Azithromycin 250 mg tablets – Summary of Product Characteristics (SmPC) for healthcare professionals

1 NAME OF THE MEDICINAL PRODUCT

Azithromycin 250 mg tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 250 mg of azithromycin (as monohydrate).

Excipient(s) with known effect

Each film-coated tablet contains 6.84 mg lactose (as monohydrate) and 0.57 mg (0.025 mmol) sodium.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet

White to off-white, oval film-coated tablets with breaking notches on both sides and the embossment “A 250“on one side.

The film-coated tablets can be divided into equal doses.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Azithromycin 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 of mild to moderate severity e.g. folliculitis, cellulitis, erysipelas
• uncomplicated Chlamydia trachomatis urethritis and cervicitis

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

4.2 Posology and method of administration

Posology

Children and adolescents over 45 kg body weight and adults In uncomplicated Chlamydia trachomatis urethritis and cervicitis the dosage is 1,000 mg as a single oral dose.

For all other indications the dose is 1,500 mg, to be administered as 500 mg per day for three consecutive days.

Elderly people

The same dose range as in adult patients may be used in the elderly. Since older elderly people 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).

Paediatric population

Azithromycin film-coated tablets should only be administered to children weighing more than 45 kg when normal adult dose should be used. For children under 45 kg other pharmaceutical forms of azithromycin, e.g. suspensions, may be used.

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). Caution should be exercised when azithromycin is administered to patients with severe renal impairment (GFR < 10 ml/min) (see section 4.4 and 5.2).

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

Azithromycin 250 mg film-coated tablet should be administered as a daily single dose. Azithromycin 250mg film-coated tablet may be taken with food.

4.3 Contraindications

Hypersensitivity to the active substance, erythromycin, 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 angioneurotic oedema and anaphylaxis (rarely fatal), dermatologic reactions including acute generalised 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 medicinal product 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.

Hepatoxicity

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.

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.

Infantile hypertrophic pyloric stenosis (IHPS)

Following the use of azithromycin in neonates (treatment up to 42 days of life), infantile hypertrophic pyloric stenosis (IHPS) has been reported. Parents and caregivers should be informed to contact their physician if vomiting or irritability with feeding occurs.

Ergot derivatives

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).

Superinfection

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

Cross resistance

Because of existing cross-resistance with erythromycin-resistant gram-positive strains and most strains of methicillin resistant staphylococci, use of azithromycin is not recommended.

Local epidemiology and susceptibility patterns should be taken into consideration.

Clostridium difficile associated diarrhea

Clostridium difficile associated diarrhea (CDAD) has been reported with 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.

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 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 case of CDAD, anti-peristaltics are contraindicated.

Pseudomembranous colitis

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

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).

Cardiovascular events

Prolonged cardiac repolarization and QT interval, imparting a risk of developing cardiac arrhythmia and torsades de pointes, have been seen in treatment with macrolides including azithromycin (see section 4.8). Therefore as the following situations may lead to an increased risk for ventricular arrhythmias (including torsade de pointes) which can lead to cardiac arrest, azithromycin should be used with caution in patients with ongoing proarrhythmic conditions (especially women and elderly patients) such as patients:

• With congenital or documented 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 hypomagnesaemia
• With clinically relevant bradycardia, cardiac arrhythmia or severe cardiac insufficiency
• Elderly patients: elderly patients may be more susceptible to drug-associated effects on the QT interval.

Carefully consider the balance of benefits and risks before prescribing azithromycin for any patients taking hydroxychloroquine or chloroquine, because of the potential for an increased risk of cardiovascular events and cardiovascular mortality (see section 4.5)

Epidemiological studies investigating the risk of adverse cardiovascular outcomes with macrolides have shown variable results. Some observational studies have identified a rare short term risk of arrhythmia, myocardial infarction and cardiovascular mortality associated with macrolides including azithromycin.

Consideration of these findings should be balanced with treatment benefits when prescribing azithromycin.

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).

Pediatric population

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

Long-term use

There is no experience on safety and effectiveness of long-term use of azithromycin in indications mentioned before. At fast recurrent infections, treatment with other antibiotics should be considered.

The following should be considered before prescribing azithromycin:

Serious infections

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

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/ 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.

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.

Azithromycin film-coated tablets contain Lactose.

