ZARAXIN 500 MG FILM-COATED TABLETS - summary of medicine characteristics

Zaraxin 500mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains azithromycin dihydrate 524.10 mg equivalent to 500 mg azithromycin base.

Excipient(s) with known effect:

Lactose monohydrate – 3,0 mg

Sodium (in the form of sodium laurilsulfate) – 0,37 mg

For the full list of excipients, see section 6.1.

Film-coated tablets.

White, oblong, biconvex, film coated tablets, scored on one side.

The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

4.1 Therapeutic indications

Zaraxin 500 mg film-coated tablets is indicated for the treatment of the following infections when known or likely to be due to one or more susceptible microorganisms to azithromycin (see section 4.4 and 5.1):

– infections of the lower respiratory tract such as bronchitis and pneumonia

– infections of the upper respiratory tract such as sinusitis, pharyngitis, tonsillitis (see 4.4 regarding streptococcal infections)

– acute otitis media

– skin and soft tissue infections

– as treatment of choice for uncomplicated urethritis and cervicitis due to Chlamydia trachomatis and non-multiresistant Neisseria gonorrhoeae

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

However, azithromycin shall not be used to empirically treat these infections if the prevalence of resistant species is equal to or higher than 10% (see section 5.1)

4.2 Posology and method of administration

This medicine should be taken in a single daily dose. The tablets should be swallowed whole and may be taken with or without food.

Azithromycin shows higher tissue affinity as compared to other antibacterial agents. The tissue concentrations can exceed the serum level up to 50-fold and the tissue halflive ranges between 2 and 4 days. For this reason, there is a difference in the posology of Azithromycin 500 mg film-coated tablets as compared to other antimicrobial agents.

The length of treatment for various infectious diseases is set out below.

Posology:

Paediatric population

Children over 45 kg body weight and adults, including elderly patients

Posology for the treatment of

– infections of the lower and the upper respiratory tract

– acute otitis media

– skin and soft tissue infections

The total dosage of azithromycin is 1500 mg which should be given in a therapy over three days or over five days.

3-days-therapy

In the course of 3 days, 500 mg azithromycin should be given once daily (500 mg once daily).

5-days-therapy

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

The efficacy of azithromycin is sufficient using the 5-days-therapy in the treatment of pneumonia. In most cases, the application of the 3-days-therapy appears to be adequate.

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

– For susceptible Neisseria gonorrhoeae the recommended dose is 1000 mg or 2000 mg of azithromycin in combination with 250 mg or 500 mg of ceftriaxone according to local clinical treatment guidelines.

For patients who are allergic to penicillin and/or cephalosporins, prescribers should consult local treatment guidelines.

Elderly

Elderly patients receive the recommended dosage for adults. Because of a tendency to exhibit irregular heartbeat and due to risk to develop cardiac arrythmia and torsades de pointes a special caution should be paid (see sections 4.4).

Paediatric population:

Children and adolescents with a body weight below 45 kg: Tablets are not indicated for these patients.

Posology for the treatment of renal impairment:

No dose adjustment is necessary in patients with mild to moderate renal impairment (GFR 10 – 80 ml/min). Caution should be exercised when azithromycin is administered to patients with severe renal impairment (GFR < 10 ml/min) (see sections 4.4 and 5.2).

Posology for the treatment of hepatic impairment:

Since azithromycin is metabolised in the liver and excreted in the bile, the drug should not be given to patients suffering from severe liver disease. No clinical data is available regarding treatment of such patients with azithromycin. Dose adjustment is not required for patients with mild to moderate hepatic dysfunction but the medicinal product should be used with caution in patients with significant hepatic diseases (see section 4.4).

4.3 Contraindications

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

4.4 Special warnings and precautions for use

Hypersensitivity:

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

Hepatotoxicity:

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 cases 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 in cases where signs and symptoms of liver dysfunction occur such as rapid developing asthenia associated with jaundice, dark urine, bleeding tendency or hepatic encephalopathy.

When severe liver impairment occurs, the treatment with azithromycin should be ceased immediately.

Ergot derivatives:

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-interval 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 repolarization (see section 4.8) therefore caution is required when treating patients:

– With congenital or documented 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 hypomagnesemia.

