This information is intended for use by health professionals

1. Name of the medicinal product

Azithromycin 250 mg film-coated tablets

2. Qualitative and quantitative composition

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

Excipient(s) with known effect:

Each film-coated tablet contains 6.84 mg lactose (as lactose 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

- 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

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 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).

Patients with hepatic impairment:

A dose adjustment is not necessary for patients with mild to moderately impaired liver function (see section 4.4).

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. (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

The use of this product is contraindicated in patients with hypersensitivity to azithromycin, erythromycin, any macrolide or ketolide antibiotic, or to any of the excipients listed in section 6.1 (see also section 4.4).

4.4 Special warnings and precautions for use

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 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, the use of azithromycin should be undertaken with caution in patients with significant hepatic disease. Cases of fulminant hepatitis potentially leading to life-threatening liver failure have been reported with azithromycin (see section 4.8). Some patients may have had pre-existing hepatic disease or may have been taking other hepatotoxic medicinal products.

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

In patients receiving 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 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, 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 was observed (see Section 5.2).

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

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

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

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

Antacids

In a pharmacokinetic study investigating the effects of simultaneous administration of antacid with azithromycin, no effect on overall bioavailability was seen although peak serum concentrations were reduced by approximately 25%. In patients receiving both azithromycin and antacids, the drugs should not be taken simultaneously.

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.

Digoxin (P-gp substrates)

Concomitant administration of macrolide antibiotics, including azithromycin, with P-glycoprotein substrates such as digoxin, has been reported to result in increased serum levels of the P-glycoprotein substrate. Therefore, if azithromycin and P-gp substrates such as digoxin are administered concomitantly, the possibility of elevated serum concentrations of the substrate should be considered.

Zidovudine

Single 1000 mg 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.

Ergot

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

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

Atorvastatin

Coadministration of atorvastatin (10 mg daily) and azithromycin (500 mg daily) did not alter the plasma 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.

Cimetidine

In a pharmacokinetic study investigating the effects of a single dose of cimetidine, given 2 hours before azithromycin, on the pharmacokinetics of azithromycin, no alteration of azithromycin pharmacokinetics was seen.

Coumarin-Type Oral Anticoagulants

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

Efavirenz

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

Fluconazole

Coadministration of a single dose of 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 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.

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 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 (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.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of azithromycin in pregnant women. In reproduction toxicity studies in animals azithromycin was shown to pass the placenta, but no teratogenic effects were observed. The safety of azithromycin has not been confirmed with regard to the use of the active substance during pregnancy. Therefore azithromycin should only be used during pregnancy if the benefit outweighs the risk.

Lactation

Azithromycin has been reported to be secreted into human breast milk, but there are no adequate and well-controlled clinical studies in nursing women that have characterized the pharmacokinetics of azithromycin excretion into human breast milk.

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.

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.

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

Infections and infestations

Uncommon:

Candidiasis, vaginal infection, pneumonia, fungal infections, bacterial infection, pharyngitis, gastroenteritis, respiratory disorder, rhinitis, oral candidiasis

Not known:

Pseudomembraneous colitis (see section 4.4)

Blood and lymphatic system disorders

Uncommon:

Leukopenia, neutropenia, eosinophilia

Not known:

Thrombocytopenia, haemolytic anaemia

Immune system disorders

Uncommon:

Angioedema, hypersensitivity

Not known:

Anaphylactic reaction (see section 4.4)

Metabolism and nutrition disorders

Uncommon:

Anorexia

Psychiatric disorders

Uncommon:

Nervousness, insomnia

Rare:

Agitation

Not known:

Aggression, anxiety, delirium, hallucination

Nervous system disorders

Common:

Headache

Uncommon:

Dizziness, somnolence, dysgeusia, paraesthesia

Not known:

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

Eye disorders

Uncommon:

Visual impairment

Ear and labyrinth disorders

Uncommon:

Ear disorder, vertigo

Not known:

Hearing impairment including deafness and/or tinnitus

Cardiac disorders

Uncommon:

Palpitations

Not known:

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

Vascular disorders

Uncommon:

Hot flush

Not known:

Hypotension

Respiratory, thoracic and mediastinal disorders

Uncommon:

Dyspnoea, epistaxis

Gastrointestinal disorders

Very common:

Diarrhea

Common:

Vomiting, abdominal pain, nausea

Uncommon:

Constipation, flatulence, dyspepsia, gastritis, dysphagia, abdominal distension, dry mouth, eructation, mouth ulceration, salivary hypersecretion

Not known:

Pancreatitis, tongue discoloration

Hepatobiliary disorders

Rare:

Hepatic function abnormal, jaundice cholestatic

Not known:

Hepatic failure (which has rarely resulted in death) (see section 4.4), hepatitis fulminant, hepatic necrosis

Skin and subcutaneous tissue disorders

Uncommon:

Rash, pruritus, urticaria, dermatitis, dry skin, hyperhidrosis

Rare:

Photosensitivity reaction, acute generalised exanthematous pustulosis (AGEP)

Not known:

Stevens-Johnson syndrome, Toxic epidermal necrolysis, erythema multiforme

Musculoskeletal and connective tissue disorders

Uncommon:

