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Azithromycin 250mg Film-Coated Tablets

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Azithromycin 250 mg Film-Coated Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 250 mg azithromycin as dihydrate.

Excipients:

For a full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Film-coated tablet.

White, oblong, biconvex film-coated tablet with imprint Al 250 on one side.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Azithromycin is indicated for the following bacterial infections induced by microorganisms susceptible to azithromycin (see sections 4.4 and 5.1):

-    infections of the lower respiratory tract: acute: bronchitis and mild to moderate community-acquired pneumonia

-    infections of the upper respiratory tract: sinusitis and pharyngitis/tonsillitis

-    Acute otitis media (see section 4.4)

-    Infections of the skin and soft tissue 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.

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).

4.2    Posology and method of administration

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.

Children and adolescents over 45 kg body weight, adults and the elderly:

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 aimed at adults and adolescents over 16 years of age. Children and adolescents under 45 kg 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.

Patients with renal impairment

No dose adjustment is necessary in patients with mild to moderate renal impairment (GFR 10-80 ml/min) (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 4.3 and 4.4).

4.3    Contraindications

Hypersensitivity to azithromycin, erythromycin any macrolide or ketolide antibiotics or to any of the excipients.

4.4    Special warnings and precautions for use

Allergic reactions

In rare cases azithromycin is reported to have caused serious allergic reactions (rarely fatal) such as angioneurotic oedema and anaphylaxis. Some of these reactions 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 10-80 ml/min). Caution is advised in patients with severe renal impairment (GFR < 10 ml/min) as systemic exposure may be increased (33% increases have been observed) (see section 5.2).

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. A similar effect with azithromycin cannot be completely ruled out in patients at increased risk for prolonged cardiac repolarisation (see section 4.8). Therefore:

-    Azithromycin should not be used in patients with congenital or documented acquired QT prolongation.

-    Azithromycin should not be used concurrently with other active substances that prolong QT interval such as antiarrhythmics of classes IA and III, cisapride and terfenadine (see section 4.5).

-    Azithromycin should not be used in patients with electrolyte disturbance, particularly in cases of hypokalaemia and hypomagnesaemia

-    Azithromycin should not be used in patients with clinically relevant bradycardia, cardiac arrhythmia or severe cardiac insufficiency.

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.

In areas with a high incidence of erythromycin A resistance, it is especially important to take into consideration the evolution of the pattern of susceptibility to azithromycin and other antibiotics.

As for other macrolides, high resistance rates of Streptococcus pneumoniae (> 30 %) 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.

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.

Superinfections

Attention should be paid to possible symptoms of superinfections caused by nonsensitive causal agents such as fungi. A superinfection may require an interruption of the azithromycin treatment and initiation of adequate measures.

Neurological or _psychiatric diseases

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

Myasthenia gravis

Exacerbations of the symptoms of myasthenia gravis and new onset of myasthenia syndrome have been reported in patients receiving azithromycin (see section 4.8).

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. 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 allpatients who present with diarrhoea following antibiotic use. A careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. Should pseudomembranous colitis be induced by azithromycin, then antiperistaltics should be contraindicated.

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.

The safety and efficacy of azithromycin for the prevention or treatment of Mycobacterium avium complex (MAC) infection 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 did fall by approximately 25 %. Azithromycin should be taken at least 1 hour before or 2 hours after the antacid.

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.

Digoxin

In some patients certain macrolide antibiotics have been reported to have impaired the metabolism of digoxin in the intestine. Consequently, in the case of patients receiving azithromycin and digoxin, the possibility of a rise in the digoxin concentrations should be borne in mind.

Zidovudine 1000 mg single doses and 1200 mg or 600 mg multiple doses of azithromycin had only a slight effect upon the pharmacokinetics of zidovudine or its glucuronide metabolite in the plasma or upon excretion in the urine. However, the administration of azithromycin increased the concentrations of phosphorylated zidovudine, the clinically active metabolite, in mononuclear cells in the peripheral circulation. The clinical significance of this finding is unclear, but it may be of benefit to patients.

Didanosine (dideoxyinosin)

Daily dosages of 1200 mg azithromycin co-administered with 400mg/day didanosine in 6 HIV-positive volunteers appeared to have no effect on the steady-state pharmacokinetics of didanosine compared to placebo.

Azithromycin does not interact significantly with the hepatic cytochrome P450 system. It is not believed to be subject to the pharmacokinetic interactions seen with erythromycin and other macrolides. Hepatic cytochrome P450 induction or inactivation via cytochrome-metabolite complex does not occur with azithromycin.

The combined use of ergot derivatives and azithromycin may in theory cause ergotism, and consequently their combined use is not recommended (see also section 4.4).

