Aziotik rompharm
Ukraine
Table of Contents
INSTRUCTIONS for medical use of the medicinal product AZIOPHTIC ROMPHARM
Composition:
Active substance: azithromycin;
1 g of solution contains 15 mg of azithromycin dihydrate, equivalent to 14.3 mg of azithromycin;
1 single-dose container (250 mg of solution) contains 3.75 mg of azithromycin dihydrate;
Excipients: medium-chain triglycerides.
Pharmaceutical form. Eye drops, solution.
Main physicochemical properties: clear, colorless or slightly yellow oily liquid, almost free from foreign particles.
Pharmacotherapeutic group. Ophthalmological medicinal products. Anti-infective agents. Antibiotics. ATC code S01A A26.
Pharmacological properties.
Pharmacodynamics.
Azithromycin is a second-generation macrolide antibiotic belonging to the azalide group.
Mode of action of azithromycin involves inhibition of bacterial protein synthesis by binding to the 50S ribosomal subunit and suppression of peptide translocation.
Mechanism of resistance
In general, resistance of various bacterial species to macrolides is associated with one of three mechanisms: modification of the target site, antibiotic inactivation, or active antibiotic efflux from the cell. Bacteria possess different efflux systems. In streptococci, efflux is largely controlled by mef genes, leading to limited resistance to macrolides (M phenotype). Modification of the target site by methylase, encoded by the erm gene (MLSB phenotype), may result in cross-resistance to different classes of antibiotics.
Complete cross-resistance exists between erythromycin, azithromycin, other macrolides, lincosamides, and streptogramin B for Streptococcus pneumoniae, beta-haemolytic group A streptococci, Enterococcus faecalis, and Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus (MRSA).
Constitutive mutants in inducible-resistant strains with erm (A) or erm (C) can be selected in vitro at low concentrations (~10-7 CFU) in the presence of azithromycin.
Breakpoint concentrations
Below are the minimum inhibitory concentrations (MICs) for microorganisms in the specified indications (see section "Indications").
It should be noted that the MIC breakpoints and in vitro spectrum of activity listed below apply to systemic use. These MIC values do not apply to topical ocular use, due to the concentrations achieved in situ and physicochemical conditions that may influence the overall antibiotic activity at the site of administration.
EUCAST (European Committee on Antimicrobial Susceptibility Testing) has established the following breakpoint concentrations for azithromycin:
- Haemophilus influenzae: susceptible ≤ 0.12 mg/L, resistant > 4 mg/L;
- Moraxella catarrhalis: susceptible ≤ 0.5 mg/L, resistant > 0.5 mg/L;
- Neisseria gonorrhoeae: susceptible ≤ 0.25 mg/L, resistant > 0.5 mg/L;
- Staphylococcus spp.*: susceptible ≤ 1.0 mg/L, resistant > 2.0 mg/L;
- Streptococcus pneumoniae: susceptible ≤ 0.25 mg/L, resistant > 0.5 mg/L;
- Streptococcus A, B, C, G: susceptible ≤ 0.25 mg/L, resistant > 0.5 mg/L.
* spp. includes all species within the genus.
EUCAST states that erythromycin may be used to determine susceptibility to azithromycin for the specified microorganisms.
The prevalence of acquired resistance may vary by geographical region and over time for individual species; therefore, local resistance data are essential, particularly when treating severe infections. Expert advice should be sought if local resistance prevalence renders the efficacy of the drug questionable for at least some types of infections.
Antibacterial spectrum of azithromycin according to indications:
Generally susceptible species
Gram-negative aerobes: Moraxella (Branhamella) catarrhalis, Neisseria gonorrhoeae1, Haemophilus influenzae$, Haemophilus parainfluenzae$.
Others: Chlamydia trachomatis*.
Species with potential for developing resistance
Gram-positive aerobes:
Staphylococcus aureus (methicillin-resistant and methicillin-susceptible),
Staphylococcus coagulase-negative (methicillin-resistant and methicillin-susceptible), Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus viridans, Streptococcus agalactiae, Streptococcus group G.
Resistant species
Gram-positive aerobes: Corynebacterium spp., Enterococcus faecium.
Gram-negative aerobes: Pseudomonas aeruginosa, Acinetobacter, Enterobacteriaceae.
* Clinical efficacy has been demonstrated for susceptible strains isolated according to approved indications.
$ Intermediate intrinsic susceptibility.
1 Conjunctivitis caused by Neisseria gonorrhoeae requires systemic treatment (see section "Special precautions for use").
Clinical trial data
- Trachomatous conjunctivitis caused by Chlamydia trachomatis
In a randomized, double-blind, two-month trial, azithromycin eye drops were compared with a single oral dose of azithromycin for the treatment of trachoma in 670 children (aged 1 to 10 years). The efficacy of azithromycin eye drops administered twice daily for 3 days (96.3%) did not differ significantly from that of orally administered azithromycin (96.6%).
