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Azithromycin 200mg/5ml Powder For Oral Suspension

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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Azithromycin 200 mg/ 5 ml Powder for Oral Suspension

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 5 ml prepared suspension contains 204.8 mg azithromycin monohydrate equivalent to 200 mg azithromycin.

Each 1 ml prepared suspension contains 40.96 mg azithromycin monohydrate equivalent to 40 mg azithromycin.

Excipients with known effect:

•    Sucrose 3.70 g/ 5 ml

•    Aspartame (E951) 0.030 g/ 5 ml

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Powder for oral suspension.

White or off-white crystalline powder.

4    CLINICAL PARTICULARS

4.1 Therapeutic indications

Azithromycin powder for oral suspension is indicated for the treatment of the following infections, when caused by microorganisms 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

-    skin and soft tissue infections

-    uncomplicated Chlamydia trachomatis urethritis and cervicitis

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

4.2 Posology and method of administration Adults

In uncomplicated Chlamydia trachomatis urethritis and cervicitis, the dosage is 1,000 mg in one single oral dose.

For all other indications the dosage is 1,500 mg, to be administered as 500 mg per day for three consecutive days. Alternatively the same total dosage (1,500 mg) can also be given over a period of 5 days with 500 mg on the first day and then 250 mg on days 2 to 5.

To treat these patients other pharmaceutical forms are also available.

Elderly

In the elderly the same dosage as for adults can be given.

Children and adolescents (< 18 years)

The total dosage in children aged 1 year and older is 30 mg/kg administered as 10 mg/kg once daily for three days, or over a period of five days starting with a single dose of 10 mg/kg on the first day, followed by doses of 5 mg/kg per day for the following 4 days, according to the tables shown below. There are limited data on use in children younger than 1 year.

Weight

(kg)

3-day therapy

5-day therapy

Contents of the bottle

Day 1-3

10 mg/kg/day

Day 1

10 mg/kg/day

Day 2-5 5 mg/kg/day

10 kg

2.5 ml

2.5 ml

1.25 ml

15 ml

12 kg

3 ml

3 ml

1.5 ml

15 ml

14 kg

3.5 ml

3.5 ml

1.75 ml

15 ml

16 kg

4 ml

4 ml

2 ml

15 ml

17 - 25 kg

5 ml

5 ml

2.5 ml

15 ml

26 - 35 kg

7.5 ml

7.5 ml

3.75 ml

22.5 ml

36 - 45 kg

10 ml

10 ml

5 ml

30 ml

> 45 kg

12.5 ml

12.5 ml

6.25 ml

22.5 ml + 15 ml

The dosage for the treatment of pharyngitis caused by Streptococcus pyogenes is an exception: in the treatment of pharyngitis caused by Streptococcus pyogenes Azithromycin has proved to be effective when it is administered to children as a single dose of 10 mg/kg or 20 mg/kg for 3 days with a maximum daily dosage of 500 mg. At these two dosages a comparable clinical effect was observed, even if the eradication of the bacteria was more significant at a daily dosage of 20 mg/kg. Penicillin is however the drug of first choice in the treatment of pharyngitis caused by Streptococcus pyogenes and the prevention of subsequent rheumatic fever.

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 (see section 4.4).

Method of administration

Before use the powder should be reconstituted with water into a white to off white coloured, homogenous suspension, see section 6.6. After reconstitution the drug can be administered using a PE/PP syringe for oral use.

After taking the suspension a bitter after-taste can be avoided by drinking fruit juice directly after swallowing. Azithromycin powder for oral suspension should be given in a single daily dosage. The suspension may be taken together with food.

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 of the excipients listed in section 6.1 (see also section 4.4).

4.4 Special warnings and precautions for use

As with erythromycin and other macrolides, rare serious allergic reactions, including angiooedema and anaphylaxis (rarely fatal), have been reported. Some of these reactions with azithromycin have resulted in recurrent symptoms and required a longer period of observation and treatment.

