Azithromycin HEXAL

Azithromycin HEXAL is indicated for the treatment of the following infections, when caused by microorganisms sensitive to Azithromycin HEXAL :

- acute bacterial sinusitis (adequately diagnosed)

- acute bacterial otitis media (adequately diagnosed)

- pharyngitis/tonsillitis

- acute exacerbation of chronic bronchitis (adequately diagnosed)

- mild to moderately severe community-acquired pneumonia

- skin and soft tissue infections

- uncomplicated Chlamydia trachomatis urethritis and cervicitis

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

Azithromycin is indicated for the treatment of the following infections when known or likely to be due to one or more susceptible microorganisms :

- bronchitis

- community-acquired pneumonia

- sinusitis

- otitis media

- skin and soft tissue infections

- uncomplicated genital infections due to Chlamydia trachomatis and Neisseria gonorrhoeae.

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

Posology

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.

Older people

The same dose range as in younger patients may be used in the elderly.

Children

Azithromycin HEXAL 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 HEXAL, 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).

Patients with hepatic impairment:

A dose adjustment is not necessary for patients with mild to moderately impaired liver function.

In the Elderly:

The same dosage as in adult patients is used in the elderly. Since elderly patients can be patients with ongoing proarrhythmic conditions a particular caution is recommended due to the risk of developing cardiac arrhythmia and torsades de pointes..

Method of administration

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

Posology:

Azithromycin HEXAL capsules should be given as a single daily dose.

In common with many other antibiotics Azithromycin HEXAL Capsules should be taken at least 1 hour before or 2 hours after food.

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

The total dose of azithromycin is 1500 mg which should be given over three days (500 mg once daily).

In uncomplicated genital infections due to Chlamydia trachomatis, the dose 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 ceftriaxone according to local clinical treatment guidelines. For patients who are allergic to penicillin and/or cephalosporins, prescribers should consult local treatment guidelines.

Paediatric population:

In children under 45 kg body weight: Azithromycin HEXAL Capsules are not suitable for children under 45 kg.

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).

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 studies have been conducted regarding treatment of such patients with azithromycin.

Method of administration:

Azithromycin HEXAL Capsules are for oral administration only.

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 HEXAL 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.

Since liver is the principal route of elimination for Azithromycin HEXAL, the use of Azithromycin HEXAL 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 HEXAL. 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 HEXAL administration should be stopped if liver dysfunction has emerged.

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 HEXAL. However, because of the theoretical possibility of ergotism, Azithromycin HEXAL and ergot derivatives should not be co-administered.

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

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Azithromycin HEXAL, 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 antibacterial agents.

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

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 HEXAL. 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 HEXAL 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

Exacerbations of the symptoms of myasthenia gravis and new onset of myasthenia syndrome have been reported in patients receiving Azithromycin HEXAL therapy.

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

Azithromycin HEXAL 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 HEXAL 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'.

Hypersensitivity

As with erythromycin and other macrolides, serious allergic reactions including angioneurotic oedema and anaphylaxis (rarely fatal), Acute Generalized Exanthematous Pustulosis (AGEP) 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.

Hepatotoxicity

Since the 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. Some patients may have had pre-existing hepatic disease or may have been taking other hepatotoxic medicinal products.

In case of signs and symptoms of liver dysfunction, such as rapid developing asthenia associated with jaundice, dark urine, bleeding tendency or hepatic encephalopathy, liver function tests/ investigations should be performed immediately. Azithromycin administration should be stopped if liver dysfunction has emerged.

Ergot derivatives

In patients receiving ergot derivatives, ergotism has been precipitated by co-administration 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 co-administrated.

Prolongation of the QT interval

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

- With congenital or documented QT prolongation

- Currently receiving treatment with other active substance known to prolong QT interval such as antiarrhythmics of Classes Ia and III, cisapride and terfenadine

- With electrolyte disturbance, particularly in case of hypokalaemia and hypomagnesemia

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

Superinfection

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

Clostridium difficile associated diarrhoea

Clostridium difficile associated diarrhoea (CDAD) has been reported with the use of nearly all antibacterial agents, including azithromycin, and may range in severity from mild diarrhoea to fatal colitis. Strains of C. difficile producing hypertoxin A and B 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. Therefore, CDAD must be considered in patients who present with diarrhoea during or subsequent to the administration of any antibiotics. Careful medical history is necessary since CDAD has been reported to occur over 2 months after the administration of antibacterial agents. Discontinuation of therapy with azithromycin and the administration of specific treatment for C. difficile should be considered.

Streptococcal infections

Penicillin is usually the first choice for treatment of pharyngitis/tonsillitis due to 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.

Myasthenia gravis

Exacerbations of the symptoms of myasthenia gravis and new onset of myasthenia syndrome have been reported in patients receiving azithromycin therapy.

Diabetes

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

This medicinal product contains sulfur dioxide which may rarely cause severe hypersensitivity reactions and bronchospasm.