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

Superinfections:

As with any antibacterial agent, observation for signs of superinfections with non-susceptible organisms (e.g. fungal infections) is recommended.

Clostridium difficile associated diarrhea:

Clostridium difficile associated diarrhea (CDAD) has been reported with the use of nearly all antibacterial agents, including azithromycin, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. Strains of 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 diarrhea during or subsequent to the administration of any antibiotic. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

Streptococcal infections:

Penicillin is usually the first choice for treatment of pharyngitis/ton­sillitis caused by Streptococcus pyogenes and also for prophylaxis of acute rheumatic fever.

Azithromycin is in general effective against streptococcus in the oropharynx, but no data are available that demonstrate the efficacy of azithromycin in preventing acute rheumatic fever.

Renal impairment:

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

Neurological or psychiatric diseases:

Azithromycin 500 mg film-coated tablets 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 therapy (see section 4.8).

Pseudomembranous colitis:

After the use of macrolide antibiotics, cases of pseudomembranous colitis have been reported. This diagnosis should therefore be considered for patients who suffer from diarrhea after start of the treatment with azithromycin and up to three weeks after the end of the treatment. 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.

Infected burns:

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

Cross-resistance

Because of an existing cross-resistance with erythromycin-resistant Gram-positive strains and most strains of Methicillin resistant staphylococci Azithromycin 500 mg film-coated tablets should not taken in these cases. The regional situation of the resistance to azithromycin and other antibiotics should be taken into acount.

Sinusitis

Azithromycin is often not the first-choice medicine for the treatment of sinusitis.

Acute otitis media

Azithromycin is often not the first-choice medicine for the treatment of acute otitis media.

Hypertrophic pyloric stenosis in infants (IHPS)

After the use of Azithromycin in newborn babies (treatment in the first 42 days after birth), cases of hypertrophic pyloric stenosis in infants (IHPS) were reported. The parents and the nursing staff are prompted to contact their doctor if any vomiting or irritation would occur at feeding.

Excipients

Lactose

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Sodium

Azithromycin 500 mg film-coated tablets contains sodium. This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

Antacids: When studying the effect of simultaneously administered antacids on the pharmacokinetics of azithromycin, no overall change has been observed in the bioavailability, although the peak serum concentrations of azithromycin were reduced by approximately 24 %. In patients receiving both azithromycin and antacids, the drugs should not be taken simultaneously. Azithromycin should be taken in a time interval of 2–3 hours from the moment of intake of antacid.

Antiviral drugs

There is insufficient data about the interactions with antiviral medicines in order to make recommendations to dosage adjustments. The following substances have been investigated:

Didanosine: Co-administration of daily doses of 1200 mg azithromycin with 400 mg/day didanosine in six HIV-positive subjects did not appear to affect the steady-state pharmacokinetics of didanosine as compared with placebo.

Nelfinavir: Co-administration of azithromycin (1200 mg) and nelfinavir at steady state (750 mg three times daily) resulted in increased azithromycin concentrations. No clinically significant adverse effects were observed and no dose adjustment is required.

Zidovudine: 1000 mg single doses and 1200 mg or 600 mg multiple doses of azithromycin had no effect upon 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 mononuclear cells in the peripheral circulation. The clinical significance of these findings is unclear, but may be of benefit to patients.

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 and colchicine: 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-glycoprotein substrates such as digoxin are administered concomitantly, the possibility of elevated digoxin serum concentrations of the substrate should be considered. Clinical monitoring and possibly serum digoxin levels, during treatment with azithromycin and after its discontinuation are necessary.

Ergot derivatives:

Due to the theoretical possibility of ergotism, the concurrent use of azithromycin with ergot derivatives is not recommended (see section 4.4).

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.

Bromocriptine: 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. Although hepatic cytochrome P450 induction or inactivation via cytochrome-metabolite complex does not occur with azithromycin, it is advised not to use azithromycin together with drugs such as bromocriptine, whose interactions with erythromycin represent a potential risk and which were not studies with azithromycin.

Pharmacokinetic studies have been conducted between azithromycin and the following drugs known to undergo significant cytochrome P450 mediated metabolism.

