Azithromycin is indicated for the treatment of the following infections when known or likely to be due to one or more susceptible microorganisms (see section 5.1): - bronchitis - community-acquired pneumonia - sinusitis - pharyngitis/tonsillitis (see section 4.4 regarding streptococcal infections) - otitis media - skin and soft tissue infections - uncomplicated genital infections due to Chlamydia trachomatis and Neisseria gonorrhoeae. Considerations should be given to official guidance regarding the appropriate use of antibacterial agents.

Posology: Azi-Once should be given as a single daily dose. Azi-Once Suspension can be taken with or without food. Children over 45 kg body weight and adults, including elderly patients: The total dose of azithromycin is 1500 mg which should be given over three days (500 mg once daily). In uncomplicated genital infections due to Chlamydia trachomatis, the dose is 1000 mg as a single oral dose. For susceptible Neisseria gonorrhoeae the recommended dose is 1000 mg or 2000 mg of azithromycin in combination with 250 mg or 500 mg ceftriaxone according to local clinical treatment guidelines. For patients who are allergic to penicillin and/or cephalosporins, prescribers should consult local treatment guidelines.

Paediatric population: In children under 45 kg body weight: Azi-Once Suspension should be used for children under 45 kg. There is no information on children less than 6 months of age. The dose in children is 10 mg/kg as a single daily dose for 3 days: Up to 15 kg (less than 3 years): Measure the dose as closely as possible using the 10 ml oral dosing syringe provided. The syringe is graduated in 0.25 ml divisions, providing 10 mg of azithromycin in every graduation. For children weighing more than 15 kg, Azi-Once Suspension should be administered using the spoon provided according to the following guidance: 15-25 kg (3-7 years): 5 ml (200 mg) given as 1 x 5 ml spoonful, once daily for 3 days. 26-35 kg (8-11 years): 7.5 ml (300 mg) given as 1 x 7.5 ml spoonful, once daily for 3 days. 36-45 kg (12-14 years): 10 ml (400 mg) given as 1 x 10 ml spoonful, once daily for 3 days. Over 45 kg: Dose as per adults. See section 6.5 for appropriate pack size to use depending on age/body weight of child. The specially supplied measure should be used to administer Azi-Once suspension to children. Renal impairment: No dose adjustment is necessary in patients with mild to moderate renal impairment (GFR 10 - 80 ml/min). Caution should be exercised when azithromycin is administered to patients with severe renal impairment (GFR < 10 ml/min) (see section 4.4 and section 5.2). Hepatic impairment: Since azithromycin is metabolised in the liver and excreted in the bile, the drug should not be given to patients suffering from severe liver disease. No studies have been conducted regarding treatment of such patients with azithromycin (see section 4.4). Method of administration: Azi-Once Suspension is for oral administration only.

Hypersensitivity As with erythromycin and other macrolides, serious allergic reactions including angioneurotic oedema and anaphylaxis (rarely fatal), Acute Generalized Exanthematous Pustulosis (AGEP) 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.

