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 Pharmacodynamic
properties):

- bronchitis-

 community-acquired pneumonia
- sinusitis
- pharyngitis/tonsillitis (see 4.4 regarding streptococcal infections)
- otitis media
- skin and soft tissue infections
- uncomplicated genital infections due to Chlamydia trachomatis.
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.

As with erythromycin and other macrolides, rare serious allergic reactions including
Dermatologic reactions 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.
If an allergic reaction occurs, the medicinal product 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.”
Angioneurotic oedema and anaphylaxis (rarely fatal), have been reported. Some of these
reactions with azithromycin have resulted in recurrent symptoms and required a longer period of
observation and treatment.
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 Undesirable effects). 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.
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.
“Prolonged cardiac repolarization and QT interval, imparting a risk of developing cardiac
arrhythmia and torsades de pointes, have been seen in treatment with macrolides including
azithromycin (see section 4.8). Therefore as the following situations may lead to an increased
risk for ventricular arrhythmias (including torsade de pointes) which can lead to cardiac arrest,
azithromycin should be used with caution in patients with ongoing proarrhythmic conditions
(especially women and elderly patients) such as patients:
• With congenital or documented QT prolongation
• Currently receiving treatment with other active substances known to prolong QT interval such
as antiarrhythmics of class IA (quinidine and procainamide ) and class III (dofetilide,
amiodarone and sotalol), cisapride and terfenadine; antipsychotic agents such as pimozide;
antidepressants such as citalopram; and fluoroquinolones such as moxifloxacin and levofloxacin
• With electrolyte disturbance, particularly in cases of hypokalaemia and hypomagnesemia
• With clinically relevant bradycardia, cardiac arrhythmia or severe cardiac insufficiency
Epidemiological studies investigating the risk of adverse cardiovascular outcomes with
macrolides have shown variable results. Some observational studies have identified a rare short
term risk of arrhythmia, myocardial infarction and cardiovascular mortality associated with
macrolides including azithromycin. Consideration of these findings should be balanced with
treatment benefits when prescribing azithromycin.”

Antacids: In a pharmacokinetic study investigating the effects of simultaneous administration of
antacid with azithromycin, no effect on overall bioavailability was seen, although peak serum
concentrations were reduced by approximately 25%. In patients receiving both azithromycin and
antacids, the drugs should not be taken simultaneously.
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.
Didanosine (Dideoxyinosine): Co-administration of 1200 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: “Digoxin and colchicine (P-gp substrates) and Concomitant administration of
macrolide antibiotics, including azithromycin, with P-glycoprotein substrates such as digoxin
and colchicine, has been reported to result in increased serum levels of the P-glycoprotein
substrate. Therefore, if azithromycin and P-gp substrates such as digoxin are administered
concomitantly, the possibility of elevated serum concentrations of the substrate should be
considered”
Zidovudine: Single 1000 mg doses and multiple 1200 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.
Ergot derivatives: Due to the theoretical possibility of ergotism, the concurrent use of
azithromycin with ergot derivatives is not recommended. (See Section 4.4).
Substances that prolong the QT interval
Azithromycin should not be used concomitantly with other active substances that prolong the QT
interval (see section 4.4).”

Pharmacokinetic studies have been conducted between azithromycin and the following drugs
known to undergo significant cytochrome P450 mediated metabolism.
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).
“However, post-marketing cases of rhabdomyolysis in patients receiving azithromycin with
statins have been reported”.
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.
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 ciclosporin, the resulting ciclosporin Cmax and AUC0-5 were found to be significantly
elevated (by 24% and 21% respectively), however no significant changes were seen in AUC0- .
Consequently, caution should be exercised before considering concurrent administration of these
drugs. If co-administration of these drugs is necessary, ciclosporin 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 1200 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 1200 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 (1200 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.
Undesirable effects).
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.
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 1200 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.

Animal reproduction studies have been performed at doses up to moderately maternally toxic
dose concentrations. In these studies, no evidence of harm to the fetus 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.
There are no data on secretion in breast milk. As many drugs are excreted in human milk,
azithromycin should not be used in the treatment of a lactating woman unless the physician feels
that the potential benefits justify the potential risks to the infant.

“Fertility: In fertility studies conducted in rat, reduced pregnancy rates were noted following
administration of azithromycin. The relevance of this finding to humans is unknown”

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

Azi-Once is well tolerated with a low incidence of side effects.
The section 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); and Not known
(cannot be estimated from the available data). Within each frequency grouping, undesirable
effects are presented in order of decreasing seriousness.
Adverse reactions possibly or probably related to azithromycin based on clinical trial
experience and post-marketing surveillance:
Infections and Infestations
Uncommon ( 1/1,000 to <1/100)
Candidiasis, oral candidiasis, vaginal infection
Not known (cannot be estimated from available data)
Pseudomembranous colitis (See Section 4.4)