Atorvastatin:

Co-administration of atorvastatin (10 mg daily) and azithromycin (500 mg daily) did not alter the plasma concentrations of atorvastatin (based on a HMG CoA-reductase inhibition assay).

Carbamazepine:

In a pharmacokinetic interaction study conducted in healthy volunteers, azithromycin had no significant effect on the plasma levels of carbamazepine or its active metabolite.

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 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.

Cyclosporin:

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 (by 24% and 21% respectively), however no significant changes were seen in AUC0-co.

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:

Coadministration of a single dose of 1200 mg azithromycin did not alter the pharmacokinetics of a single dose of 800 mg fluconazole. Total exposure and half-life of azithromycin were unchanged by the co-administration of fluconazole, however, a clinically insignificant decrease in Cmax (18%) of azithromycin was observed.

Indinavir:

Coadministration of a single dose of 1200 mg azithromycin had no statistically significant effect on the pharmacokinetics of indinavir administered as 800 mg three times daily for 5 days.

Methylprednisolone:

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

Midazolam:

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

Phenytoin:

Macrolides may increase the serum levels of phenytoin. Caution is required in case of concomitant use of both substances.

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.

Theophylline:

There is no evidence of a clinically significant pharmacokinetic interaction when azithromycin and theophylline are co-administered to healthy volunteers.

Triazolam:

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

Trimethoprim/sul­famethoxazole:

Coadministration of trimethoprim/sul­famethoxazole DS (160 mg/800 mg) for 7 days with azithromycin 1200 mg on Day 7 had no significant effect on peak concentrations, total exposure or urinary excretion of either trimethoprim or sulfamethoxazole. Azithromycin serum concentrations were similar to those seen in other studies.

CYP3A4 substrates:

Even though azithromycin does not appear to inhibit the enzyme CYP3A4, caution is advised when combining the medicinal product with quinidine, cyclosporine, cisapride, astemizole, terfenadine, ergot alkaloids, pimozide or other medicinal products with a narrow therapeutic index predominantly metabolised by CYP3A4.

Astemizol and 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.

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 torsade de pointes.

Other antibiotics:

Caution is recommended due to a possible cross-resistance between azithromycin and macrolide antibiotics (such as erythromycin) as well as lincomycin and clindamycin. A simultaneous application of multiple medicines of this substance group is therefore not recommended.

Substances that prolong the QT interval:

Azithromycin should not be used together with other actives substances that prolong the QT interval (s. section 4.4).

4.6 Fertility, pregnancy and lactation

Pregnancy:

Animal reproduction studies been performed at doses up to moderately toxic dose concentrations. In these studies, no evidence of harm to the foetus due to azithromycin was found. There are, however, no adequate and well controlled studies in pregnant women. Since animal reproduction studies are not always predictive of human response, azithromycin should be used during pregnancy only if the benefit outweighs the risk.

Breast-feeding:

No data on secretion of azithromycin in breast milk are available. As many drugs are excreted in human milk, azithromycin should not be used in the treatment of lactating women unless the physician feels that the potential benefits justify the potential risks to the infant. Among other things it could result in a sensibilization of the breast-fed infant, as well as to an irritation of the gut flora and a fungal colonization. It is recommended during the treatment and 2 days after its completion to pump and throw away the milk. After that, the breastfeeding can be resumed.

Fertility

Fertility studies with azithromycin in rats have shown a reduced fertility rate. The relevance of these results in human is not known (s. section 5.3).

4.7 Effects on ability to drive and use machines

Based on the experience so far azithromycin doesn’t show an impact on the concentration and reaction ability in general. Due to the occurrence of side effects (s. section 4.8) the ability to react could be impaired, which may affect the ability to drive or operate machinery.