Mass treatment, therapy, and prophylaxis of trachoma with azithromycin eye drops (administered twice daily for 3 days) in all population groups (from birth) were evaluated during stage IV of a multicenter, open, non-comparative study conducted in northern Cameroon (112,000 patients). In a sample of 2,400 children aged ≥1 year to <10 years, the prevalence of active trachoma, which was 31.1% before treatment with azithromycin eye drops, decreased to 6.3% after 1 year and to 3.1% at 2 and 3 years.
No serious adverse reactions were observed in the population receiving treatment with azithromycin eye drops.
- Bacterial purulent conjunctivitis
In a randomized, blinded study conducted in various geographical regions of Europe, North Africa, and India, azithromycin eye drops (administered twice daily for 3 days) were compared with tobramycin 0.3% eye drops (administered every 2 hours for 2 days, then 4 times daily for 5 days) in 1,043 patients with bacterial purulent conjunctivitis, including 109 children under 11 years of age, 5 neonates (from birth to 27 days), and 38 infants and toddlers (from 28 days to 23 months).
Clinical recovery within 9 days with azithromycin eye drops (87.8%) did not differ significantly from tobramycin treatment (89.4%). Microbiological recovery rates with azithromycin eye drops were comparable to those with tobramycin therapy.
Children
The efficacy and safety of azithromycin were demonstrated in children aged ≤18 years in a randomized, blinded, controlled study comparing azithromycin (twice daily for 3 days) with tobramycin (every 2 hours for 2 days, then 4 times daily for 5 days) in 282 children with bacterial purulent conjunctivitis (including 148 patients from birth to 24 months). On day 3, clinical recovery in the most affected eye was significantly higher in the azithromycin group (47%) compared to the tobramycin group (28%). On day 7, 89% of patients receiving azithromycin (twice daily for 3 days) were cured, compared to 78% in the tobramycin group. There was no statistically significant difference between the two groups regarding bacteriological status on day 7. Azithromycin was well tolerated in all age groups. No new adverse reactions were reported in children. The short treatment duration, low number of required administrations, and ease of instillation were positively evaluated by both children and their parents.
Pharmacokinetics.
Azithromycin was not detected in plasma of patients with bacterial conjunctivitis after administration of the drug at recommended doses (limit of detection: 0.0002 µg/mL in blood plasma). Pharmacokinetic studies in children have not been conducted.
Clinical characteristics.
Indications.
The medicinal product is indicated for local antibacterial therapy of conjunctivitis caused by sensitive strains in children from the first days of life and adults, namely:
- purulent bacterial conjunctivitis;
- trachomatous conjunctivitis caused by Chlamydia trachomatis.
Contraindications.
Hypersensitivity to azithromycin or to any other macrolide or to any other component of the medicinal product.
Interaction with other medicinal products and other forms of interaction.
No specific studies on interactions with Azithromycin Rompharm eye drops have been conducted.
Since Azithromycin Rompharm eye drops have no systemic effect when administered ophthalmically (no significant concentrations of azithromycin in blood plasma are observed; see section "Pharmacokinetics"), no interactions between azithromycin and other medicinal products administered orally are expected.
When other eye drop formulations are used concomitantly with Azithromycin Rompharm eye drops, a 15-minute interval between administrations should be maintained, with Azithromycin Rompharm eye drops administered last.
Special precautions for use
The product is not intended for oral or injectable administration, including periocular or intraocular injection.
If an allergic reaction occurs, treatment should be discontinued.
Patients should be informed that they must not continue using the product for more than 3 days, even if residual signs of bacterial conjunctivitis are still present.
Symptom relief is usually observed within 3 days of treatment. If there is no improvement after this period, the treatment regimen should be re-evaluated.
Contact lenses should not be worn during treatment for bacterial conjunctivitis.
Cases of fulminant hepatitis, potentially leading to life-threatening liver failure, have been reported with systemic use of azithromycin. This risk is not expected with topical ocular administration, as systemic exposure to the active substance is clinically insignificant (see section "Pharmacokinetics").
Hypersensitivity
As with erythromycin and other macrolides, rare but serious allergic reactions have been reported, including angioedema and anaphylaxis (rarely fatal), dermatological reactions such as acute generalized exanthematous pustulosis, Stevens–Johnson syndrome, toxic epidermal necrolysis (rarely fatal), and drug reaction with eosinophilia and systemic symptoms (DRESS). Some of these azithromycin-related reactions have been associated with recurrent symptoms and required a longer period of observation and treatment.
If allergic reactions occur, the product should be discontinued and appropriate symptomatic therapy initiated. Physicians should be aware that allergic symptoms may recur after discontinuation of symptomatic treatment.
Pediatric population
Comparative studies on efficacy and safety of Azitoptic Rompharm eye drops for the treatment of trachomatous conjunctivitis in children under 1 year of age have not been conducted. However, there are no known safety concerns or differences in the pathophysiology of the disease that would necessitate excluding its use in children under 1 year of age for this indication, considering the clinical experience in treating children from 1 year of age and the experience of using the product in neonates for the treatment of purulent bacterial conjunctivitis.
