Composition, form of production and packaging
Eye drops in the form of a transparent oily liquid from colorless to light yellow color.
azithromycin dihydrate 15 mg,
which corresponds to the content of azithromycin 14.3 mg
Excipients: medium chain triglycerides - up to 1 g.
0.25 g - single-dose vials of low-density polyethylene, welded together in the form of a tape (6) - bags sealed from a composite material (1) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2017.
Antimicrobial preparation for topical application. Azithromycin is an antibiotic of the second-generation macrolide-azalide group. Inhibits the synthesis of the bacterial protein by binding to the 50S subunit of the ribosomes and preventing the translocation of the peptides.
The mechanism of resistance
There are three mechanisms of resistance for different species of bacteria to macrolides: due to modification of the target of the action, modification of the antibiotic or due to active release of the antibiotic from the microbial cell by means of transport systems (efflux). For bacteria, various efflux systems are described. An important efflux system for streptococci is encoded by the mef- gene and leads to resistance to bounded macrolides (M-phenotype). Modification of the target of action, controlled by erm coded methylase (MLSB phenotype), leads to cross-resistance to different classes of antibiotics.
Cases of cross-resistance to erythromycin, azithromycin, other macrolides and lincosamide and streptogrammin B for Streptococcus pneumoniae,? -gemolytic group A streptococci, Enterococcus spp. and Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA). Constitutive mutants in inducibly resistant strains with erm (A) or erm (C) can be isolated in vitro at low frequencies of about 10 -7 cfu in the presence of azithromycin.
Below are the minimum inhibitory concentrations (MICs) for microorganisms at given indications.
It should be noted that the boundary values вЂ‹вЂ‹of the MIC and the spectrum of action presented below refer to systemic application. MIC data can not be used in the case of topical treatment with an eye drop preparation due to other concentrations and physicochemical conditions that may affect the overall activity of the drug at its site of action.
According to the EUCAST (European Committee for the Determination of Antibiotic Sensitivity), the following MIC boundary values вЂ‹вЂ‹were determined for azithromycin:
Haemophilus influenzae S? 0.12 mg / L and R> 4 mg / L
Moraxella catarrhalis S? 0.5 mg / l and R> 0.5 mg / l
Neisseria gonorrhoeae S? 0.25 mg / l and R> 0.5 mg / l
Staphylococcus spp. S? 1.0 mg / l and R> 2.0 mg / l
Streptococcus pneumoniae S? 0.25 mg / l and R> 0.5 mg / l
Streptococcus A, B, C, G S? 0.25 mg / l and R> 0.5 mg / l
EUCAST allows the use of erythromycin to determine the sensitivity of other species of these bacteria to azithromycin.
The frequency of acquired resistance for individual species may vary depending on the geographical region and time. In this regard, it is desirable to have local information on resistance, especially when treating severe infections. If necessary, seek the advice of a specialist when the local frequency of resistance is such that the effectiveness of the drug, at least for some types of infection, raises doubts.
Table. Antibacterial spectrum of azithromycin by types of bacteria for these indications
Species traditionally sensitive to the preparation Aerobic Gram-negative bacteria Moraxella (Branhamella) catarrhalis Neisseria gonorrhoeae 1 Haemophilus influenzae 2 Haemophilus parainfluenzae 2 Other microorganisms Chlamydia trachomatis 3 Irregularly sensitive species Aerobic gram-positive bacteria Staphylococcus aureus (methicillin-resistant and methicillin-sensitive) Staphylococcus , coagulase-negative (methicillin -resistant and methicillin-sensitive) Streptococcus pneumoniae Streptococcus pyogenes Streptococci viridans Streptococcus agalactiae Streptococcus group G Species with natural resistance Aerobic gram-positive bacteria Cor ynebacterium spp. Enterococcus faecium Aerobic Gram-negative bacteria Pseudomonas aeruginosa Acinetobacter Enterobacteriaceae
1 Conjunctivitis caused by Neisseria gonorrhoeae requires systemic treatment.
2 Natural intermediate sensitivity.
3 Clinical efficacy is demonstrated in sensitive isolated strains for approved indications.
Clinical Trials Data
Trachomatous conjunctivitis caused by Chlamydia trachomatis
A randomized, double-blind, 2-month study comparing Azidrop with oral administration of a single dose of azithromycin for the treatment of active trachoma in 670 children aged 1-10 years. The main variable efficacy was a clinical cure for 60 days, i.e. absence of active trachoma TF0 (for simplified classification of trachoma severity by WHO). On the 60th day the frequency of clinical cure with Azidrop, applied 1 drop 2 times / day for 3 days, was not lower (96.3%) than when taking azithromycin inwards (96.6%).