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); and Not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 1. Adverse reactions possibly or probably related to azithromycin based on clinical trial experience and post-marketing surveillance:

General disorders and administration site conditions

Table 2. Adverse effects caused possibly or very likely by the prophylaxis or treatment of Mycobacterium avium-infection. The data originate from clinical studies or surveys after market introduction. These side effects are different by nature or frequency from the side effects reported for a drug with an immediate or retarded release.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization 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 Yellow Card Scheme, website:

www.mhra.gov.uk/y­ellowcard

4.9 Overdose

The undesirable effects at doses in excess of those recommended were similar to those after normal doses. The typical symptoms of an overdose with macrolide antibiotics include reversible loss of hearing, severe nausea, vomiting and diarrhoea. In the event of overdose, administration of medicinal charcoal and general symptomatic treatment as well as measures to support vital functions are indicated where necessary.

5.1 Pharmacodynamic properties

General properties

Pharmacotherapeutic group: Azithromycin is a semisynthetic azalide-derivative with a 15– membered lactone ring. Azalides belong to the group of macrolide antibacterials for systemic use

ATC classification: J01FA10

Mechanism of action:

The molecule of azithromycin is constructed by adding a nitrogen atom to the lactone ring of erythromycin A. The structural change, i.e. the insertion of a nitrogen atom into the lactone ring of erythromycin A, has also changed the interaction with the cytochrome P 450 system from that of erythromycin, reducing interaction with drugs known to interact with erythromycin (e.g. theophylline, carbamazepin, warfarin, and prednisolone).

The mechanism of action of azithromycin is based upon the suppression of bacterial protein synthesis by binding to the ribosomal 50S sub-unit and inhibition of peptide translocation.

PK/PD relationship:

For azithromycin the AUC/MIC is the major PK/PD parameter correlating best with the efficacy of azithromycin. After oral dosing of azithromycin, serum concentrations do not appear sufficient to account for efficacy. Efficacy appears to be related to the sustained high levels of azithromycin in tissues and white blood cells. The efficacy observed in animal experiments is explained by the phagocyte release of azithromycin during the process of phagocytosis and degranulation at the infection foci. The phagocytes, in their natural process of fighting an infection, take up, transport and release azithromycin at the site of infection. In vitro experiments have documented the transport and delivery of bioactive azithromycin by human neutrophils.

Mechanism of resistance:

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).

– Efflux: The efflux in streptococci is conferred by the mef genes and results in a macrolide-restricted resistance (M phenotype). Resistance can be caused by increasing the number of efflux pumps in the cytoplasmic membrane, which are exclusively affected by 14– and 15-membered macrolides (so-called M-phenotype).

– Alteration of the target structure: Target modification is controlled by erm encoded methylases. Methylation of the 23S rRNA reduces the affinity to the ribosomal binding sites, leading to resistance to macrolides (M), lincosamides (L) and streptogramins of group B (SB) (so-called MLSB – phenotype).

– The enzymatic inactivation of macrolides is only of minor clinical importance.

In the M-phenotype, there is complete cross-resistance of azithromycin with clarithromycin, erythromycin, and roxithromycin, respectively. A complete cross resistance exists among erythromycin, azithromycin, other macrolides and lincosamides for Streptococcus pneumoniae, beta-haemolytic streptococcus of group A, Enterococcus spp. and Staphylococcus aureus, including methicillin resistant Staphylococcus aureus (MRSA).

Penicillin-susceptible Streptococcus pneumoniae are more likely to be susceptible to azithromycin than are penicillin resistant strains of Streptococcus pneumoniae.

Methicillin resistant Staphylococcus aureus (MRSA) is less likely to be susceptible to azithromcyin than methicillin-susceptible Staphylococcus aureus (MSSA).

The MLSß-phenotype also has cross-resistance with clindamycin and streptogramin

B. The 16-membered macrolide spiramycin has a partial cross-resistance.

Breakpoints

The EUCAST (European Committee on Antimicrobial Susceptibility Testing) susceptibility breakpoints for typical bacterial pathogens are:

– Staphylococcus spp.1: susceptible < 1 mg/l; resistant > 2 mg/l

– Haemophilus spp.1,3: susceptible < 0,12 mg/l; resistant > 4 mg/l

– Streptococcus pneumoniae and Streptococcus A, B, C, G: susceptible < 0.25 mg/l; resistant > 0.5 mg/l

– Moraxella catarrhalis: < 0.5 mg/l; resistant > 0.5 mg/l

– Neisseria gonorrhoeae: < 0.25 mg/l; resistant > 0.5 mg/l

1 Erythromycin can be used as a test substance for detecting susceptibility breakpoints to azithromycin.

2 Limits refer to a single dose of 2 g in monotherapy.

3 The current absence of data on resistant strains precludes defining any category other than “susceptible”. If strains yield MIC results other than susceptible, they should be submitted to a reference laboratory for further testing.