Pharmacokinetic studies have been conducted between azithromycin and the following agents 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 concentration of atorvastatin (based on an 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-like oral anticoagulants

In a pharmacokinetic interaction study, azithromycin did not alter the anticoagulant effect of 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 prothrombin time monitoring when azithromycin is used in patients receiving coumarin-type oral anticoagulants.

Ciclosporin

In a pharmacokinetic study with healthy volunteers given oral azithromycin 500 mg/day for 3 days then 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 agents. If combination treatment is necessary, the ciclosporin levels should be carefully monitored and the dosage should be 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.

Co-administration of a single dose of 1,200 mg azithromycin did not alter the pharmacokinetics of a single dose of 800 mg fluconazole. Total exposure and half-life of azithromycin were unchanged by the co-administration of fluconazole, however, a clinically insignificant decrease in Cmax (18%) of azithromycin was observed.

Indinavir

Co-administration of a single dose of 1,200 mg azithromycin had no statistically significant effect on the pharmacokinetics of indinavir administered as 800 mg three times daily for 5 days.

Methylprednisolone

In a pharmacokinetic interaction study in healthy volunteers, azithromycin had no significant effect on the pharmacokinetics of methylprednisolone.

Midazolam

In healthy volunteers, co-administration of azithromycin 500 mg/day for 3 days did not cause clinically significant changes in the pharmacokinetics and pharmacodynamics of a single 15 mg dose of midazolam.

Nelfinavir

Co-administration of azithromycin (1,200 mg) and nelfinavir at steady-state (750 mg three times daily) resulted in increased azithromycin concentrations. No clinically significant adverse effects were observed and no dose adjustment is required.

Rifabutin

Co-administration of azithromycin and rifabutin did not affect the serum concentrations of either agent.

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 three days) on the AUC and Cmax of sildenafil or its major circulating metabolite.

Terfenadine

In pharmacokinetic studies there are no reports of interactions 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.

Azithromycin should be administered with caution in combination with terfenadine.

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/sulphamethoxazole

Co-administration of trimethoprim/sulphamethoxazole DS (160 mg/800 mg) for 7 days with azithromycin 1,200 mg on day 7 had no significant effect on peak concentrations, total exposure or urinary excretion of either trimethoprim or sulphamethoxazole. Azithromycin serum concentrations were similar to those seen in other studies.

Cisapride

Cisapride is metabolized in the liver by the enzyme CYP3A4. Because macrolides inhibit this enzyme, concomitant administration of cisapride may cause the increase of QT interval prolongation, ventricular arrhythmias and torsade de pointes.

Astemizol, triazolam, midazolam, 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 potentiation of its effect during concomitant use of the macrolide antibiotic erythromycin.

Substances that prolong the QT interval

Azithromycin should not be used concurrently with other active substances that prolong the QT interval (see section 4.4).

4.6 Pregnancy and lactation

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 fetus due to azithromycin was found. There are, however, no adequate and well controlled studies in pregnant women. As animal studies are not always predictive of human response, azithromycin should be used during pregnancy only if clearly needed.

Lactation

There is no data on secretion in breast milk. As many agents are excreted in breast 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.

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

About 13% of patients included in clinical trials reported adverse events, most commonly gastro-intestinal disorders.

System organ class

Very common >1/10

Common >1/100, <1/10

Uncommon

>1/1000,

<1/100

Rare

>1/10000,

<1/1000

Not known

Infections

and

infestations

candidiasis oral candidiasis vaginal infection

Blood and lymphatic system disorders

lymphocyte

count

decreased

eosinophil

count increased

blood

bicarbonate

decreased

leucopenia

mtropenia

thrombocytope

nia

haemolytic

anaemia

Immune

system

disorders

angioedema

hypersensitivit

y

anaphylactic reaction (see section 4.4)

Psychiatric

disorders

nervousness

agitation depersonalisati on, in elderly patients delirium may occur.

aggression

anxiety

Nervous

system

disorders

dizziness

headache

paraesthesia

dysgeusia

hypoaesthesia

somnolence

insomnia

syncope

convulsions

psychomotor

hyperactivity

anosmia

parosmia

ageusia

myasthenia

System organ class

Very common >1/10

Common >1/100, <1/10

Uncommon

>1/1000,

<1/100

Rare

>1/10000,

<1/1000

Not known

gravis (see section 4.4)

Eye

disorders

visual

impairment

Ear and

labyrinth

disorders

deafness

hearing

impaired

tinnitus

vertigo

Cardiac

disorders

palpitations

torsades de

pointes

arrhythmia

including

ventricular

tachycardia

(see section

4.4)

electrocardiogr am QT

prolonged (see section 4.4)

Vascular

disorders

hypotension

Gastrointes

tinal

disorders

diarrhoea abdominal pain nausea flatulence

vomiting

dyspepsia

anorexia

gastritis constipation loose stools

discolouration of the teeth

tongue

discolouration pancreatitis pseudomembra nous colitis (see section 4.4)