Hepatotoxicity Since the liver is the principal route of elimination for azithromycin, the use of azithromycin should be undertaken with caution in patients with significant hepatic disease. Cases of fulminant hepatitis potentially leading to life-threatening liver failure have been reported with azithromycin (see section 4.8). Some patients may have had pre-existing hepatic disease or may have been taking other hepatotoxic medicinal products. In case of signs and symptoms of liver dysfunction, such as rapid developing asthenia associated with jaundice, dark urine, bleeding tendency or hepatic encephalopathy, liver function tests / investigations should be performed immediately. Azithromycin administration should be stopped if liver dysfunction has emerged. Ergot derivatives In patients receiving ergot derivatives, ergotism has been precipitated by co-administration of some macrolide antibiotics. There are no data concerning the possibility of an interaction between ergot and azithromycin. However, because of the theoretical possibility of ergotism, azithromycin and ergot derivatives should not be co-administrated. Prolongation of the QT interval Prolonged cardiac repolarisation and QT interval, imparting a risk of developing cardiac arrhythmia and torsades de pointes, have been seen in treatment with other macrolides. A similar effect with azithromycin cannot be completely ruled out in patients at increased risk for prolonged cardiac repolarisation (see section 4.8); therefore caution is required when treating patients: • With congenital or documented QT prolongation • Currently receiving treatment with other active substance known to prolong QT interval such as antiarrhythmics of Classes Ia and III, cisapride and terfenadine • With electrolyte disturbance, particularly in case of hypokalaemia and hypomagnesemia • With clinically relevant bradycardia, cardiac arrhythmia or severe cardiac insufficiency. Superinfection As with any antibiotic preparation, observation for signs of superinfection with non-susceptible organisms including fungi is recommended. Clostridium difficile associated diarrhoea Clostridium difficile associated diarrhoea (CDAD) has been reported with the use of nearly all antibacterial agents, including azithromycin, and may range in severity from mild diarrhoea to fatal colitis. Strains of C. difficile producing hypertoxin A and B contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. Therefore, CDAD must be considered in patients who present with diarrhoea during or subsequent to the administration of any antibiotics. Careful medical history is necessary since CDAD has been reported to occur over 2 months after the administration of antibacterial agents. Discontinuation of therapy with azithromycin and the administration of specific treatment for C. difficile should be considered. Streptococcal infections Penicillin is usually the first choice for treatment of pharyngitis/tonsillitis due to Streptococcus pyogenes and also for prophylaxis of acute rheumatic fever. Azithromycin is in general effective against streptococcus in the oropharynx, but no data are available that demonstrate the efficacy of azithromycin in preventing acute rheumatic fever. Renal impairment In patients with severe renal impairment (GFR <10 ml/min) a 33% increase in systemic exposure to azithromycin was observed (see section 5.2). Myasthenia gravis Exacerbations of the symptoms of myasthenia gravis and new onset of myasthenia syndrome have been reported in patients receiving azithromycin therapy (see section 4.8). Diabetes Caution in diabetic patients: 5 ml of reconstituted suspension contains 3.87 g of sucrose. Excipients information Azi-Once suspension contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine. Azi-Once suspension contains less than 1 mmol sodium (23 mg) per 5 ml of reconstituted suspension, that is to say essentially 'sodium-free'. Azi-Once Suspension is for oral administration only.

Antacids: In a pharmacokinetic study investigating the effects of simultaneous administration of
antacids and azithromycin, no effect on the total bio-availability was seen, although the peak
serum concentrations were reduced by approximately 25%. Azithromycin must be taken at least
1 hour before or 2 hours after antacids.
Cetirizine: In healthy volunteers, co-administration of a 5-day regimen of azithromycin with
cetirizine 20 mg at steady-state resulted in no pharmacokinetic interaction and no significant
changes in the QT interval.
Didanosins (Dideoxyinosine): Co-administration of 1,200 mg/day azithromycin with 400 mg/day
didanosine in 6 HIV-positive subjects did not appear to affect the steady-state pharmacokinetics of
didanosine as compared with placebo.

Digoxin: Some of the macrolide antibiotics have been reported to impair the microbial metabolism
of digoxin in the gut in some patients. In patients receiving concomitant azithromycin, a related
azalide antibiotic, and digoxin the possibility of raised digoxin levels should be borne in mind.
Zidovudine: Single 1,000 mg doses and multiple 1,200 mg or 600 mg doses of azithromycin had
little effect on the plasma pharmacokinetics or urinary excretion of zidovudine or its glucuronide
metabolite. However, administration of azithromycin increased the concentrations of phosphorylated
zidovudine, the clinically active metabolite, in peripheral blood mononuclear cells. The clinical
significance of this finding is unclear, but it may be of benefit to patients.
Azithromycin does not interact significantly with the hepatic cytochrome P450 system. It is not
believed to undergo the pharmacokinetic drug interactions as seen with erythromycin and other
macrolides. Hepatic cytochrome P450 induction or inactivation via cytochrome-metabolite complex
does not occur with azithromycin.
Ergotamine derivatives: Due to the theoretical possibility of ergotism, the concurrent use of
azithromycin with ergot derivatives is not recommended (see section 4.4).
Pharmacokinetic studies have been conducted between azithromycin and the following drugs known
to undergo significant cytochrome P450 mediated metabolism.