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

Azithromycin film-coated tablets contains 0.025 mmol (0.57 mg) sodium per dose which is less than 1 mmol sodium (23 mg), that is to say essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

Effects of other medicinal products on azithromycin:

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 24%. In patients receiving both azithromycin and antacids, the medicinal products should not be taken simultaneously. Azithromycin must be taken at least 1 hour before or 2 hours after the antacids.

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

Nelfinavir

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

Rifabutin

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

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).

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.

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.

Effect of azithromycin on other medicinal products:

Ergot derivatives

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

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.

Coumarin-Type Oral Anticoagulants

In a pharmacokinetic interaction study, azithromycin did not alter the anticoagulant effect of a single 15-mg dose of warfarin administered to healthy volunteers. There have been reports received in the post-marketing period of potentiated anticoagulation subsequent to coadministration of azithromycin and coumarin-type oral anticoagulants. Although a causal relationship has not been established, consideration should be given to the frequency of monitoring prothrombin time when azithromycin is used in patients receiving coumarin-type oral anticoagulants

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 C_max and AUC_0-5 were found to be significantly elevated. Consequently, caution should be exercised before considering concurrent administration of these drugs. If coadministration of these drugs is necessary, cyclosporin levels should be monitored and the dose adjusted accordingly.

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.

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.

Zidovudine

Single 1000 mg doses and multiple 1200 mg or 600 mg doses of azithromycin had little effect on the plasma pharmacokinetics or urinary excretion of zidovudine or its glucuronide metabolite. However, administration of azithromycin increased the concentrations of phosphorylated zidovudine, the clinically active metabolite, in peripheral blood mononuclear cells. The clinical significance of this finding is unclear, but it may be of benefit to patients.

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

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

Coadministration of atorvastatin (10 mg daily) and azithromycin (500 mg daily) did not alter the plasma concentrations of atorvastatin (based on a HMG CoA-reductase inhibition assay). However, post-marketing cases of rhabdomyolysis in patients receiving azithromycin with statins have been reported.

Carbamazepine

In a pharmacokinetic interaction study in healthy volunteers, no significant effect was observed on the plasma levels of carbamazepine or its active metabolite in patients receiving concomitant azithromycin.

Chloroquine / Hydroxychloroquine

Observational data have shown that co-administration of azithromycin with hydroxychloroquine in patients with rheumatoid arthritis is associated with an increased risk of cardiovascular events and cardiovascular mortality. Carefully consider the balance of benefits and risks before prescribing azithromycin for any patients taking hydroxychloroquine. Similar careful consideration of the balance of benefits and risk should also be undertaken before prescribing azithromycin for any patients taking chloroquine, because of the potential for a similar risk with chloroquine

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.

Cetirizine

In healthy volunteers, coadministration of a 5-day regimen of azithromycin with cetirizine 20 mg at steady-state resulted in no pharmacokinetic interaction and no significant changes in the QT interval.

Didanosine (Dideoxyinosine)

Coadministration of 1200 mg/day azithromycin with 400 mg/day didanosine in 6 HIV-positive subjects did not appear to affect the steady-state pharmacokinetics of didanosine as compared with placebo.

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.

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.

Sildenafil

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

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.

Other antibiotics

On a possible co-resistance between macrolide antibiotics and azithromycin (e.g. erythromycin) as well as lincomycin and clindamycin is to look at. Concomitant use of several medicinal products from the same group of substances is not recommended.

Medicinal products known to prolong the QT interval

Azithromycin should not be co-administered with other medicinal products, known to 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 (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 the benefit outweighs the risk.

Breastfeeding

Azithromycin has been reported to be secreted into human breast milk. Limited information available from published literature indicates that azithromycin is present in human milk at an estimated highest median daily dose of 0.1 to 0.7 mg/kg/day. 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

There is no evidence to suggest that azithromycin may have an effect on a patient’s ability to drive or operate machinery. However, certain adverse reactions (see section 4.8) that have been reported with azithromycin may affect some patients' ability to drive or operate machinery.

4.8 Undesirable effects

The table below lists the adverse reactions identified through clinical trial experience and postmarketing surveillance by system organ class and frequency.

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. Approximately 13% of patients in clinical trials reported adverse events, wherein gastrointestinal disorders were the most.

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

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

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

4.9 Overdose

Adverse events experienced in higher than recommended doses were similar to those seen at 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, the administration of medicinal charcoal and general symptomatic treatment 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 macrolid 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

The efficacy of azithromycin is best described by the relationship AUC/MIC, where AUC describes the area under the curve and MIC represents the mean inhibitory concentration of the microbe concerned.

