AZITHROMYCIN 200 MG / 5ML POWDER FOR SUSPENSION - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Azithromycin 200 mg/5 ml powder for oral suspension

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

5 ml of reconstituted oral suspension contains 200 mg azithromycin (as dihydrate).

Each ml of reconstituted oral suspension contains 40 mg azithromycin (as dihydrate).

Excipients with known effect:

Benzyl alcohol: 0.65 microgram/5 ml (equivalent to 0.13 microgram/ml)

Sodium: 35.2 mg/5 ml (equivalent to 7.1 mg/ml)

Sucrose: 3.75 g/5 ml (equivalent to 0.75 g/ml)

Sulphites: 0.74 microgram/5 ml (equivalent to 0.148 microgram/ml)

Sulphur dioxide: 0.11 microgram/5 ml (equivalent to 0.02 microgram/ml)

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Powder for oral suspension.

White to yellowish -white powder.

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

– Infections of the skin and soft tissue of mild to moderate severity e.g. folliculitis, cellulites, 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

Posology

The duration of treatment in each of the infectious diseases is given below.

Paediatric population over 45 kg body weight, adults

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.

Other pharmaceutical forms are available to treat patients weighing more than 45 kg.

Paediatric population under 45 kg body weight

Azithromycin suspension should be used for children under 45 kg. The following recommendations refer to the reconstituted 40 mg/ ml (200 mg/5 ml) suspension.

With as only exception the treatment of Streptococci pharyngitis, the total dose in children 1 year and older is 30 mg/kg, to be administered as one single daily dose of 10 mg/kg for three days. As an alternative azithromycin can also be administered over a period of 5 days with one single dose of 10 mg/kg on day 1, followed by one single daily dose of 5 mg/kg on days 2 through 5.

For children with a weight of 10 to 15 kg azithromycin suspension should be measured as accurately as possible with the assistance of the enclosed dosage syringe, which is graduated in 0.5 ml divisions, providing 20 mg of azithromycin in every division.

For children who weigh more than 15 kg, azithromycin suspension should be administered with the assistance of the dosage spoon, which provides 2.5, 3.75 or 5 ml doses, corresponding to 100, 150 or 200 mg of azithromycin, respectively according to the following schedule:

* Separate dosage recommendations apply for streptococcal pharyngitis and are described below.

For the treatment of Streptococci pharyngitis in children aged 2 years or more: Azithromycin in a single dose of 10 mg/kg or 20 mg/kg for three days, in which the maximum daily dose of 500 mg should not be exceeded. However, penicillin remains the first choice for the treatment of Streptococcus pyogenes pharyngitis, among which the prophylaxis for acute rheumatism (see section 4.1).

The maximum dosage in children correlates with the common dosage in adults with 1500 mg azithromycin.

Sinusitis

For the treatment of sinusitis, limited data is available for the treament of children under 16 years of age.

Elderly

The same dosage as recommended for adult patients is used in the elderly. Since elderly 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).

Renal impairment

No dose adjustment is necessary in patients with mild to moderate renal impairment (GFR 1080 ml/min) (see section 4.4).

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).

Method of administration

Azithromycin should be given as a single daily dose. The suspension can be taken with or without food.

4.3 Contraindications

Hypersensitivity to azithromycin, erythromycin, any macrolide or ketolide antibiotic or to any of the excipients listed in Section 6.1 (List of excipients).

4.4 Special warnings and precautions for use

Allergic reactions

As with erythromycin and other macrolides, serious allergic reactions, including angioedema and anaphylaxis (rarely fatal), drug reaction with eosinophilia and systemic symptoms (DRESS) and severe dermatologic reactions such as acute generalised exanthematous pustulosis (AGEP), Stevens-Johnson-syndrome and toxic epidermal necrolysis (TEN) have been reported. Some of these reactions with azithromycin have resulted in recurrent symptoms and required a longer period of observation and treatment.

If an allergic reaction occurs, the drug should be discontinued and appropriate therapy should be instituted. Physicians should be aware that reappearance of the allergic symptoms may occur when symptomatic therapy is discontinued.

Renal impairment

No dose adjustment is necessary in patients with mild to moderate renal impairment (GFR 1080 ml/min).

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

Abnormal liver function, hepatitis, cholestatic jaundice, hepatic necrosis, and hepatic failure have been reported, some of which have resulted in death. Discontinue azithromycin immediately if signs and symptoms of hepatitis occur.

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

In patients receiving ergot derivatives, ergotism has been precipitated by coadministration of some macrolide antibiotics. There are no data concerning the possibility of an interaction between ergot and azithromycin. However, because of the theoretical possibility of ergotism, azithromycin and ergot derivatives should not be coadministered.

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 torsades 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 QT prolongation

– Currently receiving treatment with other active substances known to 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

– With electrolyte disturbance, particularly in cases of hypokalaemia and hypomagnesemia – With clinically relevant bradycardia, cardiac arrhythmia or severe cardiac insufficiency.

The following should be considered before prescribing azithromycin:

Azithromycin is 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.

