Azyter

Azyter

azithromycin

Manufacturer:

Théa

Distributor:

DCH Auriga

Marketer:

TRB Chemedica
Full Prescribing Info
Contents
Azithromycin dihydrate.
Description
Azithromycin 14.3 mg as Azithromycin dihydrate 15 mg for 1 g of solution.
Excipient/Inactive Ingredient: Triglycerides, medium chain.
Action
Pharmacotherapeutic Group: Antibiotic. ATC Code: S01AA26.
Pharmacology: Pharmacodynamics: Mode of action: Azithromycin is a second-generation macrolide antibiotic belonging to the azalide group.
It inhibits the synthesis of bacterial proteins by binding to the 50S ribosomal subunit and preventing peptide translocation.
Mechanism of resistance: Generally, the resistance of different bacterial species to macrolides has been reported to occur by three mechanisms associated with target site alteration, antibiotic modification, or altered antibiotic transport (efflux). Various efflux pump systems have been described in bacteria. An important efflux system in streptococci is conferred by the mef genes and results in a macrolide-restricted resistance (M phenotype). Target modification is controlled by erm encoded methylases (MLSB phenotype) and results in cross-resistance to several classes of antibiotics (see as follows).
A complete cross-resistance exists among erythromycin, azithromycin, other macrolides and lincosamides and streptogramin B for Streptococcus pneumoniae, beta-haemolytic streptococci of group A, Enterococcus spp. and Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA).
Penicillin-sensitive S. pneumoniae are more likely to be susceptible to azithromycin than are penicillin-resistant strains of S. pneumoniae. Methicillin-resistant S. aureus (MRSA) is less likely to be susceptible to azithromycin than methicillin-sensitive S. aureus (MSSA).
Constitutive mutants in inducibly resistant strains with erm(A) or erm(C) can be selected in vitro at low frequencies ~ 10-7 cfu in the presence of azithromycin.
Note that the breakpoints and in-vitro activity spectrum presented hereafter are those applicable to systemic use. These breakpoints may not be applicable to topical ocular application of the drug product due to the local concentrations that are reached and the local physicochemical conditions that may influence the overall activity of the agent at the site of application.
According to the EUCAST (European Committee on Antimicrobial Susceptibility Testing) the following breakpoints have been defined 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.
*spp includes all the species of the genus.
The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence is such that the utility of the agent in at least some types of infections is questionable. (See table.)

