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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Azithromycin 500 mg Film-coated Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Azithromycin 500 mg Film-coated Tablets:

Each film-coated tablet contains 500 mg azithromycin (as azithromycin monohydrate).

Excipients:

Azithromycin 500 mg Film-coated Tablets: Each film-coated tablet contains 0.36 mg of soya lecithin.

For a full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Film-coated tablet.

Azithromycin 500 mg Film-coated Tablets: white to off-white, elongated, with a breakline on one side and a dividing line on the other side.

Azithromycin 500 mg Film-coated Tablets only: The tablet can be divided into equal doses.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

For treatment of the following infections, when caused by micro-organisms sensitive to azithromycin (see section 4.4 and 5.1):

•    Acute bacterial sinusitis (adequately diagnosed)

•    Acute bacterial otitis media (adequately diagnosed)

Pharyngitis, tonsillitis

•    Acute exacerbation of chronic bronchitis (adequately diagnosed)

•    Mild to moderately severe community acquired pneumonia

•    Infections of the skin and soft tissues of mild to moderate severity e.g. folliculitis, cellulitis, erysipelas

•    Uncomplicated Chlamydia trachomatis urethritis and cervicitis

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2 Posology and method of administration

For oral use.

Azithromycin tablets should be given as a single daily dose. The tablets can be taken with or without food. The duration of treatment in each of the infectious diseases is given below.

Adults, elderly, children and adolescents over 45 kg body weight

The total dosage of azithromycin is 1500 mg which is spread over three days (500 mg once daily).

Alternatively, the dosage can be spread over five days (500 mg as a single dose on the first day and thereafter 250 mg once daily).

In uncomplicated Chlamydia trachomatis urethritis and cervicitis the dosage is 1000 mg as a single oral dose.

For sinusitis, treatment is indicated for adults and adolescents 16 years of age and over.

Children and adolescents 45 kg and under body weight

Tablets are not indicated for these patients. Other pharmaceutical forms of azithromycin, e.g. suspensions may be used.

Elderly

No dose adjustments are required for elderly patients. Since elderly patients can be patients with ongoing proarrhythmic conditions a particular caution is recommended due to the risk of developing cardiac arrhythmia and torsades de pointes (see section 4.4).

Patients with renal impairment

No dose adjustment is necessary in patients with mild to moderate renal impairment (GFR 30-80 ml/min/1.73m²) (see section 4.4).

Patients with hepatic impairment

A dose adjustment is not necessary for patients with mild to moderately impaired liver function (Child-Pugh class A or B) (see section 4.4).

4.3 Contraindications

The use of this product is contraindicated in patients with hypersensitivity to azithromycin, erythromycin, any macrolide or ketolide antibiotic, or to any excipient listed in section 6.1.

Azithromycin contains soya oil. If you are allergic to peanut or soya, do not use this medicinal product.

4.4 Special warnings and precautions for use

Allergic reactions

As with erythromycin and other macrolides, rare serious allergic reactions (rarely fatal) 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.

Renal impairment

No dose adjustment is necessary in patients with mild to moderate renal impairment (GFR 30-80 ml/min/1.73m²). Caution is advised in patients with severe renal impairment (GFR < 30 ml/min/1.73m²) as systemic exposure may be increased (see section 5.2).

Hepatic impairment

Since 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 alkaloids and azithromycin

The concurrent use of ergot alkaloids and macrolide antibiotics has been found to accelerate the development of ergotism. The interactions between ergot alkaloids and azithromycin have not been studied. The development of ergotism is however possible, so that azithromycin and ergot alkaloid derivatives should not be administered simultaneously.

QT prolongation

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 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 acquired QT prolongation.

•    concurrently with other active substances that 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 (see section 4.5).

•    with electrolyte disturbance, particularly in cases of hypokalaemia and hypomagnesaemia

•    with clinically relevant bradycardia, cardiac arrhythmia or severe cardiac insufficiency.

Myasthenia gravis and azithromycin

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).

Superinfections

As with any antibiotic preparation, observation for signs of superinfection with nonsusceptible organisms, including fungi is recommended.

Clostridium difficile associated diarrhoea

Clostridium difficile associated diarrhoea (CDAD) has been reported with use of nearly all antibacterial agents, including azithromycin, and may range in severity from mild diarrhoea 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 diarrhoea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

The following should be considered before prescribing azithromycin:

Azithromycin film-coated tablets are not suitable for treatment of severe infections where a high concentration of the antibiotic in the blood is rapidly needed.