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.

Mechanism of resistance

Resistance to azithromycin may be inherent or acquired. There are 3 main mechanisms of resistance affecting azithromycin:

• Efflux: resistance may be due to an increase in the number of efflux pumps on the cell membrane. In particular, 14- and 15-link macrolides are affected. (M-phenotype)
• Alterations of the cell structure: methylisation of the 23s rRNS may reduce the affinity of the ribosomal binding sites, which can result in microbial resistance to macrolides, lincosamides and group B streptogramins (S_B) (MLS_B-phenotype).
• Enzymatic deactivation of macrolides is only of limited clinical significance.

In the presence of the M-phenotype, complete cross resistance exists between azithromycin and clarithomycin, erythromycin and roxithromycin. With the MLS_B-phenotype, additional cross resistance exists with clindamycin and streptogramin B. A partial cross resistance exists with spiramycin.

Breakpoints

According to EUCAST (European Committee on Antimicrobial Susceptibility Testing) the following breakpoints have been defined for azithromycin (v. 9.0):

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-positive microorganisms

Mycobacterium avium^°

Streptococcus pyogenes¹

Aerobic Gram-negative microorganisms

Legionella pneumophila ^°

Moraxella catarrhalis

Neisseria gonorrhoeae

Other microorganisms

Chlamydophila pneumoniae

Chlamydia trachomatis^°

Mycoplasma pneumonia^°

Species for which acquired resistance may be a problem

Aerobic Gram-positive microorganisms

Staphylococcus aureus(methicillin-susceptible)

Staphylococcus aureus (methicillin-resistant)⁺

Staphylococcus epidermidis

Staphylococcus haemolyticus

Staphylococcus hominis

Streptococcus agalactiae

Streptococcus pneumoniae

Inherently resistant organisms

Aerobic Gram-negative microorganisms

Escherichia coli

Pseudomonas aeruginosa

^° At the time of publication there are no current data. In primary literature, standard works and treatment guidelines susceptibility is assumed. ⁺ Resistance rate more than 50% in at least one region within the EU. ¹ Resistance rate in some studies ≥10%.

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. (C_max after a single dose of 500 mg orally was approximately 0.4 mg/l).

Distribution

Kinetic studies have shown markedly higher azithromycin levels in tissue than in plasma (up to 50 times the maximum observed concentration in plasma) indicating that the active substance is heavily tissue bound (steady state distribution volume of approximately 31 l/kg). Concentrations in target tissues such as lung, tonsil, and prostate exceed the MIC₉₀ for likely pathogens after a single dose of 500 mg.

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

In serum the protein binding of azithromycin is variable and depending on the serum concentration varies from 50% in 0.05 mg/l to 12% in 0.5 mg/l.

Elimination

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

Approximately 12% of an intravenously administered dose of azithromycin is excreted unchanged in urine within the following three days; the majority in the first 24 hours. Biliary excretion of azithromycin, predominantly in unchanged form, is a major route of elimination. In the same source, 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.

Pharmacokinetics in Special Populations

Renal insufficiency

Following a single oral dose of azithromycin 1 g, mean C_max and AUC_0-120 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 C_max and AUC_0-120 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 C_max achieved is slightly lower than adults with 224 ug/l in children aged 0.6-5 years and after 3 days dosing and 383 ug/l in those aged 6-15 years. The t_1/2 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.

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 retardations in foetal ossification and in maternal weight gain. In peri- and postnatal studies in rats, mild retardation in physical development and delay in reflex development following treatment with 50 mg/kg/day azithromycin and above were observed.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core

Microcrystalline cellulose

Maize starch

Sodium starch glycolate

Silicium dioxide

Magnesium stearate

Sodium laurylsulphate

Film-coating

Lactose monohydrate

Hypromellose

Macrogol 4000

Titanium dioxide

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

Do not store above 25°C.

6.5 Nature and contents of container

The film-coated tablets are packed in aluminium/polyvinylchloride blisters.

Packs containing 2, 3, 4, 6, 9, 12 and 24 film-coated tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

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

7 MARKETING AUTHORISATION HOLDER

Sandoz Limited

Park View, Riverside Way

Watchmoor Park

Camberley, Surrey

GU15 3YL

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 04416/1235

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

28/05/2008

10 DATE OF REVISION OF THE TEXT

01/06/2022