Pneumonia

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.

Soft tissue infection

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.

Superinfections

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

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).

Clostridioides difficile-associated diarrhoea

Clostridiioides 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. A careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

Pseudomembranous colitis

Pseudomembranous colitis has been reported with the use of macrolide antibiotics. This diagnosis should therefore be considered in patients who develop diarrhea after starting treatment with azithromycin.

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.

Mycobacterium Avium Complex (MAC) infection in children

In children aged under 6 months, evidence of the safety of azithromycin is limited.

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

Excipients

Benzyl alcohol

Benzyl alcohol may cause allergic reactions.

Benzyl alcohol has been linked with the risk of severe side effects including breathing problems (called “gasping syndrome”) in young children.

Must not be used for more than a week in young children (less than 3 years old), because of an increased risk due to accumulation.

Sodium

This medicinal product contains 35.2 mg sodium per 5 ml of reconstituted suspension, equivalent to 1.8% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Sucrose

This medicinal product contains sucrose (3.75 g/5 ml of reconstituted suspension).

This should be taken into account in patients with diabetes mellitus.Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

Sulphites and sulphur dioxide

May rarely cause severe hypersensitivity reactions and bronchospasm.

4.5 Interaction with other medicinal products and other forms of interaction

Antacids

In a pharmacokinetic study investigating the effects of simultaneous administration of antacid with azithromycin, no effect on overall bioavailability was seen although peak serum concentrations were reduced by approximately 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.

Coadministration of azithromycin prolonged-release granules for oral suspension with a single 20 ml dose of co-magaldrox (aluminium hydroxide and magnesium hydroxide) did not affect the rate and extent of azithromycin absorption.

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 1,200 mg/day azithromycin with 400 mg/day didanosine in 6 HIVpositive subjects did not appear to affect the steady-state pharmacokinetics of didanosine as compared with placebo.

Digoxin and colchicine (P-gp substrates)

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

Cytochrome P450

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.

Atorvastatin

Coadministration 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). 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.

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 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

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 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 coadministration of fluconazole, however, a clinically insignificant decrease in Cmax (18%) of azithromycin was observed.

Indinavir

Coadministration 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 conducted in healthy volunteers, azithromycin had no significant effect on the pharmacokinetics of methylprednisolone.

Midazolam

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

Nelfinavir

Coadministration 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

Coadministration of azithromycin and rifabutin did not affect the serum concentrations of either drug.

Neutropenia was observed in subjects receiving concomitant treatment of azithromycin and rifabutin. Although neutropenia has been associated with the use of rifabutin, a causal relationship to combination with azithromycin has not been established (see section 4.8).

Sildenafil

In normal healthy male volunteers, there was no evidence of an effect of azithromycin (500 mg daily for 3 days) on the AUC and Cmax, of sildenafil or its major circulating metabolite.

Terfenadine

Pharmacokinetic studies have reported no evidence of an interaction between azithromycin and terfenadine. There have been rare cases reported where the possibility of such an interaction could not be entirely excluded; however there was no specific evidence that such an interaction had occurred.

As with other macrolides,azit­hromycin should be administered with caution in combination with terfenadine.

Theophylline

There is no evidence of a clinically significant pharmacokinetic interaction when azithromycin and theophylline are coadministered 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 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.

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 torsades de pointes.

Astemizole, alfentanil

No data are available on interactions with astemizole and alfentanil. Caution should be exercised with concomitant use of these drugs 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 Fertility, pregnancy and lactation

Pregnancy

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. 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.

Breast-feeding

Azithromycin has been reported to be secreted 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.

No serious adverse effects of azithromycin on the breast-fed infants were observed. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from azithromycin therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

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

Azithromycin has no or negligible influence on the ability to drive and use machines.

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. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

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

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

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:

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 the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

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.

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.

(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 (European Committee on Antimicrobial Susceptibility Testing) Breakpoints (2021, v. 11.0):

1 Erythromycin can be used to determine susceptibility to azithromycin.

2 Clinical evidence for the efficacy of macrolides in H. influenzae respiratory infections is conflicting due to high spontaneous cure rates. Should there be a need to test any macrolide against this species, the epidemiological cut-offs (ECOFFs) should be used to detect strains with acquired resistance. The ECOFF for azithromycin is 4 mg/L.

3 Azithromycin is always used in conjunction with another effective agent. For testing purposes with the aim of detecting acquired resistance mechanisms, the ECOFF is 1 mg/L.

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.

