SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Azithromycin 500mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 500 mg azithromycin as dihydrate.

For full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablets.

Azithromycin 500mg Tablets are light blue, oval, biconvex tablets imprinted with PLIVA on one side and 500 on the other side.

4 CLINICAL PARTICULARS

4.1    Therapeutic indications

Treatment of confirmed asymptomatic Chlamydia trachomatis genital infection in individuals aged 16 years and over and the epidemiological treatment of their sexual partners.

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

4.2    Posology and method of administration

A single 1g (2 x 500mg tablets) dose.

It is not necessary to alter the dose in elderly.

4.3    Contraindications

Azithromycin is contraindicated in patients with known hypersensitivity to azithromycin or any macrolide antibiotic, or to any of the excipients.

Relative for Azithromycin sold as a Pharmacy Medicine.

Symptomatic infection.

Symptoms suggestive of other STIs e.g. any unusual genital or anal swellings or lesions.

Children aged under 16 years.

Renal or hepatic impairment.

History of cardiac disease.

Individuals receiving ciclosporin, digoxin, ergotamine, terfenadine, theophylline, disopyramide, rifabutin and coumarin anticoagulant therapy, such as warfarin.

Individuals receiving azithromycin for treatment of other infections.

Pregnancy and breast feeding.

4.4 Special warnings and precautions for use

As with erythromycin and other macrolides, rare serious allergic reactions including angioneurotic oedema and anaphylaxis (rarely fatal), have been reported with azithromycin (see section 4.8 Undesirable Effects) . Some of these reactions with azithromycin have resulted in recurrent symptoms and required a longer period of observation and treatment.

Vomiting: To reduce the risk of vomiting, advise the individual to take the dose before bed and at least 2hrs after food or drink. If vomiting occurs after taking the dose pharmacist advice should be sought.

Oral contraception: if vomiting or diarrhoea occurs whilst taking Azithromycin 500mg tablets, refer to the oral contraceptive’s instructions for measures to minimise the risk of contraception failure.

Diarrhoea/pseudomembranous colitis caused by Clostridium difficile has occurred. Due to this, patients with diarrhoea should be carefully monitored.

4.5 Interaction with other medicinal products and other forms of interaction

In individuals receiving azithromycin and antacids, azithromycin should be taken at least 1 hour before or 2 hours after the antacid.

Nelfinavir:

Co-administration of 1200 mg azithromycin and steady state nelfinavir (750 mg 3 times daily) resulted in a mean decrease of AUC of 16% for nelfinavir, an increase of AUC of azithromycin of 113%, and an increase of Cmax of 136%. Dose adjustment is not necessary, but the increased potential for known side-effects of azithromycin should be considered.

CYP3A4:

Although azithromycin does not seem to inhibit the enzyme CYP3A4, possible inhibition of this enzyme cannot be excluded. Consequently, caution is advised when given in combination with pimozide and other drugs with a narrow therapeutic window and a metabolism catalysed by CYP3A4.

Due to interaction, Azithromycin 500mg tablets are contraindicated if individual is concomitantly taking any of the following medications (see also section 4.3 Contraindications):

Ciclosporin:

Some of the related macrolide antibiotics interfere with the metabolism of ciclosporin. In the absence of conclusive pharmacokinetic studies or data investigating the potential for an interaction between azithromycin and ciclosporin, Azithromycin 500 mg tablets are contraindicated.

Coumarin-Type Oral Anticoagulants:

In a pharmacodynamic interaction study, azithromycin did not alter the anticoagulant effect of a single 15mg dose of warfarin administered to healthy volunteers. There have been reports received in the post-marketing period of potentiated anticoagulation subsequent to co-administration of azithromycin and coumarin-type oral anticoagulants. Although a causal relationship has not been established, Clamelle 500mg tablets are contraindicated.

Digoxin:

Some of the macrolide antibiotics have been reported to impair the metabolism of digoxin (in the gut) in some individuals. Since there is a possibility of raised digoxin levels, Azithromycin 500 mg tablets are contraindicated.