Susceptibility

The prevalence of acquired resistance may vary geographically and with time for individual 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. Particularly in the case of severe infections or therapy failures, a microbiological diagnosis with the pathogen detection and its sensitivity to azithromycin should be sought.

Table 3. Antibacterial spectrum of Azithromycin

Commonly susceptible species.

Aerobic Gram-negative microorganisms

Haemophilus influenzae___________­_____

Legionella pneumophila°

Moraxella catarrhalis°

Other microorganisms

Chlamydophila pneumoniae °

Chlamydia trachomatis°

Mycoplasma pneumoniae°__________­____

Mycobacterium avium-intracellulare MAC°

Species for which acquired resistance may be a problem (>10% in at least one country of the European Union)

Aerobic Gram-positive microorganisms

Staphylococcus aureus (methicillin-susceptible)

Streptococcus pneumoniae (penicillin-intermediate, penicillin-resistant)°

Streptococcus pyogenes (erythromycin-intermediate)

Inherently resistant microorganisms

Aerobic Gram-positive microorganisms

Enterococci

Aerobic Gram-negative microorganisms Pseudomonas spp.

Anaerobic microorganisms and Gram negative intestinal bacteria

Clostridium difficile__________­________________________­________________________­_____________

° Species for which activity has been shown in clinical studies (susceptible species).

Macrolide-resistant isolates are encountered relatively frequently among aerobic and facultative Gram-positive bacteria, in particular among methicillin-resistant S. aureus (MRSA) and penicillin-resistant S. pneumoniae (PRSP).

Cardiac Electrophysiology:

QTc interval prolongation was studied in a randomized, placebo-controlled parallel trial in 116 healthy subjects who received either chloroquine (1000 mg) alone or in combination with azithromycin (500 mg, 1000 mg, and 1500 mg once daily). Coadministration of azithromycin increased the QTc interval in a dose- and concentration-dependent manner. In comparison to chloroquine alone, the maximum mean (95% upper confidence bound) increases in QTcF were 5 (10) ms, 7 (12) ms and 9 (14) ms with the co-administration of 500 mg, 1000 mg and 1500 mg azithromycin, respectively.

5.2 Pharmacokinetic properties

Absorption

Bioavailability after oral administration is approximately 37%. Peak concentrations in the plasma are attained 2–3 hours after taking the medicinal product.

PK nonlinearity

Study data suggest a non-linear pharmacokinetics of azithromycin in the therapeutic range.

Distribution

Orally administered azithromycin is widely distributed throughout the body.

The table below describes the mean serum concentrations (^g/ml) following administration of 500 mg azithromycin given to 36 healthy male volunteers as two 250 mg film-coated tablets.

In man, pharmacokinetic studies have shown markedly higher azithromycin levels in tissue (lung, tonsil, and prostate) than in plasma (from 10 to 50 times the observed concentration in plasma) indicating that the drug is heavily tissue bound. Concentrations observed in sinus secretions and in the sputum varied widely. Concentrations in target tissues, such as lung, tonsil and prostate exceed the MIC 90 for likely pathogens after a single dose of 500 mg. The serum protein binding of azithromycin is of the order of 20 %.

Very low concentrations (< 0.1 ^g/ml) were found in the cerebrospinal fluid in the presence of non-inflamed meninges.

Mean peak concentrations observed in peripheral leukocytes, the site of MAC infection, were 140 ^g/ml and remained above 32 ^g/ml for approximately 60 hours following a single 1200 mg oral dose. In animal studies, high azithromycin concentrations have been observed in phagocytes. In experimental models, higher concentrations of azithromycin are released during active phagocytosis than from non-stimulated phagocytes. In animal models this results in high concentrations of azithromycin being delivered to the site of infection.