Since 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.

In patients receiving ergotamine derivatives, ergotism has been precipitated by coadministration of some macrolide antibiotics. There are no data concerning the possibility of an interaction between ergotamine derivatives and azithromycin. However, because of the theoretical possibility of ergotism, azithromycin and ergot derivatives should not be co-administered (see section 4.5).

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

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 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 antimicrobial agents.

In patients with severe renal impairment (GFR < 10 ml/min) a 33% increase in systemic exposure to azithromycin was observed (see section 5.2).

Prolonged cardiac repolarisation and QT interval, imparting a risk of developing cardiac arrhythmia and torsades de pointes, have been seen in treatment with other macrolides. A similar effect with azithromycin cannot be completely ruled out in patients at increased risk for prolonged cardiac repolarisation (see section 4.8). Therefore caution is required when treating patients:

-    With congenital or documented acquired QT prolongation.

-    Currently receiving treatment with other active substances known to prolong QT interval such as antiarrhythmics of classes IA and III, cisapride and terfenadine.

-    With electrolyte disturbance, particularly in cases of hypokalaemia and hypomagnesaemia

-    With clinically relevant bradycardia, cardiac arrhythmia or severe cardiac insufficiency.

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

Safety and efficacy for the prevention or treatment of MAC (Mycobacterium avium complex) in children have not been established.

The following should be considered before prescribing azithromycin:

Azithromycin powder for oral solution is not suitable for treatment of severe infections where a high concentration of the antibiotic in the blood is rapidly needed.

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

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.

Pharyngitis/ tonsilitis

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.

Skin and soft tissue infections

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.

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. palladium should be excluded.

Neurological or psychiatric diseases

Azithromycin should be used with caution in patients with neurological or psychiatric disorders.

Caution in diabetic patients: 5 ml of reconstituted suspension contain 3.70 g of sucrose.

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine since it contains sucrose.

Azithromycin 200mg/5 ml contain aspartame which is a source of phenylalanine. It may be harmful for people with phenylketonuria.

4.5 Interaction with other medicinal products and other forms of interaction

Antacids: In a pharmacokinetic study investigating the effects of simultaneous administration of antacids and azithromycin, no effect on the total bio-availability was seen, although the peak serum concentrations were reduced by approximately 25%. Azithromycin must be taken at least 1 hour before or 2 hours after antacids.

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.

Didanosins (Dideoxyinosine): Co-administration of 1,200 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: 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 1,000 mg doses and multiple 1,200 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.

Ergotamine 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.

Astemizole, alfentanil

There are no known data on interactions with astemizole or alfentanil. Caution is advised in the co-administration of these medicines with Azithromycin because of the known enhancing effect of these medicines when used concurrently with the macrolid antibiotic erythromycin.

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.

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 postmarketing period of potentiated anticoagulation subsequent to co-administration of azithromycin and coumarin-type oral anticoagulants. Although a causal relationship has not been established, consideration should be given to the frequency of

monitoring prothrombin time when azithromycin is used in patients receiving coumarin-type oral anticoagulants.

Ciclosporin: In a pharmacokinetic study with healthy volunteers that were administered a 500 mg/day oral dose of azithromycin for 3 days and were then administered a single 10 mg/kg oral dose of cyclosporin, the resulting cyclosporin Cmax and AUC0-5 were found to be significantly elevated. Consequently, caution should be exercised before considering concurrent administration of these drugs. If co-administration of these drugs is necessary, cyclosporin levels should be monitored and the dose adjusted accordingly.

Efavirenz: Co-administration of a 600 mg single dose of azithromycin and 400 mg efavirenz daily for 7 days did not result in any clinically significant pharmacokinetic interactions.

Fluconazole: Co-administration of a single dose of 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 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. As interactions of other macrolides with theophylline have been reported, alertness to signs that indicate a rise in theophylline levels is advised.