Click on icon to see table/diagram/image

Information from clinical trials: Trachomatous conjunctivitis caused by Chlamydia trachomatis: Azyter was evaluated in a two-month, randomised, double-masked study comparing Azyter with a single oral dose of azithromycin for the treatment of trachoma in 670 children (1-10 years). The primary efficacy variable was the clinical cure at Day 60, i.e. a grade TF0 (simplified WHO grading scale). At Day 60, clinical cure rate of Azyter instilled twice daily for 3 days (96.3%) was non-inferior to that of oral azithromycin (96.6%).
The clinical efficacy of Azyter (instilled twice daily for 3 days) in mass curative and prophylactic treatment of trachoma in an entire population (from birth) in a northern Cameroon district (112 000 subjects) was assessed in a multicentre, open-label, single-arm, phase IV study. Three annual treatment periods were performed. The primary efficacy endpoint was the prevalence of active trachoma, i.e. trachomatous inflammation-follicular or trachomatous inflammation-intense (TF+TI0 or TF+TI+). For analysis, clinical assessment of trachoma was performed each year in a sample of 2400 children aged ≥1 and < 10 years old selected using a random cluster sampling. The prevalence of active trachoma (TF+TI0 or TF+TI+) was 31.1% at Year 0 (before Azyter instillations) and decreased to 6.3% at Year 1, 3.1% at Year 2 and 3.1% at Year 3.
In the whole population, there was no serious adverse event in relation with the study drug.
Purulent bacterial conjunctivitis: Azyter was evaluated in a randomised, investigator-masked study comparing Azyter, instilled twice daily for 3 days, with tobramycin 0.3% eye drops, instilled every two hours for 2 days then four times daily for 5 days, for the treatment of purulent bacterial conjunctivitis in 1043 patients (ITT set), including 109 children up to the age of 11 years from whom 5 were newborn infants (0 to 27 days) and 38 infants and toddlers (28 days to 23 months of age). In the Per Protocol set (n=471), there were no newborns and only 16 infants and toddlers. The clinical study was performed in different areas in Europe, North Africa, and India. The primary efficacy variable was the clinical cure at Day 9 in the PP set, defined as a score of 0 for both the bulbar conjunctival injection and the purulent discharge. At Day 9, clinical cure rate of Azyter (87.8%) was non-inferior to that of tobramycin (89.4%). Microbiological resolution rate of Azyter was comparable to that of tobramycin.
Paediatric population: The efficacy and safety of Azyter in paediatric patients ≤ 18 years of age was demonstrated in a randomised, investigator-masked study compared with tobramycin in 282 analysed patients diagnosed with purulent bacterial conjunctivitis (including 148 patients in the subgroup 0 day - < 24 months). Patients received either Azyter, instilled twice daily for 3 days or tobramycin 0.3% eye drops, instilled every two hours for 2 days then four times daily for 5 days. The primary efficacy endpoint was the clinical cure in the worse eye on D3 for patients with D0 positive bacterial cultures. Clinical cure in the worse eye on D3 was demonstrated to be significantly superior for Azyter (47%) than for tobramycin (28%). At D7, 89% of patients treated with Azyter were cured versus 78% with tobramycin. No statistical difference was found between treatment groups for the bacteriological resolution at D7.
Azyter (instilled twice daily for 3 days) was well tolerated in all age groups in this large study in paediatric population. The events observed in paediatric subjects were a subset of those previously observed in adults; no new adverse events were identified in paediatric subjects. Furthermore, no age-related patterns of clinical concern were evident. The short duration of Azithromycin 1.5% treatment, the low number of instillations needed and the easiness of instilling drops in children were appreciated by both children and parents.
Pharmacokinetics: Azithromycin was not detected in the blood of patients with bacterial conjunctivitis after instillation of Azyter at the recommended dose (detection limit: 0.0002 μg/mL of plasma).
Paediatric population: Pharmacokinetic studies have only been performed in adults.
Toxicology: Pre-Clinical Safety Data: In animals, azithromycin caused reversible phospholipids. This effect was seen after oral exposures which were about 300 times in excess of the maximum human exposure after ocular administration indicating little relevance to clinical use.
Electrophysiological investigations have shown that azithromycin prolongs the QT interval.
Carcinogenic potential: Long-term studies in animals have not been performed to evaluate carcinogenic potential.
Mutagenic potential: There was no evidence of a potential for genetic and chromosome mutations in in vivo and in vitro test models.
Reproductive toxicity: No teratogenic effects were observed in embryotoxicity studies in rates after oral administration of azithromycin. In rats, azithromycin dosages of 100 and 200 mg/kg body weight/day led to mild retardations in fetal ossification and in maternal weight gain. In peri- and postnatal studies in rats, mild retardations following treatment with 50 mg/kg/day azithromycin and above were observed. These effects were seen after oral administation at exposures which were about 1000 times in excess of the maximum human exposures after ocular administration. Because of the high safety margin, these findings do not point to a relevant risk for human reproduction.
Ocular toxicity: Ocular administration of Azyter eye drops to animals twice or three times a day during 28 days did not demonstrate any local or systemic toxic effect.
Indications/Uses
Local antibacterial curative treatment of conjunctivitis caused by susceptible strains: Purulent bacterial conjunctivitis in children (aged from birth to 17 years) and adults.
Trachomatous conjunctivitis caused by Chlamydia trachomatis in children (aged from birth to 17 years) and adults.
Consideration should be given to official guidance on the appropriate use of antibacterial agents.
Dosage/Direction for Use
Adult and paediatric patients from birth: Instill one drop in the conjunctival fornix twice a day, morning and evening, for three days.
It is unnecessary to prolong treatment beyond three days.
Adherence to the dosing regimen is important for the success of treatment.
Elderly patients: No dose adjustment is necessary.
Paediatric population (<2 years of age): No dose adjustment is necessary.
Method of administration: Ocular use.
The patient should be advised to: thoroughly wash hands before and after the installation,
avoid touching the eye or eyelids with the dropper tip of the single-dose container,
discard the single-dose container after use, and not keep it for subsequent use.
Overdosage
The total amount of azithromycin in a single-dose container, containing a sufficient quantity for treating both eyes, is too small to induce adverse effects after inadvertent intravenous or oral administration.
Contraindications
Azyter is contraindicated in patients: Hypersensitivity to azithromycin, to any other macrolides or to excipients.
Special Precautions
