Azithromycin dihydrate

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

- 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.

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

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 dihydrate 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 dihydrate, the use of Azithromycin dihydrate 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 dihydrate. 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 dihydrate 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 dihydrate. However, because of the theoretical possibility of ergotism, Azithromycin dihydrate 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 dihydrate, 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 dihydrate 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 dihydrate. 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 dihydrate 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 dihydrate therapy.

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

Azithromycin dihydrate 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 dihydrate 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'.

There is no evidence to suggest that Azithromycin dihydrate 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 dihydrate 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.

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.

General properties

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

ATC code: J01FA10

Mode of action

The mechanism of action of Azithromycin dihydrate 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 dihydrate acts bacteriostatic.

PK/PD Relationship

The efficacy of Azithromycin dihydrate 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 dihydrate may be natural or acquired. There are 3 main mechanisms of resistance affecting Azithromycin dihydrate:

- 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 dihydrate 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 dihydrate (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.

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 dihydrate is widely distributed throughout the body.

In pharmacokinetic studies it has been demonstrated that the concentrations of Azithromycin dihydrate 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 dihydrate/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 dihydrate is excreted unchanged in urine within the following three days. Particularly high concentrations of unchanged Azithromycin dihydrate 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 dihydrate are not microbiologically active.

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

Pharmacokinetics in Special Populations

Renal insufficiency

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

Elderly

The pharmacokinetics of Azithromycin dihydrate 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.

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

Not applicable

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