Disopyramide:

Some of the related macrolide antibiotics have been reported to increase serum disopyramide levels, which can result in ventricular fibrillation.

Ergot derivatives:

Because of the theoretical possibility of ergotism, azithromycin and ergot derivatives should not be co-administered.

Rifabutin:

Co-administration 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.

Terfenadine:

There is a theoretical risk of serious dysrhythmias due to prolongation of QTc interval.

Theophylline:

Theophylline levels may be increased in patients taking azithromycin.

Azithromycin 500 mg Tablets are contraindicated during pregnancy and lactation..

4.7 Effects on ability to drive and use machines

Azithromycin has the potential to cause dizziness and somnolence. If affected, the individual should not drive or operate machinery.

4.8 Undesirable effects

Azithromycin is well tolerated with a low incidence of side effects. The most commonly reported adverse events are gastrointestinal in nature.

Infections and infestations

-    Rare (>1/10,000 to <1/1,000): candidiasis

Blood and lymphatic system disorders

-    Rare (>1/10,000 to <1/1,000):

neutropenia - transient mild reductions in neutrophil counts have occasionally been observed in clinical trials, however a causal relationship has not been confirmed thrombocytopenia

Psychiatric system disorders

-    Rare (>1/10,000 to <1/1,000): aggressiveness, restlessness, anxiety and nervousness

Nervous system disorders

-    Uncommon (1/>1,000 to <1/100):

dizziness, vertigo, convulsions (as seen with other macrolides), headache, somnolence, taste and smell perversion, syncope.

-    Rare (>1/10,000 to <1/1,000): paraesthesia, hyperactivity, asthenia, insomnia

Ear and labyrinth disorders

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

Hearing impairment has been reported with macrolide antibiotics. There have been rare reports of hearing impairment, including hearing loss, deafness and tinnitus in some patients receiving azithromycin. Many of these have been associated with prolonged use of high doses in investigational studies. In those cases where follow-up information was available, the majority of these events were reversible.

Cardiac disorders

-    Rare (>1/10,000 to <1/1,000):

palpitations and arrhythmias including ventricular tachycardia (as seen with macrolides) have been reported. There have been rare reports of QT prolongation and torsades de pointes, especially in patients at risk for prolonged cardiac repolarisation (see section 4.3 Contraindications).

Vascular disorders

-    Rare (>1/10,000 to <1/1,000): hypotension

Gastrointestinal disorders

-    Common (>1/100 to<1/10):

nausea, vomiting, diarrhoea, (rarely resulting in dehydration) abdominal discomfort (pain/cramps)

-    Uncommon (1/>1,000 to <1/100):

loose stools, flatulence, digestive disorders, anorexia, dyspepsia

-    Rare (>1/10,000 to <1/1,000):

constipation, discoloration of tongue, pancreatitis, pseudomembranous colitis. Hepatobiliary disorders

-    Rare (>1/10,000 to <1/1,000):

abnormal liver function, including hepatitis and cholestatic jaundice, as well as rare cases of hepatic necrosis and hepatic failure

Skin and subcutaneous tissue disorders

-    Uncommon (>1/1,000 to <1/100): allergic reactions including pruritus and rash

-    Rare (>1/10,000 to <1/1,000):

serious allergic reactions including photosensitivity, oedema, urticaria, angioneurotic oedema,

serious skin reactions such as erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis.

Musculoskeletal, connective tissue and bone disorders

-    Uncommon (>1/1,000 to <1/100): arthralgia

Renal and urinary disorders

-    Rare (>1/10,000 to <1/1,000):

interstitial nephritis and acute renal failure have been reported

Reproductive system and breast disorders

-    Uncommon (>1/1,000 to <1/100): vaginitis

General disorders

-    Rare (>1/10,000 to <1/1,000):

anaphylaxis (see section 4.4 Warnings and Special Precautions for Use), fatigue, malaise

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

ATC code: J01FA10

Mode of action:

Azithromycin is an azalide, a subclass of the macrolide antibiotics. The mode of action of azithromycin is based upon suppression of bacterial RNA-dependent protein synthesis, by reversibly binding to the 23S ribosomal RNA in the 50S subunit of the ribosomes.

