketing Authorization Holder

Laboratoires Théa (France)

Manufactured By

Laboratoire Unither (France)

Contact Information

TEA FARMA LLC (Russia)

ATC Code

S01AA26 (Azithromycin)

Active Substance

Azithromycin (Rec.INN registered by WHO)

Dosage Form

Azydrop

Eye drops 15 mg/1 g: bottle 0.25 g 6 pcs.

Dosage Form, Packaging, and Composition

Eye drops as a clear, oily liquid from colorless to light yellow.

Excipients: medium-chain triglycerides – up to 1 g.

0.25 g – single-dose bottles made of low-density polyethylene, welded together in the form of a strip (6) – hermetically sealed sachets made of combined material (1) – cardboard packs.

Clinical-Pharmacological Group

Antibiotic for topical use in ophthalmology

Pharmacotherapeutic Group

Antibiotic-azalide

Pharmacological Action

Mechanism of action

Azithromycin is an antibiotic of the second-generation macrolide-azalide group. It inhibits bacterial protein synthesis by binding to the 50S ribosomal subunit and preventing peptide translocation.

Mechanism of resistance

Three mechanisms of resistance to macrolides are noted for different bacterial species: due to target site modification, antibiotic modification, or active efflux of the antibiotic from the microbial cell via transport systems (efflux). Various efflux systems have been described for bacteria. An important efflux system for streptococci is encoded by the mef gene and leads to resistance limited to macrolides (M-phenotype). Target site modification, controlled by erm encoded methylase (MLSB-phenotype), leads to cross-resistance to various classes of antibiotics.

Cases of cross-resistance to erythromycin, azithromycin, other macrolides, lincosamides, and streptogramin B have been described for Streptococcus pneumoniae, β-hemolytic group A streptococci, Enterococcus spp. and Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus (MRSA). Constitutive mutants in inducibly resistant strains with erm (A) or erm (C) can be isolated in vitro at low frequencies of approximately 10^-7CFU in the presence of azithromycin.

Breakpoint values

The minimum inhibitory concentrations (MIC) for microorganisms for the given indications are presented below.

It should be noted that the MIC breakpoint values and spectrum of activity presented below relate to systemic use. These MIC data cannot be used for topical treatment with the drug in the form of eye drops due to different concentrations and physicochemical conditions that may affect the overall activity of the drug at the site of action.

According to EUCAST (European Committee on Antimicrobial Susceptibility Testing), the following MIC breakpoint values are defined for azithromycin

* spp. includes all species of the genus

EUCAST allows the use of erythromycin to determine the susceptibility of other specified bacterial species to azithromycin.

The frequency of acquired resistance for individual species may vary by geographic region and time. Therefore, it is desirable to have local information on resistance, especially when treating severe infections. If necessary, specialist advice should be sought when the local resistance frequency is such that the efficacy of the drug, at least for some types of infection, is questionable.

Antibacterial spectrum of azithromycin by bacterial species for these indications

¹ Conjunctivitis caused by Neisseria gonorrhoeae requires systemic treatment.

² Natural intermediate susceptibility.

³ Clinical efficacy has been demonstrated on sensitive isolated strains for approved indications.

Clinical trial data

Trachomatous conjunctivitis caused by Chlamydia trachomatis

A randomized, double-blind, comparative study of 2 months duration was conducted comparing Azydrop with a single oral dose of azithromycin for the treatment of active trachoma in 670 children aged 1-10 years. The primary efficacy variable was clinical cure on day 60, i.e., absence of active trachoma TF0 (according to the WHO simplified trachoma severity classification). On day 60, the clinical cure rate for Azydrop, administered as 1 drop twice daily for 3 days, was not inferior (96.3%) to oral azithromycin (96.6%).

The clinical efficacy of Azydrop, administered as 1 drop twice daily for 3 days, for the treatment and prevention of trachoma in the entire population (from birth) in Northern Cameroon (112,000 subjects) was evaluated in a multicenter, open, non-comparative phase IV study. Treatment was carried out in 3 periods lasting 1 year each. The primary efficacy criterion was the prevalence of active trachoma, i.e., trachomatous follicular inflammation or intense trachomatous inflammation (TF+TI0 or TF+TI+). For analysis, clinical assessment of trachoma was performed each year in 2400 children aged ≥1 and <10 years, selected by random cluster sampling. The prevalence of active trachoma (TF+TI0 or TF+TI+) was observed in 31.1% of cases before instillation of Azydrop in “year 0” and decreased to 6.3% (year 1), 3.1% (year 2), and 3.1% (year 3). Overall, no serious adverse reactions to the study drug were observed in the population.