Hepatobilia

ry

disorders

hepatitis aspartate aminotransfera se increased alanine

aminotransfera se increased blood bilirubin increased

hepatic

function

abnormal

hepatic failure

which has

rarely resulted

in death (see

section 4.4)

hepatitis

fulminant

hepatic

necrosis

jaundice

cholestatic

Skin and subcutaneo us tissue disorders

rash

pruritus

Stevens-

Johnson

syndrome

photosensitivit

y reaction

urticaria

maculopapular

rash

toxic epidermal necrolysis erythema multiforme

Musculoske

letal,

connective tissue and bone disorders

arthralgia

System organ class

Very common >1/10

Common >1/100, <1/10

Uncommon

>1/1000,

<1/100

Rare

>1/10000,

<1/1000

Not known

Renal and urinary tract disorders

blood urea

increased

blood

creatinine

increased

interstitial nephritis acute renal failure'

Reproducti ve system and breast disorders

vaginitis

General

disorders

and

administrat ion site conditions

fatigue

chest pain oedema malaise asthenia

pain

Investigatio

ns

blood

potassium

abnormal

4.9 Overdose

The undesirable effects at dosages in excess of the recommended dosages were similar to those after normal dosages.

Symptoms

The typical symptoms of an overdose with macrolide antibiotics include reversible loss of hearing, severe nausea, vomiting and diarrhoea.

Treatment

In cases of overdose the administration of medicinal charcoal and general symptomatic treatment and measures to support vital functions are indicated where necessary.

5 PHARMACOLOGICAL PROPERTIES

5.1 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 lactone 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.

Mode 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.

(Cross)-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 (2009):

•    Staphylococcus spp.: susceptible < 1 mg/l and resistant >2 mg/l

•    Haemophilus influenzae: susceptible < 0.12 mg/l and resistant > 4 mg/l

•    Moraxella catarrhalis: susceptible < 0.5 mg/l and resistant > 0.5 mg/l

•    Streptococcus spp. including groups A, B, C, G and Streptococcus pneumoniae: susceptible < 0.25 mg/l and resistant > 0.5 mg/l

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.

Species for which acquired 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 Chlamydia trachomatis

Listeria spp.

Mycobacterium avium Complex

Mycoplasma pneumoniae

Ureaplasma urealyticum

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

Species

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.

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.

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) than in the plasma. This indicates that the substance is extensively bound in the tissues (steady-state volume of distribution approximately 31 l/kg). The mean maximum concentration observed (Cmax) after a single dose of 500 mg is approximately 0.4 pg/ml, 2-3 hours after administration. 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. Three days after administration of 500 mg as a single dose or in divided doses concentrations of 1.3-4.8 pg/g, 0.6-2.3 gg/g, 2.0-2.8 gg/g and 0-0.3 gg/ml are found in lung, prostate, tonsil and serum respectively.

Mean peak concentrations measured in peripheral leukocytes are higher than the MIC90 of the most common pathogens.

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

The binding of azithromycin to plasma proteins is variable and varies from 52% at 0.005 gg/ml to 18% at 0.5 gg/ml, depending on the serum concentration.

Metabolism and excretion

The terminal plasma elimination half-life follows the tissue depletion half-life of 2 to 4 days. 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. 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 gg/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). A comparison of HPLC and microbiological determination suggests that the metabolites do not play a role in the micro-biological activity of azithromycin.

Pharmacokinetics in special populations Renal insufficiency

Following a single oral dose of azithromycin 1g, 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 (GFR < 10 ml/min), the mean Cmax and AUC0-120 increased 61% and 35% 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. 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.

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 gg/l in children aged 0.6-5 years and after 3 days dosing and 383 gg/l in those aged 6-15 years. The t1/2 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 foetal 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

Core:

Calcium hydrogen phosphate, anhydrous

Hypromellose

Maize starch

Starch, pregelatinised

Cellulose, microcrystalline

Magnesium stearate Sodium laurilsulfate.

Coating:

Hypromellose Titanium dioxide (E171)

Polysorbate 80 Talc

6.2    Incompatibilities

Not applicable.

6.3    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

Azithromycin 250 mg tablets are packed in PVC/Aluminium blisters. Pack sizes: 2, 4, 6, 10 tablets.

Not all pack sizes may be marketed.

6.6    Special precautions for disposal

No special requirements.

7    MARKETING AUTHORISATION HOLDER

TEVA UK Limited Brampton Road, Hampden Park Eastbourne, BN22 9AG England

8    MARKETING AUTHORISATION NUMBER(S)

PL 00289/0584

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

27th July 2006

10    DATE OF REVISION OF THE TEXT

09/07/2011