As for other macrolides, high resistance rates of Streptococcus pneumoniae have been reported for azithromycin in some European countries (see section 5.1). This should be taken into account when treating infections caused by Streptococcus pneumoniae.

The main causative agent of soft tissue infections, Staphylococcus aureus, is frequently resistant to azithromycin. Therefore, susceptibility testing is considered a precondition for treatment of soft tissue infections with azithromycin.

Pharyngitis/tonsillitis

Azithromycin is not the substance of first choice for the treatment of pharyngitis and tonsillitis caused by Streptococcus pyogenes. For this and for the prophylaxis of acute rheumatic fever penicillin is the treatment of first choice.

Sinusitis

Often, azithromycin is not the substance of first choice for the treatment of sinusitis.

Acute otitis media

Often, azithromycin is not the substance of first choice for the treatment of acute otitis media.

Infected burn wounds

Azithromycin is not indicated for the treatment of infected burn wounds.

Sexually transmitted disease

In case of sexually transmitted diseases a concomitant infection by T. pallidum should be excluded.

Neurological or psychiatric diseases

Azithromycin should be administered with caution to patients suffering from neurological or psychiatric diseases.

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.

Due to cross-resistance existing among macrolides, in areas with a high incidence of erythromycin resistance, it is especially important to take into consideration the evolution of the pattern of susceptibility to azithromycin and other macrolides (see section 5.1).

Azithromycin is not the first choice for the empirical treatment of infections in areas where the prevalence of resistant isolates is 10% or more (see section 5.1).

Paediatric population

Safety and efficacy for the prevention or treatment of Mycobacterium Avium Complex in children have not been established.

4.5 Interaction with other medicinal products and other forms of interaction

Antacids

When studying the effect of simultaneously administered antacid on the pharmacokinetics of azithromycin, no overall change has been observed in the bioavailability, although the peak concentrations of azithromycin measured in the plasma reduced by approximately 25 %. In patients receiving both azithromycin and antacids, the drugs should not be taken simultaneously. Azithromycin should be taken at least 1 hour before or 2 hours after the antacid.

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 (Dideoxyinosine)

Coadministration 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(P-gp substrates)

Concomitant administration of macrolide antibiotics , including azithromycin, with P-glycoprotein substrates such as digoxin, 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

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 and alfentanil

No data are available on interactions with astemizole 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.

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). 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.

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 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 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 C_max and AUC_0-5 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 pharmacokinetic 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 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

Coadministration 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

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 C_max, 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, 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.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from use of azithromycin in pregnant women. In reproduction toxicity studies in animals, azithromycin was shown to pass the placenta, but no teratogenic effects were observed. The safety of azithromycin has not been confirmed with regard to the use of the active substance during pregnancy. Therefore, azithromycin should only be used during pregnancy if the benefit outweighs the risk.

Breastfeeding

Azithromycin passes into human breast milk, but there are no adequate and well-controlled clinical studies in nursing women that have characterized the pharmacokinetics of azithromycin excretion into human breast milk. Because it is not known whether azithromycin may have adverse effects on the breast-fed infant, nursing should be discontinued during treatment with azithromycin. Among other things diarrhoea, fungus infection of the mucous membrane as well as sensitisation is possible in the nursed infant. It is recommended to discard the milk during treatment and up until 2 days after discontinuation of treatment. Nursing may be resumed thereafter.

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.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. However, the possibility of undesirable effects like dizziness and convulsions should be taken into account when performing these activities.

4.8 Undesirable effects

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 (>1A0); 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:

	Very Common	Common	Uncommon	Rare	Not Known
Infections and Infestations			Candidiasis, vaginal infection, pneumonia, fungal infection, bacterial infection, pharyngitis, gastroenteritis, respiratory disorder, rhinitis, oral candidiasis		Pseudomembranous colitis (see section 4.4)
Blood and Lymphatic System Disorders			Leukopenia, neutropenia, eosinophilia		Thrombocytopenia, haemolytic anaemia
Immune System Disorders			Angioedema, hypersensitivity		Anaphylactic reaction (see section 4.4)
Metabolism and Nutrition Disorders			Anorexia
Psychiatric Disorders			Nervousness, insomnia	Agitation	Aggression, anxiety, delirium, hallucination
Nervous System Disorders		Headache	Dizziness, somnolence, dysgeusia, paraesthesia		Syncope, convulsion, hypoaesthesia, psychomotor hyperactivity, anosmia, ageusia, parosmia, myasthenia gravis (see Section 4.4)
Eye Disorders			Visual impairment
Ear and Labyrinth Disorders			Ear disorder, vertigo		Hearing impairment including deafness and/or tinnitus
Cardiac Disorders			Palpitations		Torsades de pointes (see section 4.4), arrhythmia (see section 4.4)    including ventricular tachycardia, Electrocardiogram QT prolonged (see section 4.4)
Vascular Disorders			Hot flush		Hypotension
Respiratory, thoracic and mediastinal disorders			Dyspnoea, epistaxis
Gastrointestinal Disorders	Diarrhoea	Vomiting, abdominal pain, nausea	Constipation, flatulence, dyspepsia, gastritis, dysphagia,		Pancreatitis, tongue discolouration

			abdominal distension, dry mouth, eructation, mouth ulceration, salivary hypersecretion
Hepatobiliary Disorders			Hepatitis	Hepatic function abnormal, jaundice cholestatic	Hepatic failure (which has rarely resulted in death) (see section 4.4), Hepatitis fulminant, Hepatic necrosis
Skin and Subcutaneous Tissue Disorders			Rash, pruritus, urticaria, dermatitis, dry skin, hyperhidrosis	Photosensitivity reaction	Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme
Musculoskeletal and Connective Tissue Disorders			Osteoarthritis, myalgia, back pain, neck pain		Arthralgia
Renal and Urinary Disorders			Dysuria, renal pain		Renal failure acute, nephritis interstitial
Reproductive system and breast disorders			Metrorrhagia, testicular disorder
General Disorders and Administration Site Conditions			Oedema, asthenia, malaise, fatigue, face oedema, chest pain, pyrexia, pain, peripheral oedema
Investigations		Lymphocyte count decreased, eosinophil count increased, blood bicarbonate decreased, basophils increased, monocytes increased, neutrophils increased	Aspartate aminotransferase increased, alanine aminotransferase increased, blood bilirubin increased, blood urea increased, blood creatinine increased, blood potassium abnormal, blood alkaline phosphatase increased, chloride increased, glucose increased, platelets increased, haematocrit decreased, bicarbonate increased, abnormal sodium
Injury, poisoning and procedural complications			Post procedural complication

Adverse reactions possibly or probably related to Mycobacterium Avium Complex prophylaxis and treatment based on clinical trial experience and post-marketing surveillance.

These adverse reactions differ from those reported with immediate release or the prolonged release formulations, either in kind or in frequency:

	Very Common	Common	Uncommon
Metabolism and Nutrition Disorders		Anorexia
Nervous System Disorders		Dizziness, headache, paraesthesia, dysgeusia	Hypoaesthesia
Eye Disorders		Visual impairment
Ear and Labyrinth Disorders		Deafness	Hearing impaired, tinnitus
Cardiac Disorders			Palpitations
Gastrointestinal Disorders	Diarrhoea, abdominal pain, nausea, flatulence, abdominal discomfort, loose stools
Hepatobiliary Disorders			Hepatitis
Skin and Subcutaneous Tissue Disorders		Rash, pruritus	Stevens-Johnson syndrome, photosensitivity reaction
Musculoskeletal and Connective Tissue Disorders		Arthralgia
General Disorders and Administration Site Conditions		Fatigue	Asthenia, malaise

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via www.mhra.gov.uk/yellowcard

4.9 Overdose

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.

5 PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

Pharmacotherapeutic group: Antibacterials for systemic use; macrolides. ATC Code: J01FA10.

Azithromycin is a macrolide antibiotic belonging to the azalide group.

The molecule is constructed by adding a nitrogen atom to the Iactone ring of erythromycin A. The chemical name of azithromycin is 9-deoxy-9a-aza-9a-methyl-9a-homo-erythromycin A. The molecular weight is 749.0.

Mechanism of action

The action mechanism of azithromycin is based upon the suppression of bacterial protein synthesis, by binding to the 50 S subunit and thus inhibiting the translocation of peptides.