Triazolam: In 14 healthy volunteers, co-administration of azithromycin 500 mg on Day 1 and 250 mg on Day 2 with 0.125 mg triazolam on Day 2 had no significant effect on any of the pharmacokinetic variables for triazolam compared to triazolam and placebo.

Trimethoprim/sulfamethoxazole: Co-administration of

trimethoprim/sulfamethoxazole DS (160 mg/800 mg) for 7 days with azithromycin 1,200 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

There are no adequate data from the 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 (see section 5.3). 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 definitely indicated.

Azithromycin passes into 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.

4.7 Effects on ability to drive and use machines

There is no evidence to suggest that azithromycin may have an effect on a patient's ability to drive or operate machinery. When performing these functions, account should be taken of the occurrence of the adverse effects of dizziness and convulsions.

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 (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1,000 to < 1/100); rare (> 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data).

Within each frequency group, undesirable effects are listed in order of decreasing seriousness.

Adverse reactions possibly or probably related to azithromycin based on clinical trial experience and post-marketing surveillance:

System Organ Class

Frequency

Adverse reaction

Infections and infestations

Uncommon

Candidiasis, oral candidiasis, vaginal infection

Not known

Pseudomembranous colitis (see section 4.4)

Blood and lymphatic system disorders

Common

Lymphocyte count decreased, eosinophil count increased

Uncommon

Leukopenia, neutropenia

Rare

Thrombocytopenia, haemolytic anaemia

Immune system disorders

Uncommon

Angioedema, hypersensitivity

Not known

Anaphylactic reaction (see section 4.4)

Metabolism and nutrition disorders

Common

Anorexia

Psychiatric disorders

Uncommon

Nervousness

Rare

Agitation, depersonalisation

Not known

Aggression, anxiety

Nervous system disorders

Common

Dizziness, headache, paraesthesia, dysgeusia

Uncommon

Hypoaesthesia, somnolence, insomnia

Not known

Syncope, convulsion, psychomotor hyperactivity, anosmia, ageusia, parosmia, myasthenia gravis (see section 4.4).

Eye disorders

Common

Visual impairment

Ear and labyrinth disorders

Common

Deafness

Uncommon

Hearing impaired, tinnitus

Rare

Vertigo

Cardiac disorders

Uncommon

Palpitations

Not known

Torsades depointes (see section 4.4), arrhythmia (see section 4.4) including ventricular tachycardia, electrocardiogram QT prolonged (see section 4.4)

Vascular disorders

Not known

Hypotension

Gastrointestinal

disorders

Very common

Diarrhoea, abdominal pain, nausea, flatulence

Common

Vomiting, dyspepsia

Uncommon

Gastritis, constipation

Not known

Pancreatitis, tongue discolouration

Hepatobiliary disorders

Uncommon

Hepatitis, aspartate aminotransferase increased, alanine aminotransferase increased, blood bilirubine increased

Rare

Hepatic function abnormal

Not known

Hepatic failure (see section 4.4)*, hepatitis fulminant, hepatic necrosis, jaundice cholestatic

Skin and subcutaneous tissue disorders

Common

Rash, pruritus

Uncommon

Steven-Johnson syndrome, photosensitivity reaction, urticaria

Not known

Toxic epidermal necrolysis, erythema multiforme

Musculoskeletal and connective tissue disorders

Common

Arthralgia

Renal and urinary disorders

Uncommon

Blood urea increased

Rare

Renal failure acute, nephritis interstitial

General disorders and administration site conditions

Common

Fatigue

Uncommon

Chest pain, oedema, malaise, asthenia

Investigations

Common

Blood bicarbonate decreased

Uncommon

Blood creatinine increased, blood potassium abnormal

* which has rarely resulted in death

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

5.1 Pharmacodynamic properties

General properties

Pharmacotherapeutic group: antibacterials for systemic use; macrolides; azithromycin, ATC code: J01FA10

Mode of action

Azithromycin is an azalide, a sub-class of the macrolide antibiotics. By binding to the 50S-ribosomal sub-unit, azithromycin avoids the translocation of peptide chains from one side of the ribosome to the other. As a consequence of this, RNA-dependent protein synthesis in sensitive organisms is prevented.