Astemizole, alfentanil
There are no known data on interactions with astemizole or alfentanil. Caution is advised in the coadministration
of these medicines with Azithromycin because of the known enhancing effect of
these medicines when used concurrently with the macrolid antibiotic erythromycin.
Atorvastatin: Co-administration of atorvastatin (10 mg daily) and azithromycin (500 mg daily) did
not alter the plasma concentrations of atorvastatin (based on a HMG CoA-reductase inhibition
assay).

Carbamazepine: In a pharmacokinetic interaction study in healthy volunteers, no significant effect
was observed on the plasma levels of carbamazepine or its active metabolite in patients receiving
concomitant azithromycin.
Cisapride
Cisapride is metabolized in the liver by the enzyme CYP 3A4. Because macrolides inhibit this
enzyme, concomitant administration of cisapride may cause the increase of QT interval
prolongation, ventricular arrhythmias and torsades de pointes.
Cimetidine: In a pharmacokinetic study investigating the effects of a single dose of cimetidine, given
2 hours before azithromycin, on the pharmacokinetics of azithromycin, no alteration of azithromycin
pharmacokinetics was seen.
Coumarin-Type Oral Anticoagulants: In a pharmacokinetic interaction study, azithromycin did not
alter the anticoagulant effect of a single 15-mg dose of warfarin administered to healthy volunteers.
There have been reports received in the post-marketing period of potentiated anticoagulation
subsequent to co-administration of azithromycin and coumarin-type oral anticoagulants. Although a
causal relationship has not been established, consideration should be given to the frequency of
monitoring prothrombin time when azithromycin is used in patients receiving coumarin-type oral
anticoagulants.

Ciclosporin: In a pharmacokinetic study with healthy volunteers that were administered a 500
mg/day oral dose of azithromycin for 3 days and were then administered a single 10 mg/kg oral dose
of cyclosporin, the resulting cyclosporin Cmax and AUC0-5 were found to be significantly elevated.
Consequently, caution should be exercised before considering concurrent administration of these
drugs. If co-administration of these drugs is necessary, cyclosporin levels should be monitored and
the dose adjusted accordingly.

Efavirenz: Co-administration of a 600 mg single dose of azithromycin and 400 mg efavirenz daily
for 7 days did not result in any clinically significant pharmacokinetic interactions.
Fluconazole: Co-administration of a single dose of 1,200 mg azithromycin did not alter the
pharmacokinetics of a single dose of 800 mg fluconazole. Total exposure and half-life of
azithromycin were unchanged by the co-administration of fluconazole, however, a clinically
insignificant decrease in Cmax (18%) of azithromycin was observed.
Indinavir: Co-administration of a single dose of 1,200 mg azithromycin had no statistically
significant effect on the pharmacokinetics of indinavir administered as 800 mg three times daily for
5 days.
Methylprednisolone: In a pharmacokinetic interaction study in healthy volunteers, azithromycin had
no significant effect on the pharmacokinetics of methylprednisolone.
Midazolam: In healthy volunteers, co-administration of azithromycin 500 mg/day for 3 days did not
cause clinically significant changes in the pharmacokinetics and pharmacodynamics of a single 15
mg dose of midazolam.

Nelfinavir: Co-administration of azithromycin (1,200 mg) and nelfinavir at steady state (750 mg
three times daily) resulted in increased azithromycin concentrations. No clinically significant
adverse effects were observed and no dose adjustment is required.
Rifabutin: Co-administration of azithromycin and rifabutin did not affect the serum concentrations
of either drug.
Neutropenia was observed in subjects receiving concomitant treatment of azithromycin and
rifabutin. Although neutropenia has been associated with the use of rifabutin, a causal relationship to
combination with azithromycin has not been established (see section 4.8).