Osteoarthritis, myalgia, back pain, neck pain

Not known:

Arthralgia

Renal and urinary disorders

Uncommon:

Dysuria, renal pain

Not known:

Renal failure acute, nephritis interstitial

Reproductive system and breast disorders

Uncommon:

Metrorrhagia, testicular disorder

General disorders and administration site conditions

Uncommon:

Oedema, asthenia, malaise, fatigue, face edema, chest pain, pyrexia, pain, peripheral edema

Investigations

Common:

Lymphocyte count decreased, eosinophil count increased, blood bicarbonate decreased, basophils increased, monocytes increased, neutrophils increased

Uncommon:

Aspartate aminotransferase increased, alanine aminotransferase increased, blood bilirubin increased, blood urea increased, blood bilirubin increased, blood urea increased, blood creatinine increased, blood potassium abnormal, blood alkaline phosphatase increased, chloride increased, glucose increased, platelets increased, hematocrit decreased, bicarbonate increased, abnormal sodium

Injury and poisoning

Uncommon:

post procedural complication

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:

Metabolism and nutrition disorders

Common:

Anorexia

Nervous system disorders

Common:

Dizziness, headache, paraesthesia, dysgeusia

Uncommon:

Hypoaesthesia

Eye disorders

Common:

Visual impairment

Ear and labyrinth disorders

Common:

Deafness

Uncommon:

Hearing impaired, tinnitus

Cardiac disorders

Uncommon:

Palpitations

Gastrointestinal disorders

Very common:

Diarrhea, abdominal pain, nausea, flatulence, abdominal discomfort, loose stools

Hepatobiliary disorders

Uncommon:

Hepatitis

Skin and subcutaneous tissue disorders

Common:

Rash, pruritus

Uncommon:

Stevens-Johnson syndrome, photosensitivity reaction

Musculoskeletal and connective tissue disorders

Common:

Arthralgia

General disorders and administration site conditions

Common:

Fatigue

Uncommon:

Asthenia, malaise

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. In the event of overdosage, general symptomatic and supportive measures are indicated as required.

5. Pharmacological properties
5.1 Pharmacodynamic properties

General properties

Pharmacotherapeutic group: antibacterials for systemic use, macrolides, azithromycin,

ATC code: J01FA10

Mode of action

The mechanism of action of azithromycin 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 acts bacteriostatic.

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.

Mechanism of resistance

Resistance to azithromycin may be natural 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 (SB) (MLSB-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 MLSB-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 (2009-06-01):

Species

Susceptible

Resistant

Staphylococcus spp.

≤ 1 mg/l

> 2 mg/l

Streptococcus (Group A,B,C,G)

≤ 0,25 mg/l

> 0,5 mg/l

Streptococcus pneumoniae

≤ 0,25 mg/l

> 0,5 mg/l

Haemophilus influenzae

≤ 0,12 mg/l

> 4 mg/l

Moraxella catarrhalis

≤ 0,5 mg/l

> 0,5 mg/l

Neisseria gonorrhoeae

≤ 0,25 mg/l

> 0,5 mg/l

Susceptibility

The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.

Pathogens for which resistance may be a problem: prevalence of resistance is equal to or greater than 10% in at least one country in the European Union.

Table of Susceptibility

Commonly susceptible species

Aerobic Gram-negative microorganisms

Haemophilus influenzae *

Moraxella catarrhalis *

Neisseria gonorrhoeae

Other microorganisms

Chlamydophila pneumoniae

Chlamydia trachomatis

Legionella pneumophila

Mycobacterium avium

Mycoplasma pneumonia *

Species for which acquired resistance may be a problem

Aerobic Gram-positive microorganisms

Staphylococcus aureus *

Streptococcus agalactiae

Streptococcus pneumoniae *

Streptococcus pyogenes *

Other microorganisms

Ureaplasma urealyticum

Inherently resistant organisms

Staphylococcus aureus – methicillin resistant and erythromycin resistant strains

Streptococcus pneumoniae – penicillin resistant strains

Escherichia coli

Pseudomonas aeruginosa

Klebsiella spp.

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

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.

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.

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/ml serum. The mean volume of distribution at steady state (VVss) 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 is excreted unchanged in urine within the following three days. Particularly high concentrations of unchanged azithromycin 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 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 than are released from inactive phagocytes. In animal models the azithromycin concentrations measured in inflammation foci were high.

Pharmacokinetics in Special Populations

Renal insufficiency

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

Hepatic insufficiency

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

Elderly

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

Infants, toddlers, children and adolescents

Pharmacokinetics have been studied in children aged 4 months – 15 years taking capsules, granules or suspension. At 10 mg/kg on day 1 followed by 5 mg/kg on days 2-5, the Cmax achieved is slightly lower than adults with 224 ug/l in children aged 0.6-5 years and after 3 days dosing and 383 ug/l in those aged 6-15 years. The t1/2 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

200 Frimley Business Park

GB- Frimley,

Camberley,

Surrey GU16 7SR

8. Marketing authorisation number(s)

PL 04416/1235

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 25/06/2004

Date of latest renewal: 28/05/2008

10. Date of revision of the text

15/03/2018