PK/PD relationship

For azithromycin the AUC/MIC is the major PK/PD parameter correlating best with the efficacy of azithromycin.

Mechanism of resistance

Resistance to azithromycin may be inherent or acquired. There are three main mechanisms of resistance in bacteria: target site alteration, alteration in antibiotic transport and modification of the antibiotic.

Complete cross resistance exists among Streptococcus pneumoniae, betahaemolytic streptococcus of group A, Enterococcus faecalis and Staphylococcus aureus, including methicillin resistant S. aureus (MRSA) to erythromycin, azithromycin, other macrolides and lincosamides.

Breakpoints

EUCAST (European Committee on Antimicrobial Susceptibility Testing)

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

< 0.125

> 4

Moraxella catarrhalis

< 0.5

> 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 of susceptibility Commonly susceptible species

Aerobic Gram-negative microorganisms Haemophilus influenzae *

Moraxella catarrhalis*

Other microorganisms Chlamydophila pneumoniae Chlamydia trachomatis Legionella pneumophila Mycobacterium avium Mycoplasma pneumonia*

Species for which acquired resistance may be a problem

Aerobic Gram-positive microorganisms Staphylococcus aureus*

Streptococcus agalactiae Streptococcus pneumoniae*

Streptococcus pyogenes*

Other microorganisms Ureaplasma urealyticum Inherently resistant organisms Aerobic Gram-positive microorganisms

Staphylococcus aureus - methicillin resistant and erythromycin resistant strains

Streptococcus pneumoniae - penicillin resistant strains

Aerobic Gram-negative microorganisms Escherichia coli


Pseudomonas aeruginosa Klebsiella spp.

Anaerobic Gram-negative microorganisms Bacteroides fragilis-group

* Clinical effectiveness is demonstrated by sensitive isolated organisms for approved clinical indications.

5.2 Pharmacokinetic properties

Absorption

The biological availability of azithromycin after oral administration is approximately 37%. Peak plasma levels are achieved 2-3 hours after taking the medicinal product.

Distribution

After oral administration, azithromycin is distributed throughout the entire body. Pharmacokinetic studies have shown clearly higher azithromycin levels in the tissues than in the plasma (up to 50 times the maximum observed concentration in plasma). This indicates that the substance is bound in the tissues in considerable quantities.

Concentrations in the infected tissues, such as lungs, tonsil and prostate are higher than the MRC90 of the most frequently occurring pathogens after a single dose of 500 mg.

The protein binding of azithromycin in serum is variable and varies, depending on the serum concentration, from 52% at 0.05 mg/l to 12% at 0.5 mg/l. The steady state distribution volume is 31.1 l/kg.

Elimination

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

Approximately 12% of an intravenously administered dose of azithromycin is, over a period of 3 days, excreted unchanged in the urine. High concentrations of unchanged azithromycin were found in human bile. In this, ten metabolites were also detected (formed by N- and O- desmethylation, by hydroxylation of the desosamin and aglycon rings and by splitting the cladinose conjugate). A comparison of fluid chromatography and microbiological assessment methods shows that the metabolites are microbiologically inactive.

In animal models high concentrations of azithromycin were found in phagocytes.

Also it has been shown that during active phagocytosis higher concentrations of azithromycin are released than during inactive phagocytosis. In animal models this process was shown to contribute to the accumulation of azithromycin in infectious tissue.

Pharmacokinetics in special populations

Renal insufficiency

Following a single oral dose of azithromycin 1 g, mean Cmax and AUC0.120 increased by 5.1 % and 4.2% respectively, in subjects with mild to moderate renal impairment (glomerular filtration rate of 10-80 ml/min) compared with normal renal function (GFR > 80 ml/min). In subjects with severe renal impairment, the mean Cmax and AUC0-120 increased 61% and 33% respectively compared to normal.