Sildenafil: In normal healthy male volunteers, there was no evidence of an effect of azithromycin
(500 mg daily for 3 days) on the AUC and Cmax of sildenafil or its major circulating metabolite.
Terfenadine: Pharmacokinetic studies have reported no evidence of an interaction between
azithromycin and terfenadine. There have been rare cases reported where the possibility of such an
interaction could not be entirely excluded; however there was no specific evidence that such an
interaction had occurred.
Theophylline: There is no evidence of a clinically significant pharmacokinetic interaction when
azithromycin and theophylline are co-administered to healthy volunteers. As interactions of other
macrolides with theophylline have been reported, alertness to signs that indicate a rise in
theophylline levels is advised.
Triazolam: In 14 healthy volunteers, co-administration of azithromycin 500 mg on Day 1 and 250
mg on Day 2 with 0.125 mg triazolam on Day 2 had no significant effect on any of the
pharmacokinetic variables for triazolam compared to triazolam and placebo.
Trimethoprim/sulfamethoxazole: Co-administration of trimethoprim/sulfamethoxazole DS (160
mg/800 mg) for 7 days with azithromycin 1,200 mg on Day 7 had no significant effect on peak
concentrations, total exposure or urinary excretion of either trimethoprim or sulfamethoxazole.
Azithromycin serum concentrations were similar to those seen in other studies.

Pregnancy Animal reproduction studies have been performed at doses up to moderately maternally toxic dose concentrations. In these studies, no evidence of harm to the foetus due to azithromycin was found. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, azithromycin should be used during pregnancy only if clearly needed. Breast-feeding Limited information available from published literature indicates that azithromycin is present in human milk at an estimated highest median daily dose of 0.1 to 0.7 mg/kg/day. No serious adverse effects of azithromycin on the breast-fed infants were observed. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from azithromycin therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

There is no evidence to suggest that Azi-Once may have an effect on a patient's ability to drive or operate machinery.

The table below lists the adverse reactions identified through clinical trial experience and postmarketing
surveillance by system organ class and frequency. Adverse reactions identified from
post-marketing experience are included in italics. The frequency grouping is defined using the
following convention:
Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare
(≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the
available data).
Within each frequency group, undesirable effects are listed in order of decreasing seriousness.

Adverse reactions possibly or probably related to azithromycin based on clinical trial
experience and post-marketing surveillance:

* which has rarely resulted in death 

To report any side effect(s):
• Saudi Arabia:
The National Pharmacovigilance and Drug Safety Centre (NPC)
Fax: +966-11-205-7662
Call NPC at +966-11-2038222,
Exts: 2317-2356-2340.
Toll free phone: 19999
E-mail: npc.drug@sfda.gov.sa
Website: https://ade.sfda.gov.sa/
• Other GCC States:
− Please contact the relevant competent authority

Adverse events experienced in higher than recommended doses were similar to those seen at normal
doses. In the event of overdosage, general symptomatic and supportive measures are indicated as
required.

General properties
Pharmacotherapeutic group: antibacterials for systemic use; macrolides; azithromycin, ATC
code: J01FA10
Mode of action
Azithromycin is an azalide, a sub-class of the macrolide antibiotics. By binding to the 50Sribosomal
sub-unit, azithromycin avoids the translocation of peptide chains from one side of the
ribosome to the other. As a consequence of this, RNA-dependent protein synthesis in sensitive
organisms is prevented.
PK/PD relationship
For azithromycin the AUC/MIC is the major PK/PD parameter correlating best with the efficacy
of azithromycin.
Mechanism of resistance
Resistance to azithromycin may be inherent or acquired. There are three main mechanisms of
resistance in bacteria: target site alteration, alteration in antibiotic transport and modification of
the antibiotic.