Mechanism of resistance

Generally, the resistance of different bacterial species to macrolides has been reported to occur by three mechanisms associated with target site alteration, antibiotic modification, or altered antibiotic transport (efflux). The efflux in streptococci is conferred by the mef genes and results in a macrolide-restricted resistance (M phenotype). Target modification is controlled by erm encoded methylases.

A complete cross-resistance exists among erythromycin, azithromycin, other macrolides and lincosamides for Streptococcus pneumoniae, beta-haemolytic streptococci of group A, Enterococcus spp. and Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA).

Penicillin-sensitive S. pneumoniae are more likely to be susceptible to azithromycin than are penicillin-resistant strains of S. pneumoniae. Methicillin-resistant S. aureus (MRSA) is less likely to be susceptible to azithromycin than methicillin-sensitive S. aureus (MSSA).

The induction of significant resistance in both in vitro and in vivo models is <1 dilution rise in MICs for S. pyogenes, H. influenzae and Enterobacterciae after nine sub-lethal passages of active substance and three dilution increase for S. aureus and development of in vitro resistance due to mutation is rare.

Breakpoints:

Azithromycin susceptibility breakpoints for typical bacterial pathogens:

EUCAST (European Committee on Antimicrobial Susceptibility Testing, version 3.1, 11-02-2013)

	MIC breakpoint (mg/L)
Pathogens	Susceptible (mg/L)	Resistant (mg/L)

Staphylococcus spp.	< 1	> 2
Streptococcus spp. (Group A, B, C, G)	< 0.25	> 0.5
Streptococcus pneumoniae	< 0.25	> 0.5
Haemophilus influenzae	< 0.12	> 4
Moraxella catarrhalis	< 0.25	> 0.5
Neisseria gonorrhoeae	< 0.25	> 0.5

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 1: Antibacterial spectrum of azithromycin

Species
Commonly susceptible species
Aerobic Gram-positive
Corynebacterium diphteriae
Streptococcus pneumoniae Erythromycin-sensitive Penicillin-sensitive
Streptococcus pyogenes Erythromycin-sensitive
Aerobic Gram-negative
Bordetella pertussis
Escherichia coli-ETEC
Escherichia coli-EAEC
Haemophilus influenzae Haemophilus ducreyi
Legionella spp.
Moraxella catarrhalis Erythromycin-sensitive Erythromycin-intermediate
Pasteurella multocida
Anaerobic
Fusobacterium nucleatum Fusobacterium necrophorum
Prevotella spp.
Porphyromonas spp.
Propionibacterium spp.
Other micro-organisms
Chlamydia pneumoniae

Species
Chlamydia trachomatis
Listeria spp.
Mycobacterium avium Complex
Mycoplasma pneumoniae
Species for which acquired resistance may be a problem
Aerobic Gram-positive
Staphylococcus aureus Methicillin-susceptible
Coagulase-neg. staphylococci Methicillin-susceptible+
Streptococcus pneumoniae Penicillin-intermediate Penicillin-resistant Erythromycin-intermediate
Streptococcus pyogenes Erythromycin-intermediate
Streptococci viridans group Penicillin-intermediate
Aerobic Gram-negative
Moraxella catarrhalis Erythromycin-resistant
Anaerobic
Peptostreptococcus spp.
Inherently resistant organisms
Aerobic Gram positive
Corynebacterium spp.

Species
Enterococcus spp.
Staphylococci MRSA, MRSE
Streptococcus pneumoniae Erythromycin-resistant Penicillin & Erythromycin resistant
Streptococcus pyogenes Erythromycin-resistant
Streptococci viridans group Penicillin-resistant Erythromycin-resistant
Aerobic Gram-negative
Pseudomonas aeruginosa
Anaerobic
Bacteroides fragilis group

+ Resistance is greater than 50%.

5.2 Pharmacokinetic properties

Absorption

Following oral administration the bio-availability of azithromycin is approximately 37%. Peak plasma levels are reached after 2-3 hours. The mean maximum concentration observed (Cmax) after a single dose of 500 mg is approximately 0.4 pg/ml.