The clinical efficacy of Azidrop, applied 1 drop 2 times / day for 3 days, for treatment and prevention of trachoma of the whole population (since birth) in Northern Cameroon (112,000 subjects) was assessed in a multicentre, open, non-comparative phase IV study. The treatment was carried out for 3 periods of 1 year. The primary criterion of effectiveness was the predominance of active trachoma, i.e. trachomatous follicular inflammation or severe trachomatous inflammation (TF + TI0 or TF + TI +). For the analysis, a clinical evaluation of trachoma was performed every year in 2,400 children aged в‰Ґ1 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 the instillation of Azidrop in year 0 and decreased to 6.3% (Year 1), 3.1% (Year 2) and 3.1% 3 rd year). In general, the population did not observe any serious adverse reactions to the study drug.
Purulent bacterial conjunctivitis
A randomized, blind comparative study of the preparation Azidrop was performed, applied 1 drop 2 times / day for 3 days, with tobramycin (eye drops, 0.3%), applied 1 drop every 2 hours for 2 days, and then 4 times / day for 5 days, for treatment of purulent bacterial conjunctivitis in 1043 patients (ITT group), including 109 children under the age of 11 years, 5 of whom were newborns (0 to 27 days), 38 infants and toddlers (from 28 days up 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 different regions of Europe, North Africa and India. The primary efficacy variable was a clinical cure for day 9 in the PP group and was defined as 0 for bulbar conjunctiva injection and for purulent discharge. On day 9, the frequency of clinical cure with Azidrop (87.8%) was not lower than with tobramycin (89.4%). The microbiological efficacy of azithromycin was comparable to that of tobramycin.
Efficacy and safety of Azidrop in children and adolescents under the age of 18 years were shown in a randomized study with masking of the researcher in comparison with tobramycin in 282 patients with diagnosis of purulent bacterial conjunctivitis (including 148 patients in the subgroup 0 days- <24 months). Patients received either Azidrop (1 drop 2 times / day for 3 days), or tobramycin, eye drops, 0.3% (1 drop every 2 hours for 2 days, and then 4 times / day for 5 days). The main efficacy criterion was the clinical cure of the more affected eye on day 3 in patients with positive bacteriological analysis at day 0. In patients using Azidrop, the clinical cure of the more affected eye on day 3 exceeded (47%) this value in comparison with patients who used tobramycin (28%). On the 7th day, 89% of patients treated with Azidrop were fully cured, whereas among the patients receiving tobramycin, a complete cure was noted in 78% of cases. There were no statistical differences between treated groups with regard to bacteriological resolution on day 7. Azidrop, applied 1 drop 2 times / day for 3 days, was well tolerated in all age groups in the study of a large group of children. Undesirable reactions noted in children have also been found in adults; no new unwanted reactions in children have been identified. Moreover, no age-related clinical problems were noted. Short duration of therapy with azithromycin (eye drops 1.5%), a small number of necessary instillations, and ease of instillation of drops to children have been taken into account by both children and parents.
After instillation of eye drops Azidrop in the treatment of bacterial conjunctivitis in the recommended dose azithromycin is not found in the blood of patients (detection limit: 0.0002 Ојg / ml).
Pharmacokinetic studies were conducted only in adults.
Treatment of conjunctivitis caused by microorganisms sensitive to the preparation:
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).
Adults instill 1 drop into the conjunctival sac of the affected eye 2 times / day (morning and evening) for 3 days.
If there is no positive dynamics within 3 days of the drug, you should consult your doctor and revise the treatment regimen and diagnosis.
Older patients do not need a dose adjustment.
Children do not need a dose adjustment.
Mode of application
Eye drops are buried in the conjunctival sac of the affected eye.
Patients should follow the following guidelines:
- Wash hands thoroughly before instillation and after the procedure;
- do not touch the eye and eyelids with the tip of the dropper;
- after a single use, the vial should be discarded with the remaining residue. Do not use the remaining solution in the vial for the next instillation.
Adverse reactions that have been observed in clinical trials and post-marketing studies
From the immune system: infrequently (? 1/1000, <1/100) - hypersensitivity.
From the side of the organ of vision: very often (? 1/10) - eye discomfort (itching, burning, tingling) after instillation of the drug; often (? 1/100, <1/10) - blurred vision, a feeling of "sticking together of the eyelids," a foreign body in the eye after instillation of the drug; infrequently (? 1/1000, <1/100) - hyperemia of the conjunctiva, lacrimation, erythema of the eyelids.