Complete cross resistance exists among Streptococcus pneumoniae, betahaemolytic
streptococcus of group A, Enterococcus faecalis and Staphylococcus aureus, including
methicillin resistant S. aureus (MRSA) to erythromycin, azithromycin, other macrolides and
lincosamides.
Breakpoints
EUCAST (European Committee on Antimicrobial Susceptibility Testing)

Susceptibility
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 of resistance
is such that the utility of the agent in at least some types of infections is questionable.
Pathogens for which resistance may be a problem: prevalence of resistance is equal to or greater
than 10% in at least one country in the European Union.

Table of susceptibility

* Methycillin-resistant staphylococci have a very high prevalence of acquired resistance to macrolides and have been placed here because they are rarely susceptible to azithromycin. Paediatric population Following the assessment of studies conducted in children, the use of azithromycin is not recommended for the treatment of malaria, neither as monotherapy nor combined with chloroquine or artemisinin based drugs, as non-inferiority to anti-malarial drugs recommended in the treatment of uncomplicated malaria was not established.

Absorption Bioavailability after oral administration is approximately 37%. Peak plasma concentrations are attained 2 to 3 hours after taking the medicinal product. Distribution Orally administered azithromycin is widely distributed throughout the body. In pharmacokinetic studies it has been demonstrated that the concentrations of azithromycin measured in tissues are noticeably higher (as much as 50 times) than those measured in plasma, which indicates that the agent strongly binds to tissues. Binding to serum proteins varies according to plasma concentration and ranges from 12% at 0.5 microgram/ml up to 52% at 0.05 microgram azithromycin/ml serum. The mean volume of distribution at steady state (VVss) has been calculated to be 31.1 l/kg. Elimination The terminal plasma elimination half-life closely reflects the elimination half-life from tissues of 2 to 4 days. Approximately 12% of an intravenously administered dose of azithromycin is excreted unchanged in urine within the following three days. Particularly high concentrations of unchanged azithromycin have been found in human bile. Also in bile, ten metabolites were detected, which were formed through N- and O- demethylation, hydroxylation of desosamine and aglycone rings and cleavage of cladinose conjugate. Comparison of the results of liquid chromatography and microbiological analyses has shown that the metabolites of azithromycin are not microbiologically active. In animal tests, high concentrations of azithromycin have been found in phagocytes. It has also been established that during active phagocytosis higher concentrations of azithromycin are released from inactive phagocytes. In animal models this results in high concentrations of azithromycin being delivered to the site of infection.

Phospholipidosis (intracellular phospholipid accumulation) has been observed in several tissues (e.g. eye, dorsal root ganglia, liver, gallbladder, kidney, spleen, and/or pancreas) of mice, rats, and dogs given multiple doses of azithromycin. Phospholipidosis has been observed to a similar extent in the tissues of neonatal rats and dogs. The effect has been shown to be reversible after cessation of azithromycin treatment. The significance of the finding for animals and humans is unknown. Carcinogenic potential: Long-term studies in animals have not been performed to evaluate carcinogenic potential as the drug is indicated for short-term treatment only and there were no signs indicative of carcinogenic activity. Mutagenic potential: There was no evidence of a potential for genetic and chromosome mutations in in-vivo and in-vitro test models. Reproductive toxicity: In animal studies for embryotoxic effects of the substance, no teratogenic effect was observed in mice and rats. In rats, azithromycin doses of 100 and 200 mg/kg bodyweight/day led to mild retardation of foetal ossification and in maternal weight gain. In peri- and postnatal studies in rats, mild retardation following treatment with 50 mg/kg/day azithromycin and above was observed.

Xanthan Gum
Trisodium phosphate monohydrate
Hydroxy propyl cellulose
Banana Flavour
Fantasy flavour permaseal
Fresh co forte flavour permaseal
Colloidal silicon dioxide
Sucrose
Purified water for reconstitution

Not applicable.

Store dry powder at temperature not exceeding 30 ºC, and after reconstitution store at temperature not exceeding 30 ºC. Discard any unused portion after 5 days of reconstitution

Azi-Once™ Suspension available in three packages containing an oral dosing syringe and : powder to make 15ml (600 mg), powder to make 22.5 ml (900 mg) and powder to make 30 ml (1200 mg). Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.