Purulent bacterial conjunctivitis

A randomized, blind, comparative study was conducted of Azydrop, administered as 1 drop twice daily for 3 days, versus tobramycin (eye drops, 0.3%), administered as 1 drop every 2 hours for 2 days, then 4 times/day for 5 days, for the treatment of purulent bacterial conjunctivitis in 1043 patients (ITT group), including 109 children under 11 years of age, 5 of whom were newborns (0 to 27 days), 38 infants and toddlers (28 days to 23 months). According to the protocol, the population (n=471) (PP group) included 16 infants and toddlers and did not include newborns. The clinical study was conducted in various regions of Europe, North Africa, and India. The primary efficacy variable was clinical cure on day 9 in the PP group and was defined as a score of 0 for bulbar conjunctival injection and for purulent discharge. On day 9, the clinical cure rate for Azydrop (87.8%) was not inferior to that of tobramycin (89.4%). The microbiological efficacy of azithromycin was comparable to that of tobramycin.

Pediatric population

The efficacy and safety of Azydrop in children and adolescents under 18 years of age were shown in a randomized, investigator-masked study versus tobramycin in 282 study patients diagnosed with purulent bacterial conjunctivitis (including 148 patients in the subgroup 0 days <24 months). Patients received either Azydrop (1 drop twice daily for 3 days) or tobramycin eye drops, 0.3% (1 drop every 2 hours for 2 days, then 4 times/day for 5 days). The primary efficacy criterion was clinical cure of the more affected eye on day 3 in patients with positive bacteriology results on day 0. In patients using Azydrop, clinical cure of the more affected eye on day 3 was superior (47%) compared to patients using tobramycin (28%). On day 7, 89% of patients treated with Azydrop were completely cured, whereas among patients treated with tobramycin, complete cure was noted in 78% of cases. No statistical differences were observed between the treatment groups regarding bacteriological resolution on day 7. Azydrop, administered as 1 drop twice daily for 3 days, was well tolerated in all age groups in the large pediatric study. Adverse reactions noted in children were also found in adults; no new adverse reactions were identified in children. Furthermore, no age-related clinical issues were noted. The short duration of azithromycin therapy (1.5% eye drops), the small number of required instillations, and the ease of drop administration to children were appreciated by both children and parents.

Pharmacokinetics

After instillation of Azydrop eye drops for the treatment of bacterial conjunctivitis at the recommended dose, Azithromycin is not detected in the blood of patients (detection limit: 0.0002 µg/ml).

Pharmacokinetic studies were conducted only in adults.

Indications

Treatment of conjunctivitis caused by microorganisms sensitive to the drug

• Purulent bacterial conjunctivitis in adults and children (from birth to 17 years);
• Trachomatous conjunctivitis caused by Chlamydia trachomatis in adults and children (from birth to 17 years).

Official guidelines on the appropriate use of antibacterial agents should be considered.

ICD codes

Dosage Regimen

Adults instill 1 drop into the conjunctival sac of the affected eye twice daily (morning and evening) for 3 days.

If there is no positive dynamics within 3 days of using the drug, you should consult a doctor and review the treatment regimen and diagnosis.

Elderly patients dose adjustment is not required.

Children dose adjustment is not required.

Method of administration

Eye drops are instilled into the conjunctival sac of the affected eye.

Patients should follow the following recommendations

• Wash hands thoroughly before and after instillation of the drug;
• Do not touch the eye and eyelid with the tip of the bottle dropper;
• After single use, the bottle must be discarded along with the remaining solution. Do not use the solution remaining in the bottle for the next instillation.

Adverse Reactions

Adverse reactions that have been observed in clinical trials and according to post-registration safety data for Azydrop

Immune system disorders uncommon (≥1/1000, <1/100) – hypersensitivity.

Eye disorders very common (≥1/10) – eye discomfort (itching, burning, tingling) after instillation of the drug; common (≥1/100, <1/10) – blurred vision, sensation of “sticky eyelids”, foreign body sensation in the eye after instillation of the drug; uncommon (≥1/1000, <1/100) – conjunctival hyperemia, lacrimation, eyelid erythema.