Azithromycin HEXAL capsules are for oral administration only.

There is no evidence to suggest that Azithromycin HEXAL may have an effect on a patient's ability to drive or operate machinery.

There is no evidence to suggest that Azithromycin HEXAL may have an effect on a patient's ability to drive or operate machinery.

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.

Adverse reactions possibly or probably related to Azithromycin HEXAL 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 (www.mhra.gov.uk/yellowcard) or search for MHRA Yellow Card in the Google Play or Apple App Store.

Azithromycin HEXAL is well tolerated with a low incidence of side effects.

The section below lists the adverse reactions identified through clinical trial experience and postmarketing 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.

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

Infections and Infestations

Uncommon (>1/1,000 to <1/100)

Candidiasis, oral candidiasis, vaginal infection

Not known (cannot be estimated from available data)

Pseudomembranous colitis

Blood and Lymphatic System Disorders

Uncommon (> 1/1,000 to < 1/100)

Leukopenia, neutropenia

Not known (cannot be estimated from available data)

Thrombocytopenia, haemolytic anaemia

Immune System Disorders

Uncommon (>1/1,000 to <1/100)

Angioedema, hypersensitivity

Not known (cannot be estimated from available data)

Anaphylactic reaction

Metabolism and Nutrition Disorders

Common (> 1/100, < 1/10)

Anorexia

Psychiatric Disorders

Uncommon (>1/1,000 to <1/100)

Nervousness

Rare (> 1/10000, < 1/1000)

Agitation

Not known (cannot be estimated from available data)

Aggression, anxiety

Nervous System Disorders

Common (> 1/100, < 1/10)

Dizziness, headache, paraesthesia, dysgeusia

Uncommon (>1/1,000 to <1/100)

Hypoaesethesia, somnolence, insomnia

Not known (cannot be estimated from available data)

Syncope, convulsion, psychomotor hyperactivity, anosmia, ageusia, parosmia, Myasthenia gravis.

Eye Disorders

Common (> 1/100, < 1/10)

Visual impairment

Ear and Labyrinth Disorders

Common (> 1/100, < 1/10)

Deafness

Uncommon (>1/1,000 to <1/100)

Hearing impaired, tinnitus

Rare (> 1/10000, < 1/1000)

Vertigo

Cardiac Disorders

Uncommon (>1/1,000 to <1/100)

Palpitations

Not known (cannot be estimated from available data)

Torsades de pointes , arrhythmia including ventricular tachycardia

Vascular Disorders

Not known (cannot be estimated from available data)

Hypotension

Gastrointestinal Disorders

Very common (>1/10)

Diarrhoea, abdominal pain, nausea, flatulence

Common (> 1/100, < 1/10)

Vomiting, dyspepsia

Uncommon (> 1/1000, < 1/100)

Gastritis, constipation

Not known (cannot be estimated from available data)

Pancreatitis, tongue discolouration

Hepatobiliary Disorders

Uncommon (> 1/1000, < 1/100)

Hepatitis

Rare (> 1/10000, < 1/1000)

Hepatic function abnormal

Not known (cannot be estimated from available data)

Hepatic failure , which has rarely resulted in death, hepatitis fulminant, hepatic necrosis, jaundice cholestatic

Skin and Subcutaneous Tissue Disorders

Common (> 1/100, < 1/10)

Pruritus and rash

Uncommon (> 1/1000, < 1/100)

SJS, photosensitivity reaction, urticarial

Rare (>1/10,000 to <1/1,000)

Acute Generalized Exanthematous Pustulosis (AGEP)^*§

Very Rare (< 1/10,000)

DRESS

Not known (cannot be estimated from available data)

TEN, erythema multiforme

Musculoskeletal, Connective Tissue Disorders

Common (> 1/100, < 1/10)

Arthralgia

Renal and Urinary Disorders

Not known (cannot be estimated from available data)

Renal failure acute, nephritis interstitial

General disorders and Administration Site Conditions

Common (> 1/100, < 1/10)

Fatigue

Uncommon (> 1/1000, < 1/100)

Chest pain, oedema, malaise, asthenia

Investigations

Common (> 1/100, < 1/10)

Lymphocyte count decreased, eosinophil count increased, blood bicarbonate decreased

Uncommon (> 1/1000, < 1/100)

Aspartate aminotransferase increased, alanine aminotransferase increased, blood bilirubin increased, blood urea increased, blood creatinine increased, blood potassium abnormal

Not known (cannot be estimated from available data)

Electrocardiogram QT prolonged

*ADR identified post-marketing

^§ADR frequency represented by the estimated upper limit of the 95% confidence interval calculated using the “Rule of 3”.

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.

Adverse events experienced in higher than recommended doses were similar to those seen at normal doses. In the event of overdosage, general symptomatic and supportive measures are indicated as required.

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.