Use in newborns
Based on international consensus regarding eye and genital infections transmissible to newborns, non-trachomatous (chlamydial) conjunctivitis caused by Chlamydia trachomatis, as well as conjunctivitis caused by Neisseria gonorrhoeae, require systemic treatment.
In newborns and infants under 3 months of age, systemic infections (e.g., pneumonia, bacteremia) caused by Chlamydia trachomatis may be associated with conjunctivitis. In such cases, differential diagnosis should be established and systemic treatment initiated if necessary.
Azitoptic Rompharm eye drops are not used for prophylaxis of bacterial conjunctivitis in newborns.
Use during pregnancy or breastfeeding
Pregnancy. No effects on pregnancy are expected, as systemic exposure to azithromycin is negligible. Azitoptic Rompharm may be used during pregnancy.
Breastfeeding . Limited data indicate that azithromycin is excreted in breast milk. However, due to low concentration and minimal systemic bioavailability, the amount received by the infant is negligible. Therefore, breastfeeding may be continued during treatment.
Reproductive function
Animal studies do not indicate any effect of azithromycin on male or female reproductive function. The effect on human reproductive function has not been studied. However, since systemic exposure to azithromycin is clinically insignificant, no effect on reproductive function is expected.
Ability to affect reaction speed when driving or operating machinery
Blurred vision may occur temporarily after instillation. In such cases, patients should wait until vision returns to normal before driving or operating machinery.
Method of Administration and Dosage
The medication is intended for instillation into the eyes.
The physician should provide the patient with instructions on the proper use of the antibacterial agent.
Adults
Instill 1 drop into the conjunctival sac twice daily – in the morning and evening. Treatment duration is 3 days.
There is no need to continue treatment beyond 3 days.
Adherence to the prescribed dosage regimen is essential for successful treatment.
Elderly Patients
Dosage adjustment is not required.
Instructions for Use
- Wash your hands and sit or stand comfortably.
- Gently pull the lower eyelid of the affected eye downward with your finger.
- Bring the tip of the open single-dose container as close to the eye as possible without touching the eye.
- Gently squeeze the container so that one drop enters the eye, then release the lower eyelid.
Close your eyes and press with your finger against the inner corner of the treated eye for 1 minute. 2. Repeat all the above steps for the second eye, if so directed by the physician. 3. The single-dose container with any remaining solution should be discarded immediately after use. Do not save it for future use.
When using multiple ophthalmic topical agents, administer them at intervals of at least 15 minutes.
Children
The medication may be used in children from birth. Dosage is as specified for adults in the section "Method of Administration and Dosage." Dosage adjustment in children is not required (see sections "Pharmacodynamics" and "Special Warnings").
Overdose
The total amount of azithromycin administered for treatment of both eyes is too small to cause symptoms of overdose if the contents of a single-dose container were administered intravenously or orally.
Adverse Reactions
Adverse reactions are categorized by frequency as follows: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10,000, < 1/1000), very rare (< 1/10,000), frequency not known (cannot be estimated from the available data).
Immune system disorders
Uncommon: Angioedema*, hypersensitivity reactions.
Eye disorders (at site of administration)
Very common: Eye discomfort (itching, burning, stinging).
Common: Blurred vision, sensation of eyelid sticking together, foreign body sensation.
Uncommon: Conjunctivitis*, allergic conjunctivitis*, keratitis*, eyelid eczema*, eyelid swelling*, eye allergy*, conjunctival hyperemia, increased lacrimation, eyelid erythema.
Skin and subcutaneous tissue disorders
Frequency not known: Toxic epidermal necrolysis$, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome)$, Stevens–Johnson syndrome$, exfoliative dermatitis$, acute generalized exanthematous pustulosis.
* These adverse reactions were not observed during clinical trials of azithromycin. These adverse reactions were reported during post-marketing surveillance of azithromycin use. The frequency was estimated using the formula 3/X, where X is the total number of individuals included in all studies and clinical trials, or corresponds to a frequency of 3/879 – "uncommon".
$ Extrapolated from systemic effects.
Paediatric population. Clinical studies in paediatrics have demonstrated that the safety profile in children is not different from that in adults. No new adverse effects were identified. Safety profiles were also similar across different paediatric subgroups (see section "Pharmacological properties").
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.
Shelf life. 3 years.
After first opening of the single-dose container, its contents should be used immediately and the single-dose container discarded.
Storage conditions.
Store at 2 to 8 °C.
Store single-dose containers in sachets to protect from light.
Keep out of reach of children.
Packaging.
250 mg in a single-dose container, 6 containers in a sachet, with one sachet in a cardboard box.
Prescription status.
Prescription only.
Manufacturer.
C.T. ROMPHARM COMPANY S.R.L.
Manufacturer's address and place of business.
Strada Eroilor No. 1A, Otopeni, 075100, Ilfov County, Romania – Building Rompharm 1 and Rompharm 2.