Azithromycin is indicated for the treatment of the following infections, when caused
by microorganisms sensitive to azithromycin (see section 4.4 and 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
Consideration should be given to official guidance on the appropriate use of
antibacterial agents. Azithromacin is not the first choice for the empiric treatment of
infections in areas where the prevalence of resistant isolates is 10% or more (see
section 5.1).
 

Adults
In uncomplicated genital infections due to Chlamydia trachomatis the dosage is 1000
mg as a single oral dose.
For all other indications the dose is 1500 mg, to be administered as 500 mg per day
for three consecutive days.
Elderly patients
The same dose range as in younger patients may be used in the elderly.
Children
Azithromycin tablets should only be administered to children weighing more than 45
kg when normal adult dose should be used. For children under 45 kg other
pharmaceutical forms of azithromycin, e.g. suspensions, may be used.
Patients with 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 <10ml/min) (see section 4.4).
Patients with hepatic impairment:
A dose adjustment is not necessary for patients with mild to moderately impaired
liver function. Since azithromycin is metabolised in the liver and excreted in bile, the
drug should not be given to patients suffering from severe liver disease. No studies
have been conducted regarding treatment of the use of azithromycin (see section
4.4).
Method of Administration:
< Azithromycin 250 mg film-coated tablet > should be administered as a daily single
dose. < Azithromycin 250mg film-coated tablet > may be taken with meals.
 

As with erythromycin and other macrolides, serious allergic reactions including
angioneurotic oedema and anaphylaxis (rarely fatal), have been reported. Some of
these reactions with azithromycin have caused recurrent symptoms and have
required longer 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). Liver function tests
/investigations should be performed in cases where signs and symptoms of liver
dysfunction occur, such as rapidly developing asthenia associated with jaundice, dark
urine, bleeding tendency or hepatic encephalopathy.
Renal failure: No dose adjustment is necessary in patients with mild to moderate
renal impairment (GFR 10–80 ml/min). Caution is advised in patients with severe
renal impairment (GFR < 10 ml/min) as systemic exposure to azithromycin may be
increased (see section 5.2).
In patients receiving ergotamine derivatives, ergotism has been precipitated by
coadministration 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 coadministered (see section 4.5).
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 acquired QT prolongation.
- currently receiving treatment with other active substances that prolong QT interval
such as antiarrhythmics of classes IA and III, cisapride and terfenadine.
- with electrolyte disturbance, particularly in cases of hypokalaemia and
hypomagnesaemia
- with clinically relevant bradycardia, cardiac arrhythmia or severe cardiac
insufficiency.
Exacerbations of the symptoms of myasthenia gravis and new onset of myasthenia
syndrome have been reported in patients receiving azithromycin therapy.
Neurological or psychiatric diseases: Azithromycin should be administered with
caution to patients suffering from neurological or psychiatric diseases.
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly
all antibacterial agents, including azithromycin, and may range in severity from mild
diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora
of the colon leading to overgrowth of C. difficile.
C. difficile produces toxins A and B which 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. CDAD must be considered in all patients who present with diarrhea
following antibiotic use. Careful medical history is necessary since CDAD has been
reported to occur over two months after the administration of antibacterial agents.
Superinfections: As with any antibacterial agent, observation for signs of
superinfection with non-susceptible organisms, including fungi, is recommended.
Long term use: There is no experience regarding the safety and efficacy of long term
use of azithromycin for the mentioned indications. In case of rapid recurrent
infections, treatment with another antibiotic should be considered.
Streptococcal infections: Penicillin is usually the first choice for treatment of
streptococcus pyogenes-pharyngitis/tonsillitis and comprises prophylaxis of acute
rheumatic fever. Azithromycin is in general effective against streptococcus in
oropharynx, but no data is available that shows efficacy of azithromycin in
preventing acute rheumatic fever.
These medicinal products contain lactose. Patients with rare hereditary problems of
fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase
insufficiency should not take this medicine.
 