Adverse reactions not observed during clinical trials

The inclusion of the listed adverse reactions is based on post-marketing data. Frequency is determined based on 3/X, where X represents the total sample size summed across all relevant clinical studies, which at 3/879 gives the “uncommon” category.

Immune system disorders uncommon (≥1/1000, <1/100) – angioedema (Quincke’s edema).

Eye disorders uncommon (≥1/1000, <1/100) – conjunctivitis, allergic conjunctivitis, keratitis, eyelid eczema, eyelid edema, allergic eye reactions.

The adverse reaction profile in children corresponds to the adult population; no additional side effects were identified. The safety profile for different pediatric groups was also identical.

Contraindications

• Hypersensitivity to azithromycin and other components of the drug;
• Hypersensitivity to other antibiotics of the macrolide group.

Use in Pregnancy and Lactation

Since systemic exposure to azithromycin is negligible, no negative effects of the drug during pregnancy are expected. The use of Azydrop eye drops in pregnant women is possible.

There are limited data that Azithromycin is excreted in breast milk, but given the low doses and low systemic availability, the dose reaching the newborn’s body is extremely insignificant. Thus, the use of Azydrop during breastfeeding is acceptable.

Animal studies have not confirmed the effect of azithromycin on male and female fertility. Results from human studies are lacking. Since the systemic effect of azithromycin on the body is negligible, no effect of the drug on fertility is expected.

Pediatric Use

Dose adjustment is not required for children.

Geriatric Use

Dose adjustment is not required for elderly patients.

Special Precautions

Eye drops should not be administered by injection or swallowed.

Eye drops should not be administered as peri- and intraocular injections.

If an allergic reaction to the drug develops, treatment should be discontinued.

The patient should be informed not to instill the eye drops after completing the 3-day course of therapy, even if residual signs of bacterial conjunctivitis persist.

Symptom relief usually occurs within 3 days. If there is no improvement after 3 days, the diagnosis should be reconsidered.

Patients with bacterial conjunctivitis should not wear contact lenses.

Cases of fulminant hepatitis, which can potentially lead to life-threatening liver failure, have been reported with systemic use of azithromycin. When using the drug in ophthalmology, such a risk does not exist, since the systemic exposure of the active substance is extremely low.

Use in pediatrics

Comparative studies of efficacy and safety for the treatment of trachomatous conjunctivitis in children under 1 year of age have not been conducted. However, taking into account the clinical experience of use in children of this age group for trachomatous conjunctivitis and considering the experience of treating newborn children with purulent bacterial conjunctivitis with Azydrop, there are no safety concerns or differences in the pathological process that would preclude the use of Azydrop eye drops in children under 1 year of age for this indication.

According to existing international guidelines for the treatment of eye and genitourinary tract diseases that are highly likely to be transmitted to newborns, systemic therapy is necessary for non-trachomatous conjunctivitis caused by Chlamydia trachomatis and conjunctivitis caused by Neisseria gonorrhoeae.

In newborns and children under 3 months of age, systemic infections (such as pneumonia and bacteremia) caused by Chlamydia trachomatis may be accompanied by conjunctivitis. If such conditions are suspected, systemic therapy is necessary.

The drug is not intended for the prevention of bacterial conjunctivitis in newborns.

Effect on ability to drive vehicles and machinery

The effect on the ability to drive vehicles and machinery has not been studied.

Transient blurred vision may occur after using the eye drops. In this case, it is not recommended to drive vehicles or operate machinery until vision is restored.

Overdose

The single-use package contains Azithromycin in an amount sufficient to treat both eyes, but insufficient to cause adverse reactions in case of accidental intravenous administration or oral ingestion of the solution.

Drug Interactions

Specific drug interaction studies for Azydrop have not been conducted.

Due to the absence of detectable azithromycin concentrations in plasma when instilling Azydrop eye drops, no interaction is expected with any of the drugs that interacted with oral azithromycin.

In case of concomitant treatment with other ophthalmic drugs, Azydrop should be instilled last, 15 minutes after instillation of the other drug.

Storage Conditions

The drug should be stored out of the reach of children, protected from light, at a temperature of 2°C (35.6°F) to 8°C (46.4°F).

Shelf Life

The shelf life is 3 years. Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.