Mechanism of resistance:

Stable resistance to azithromycin has not been described for Chlamydia trachomatis.

In vitro evidence to date indicates that whilst certain point mutations in the 23 S rRNA gene may lead to decreased sensitivity to macrolides, including azithromycin, such strains seem to carry a prohibitive physiological cost which may make their maintenance in the wild (i.e. dissemination in clinical cases) presently unlikely.

Breakpoints:

Chlamydiae are obligate intra-cellular pathogens. Determination of sensitivity/ resistance to antibiotics in vitro requires a cell culture technique which is inappropriate for routine monitoring of resistance. The complexity of the chlamydial life cycle is such that a universally agreed method for determining minimal inhibitory concentrations and breakpoints of antibiotics is not available. Comparative activity of antibiotics on chlamydia can be compared within a laboratory using the same method. Qualitative results can be compared between laboratories, but caution is required when applying numerical values to comparative data in this setting.

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.

Stable resistance to azithromycin has not been described for Chlamydia trachomatis.

5.2 Pharmacokinetic properties

Absorption

Azithromycin is well absorbed following oral administration and rapidly passes from serum to tissues and various organs. After a single 500 mg oral dose of azithromycin, 37% of the drug is absorbed, and a peak plasma concentration (0.41 pg/ml) is achieved in 2-3 hours.

Distribution

Azithromycin is widely distributed throughout the body, achieving high tissue concentration (up to 50 times higher than observed concentration in plasma). Volume of distribution is approximately 31 l/kg.

Azithromycin is rapidly distributed to a wide range of tissues and achieves high tissue concentrations ranging between 1 and 9 pg/ml, depending on the tissue. Therapeutic concentrations of azithromycin are maintained in tissues for five to seven days after the ingestion of last oral dose.

Azithromycin achieves very high intracellular concentrations in phagocytic cells and exhibits very good intracellular activity.

Excretion

Plasma terminal elimination half-life closely reflects the tissue depletion halflife of 2-4 days. Biliary excretion of azithromycin is a major route of elimination. Approximately 50% biliary excretion is in the form of unchanged compound. The other half are 10 metabolites formed by N- and O-demethylation, by hydroxylation of desosamine and aglycone rings, and by cleavage of the cladinose conjugate. Comparison of HPLC and microbiological assay suggests that metabolites play no part in the microbiological activity of azithromycin. Approximately 6% of administered dose is excreted in urine.

In elderly volunteers (> 65 years), slightly higher (30%) AUC values were seen than in younger volunteers (< 45 years), but this is not considered clinically significant and hence no dose adjustment is recommended.

In higher-dose animal studies azithromycin has been noted to cause reversible phospholipidosis, generally without discernible toxicological consequences.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Core:

Calcium hydrogen phosphate, anhydrous

Hypromellose

Maize starch

Pregelatinised starch

Microcrystalline cellulose

Sodium laurylsulfate

Magnesium stearate

Film-coating:

Hypromellose Colour Indigotin (E132)

Titanium dioxide (E171)

Polysorbate 80 Talc

6.2 Incompatibilities

Not applicable.

Shelf life

36 months.

Special precautions for storage

Store below 25 °C. in a dry place, in original packaging

6.5 Nature and contents of container

Blisters (PVC/Al foil) packed in a carton box containing 2 tablets.

6.6 Special precautions for disposal

There are no special instructions for use and handling.

7 MARKETING AUTHORISATION HOLDER

PLIVA Pharma Ltd.

Vision House Bedford Road Petersfield

Hampshire, GU32 3QB

MARKETING AUTHORISATION NUMBER(S)

PL10622/0315

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

21/01/2011

10    DATE OF REVISION OF THE TEXT

21/01/2011