Distribution

Orally administered azithromycin is widely distributed throughout the body. Pharmacokinetic studies have shown considerably higher azithromycin concentrations in the tissues (up to 50 times the maximum concentration observed in the plasma). This indicates that the substance is extensively bound in the tissues (steady-state volume of distribution approximately 31 l/kg). With the recommended dosage no accumulation in the serum/plasma occurs. Accumulation does occur in the tissues where the levels are much higher than in the serum/plasma. Concentrations in target tissues such as lung, tonsil, and prostate exceed the MIC90 for likely pathogens after a single dose of 500 mg.

In experimental in vitro and in vivo studies, azithromycin accumulates in phagocytes; release is promoted by active phagocytosis. In animal models this process appears to contribute to the accumulation of azithromycin in tissue.

The binding of azithromycin to plasma proteins is variable and varies from 52% at 0.005 pg/ml to 18% at 0.5 pg/ml.

Biotransformation and Excretion

The terminal plasma elimination half-life follows the tissue depletion half-life of 2 to 4 days.

Approximately 12% of an intravenously administered dose is excreted in unchanged form with the urine over a period of 3 days; the major proportion in the first 24 hours. Concentrations of up to 237 pg/ml azithromycin, 2 days after a 5-day course of treatment, have been found in human bile, together with 10 metabolites (formed by N- and O-demethylation, by hydroxylation of the desosamine and aglycone rings, and by splitting of the cladinose conjugate). Investigations suggests that the metabolites do not play a role in the micro-biological activity of azithromycin.

Pharmacokinetics in special _populations Renal impairment

Following a single oral dose of azithromycin 1g, mean C_max and AUC₀_i₂₀ increased by 5.1 % and 4.2% respectively, in subjects with mild to moderate renal impairment (glomerular filtration rate of 30-80 ml/min) compared with normal renal function (GFR > 80 ml/min/1.73m²). In subjects with severe renal impairment (GFR < 30 ml/min/1.73m²), the mean C_max and AUC₀_i₂₀ increased 61% and 35% respectively compared to normal.

Hepatic impairment

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. There are no data on azithromycin use in cases of more severe hepatic impairment.

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.

In elderly volunteers (>65 years), higher (29 %) AUC values were always observed after a 5-day course than in younger volunteers (<45 years). However, these differences are not considered to be clinically relevant; no dose adjustment is therefore recommended.

Paediatric population

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 C_max achieved is slightly lower than adults with 224 pg/l in children aged 0.65 years and after 3 days dosing and 383 pg/l in those aged 6-15 years. The t_1/2 of 36h in the older children was within the expected range for adults.

5.3 Preclinical safety data

In animal studies using exposures 40 times those achieved at the clinical therapeutic dosages, azithromycin was found to have caused reversible phospholipidosis, but as a rule there were no associated toxicological consequences. The relevance of this finding to humans receiving azithromycin in accordance with the recommendations is unknown.

Electrophysiological investigations have shown that azithromycin prolongs the QT interval.

Carcinogenic potential

Long-term studies in animals have not been performed to evaluate carcinogenic potential.

Mutagenic _ potential

There was no evidence of a potential for genetic and chromosome mutations in in vivo and in vitro test models.

Reproductive toxicity

No teratogenic effects were observed in embryotoxicity studies in rats after oral administration of azithromycin. In rats, azithromycin dosages of 100 and 200 mg/kg body weight/day led to mild retardations in fetal ossification and in maternal weight gain. In peri- and postnatal studies in rats, mild retardations following treatment with 50 mg/kg/day azithromycin and above were observed

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Tablet Core:

Microcrystalline cellulose (E460)

Pregelatinised starch (maize starch)

Sodium starch glycolate (Type A)

Anhydrous colloidal silica (E551)

Sodium lauryl sulphate Magnesium stearate (E470b)

Tablet Film-coating:

Polyvinyl alcohol (partially hydrolysed)

Titanium dioxide (E171)

Talc (E553b)

Soya lecithin Xanthan gum (E415).

Incompatibilities

Not applicable.

Shelf life

3 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

PVC/PVDC/aluminium blister pack.

Pack sizes:

Azithromycin 500 mg Film-coated Tablets: 2, 3, 6, 12, 24, 30, 50 and 100 film-coated tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

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

7    MARKETING AUTHORISATION HOLDER

Generics [UK] Limited t/a Mylan

Station Close

Potters Bar

Hertfordshire

EN6 1TL

United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 04569 0926

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

01/01/2012

10    DATE OF REVISION OF THE TEXT

03/12/13