Antacids: When studying the effect of simultaneously administered antacids on the
pharmacokinetics of azithromycin, no overall change has been observed in the
bioavailability, although the peak concentrations of azithromycin measured in the
plasma fell by approximately 25%. < Azithromycin 250mg film-coated tablet > should
be taken at least 1 hour before or 2 hours after the antacid.
Astemizol, Alfentanil:
No data are available on interactions with Astemizol and Alfentanil. Caution should
be exercised with concomitant use of these agents and azithromycin in view of the
described potentation of its effect during concomitant use of the macrolide
antibiotic erythromycin.
Cetirizine: In healthy volunteers, coadministration 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: Coadministration of daily doses of 1200 mg azithromycin with
didanosine in 6 HIV-positive subjects did not appear to affect the pharmakokinetics
of didanosine as compared with placebo.
Digoxin: In some patients certain macrolide antibiotics have been reported to have
impaired the metabolism of digoxin in the intestine. Consequently, in patients
receiving Azithromycin and digoxin, the possibility of a rise in the digoxin
concentrations should be borne in mind and digoxin levels monitored.
Zidovudine: 1000 mg single doses and 1200 mg or 600 mg multiple doses of
azithromycin had little effect upon the pharmacokinetics of zidovudine or its
glucuronide metabolite in the plasma or upon excretion in urine. However,
administration of azithromycin increased the concentrations of phosphorylated
zidovudine, the clinically active metabolite, in mononuclear cells in the peripheral
circulation. The clinical significance of these findings is unclear, but 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.
Cisapride: Cisapride is metabolized in the liver by the enzyme CYP 3A4. Because
other macrolides inhibit this enzyme, concomitant administration of cisapride may
cause the increase of QT interval prolongation, ventricular arrhythmias and torsade
de pointes.
Ergotamine derivatives: Due to the theoretical possibility of ergotism, the concurrent
use of azithromycin and 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.
Atorvastatin: Coadministration 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.
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 postmarketing period of potentiated anticoagulation subsequent to coadministration 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 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. Consequently, caution should be
exercised before considering concurrent administration of these drugs. If
coadministration of these drugs is necessary, ciclosporin levels should be monitored
and the dose adjusted accordingly.
Efavirenz: Coadministration of a 600 mg single dose of azithromycin and 400 mg
efavirenz daily for 7 days did not result in any clinically significant pharmacokinetlc
interactions.
Fluconazole: Coadministration 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 coadministration of fluconazole,
however. a clinically insignificant decrease in Cmax (18%) of azithromycin was
observed.
Indinavir: Coadministration 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 conducted in healthy
volunteers, azithromycin had no significant effect on the pharmacokinetics of
methylprednisolone.
Midazolam: In healthy volunteers, coadministration 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: Concomitant administration of 1200 mg azithromycin and steady state
nelfinavir (750 mg 3 times daily) resulted in on average 16% decrease of nelfinavir
AUC, an increase of azithromycin AUC and Cmax with 113% and 136% respectively. No
dose adjustment is necessary but patients should be monitored for known side
effects of azithromycin.
Rifabutin: Coadministration 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: Azithromycin has not affected the pharmacokinetics of theophylline
when healthy volunteers received Azithromycin and theophylline simultaneously.
The combined use of Theophyllin and other macrolide antibiotics sometimes led to
an increasing serum level of theophylline.
Triazolam: In 14 healthy volunteers, coadministration 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: Coadministration 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 wellcontrolled 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.
 

Experience to date indicates that, in general, azithromycin has no effect on ability to
concentrate and react. However, undesirable effects of treatment, such as dizziness,
somnolence and convulsions (see section 4.8), can influence the ability to drive and
operate machinery.
 

a. Summary of safety:
Azithromycin 250 mg capsule is generally safe and well tolerated
b. Tabulated list of Adverse reaction:
The table below lists the adverse reactions identified through clinical trial experience
and post-marketing 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 form 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:

c. Description of selected adverse reaction:
NA
d. Pediatric population
Azithromycin tablets should only be administered to children weighing more than
45 kg when normal adult dose should be used. For children under 45 kg other
pharmaceutical forms of azithromycin, e.g. suspensions, may be used.
e. Other special population
Elderly patients
The same dose range as in younger patients may be used in the elderly.
Patients with 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
<10ml/min) (see section 4.4).
Patients with hepatic impairment:
A dose adjustment is not necessary for patients with mild to moderately
impaired liver function. Since azithromycin is metabolised in the liver and
excreted in bile, the drug should not be given to patients suffering from
severe liver disease. No studies have been conducted regarding treatment of
the use of azithromycin (see section 4.4).