Blood and Lymphatic System Disorders
Uncommon ( 1/1,000 to < 1/100)
Leukopenia, neutropenia
Not known (cannot be estimated from available data)
Thrombocytopenia, haemolytic anaemia
Immune System Disorders
Uncommon ( 1/1,000 to <1/100)
Angioedema, hypersensitivity
Not known (cannot be estimated from available data)
Anaphylactic reaction (See Section 4.4)
Metabolism and Nutrition Disorders
Common (> 1/100, < 1/10)
Anorexia
Psychiatric Disorders
Uncommon ( 1/1,000 to <1/100)
Nervousness
Rare (> 1/10000, < 1/1000)
Agitation

Not known (cannot be estimated from available data)
Aggression, anxiety
Nervous System Disorders
Common (> 1/100, < 1/10)
Dizziness, headache, paraesthesia, dysgeusia
Uncommon ( 1/1,000 to <1/100)
Hypoaesethesia, somnolence, insomnia
Not known (cannot be estimated from available data)
Syncope, convulsion, psychomotor hyperactivity, anosmia, ageusia, parosmia, Myasthenia gravis
(See Section 4.4).
Eye Disorders
Common (> 1/100, < 1/10)
Visual impairment
Uunknown side effects: Visual impairment, blurred vision
Ear and Labyrinth Disorders
Common (> 1/100, < 1/10)
Deafness
Uncommon ( 1/1,000 to <1/100)
Hearing impaired, tinnitus

Rare (> 1/10000, < 1/1000)
Vertigo
Cardiac Disorders
Uncommon ( 1/1,000 to <1/100)
Palpitations
Not known (cannot be estimated from available data)
Torsades de pointes (See Section 4.4), arrhythmia (See Section 4.4) including ventricular
tachycardia
Vascular Disorders
Not known (cannot be estimated from available data)
Hypotension
Gastrointestinal Disorders
Very common ( 1/10)
Diarrhoea, abdominal pain, nausea, flatulence
Common (> 1/100, < 1/10)
Vomiting, dyspepsia
Uncommon (> 1/1000, < 1/100)
Gastritis, constipation
Not known (cannot be estimated from available data)

Pancreatitis, tongue discolouration
Hepatobiliary Disorders
Uncommon (> 1/1000, < 1/100)
Hepatitis
Rare (> 1/10000, < 1/1000)
Hepatic function abnormal
Not known (cannot be estimated from available data)
Hepatic failure (See Section 4.4), which has rarely resulted in death, hepatitis fulminant, hepatic
necrosis, jaundice cholestatic
Skin and Subcutaneous Tissue Disorders
Rare : Acute generalised exanthematous pustulosis (AGEP), Drug reaction with eosinophilia and
systemic symptoms (DRESS)*&#167;”
Common (> 1/100, < 1/10)
Pruritus and rash
Uncommon (> 1/1000, < 1/100)
Stevens-Johnson syndrome, photosensitivity reaction, urticaria
Not known (cannot be estimated from available data)

Toxic epidermal necrolysis, erythema multiforme
Musculoskeletal, Connective Tissue Disorders
Common (> 1/100, < 1/10)
Arthralgia
Renal and Urinary Disorders
Not known (cannot be estimated from available data)
Renal failure acute, nephritis interstitial
General disorders and Administration Site Conditions
Common (> 1/100, < 1/10)
Fatigue
Uncommon (> 1/1000, < 1/100)
Chest pain, oedema, malaise, asthenia
Investigations
Common (> 1/100, < 1/10)
Lymphocyte count decreased, eosinophil count increased, blood bicarbonate decreased

Uncommon (> 1/1000, < 1/100)
Aspartate aminotransferase increased, alanine aminotransferase increased, blood bilirubin
increased, blood urea increased, blood creatinine increased, blood potassium abnormal
Not known (cannot be estimated from available data)
Electrocardiogram QT prolonged (See Section 4.4)

*ADR identified post-marketing
§ADR frequency represented by the estimated upper limit of the 95% confidence interval
calculated using the “Rule of 3”.
Reporting of suspected adverse reactions
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. The typical symptoms of an overdose with macrolide antibiotics include reversible
loss of hearing, severe nausea, vomiting and diarrhoea. In the event of overdose, the
administration of medicinal charcoal and general symptomatic treatment and supportive
measures are indicated as required.

General properties
Antibacterials for systemic use. ATC code: J01FA10
Mode of action:
Azi-Once is a macrolide antibiotic belonging to the azalide group. The molecule is constructed
by adding a nitrogen atom to the lactone ring of erythromycin A. The chemical name of
azithromycin is 9-deoxy-9a-aza-9a-methyl-9a-homoerythromycin A. The molecular weight is
749.0. The mechanism of action of azithromycin is based upon the suppression of bacterial
protein synthesis by means of binding to the ribosomal 50s sub-unit and inhibition of peptide

translocation.
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
Azithromycin susceptibility breakpoints for typical bacterial pathogens are:
NCCLS:
• Susceptible 2mg/l; resistant 8mg/l
• Haemophilus spp.: susceptible 4mg/l
• Streptococcus pneumoniae and Streptococcus pyogenes:
Susceptible 0.5 mg/l; resistant 2 mg/l
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.
Table: Antibacterial spectrum of Azithromycin

* 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 2-3 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
2-4 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 for 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 invitro
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 Dry Flavour
Fantasy flavour
Fresh co forte flavour
Colloidal silicon dioxide
Sucrose
Purified water for reconstitution

None known

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.