General properties

Pharmacotherapeutic group: antibacterials for systemic use, macrolides, Azithromycin HEXAL,

ATC code: J01FA10

Mode of action

The mechanism of action of Azithromycin HEXAL is based on the suppression of bacterial protein synthesis, that is to say that it binds to the ribosomal 50s sub-unit and inhibits the translocation of peptides. Azithromycin HEXAL acts bacteriostatic.

PK/PD Relationship

The efficacy of Azithromycin HEXAL 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.

Mechanism of resistance

Resistance to Azithromycin HEXAL may be natural or acquired. There are 3 main mechanisms of resistance affecting Azithromycin HEXAL:

- 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 HEXAL 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 HEXAL (2009-06-01):

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

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

General properties

Pharmacotherapeutic group: Antibacterials for systemic use. ATC code: J01FA10

Mode of action:

Azithromycin HEXAL 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-homoerythromycin A. The molecular weight is 749.0. The mechanism of action of azithromycin is based upon the suppression of bacterial protein synthesis by means of binding to the ribosomal 50S sub-unit and inhibition of peptide translocation.

Mechanism of resistance:

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

Azithromycin demonstrates cross resistance with erythromycin resistant gram positive isolates. A decrease in macrolide susceptibility over time has been noted particularly in Streptococcus pneumoniae and Staphylococcus aureus. Similarly, decreased susceptibility has been observed among Streptococcus viridans and Streptococcus agalactiae (Group B) streptococcus against other macrolides and lincosamides.

Breakpoints

Azithromycin susceptibility breakpoints for typical bacterial pathogens, as published by EUCAST are:

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.

Table: Antibacterial spectrum of Azithromycin

* Methycillin-resistant staphylococci have a very high prevalence of acquired resistance to macrolides and have been placed here because they are rarely susceptible to azithromycin.

Absorption

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

Distribution

Orally administered Azithromycin HEXAL is widely distributed throughout the body.

In pharmacokinetic studies it has been demonstrated that the concentrations of Azithromycin HEXAL measured in tissues are noticeably higher (as much as 50 times) than those measured in plasma.

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

Binding to serum proteins varies in dependence on exposure in concentration range from 12% in 0.5 microgram/ml up to 52% in 0.05 microgram Azithromycin HEXAL/ml serum. The mean volume of distribution at steady state (VV_ss) has been calculated to be 31.1 l/kg.

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 HEXAL is excreted unchanged in urine within the following three days. Particularly high concentrations of unchanged Azithromycin HEXAL have been found in human bile. 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 HEXAL are not microbiologically active.

In animal tests, high concentrations of Azithromycin HEXAL have been found in phagocytes. It has also been established that during active phagocytosis higher concentrations of Azithromycin HEXAL are released than are released from inactive phagocytes. In animal models the Azithromycin HEXAL concentrations measured in inflammation foci were high.

Pharmacokinetics in Special Populations

Renal insufficiency

Following a single oral dose of Azithromycin HEXAL 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 HEXAL compared to normal hepatic function. In these patients, urinary recovery of Azithromycin HEXAL appears to increase perhaps to compensate for reduced hepatic clearance.

Elderly

The pharmacokinetics of Azithromycin HEXAL 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.

Absorption

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

Distribution

Orally administered azithromycin is widely distributed throughout the body. In pharmacokinetic studies it has been demonstrated that the concentrations of azithromycin measured in tissues are noticeably higher (as much as 50 times) than those measured in plasma, which indicates that the agent strongly binds to tissues.

Binding to serum proteins varies according to plasma concentration and ranges from 12% at 0.5 microgram/ml up to 52% at 0.05 microgram azithromycin/ml serum. The mean volume of distribution at steady state (VVss) has been calculated to be 31.1 l/kg.

Elimination

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

In animal tests, high concentrations of azithromycin have been found in phagocytes. It has also been established that during active phagocytosis higher concentrations of azithromycin are released from inactive phagocytes. In animal models this results in high concentrations of azithromycin being delivered to the site of infection.

In animal tests in which the dosages used amounted to 40 times the clinical therapeutic dosages, Azithromycin HEXAL 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 HEXAL 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 HEXAL 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 HEXAL and above were observed.

Phospholipidosis (intracellular phospholipid accumulation) has been observed in several tissues (e.g. eye, dorsal root ganglia, liver, gallbladder, kidney, spleen, and/or pancreas) of mice, rats, and dogs given multiple doses of azithromycin. Phospholipidosis has been observed to a similar extent in the tissues of neonatal rats and dogs. The effect has been shown to be reversible after cessation of azithromycin treatment. The significance of the finding for animals and humans 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 for embryotoxic effects of the substance, no teratogenic effect was observed in mice and rats. In rats, azithromycin doses of 100 and 200 mg/kg bodyweight/day led to mild retardation of foetal ossification and in maternal weight gain. In peri- and postnatal studies in rats, mild retardation following treatment with 50 mg/kg/day azithromycin and above was observed.

Not applicable

Not applicable.

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

No special requirements

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