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: Antibacterial spectrum of azithromycin

Species__________­________________________­_____

Commonly susceptible species__________­______

Aerobic Gram-positive micro-organisms______

Corynebacterium diphteriae___________­_________

Streptococcus pneumoniae Erythromycin-sensitive

Penicillin-sensitive__________­_______________________

Streptococcus pyogenes

Erythromycin-sensitive__________­________________

Aerobic Gram-negative micro-organisms_____

Bordetella pertussis_________­____________________

Escherichia coli-ETEC_________­______________

Escherichia coli-EAEC__________­_____________

Haemophilus influenzae___________­___________

Haemophilus ducreyi___________­______________

Legionella spp.___________­______________________

Moraxella catarrhalis_________­________________

Erythromycin-sensitive__________­________________

Erythromycin-intermediate__________­___________

Pasteurella multocida__________­_______________

Anaerobic micro-organisms__________­_______

Fusobacterium nucleatum_________­____________

Fusobacterium necrophorum_________­________

Prevotella spp.___________­_______________________

Porphyromonas spp.___________­_____________

Propionibacterium spp.___________­_____________

Other micro-organisms__________­___________

Chlamydophila pneumoniae___________­_______

Chlamydia trachomatis_________­______________

Listeria spp.___________­________________________­___

Mycobacterium avium Complex________­______

Mycoplasma pneumoniae___________­________

Ureaplasma urealyticum_________­_____________

Species for which acquired resistance may be a problem________­_________________________

Aerobic Gram-positive micro-organisms______

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 micro-organisms_____

Moraxella catarrhalis

Erythromycin-resistant___________­_______________

Anaerobic micro-organisms

Peptostreptococcus spp.___________­______________

Inherently resistant organisms__________­_______

Aerobic Gram positive micro-organisms_______

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 micro-organisms______

Pseudomonas aeruginosa__________­___________

Anaerobic micro-organisms__________­________

Bacteroides fragilis group___________­_____________

+ Resistance is greater than 50%.

Paediatric population

Following the assessment of studies conducted in children, the use of azithromycin is not recommended for the treatment of malaria, neither as monotherapy nor combined with chloroquine or artemisinin based drugs, as non-inferiority to anti-malarial drugs recommended in the treatment of uncomplicated malaria was not established.

5.2 Pharmacokinetic properties

Absorption

Following oral administration the bioavailability 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 pg/g, 2.02.8 pg/g and 0–0.3 pg/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 ng/ml to 18% at 0.5 ^g/ml, depending on the serum concentration.

Biotransformation and elimination

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 ^g/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 impairment

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 (GFR < 10 ml/min), the mean Cmax and AUC0–120 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. 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.

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 Cmax achieved is slightly lower than adults with 224 jJ.g/l in children aged 0.6–5 years and after 3 days dosing and 383 jj.g/l in those aged 6–15 years. The ti/2 of 36 h in the older children was within the expected range for adults.

5.3 Preclinical safety data

6   PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Silica, colloidal anhydrous (E551)

Sucrose

Xanthan gum (E415)

Trisodium phosphate anhydrous

Hydroxypropyl cellulose

Cherry flavouring trusil (contains benzyl alcohol and sulphur dioxide E220)

Vanilla flavour (contains sulphites)

Banana flavour (contains sulphites)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

Unopened bottles: 2 years

After reconstitution (for azithromycin 15 ml and 22.5 ml): 5 days

After reconstitution (for azithromycin 30 ml and 37.5 ml): 10 days

After reconstitution: Store below 25°C

6.4 Special precautions for storage

Unopened bottles: Store below 25°C

For storage conditions after reconstitution of the medicinal product, see section 6.3

6.5 Nature and contents of container

HDPE bottles white with child-resistant PP closures.

Pack sizes:

Azithromycin 600 mg/15 ml

12.555 g of powder for the preparation of 15 ml suspension

Each bottle includes an overfill of 5ml to ensure complete dosing.

Azithromycin 900 mg/22.5 ml

18.8325 g of powder for the preparation of 22.5 ml suspension

Each bottle includes an overfill of 2.5ml to ensure complete dosing.

Azithromycin 1200 mg/30 ml

25.110 g of powder for the preparation of 30 ml suspension

Each bottle includes an overfill of 5ml to ensure complete dosing.

Azithromycin 1500 mg/37.5 ml

31.3875 g of powder for the preparation of 37.5 ml suspension

Each bottle includes an overfill of 5ml to ensure complete dosing.

Multi-dose polystyrene spoon 2.5 ml / 5 ml graduated at 3.75 ml.

Polystyrene/po­lyethylene oral dosing syringe (5 ml). The syringe is graduated at every 0.5 ml.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Preparation of the suspension:

First loosen the powder by tapping well.

For 15 ml (600 mg) bottle: add 9.5 ml water with dosing syringe.

For 22.5 ml (900 mg) bottle: add 12.0 ml water with dosing syringe.

For 30 ml (1200 mg) bottle: add 16.5 ml water with dosing syringe.

For 37.5 ml (1500 mg) bottle: add 20.0 ml water with dosing syringe.

Shake well.

Advice should be given as to whether the dose should be measured using the oral dosing syringe or the spoon provided and on correct usage.

7 MARKETING AUTHORISATION HOLDER

TEVA UK Limited

Brampton Road,

Hampden Park,

Eastbourne, East Sussex, BN22 9AG

8 MARKETING AUTHORISATION NUMBER(S)

PL 00289/0973

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

Date of first authorisation: 21/04/2008

Date of latest renewal: 08/11/2009