The eye drops solution should not be injected nor be swallowed.
The eye drops solution should not be used for peri- or intra-ocular injection.
In the event of an allergic reaction, the treatment should be discontinued.
The patient should be informed that it is not necessary to continue to instill the eye drops solution after the end of treatment on the third day, even if residual signs of bacterial conjunctivitis remained.
Symptomatic relief occurs generally within 3 days. If there are no signs of improvement after 3 days, diagnosis should be reconsidered.
Contact lenses should not be worn by patients with bacterial conjunctivitis.
As with other anti-infectives, prolonged use may result in overgrowth of non-susceptible organism, including fungi. If super-infection occurs, discontinue use and institute alternative therapy. Whenever clinical judgment dictates, the patient should be examined with the aid of magnification, such as slit-lamp biomicroscopy, and where appropriate, fluorescein staining.
With the systemic use of azithromycin, cases of fulminant hepatitis potentially leading to life-threatening liver failure have been reported. In ophthalmic use, this risk is not relevant since systemic exposure to the active ingredient is negligible.
Hypersensitivity: As with erythromycin and other macrolides, rare severe acute hypersensitivity reactions, including angioneurotic oedema and anaphylaxis (rarely fatal), severe cutaneous adverse reactions (SCARs) including acute generalised exanthematous pustulosis (AGEP), Stevens Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) (rarely fatal) and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported. Some of these reactions with azithromycin have resulted in recurrent symptoms and required a longer period of observation and treatment.
If an allergic reaction occurs, the drug should be discontinued and appropriate therapy should be instituted. Physicians should be aware that reappearance of the allergic symptoms may occur when symptomatic therapy is discontinued.
Effects on ability to drive and operate machine: No studies on the effects on the ability to drive and use machines have been performed. Vision may be transiently blurred after instillation. In this case, the patient should be advised to avoid driving or using machines until normal vision has been re-established.
Use in Children: Regarding the treatment of trachomatous conjunctivitis, comparative safety and efficacy studies have not been performed with Azyter 15 mg/g eye drops in children younger than one year, but there are no known safety concerns or differences in disease process to exclude its use in children less than one year in this indication, taking into account clinical experience in children older than one year of age in the treatment of trachomatous conjunctivitis and considering Azyter experience in children from birth in the treatment of purulent bacterial conjunctivitis.
Use in neonates: Based on the international consensus on disease involving the eye and genital tract and susceptible to be transmitted to new-borns, trachomatous conjunctivitis caused by Chlamydia trachomatis and conjunctivitis caused by Neisseria gonorrhoeae require a systemic treatment.
In neonates and infants below the age of 3 months, systemic infection (e.g. pneumonia, bacteremia) due to Chlamydia trachomatis may accompany conjunctivitis. In case of suspicion, systemic treatment is required.
This treatment is not intended to be used as prophylactic treatment of bacterial conjunctivitis in newborn infants.
Use In Pregnancy & Lactation
Pregnancy: There are no adequate and well controlled studies in pregnant women. Animal reproduction studies show passage across the placenta. No teratogenic effects were observed in rat reproduction studies. Since animal studies are not always predictive of human response, Azyter should be used with caution during pregnancy.
Breastfeeding: Limited data indicate that azithromycin is excreted in breast milk, but, considering the low dose and the low systemic availability, the doses taken by the new-born are negligible. Consequently, breast feeding is possible during the treatment. Caution should be exercised when azithromycin is administered to a nursing woman.
Adverse Reactions
During clinical trials and according to post-marketing safety data on Azyter eye drops solution, the following treatment-related signs and symptoms were reported: Immune system disorders: Uncommon (≥1/1000, <1/100): Angioedema*, hypersensitivity.
Eye disorders: Very common (≥1/10): Ocular discomfort (pruritus, burning, stinging) upon instillation. Common (≥1/100, <1/10): Blurred vision, sticky eye sensation, foreign body sensation upon instillation. Uncommon (≥1/1000, <1/100): Conjunctivitis*, allergic conjunctivitis*, keratitis*, eczema eyelids*, eyelid oedema*, eye allergy*, conjunctival hyperemia, lacrimation increased upon instillation, erythema of the eyelid.
Skin and subcutaneous tissue disorders: Not known (cannot be estimated from the available data): Severe cutaneous adverse reactions (SCARs) including toxic epidermal necrolysis$, drug reaction with eosinophilia and systemic symptoms$, Stevens-Johnson syndrome$, dermatitis exfoliative$, acute generalised exanthematous pustulosis (AGEP)$.
*adverse event has not been observed during clinical studies with Azyter. Inclusion of adverse event is based on post-marketing data. The frequency has been assigned based on 3/X, with X representing the total sample size summed up across all relevant clinical trials and studies, which is 3/879 resulting in "uncommon".
$by extrapolation of systemic exposure.
Paediatric population: In paediatric clinical trials, the safety profile was similar to that in adults and no new adverse events were identified. The safety profiles in the different paediatric subsets were also similar.
Drug Interactions
No specific interaction study has been performed with Azyter.
In view of the absence of detectable concentrations of azithromycin in the plasma during the administration of Azyter by ocular instillation, none of the interactions with other medicinal products described for orally administered azithromycin is expected with use of the eye drops solution.
In the event of concomitant treatment with another eye drops solution, an interval of 15 minutes should be respected between instillation of the two solutions. Azyter should be instilled last.
Caution For Usage
Special Precautions for Disposal: No special requirements.
Incompatibilities: Not applicable.
Storage
Special condition of storage: "Store under refrigeration at 2°C - 8°C". Keep the single-dose containers in the sachet in order to protect them from light.
Shelf-life of product in its commercial packaging: 36 months.
After opening of the single-dose container, the eye drops should be used immediately. Discard the opened single-dose container immediately after first use.
ATC Classification
S01AA26 - azithromycin ; Belongs to the class of antibiotics. Used in the treatment of eye infections.
Presentation/Packing
Eye drops (single-dose) (clear, colourless to slightly yellow, oily liquid) 15 mg/g x 6's.
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