CLAMELLE 500 MG TABLETS - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Clamelle ® 500mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

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

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet

Pale blue, oblong, biconvex film-coated tablets, with imprint 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

Posology

A single 1g (2 × 500mg tablets) dose.

Elderly

It is not necessary to alter the dose in elderly.

4.3 Contraindications

Hypersensitivity to the active substance or any macrolide antibiotic, or any of the excipients listed in section 6.1.

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

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.

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 Clamelle 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.

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).

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

4.5 Interaction with other medicinal products and other forms of interaction

Antacids:

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, Clamelle 500mg tablets are contraindicated if individual is concomitantly taking any of the following medications (see also section 4.3):

Chloroquine and Hydroxychloroquine:

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

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, Clamelle 500mg 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 and colchicine:

Concomitant administration of macrolide antibiotics, including azithromycin, with P-glycoprotein substrates such as digoxin and colchicine, has been reported to result in increased serum levels of the P-glycoprotein substrate. Therefore, if azithromycin and P-glycoprotein substrates such as digoxin are

administered concomitantly, the possibility of elevated serum digoxin concentrations should be considered. Clinical monitoring, and possibly serum digoxin levels, during treatment with azithromycin and after its discontinuation are necessary.

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.

4.6 Fertility, pregnancy and lactation

Clamelle 500mg 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

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:

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; website: 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

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

Mechanism 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 23S 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.

Paediatric population:

Following the assessment of studies conducted in children, the use of azithromycin is not recommended for the treatment of malaria, neither as monotherapy nor combined with chloroquine or artemisinin based drugs, as non-inferiority to anti-malarial drugs recommended in the treatment of uncomplicated malaria was not established.

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^g/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^g/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 concentrations in phagocytic cells, which migrate to infected sites.

Elimination

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.

Elderly

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.

5.3 Preclinical safety data

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

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

6.3 Shelf life

36 months

6.4 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.