Following oral administration of daily doses of 600 mg, mean maximum plasma concentration (Cmax) was 0.33 ^g/ml and 0.55 ^g/ml at day 1 and day 22 respectively. The time to maximum concentration (Tmax) was unchanged. Mean peak concentrations observed in leukocytes, the major site of disseminated MAC infection, were 252 ^g/ml (± 49%) and remained above 146 ^g/ml (± 33%) for 24 hours at steady state.

There are no data on the presence of azithromycin in breast milk.

Elimination

Terminal plasma elimination half-life closely reflects the elimination half-life from tissues of 2–4 days.

After oral dosing (i.e. 500 mg loading dose on day 1, followed by 250 mg on days 2 through 5) in healthy young adults, the following data were found: urinary excretion (% dose): day 1: 4.5 %; day 5: 6.5 %.

Biotransformation

In a multidose study with 12 volunteers who received a daily 500 mg azithromycin infusion for 1 hour (concentration: 1 mg / ml) for 5 days, the amount excreted in the urine over 24 h was approximately 11% after the 1st dose and 14% after the 5th dose. These values are higher than the reported respective levels after oral administration of azithromycin (6% unchanged excreted amount in the urine).

Very high levels of unchanged azithromycin have been found in human bile. Also, in bile, 10 metabolites were also detected, which were formed through N- and O-demethylation, hydroxylation of desosamine and aglycone rings and degradation of cladinose conjugate. Comparison of the results of liquid chromatography and microbiological analyses has shown that the metabolites of azithromycin are not microbiologically active.

Pharmacokinetic/phar­macodynamic relationships

In patients with community-acquired pneumonia who received daily 1-hour intravenous infusion of 500 mg azithromycin at 2 mg/ml for 2 to 5 days, the mean Cmax was 3.63 ± 1.60 jig/ml. AUC24 was 9.60 ± 4.80 jig x h/ml.

In subjects receiving a 3-hour intravenous infusion of 500 mg azithromycin at 1 mg / ml, mean Cmax and AUC24 values were 1.14 ± 0.14 jig/ml and 8.03 ± 0.86 jig x h/ml, respectively.

Pharmacokinetics in Special populations:

Renal Insufficiency:

Following a single oral dose of azithromycin 1 g there was no alteration in the pharmacokinetics in subjects with mild to moderate renal impairment (glomerular filtration rate of 10–80 ml/min).

At a glomerular filtration rate <10 ml/min, there were statistically significant differences compared to healthy patients in AUC0–120 (8.8 jig x h/ml vs. 11.7 jig x h/ml), Cmax (1.0 jig/ml vs. 1.6 jig/ml) and Clr (2.3 ml/min/kg vs. 0.2 ml/min/kg), respectively.

Hepatic insufficiency:

In patients with mild (Child-Pugh-Class A) to moderate (Child-Pugh-Class B) 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.

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.

5.3 Preclinical safety data

In mice, rats, and dogs given higher azithromycin, azithromycin was found to have caused reversible phospholipidosis in several tissues (eye, dorsal root ganglia, liver, gallbladder, kidney, spleen, and/or pancreas) was observed. Similarly, phospholipidosis was observed in the tissues of neonatal rats and dogs. Upon discontinuation of azithromycin therapy, the effect was reversible. The significance of these findings for the clinical picture 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 as the drug is indicated for short-term treatment only and there were no signs indicative of carcinogenic activity.

Mutagenic potential:

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

Reproductive toxicity:

In animal studies of the embryotoxic effects of the substance, no teratogenic effect was observed in mice and rats. In rats, azithromycin dosages of 100 and 200 mg/kg bodyweight/day led to mild retardation (delays in physical development and reflex behaviour) of foetal ossification and maternal weight gain.

In peri- and post-natal studies in rats, mild retardation was observed following treatment with 50 mg/kg/day azithromycin and above.

In neonatal studies with rats and dogs there was no higher sensitivity to azithromycin as compared to adult animals of the respective species.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

– Pregelatinized starch

– Crospovidone

– Calcium hydrogen phosphate, anhydrous

– Sodium laurylsulfate

– Magnesium stearate

Coating:

– hypromellose,

– titanium dioxide (E171)

– lactose monohydrate

– triacetin

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.