Hepatic insufficiency

In patients with mild to moderate hepatic impairment, there is no evidence of a marked change in serum pharmacokinetics of azithromycin compared to normal hepatic function. In these patients, urinary recovery of azithromycin appears to increase perhaps to compensate for reduced hepatic clearance.

Elderly

The pharmacokinetics of azithromycin in elderly men was similar to that of young adults; however, in elderly women, although higher peak concentrations (increased by 30-50%) were observed, no significant accumulation occurred.

Infants, toddlers, children and adolescents

Pharmacokinetics have been studied in children aged 4 months - 15 years taking capsules, granules or suspension.. At 10 mg/kg on day 1 followed by 5 mg/kg on days 2-5, the Cmax achieved is slightly lower than adults with 224 ug/l in children aged 0.65 years and after 3 days dosing and 383 ug/l in those aged 6-15 years. The tJ/2 of 36 h in the older children was within the expected range for adults.

5.3 Preclinical safety data

In animal tests in which the dosages used amounted to 40 times the clinical therapeutic dosages, azithromycin was found to have caused reversible phospholipidosis, but as a rule no true toxicological consequences were observed which were associated with this. The relevance of this finding to humans receiving azithromycin in accordance with the recommendations is unknown.

Electrophysiological investigations have shown that azithromycin prolongs the QT interval.

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 embryotoxicity studies in mice and rats no teratogenic effects were observed. In rats, azithromycin dosages of 100 and 200 mg/kg bodyweight/day led to slight retardations in fetal ossification and in maternal weight gain. In peri-/postnatal studies in rats, slight retardations in physical development and delay in reflex development were observed following treatment with 50 mg/kg/day azithromycin and above.

PHARMACEUTICAL PARTICULARS

6


6.1 List of excipients

Sucrose Xanthan gum Hydroxypropylcellulose Trisodium phosphate anhydrous Silica, colloidal anhydrous (E551) Aspartame (E951)

Cream caramel flavour Titanium dioxide (E171)

6.2 Incompatibilities

Not applicable.

6.3. Shelf life

Unopened bottle with dry powder: 36 months. Reconstituted suspension: 10 days.

6.4    Special precautions for storage

Unopened bottle: Do not store above 30 °C. Reconstituted suspension: Do not store above 25 °C.

6.5    Nature and contents of container

HDPE bottles with a PP/ PE- closure with retaining ring.

PE/PP-dosage syringe (10 ml), graduated in 0.25 ml divisions.

Content of the bottle after reconstitution: 15 ml (600 mg), 20 ml (800 mg),

22.5 ml (900 mg), 30 ml (1200 mg) or 37.5 ml (1500 mg).

A plastic dosage syringe (10 ml), graduated in 0.25 ml divisions is also included.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Preparation of the suspension:

Shake the dry powder loose. Add the amount of water described below to the powder.

For 15 ml (600 mg) reconstituted suspension: add 8.0 ml water.

For 20 ml (800 mg) reconstituted suspension: add 10.5 ml water.

For 22.5 ml (900 mg) reconstituted suspension: add 11.0 ml water.

For 30 ml (1,200 mg) reconstituted suspension: add 15.0 ml water.

For 37.5 ml (1,500 mg) reconstituted suspension: add 18.5 ml water.

Shake well until a white to off white coloured, homogenous suspension is achieved. For administration the syringe adapter should be placed in the neck of the bottle and the stopper should be opened.

7    MARKETING AUTHORISATION HOLDER

Sandoz Limited Frimley Business Park,

Frimley,

Camberley,

Surrey,

GU16 7SR.

United Kingdom

8    MARKETING AUTHORISATION NUMBER

PL 04416/0782

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

28/02/2012 19/06/2015