The adverse events experienced in higher than recommended dosages 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:
The mechanism of action of azithromycin is based on the suppression of bacterial
protein synthesis, that is to say that it binds to the ribosomal 50s sub-unit and
inhibits the translocation of peptides. Azithromycin acts bacteriostatic.
PK/PD Relationship:
The efficacy of azithromycin is best described by the relationship AUC/MIC, where
AUC describes the area under the curve and MIC represents the mean inhibitory
concentration of the microbe concerned.
Mechanism of resistance:
Resistance to azithromycin may be natural or acquired. There are 3 main
mechanisms of resistance affecting azithromycin:
- Efflux: resistance may be due to an increase in the number of efflux pumps on the
cell membrane. In particular, 14- and 15-link macrolides are affected. (M-phenotype)
- Alterations of the cell structure: methylisation of the 23s rRNS may reduce the
affinity of the ribosomal binding sites, which can result in microbial resistance to
macrolides, lincosamides and group B streptogramins (SB) (MLSB-phenotype).
- enzymatic deactivation of macrolides is only of limited clinical significance.
In the presence of the M-phenotype, complete cross resistance exists between
azithromycin and clarithomycin, erythromycin and roxithromycin. With the MLSBphenotype, additional cross resistance exists with clindamycin and streptogramin B.
A partial cross resistance exists with spiramycin.
Breakpoints
According to EUCAST (European Committee on Antimicrobial Susceptibility Testing)
the following breakpoints have been defined for azithromycin (2009-06-01):

Absorption
Bioavailability after oral administration is approximately 37%. Peak concentrations in
the plasma 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.
Concentrations in the infected tissues, such as lungs, tonsil and prostate are higher
than the MRC90 of the most frequently occurring pathogens after a single dose of
500 mg.
Binding to serum proteins varies in dependence on exposure in concentration range
from 12% in 0,5 microgram/ml up to 52% in 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
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. In the
same source, 10 metabolites were also detected, which were formed through N- and
O-demethylation, hydroxylation of desosamine- and aglycone rings and degradation
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 than are released from inactive phagocytes. In animal
models the azithromycin concentrations measured in inflammation foci were high.
Pharmacokinetics in Special Populations
Renal insufficiency
Following a single oral dose of azithromycin 1 g, mean Cmax and AUC0-120 increased by
5.1% and 4.2% respectively, in subjects with mild to moderate renal impairment
(glomerular filtration rate of 10-80 ml/min) compared with normal renal function
(GFR > 80 ml/min). In subjects with severe renal impairment, the mean Cmax and
AUC0-120 increased 61% and 33% respectively compared to normal.
Hepatic insufficiency
In patients with mild to moderate hepatic impairment, there is no evidence of a
marked change in serum pharmacokinetics of azithromycin compared to normal
hepatic function. In these patients, urinary recovery of azithromycin appears to
increase perhaps to compensate for reduced hepatic clearance.
Elderly
The pharmacokinetics of azithromycin in elderly men was similar to that of young
adults; however, in elderly women, although higher peak concentrations (increased
by 30-50%) were observed, no significant accumulation occurred.
Infants, toddlers, children and adolescents
Pharmacokinetics have been studied in children aged 4 months – 15 years taking
capsules, granules or suspension.. At 10 mg/kg on day 1 followed by 5 mg/kg on days
2-5, the Cmax achieved is slightly lower than adults with 224 ug/l in children aged 0.6-
5 years and after 3 days dosing and 383 ug/l in those aged 6-15 years. The t1/2 of 36 h
in the older children was within the expected range for adults.
 

In animal tests in which the dosages used amounted to 40 times the clinical
therapeutic dosages, azithromycin was found to have caused reversible
phospholipidosis, but as a rule, no true toxicological consequences were observed
which were associated with this. The relevance of this finding to humans receiving
azithromycin in accordance with the recommendations 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 invivo and in-vitro test models.
Reproductive toxicity:
In animal studies of the embryotoxic effects of the substance, no teratogenic effect
was observed in mice and rats. In rats, azithromycin dosages of 100 and 200 mg/kg
bodyweight/day led to mild retardations in foetal ossification and in maternal weight
gain. In peri- and postnatal studies in rats, mild retardation in physical development
and delay in reflex development following treatment with 50 mg/kg/day
azithromycin and above were observed.
 

Lactose, maize starch, magnesium stearate, sodium lauryl Sulphate, Talc & EGC size 0
 

Not applicable.
 

Store below 30°C.
 

PVC-PVDC/Aluminum blister pack
Packs of 6 capsules
 

No special requirements.