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:
Azithromycin capsules should be given as a single daily dose.
In common with many other antibiotics Azithromycin capsules should be taken at least 1 hour before or
2 hours after 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: Azithromycin capsules are not suitable for children under 45kg.
Renal impairment:
No dose adjustment is necessary in patients with mild to moderate renal impairment (GFR 10 - 80ml/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:
Azithromycin capsules are for oral administration only.

Hypersensitivity
As with erythromycin and other macrolides, serious allergic reactions including angioneurotic oedema
and anaphylaxis (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.

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
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucosegalactose
malabsorption should not take this medicine.
This medicinal product contains sulphur dioxide which may rarely cause severe hypersensitivity
reactions and bronchospasm.
Azithromycin capsules are for oral administration only.

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 24%. 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 20 mg
cetirizine 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 six HIV-positive subjects did not appear to affect the steady-state pharmacokinetics of
didanosine as compared to 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 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).
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).

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 dose of 15 mg 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 who 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 single dose of 600 mg 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 500mg/day azithromycin for 3 days did not
cause clinically significant changes in the pharmacokinetics and pharmacodynamics of a single dose of
15mg 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 was 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.

Triazolam: In 14 healthy volunteers, co-administration of 500mg azithromycin 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 1200mg azithromycin 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
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.

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

Azithromycin 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
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
Common (> 1/100, < 1/10)
Pruritus and rash
Uncommon (> 1/1000, < 1/100)
SJS, photosensitivity reaction, urticarial
Very Rare (< 1/10,000)
DRESS
Not known (cannot be estimated from available data)
TEN, 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)

To reports 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: 2317-2356-2353-2354-2334-2340.

Toll free phone: 8002490000

E-mail: npc.drug@sfda.gov.sa

Website: www.sfda.gov.sa/npc

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
Pharmacotherapeutic group: Antibacterials for systemic use. ATC code: J01FA10
Mode of action:
Azithromycin 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.
Azithromycin demonstrates cross resistance with erythromycin resistant gram positive isolates. A
decrease in macrolide susceptibility over time has been noted particularly in Streptococcus
pneumoniae and Staphylococcus aureus. Similarly, decreased susceptibility has been observed
among Streptococcus viridans and Streptococcus agalactiae (Group B) streptococcus against other
macrolides and lincosamides.
Breakpoints
Azithromycin susceptibility breakpoints for typical bacterial pathogens, as published by EUCAST are:

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.

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 2-4
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 Nand
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.

Maize Starch
Sodium Lauryl Sulfate
Magnesium Stearate
Lactose Anhydrous

Not applicable.

Do not store above 30°C.

Azithromycin capsules are available as:
Pack of 6 capsules. Aluminium-PVC/PVDC blister

No special requirements
Any unused medicinal product or waste material should be disposed of in accordance with local
requirements.