Adverse reactions that were observed in post-marketing studies
Inclusion of these unwanted reactions is based on post-registration data. The frequency is determined from 3 / X, where X is the total sample size summarized for all relevant clinical trials, which at 3/879 gives the category "infrequently".
From the immune system: infrequently (? 1/1000, <1/100) - angioedema (Quincke's edema).
From the side of the organ of vision: infrequently (? 1/1000, <1/100) - conjunctivitis, allergic conjunctivitis, keratitis, eczema eyelids, eyelid edema, eye allergy.
The profile of adverse reactions in children corresponds to the adult population, no side effects have been identified. The safety profile for the different pediatric groups was also identical.
- hypersensitivity to azithromycin and other components of the drug;
- hypersensitivity to other antibiotics of the macrolide group.
PREGNANCY AND LACTATION
Since systemic exposure of azithromycin is negligible, no adverse effect of the drug is expected during pregnancy. Application of the drug Azidrop, eye drops, in pregnant women is possible.
There is limited evidence that azithromycin is excreted in breast milk, but given the low dose and low systemic availability, the dose that enters the body of the newborn is extremely low. Thus, the use of Azidrop in the period of breastfeeding is acceptable.
Animal studies have not confirmed the effect of azithromycin on male and female fertility. The results of studies in humans are absent. Since the systemic effect of azithromycin on the body is insignificant, the effect of the drug on fertility is not expected.
APPLICATION FOR CHILDREN
Contraindicated use of the drug Azidrop in children under 1 year.
APPLICATION IN ELDERLY PATIENTS
Older patients do not need a dose adjustment.
The drug should not be injected or swallowed, or administered as peri-and intraocular injections.
Eye drops should not be injected or swallowed.
Eye drops can not be administered as peri- and intraocular injections.
If the allergic reaction to the drug develops, treatment should be discontinued.
With simultaneous treatment with other ophthalmic drugs, Azidrop should be instilled in the last place, 15 minutes after instillation of another drug.
The patient should be informed that eye drops should not be instilled after the 3-day course of therapy, even if the residual signs of bacterial conjunctivitis persist.
Relief of symptoms usually occurs within 3 days. If there is no sign of improvement after 3 days, the diagnosis should be reviewed.
Patients suffering from bacterial conjunctivitis should not use contact lenses.
Against the background of systemic use of azithromycin, there have been reports of the development of lightning-fast hepatitis, which can potentially lead to life-threatening liver failure. When using the drug in ophthalmology, such a risk does not exist, since the systemic effect of the active substance is extremely low.
Use in Pediatrics
Comparative studies of the efficacy and safety of the drug during trachomatous conjunctivitis in children younger than 1 year have not been conducted. However, taking into account the experience of clinical use in children of this age group with trachomatous conjunctivitis and taking into account the experience of therapy with Azidrop of newborn children with purulent bacterial conjunctivitis, fears of safety and differences in the pathological process, which make it possible to exclude the use of eye drops Azidrop in children younger 1 year on this indication for use, are absent.
According to the current international guidelines for the treatment of eye and genitourinary diseases, which can be transmitted to newborns with high probability, conjunctivitis of non-trachomatous origin caused by Chlamydia trachomatis and conjunctivitis caused by Neisseria gonorrhoeae requires systemic therapy.
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 you suspect such conditions, you need systemic therapy.
The drug is not intended for the prevention of bacterial conjunctivitis in newborns.
Impact on the ability to drive vehicles and manage mechanisms
The impact on the ability to drive vehicles and mechanisms has not been studied.
After the application of eye drops, there may be a transient fogging of vision. Patients who, after the application of eye drops, experience a transient fogging of vision, it is not recommended to drive vehicles or work with mechanisms until vision is restored.
In a single-use package, azithromycin is contained in an amount sufficient to treat both eyes, but not sufficient to cause undesired reactions with occasional in / in administration or solution administration inside.
Special studies of the interaction of the drug Azidrop with other drugs have not been conducted.
In connection with the absence of detectable concentrations of azithromycin in the blood plasma when instilling eye drops Azidrop, no interaction with any of those drugs that interacted with azithromycin during ingestion is expected.
In the case of concomitant treatment with other ophthalmic drugs, Azidrop should be instilled last, 15 minutes after instillation of another drug.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be stored out of reach of children, protected from light at a temperature of 2 В° C to 8 В° C. Shelf life - 3 years.