SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

ERYTHROMYCIN 250 mg Capsules Hicyn 250mg Capsules Kerymax 250mg Capsules

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 250mg of erythromycin.

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Gastro-resistant capsule, hard.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

For the prophylaxis and treatment of infections caused by erythromycin-sensitive organisms

Erythromycin is effective in the treatment of a variety of clinical infections such as:

1.    Upper Respiratory Tract infections: tonsillitis, peritonsillar abscess, pharyngitis, laryngitis, sinusitis, secondary infections in influenza and common colds

2.    Lower Respiratory Tract infections: tracheitis, acute and chronic bronchitis, pneumonia (lobar pneumonia, bronchopneumonia, primary atypical pneumonia), bronchiectasis, Legionnaire’s disease

3.    Ear infection: otitis media and otitis externa, mastoiditis

4.    Oral infections: gingivitis, Vincent’s angina

5.    Eye infections: blepharitis

6.    Skin and soft tissue infections: boils and carbuncles, paronychia, abscesses, pustular acne, impetigo, cellulitis, erysipelas

7.    Gastrointestinal infections: cholecystitis, staphylococcal enterocolitis

8.    Prophylaxis: pre- and post- operative trauma, burns, rheumatic fever, bacterial endocarditis in patients allergic to penicillin with congenital heart disease, or rheumatic or other acquired valvular heart disease when undergoing dental procedures or surgical procedures of the upper respiratory tract.

9.    Other infections: osteomyelitis, urethritis, gonorrhoea, syphilis, lymphogranuloma venereum, diphtheria, prostatitis, scarlet fever

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

4.2 Posology and method of administration

Oral use

Adults and elderly

250 mg every six hours - before or with meals. 500 mg every twelve hours may be given if desired; b.i.d. dosage should not be used if dosage exceeds one gram.

Children

The usual dose is 30-50 mg/kg/day erythromycin, in divided doses given twice daily or every six hours. In severe infections, this dose may be doubled; elevated doses should be given every six hours. The drug should be given before or with meals.

Note: Erythromycin 250 mg Capsules may be given to children of any age who can swallow the capsules whole.

The capsules should be swallowed whole either before or with food; they should not be chewed.

Streptococcal Infections:

For active infection - a full therapeutic dose is given for at least ten days.

For continuous prophylaxis against recurrences of streptococcal infections in patients with evidence of rheumatic fever or heart disease, the dose is 250 mg b.i.d.

For the prevention of bacterial endocarditis in patients with valvular disease scheduled for dental or surgical procedures of the upper respiratory tract, the adult dose is 1 gram (children 20 mg/kg) 2 hours before surgery. Following surgery, the dose is 500 mg for adults (children 10mg/kg) orally every six hours for 8 doses.

Primary Syphilis: 30-40 grams given in divided doses over a period of 10-15 days.

Intestinal Amoebiasis: 250 mg four times daily for 10 to 14 days for adults: 30 to 50 mg/kg/day in divided doses for 10 to 14 days for children.

Legionnaires’ disease: 1-4 g daily until clinical signs and symptoms indicate a clinical cure. Treatment may be prolonged.

Pertussis: 30-50 mg/kg/day given in divided doses for 5 - 14 days, depending upon eradication of a positive culture.

Acne: initially, 250 mg twice daily, which may be reduced to a maintenance dose of 250 mg once daily after one month according to response.

4.3    Contraindications

Use in patients hypersensitive to erythromycin or to any of the excipients, and in patients taking astemizole, terfenadine, cisapride, pimozide, ergotamine, dihydroergotamine, simvastatin, tolterodine, mizolastine, amisulpride or sertindole.

This product contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

4.4    Special warnings and precautions for use

Rhabdomyolysis has been reported with concomitant use of erythromycin and HMG-CoA reductase inhibitors (see sections 4.3 and 4.5)

Patients receiving erythromycin concurrently with drugs which can cause prolongation of the QT interval should be carefully monitored; the concomitant use of erythromycin with some of these drugs is contraindicated (see sections 4.3 and 4.5).

In patients with impaired hepatic function, liver function should be monitored, since there have been a few reports of hepatic dysfunction in patients taking erythromycin as the estolate, base or stearate. Extended administration requires regular evaluation particularly of liver function. Therapy should be discontinued if significant hepatic dysfunction occurs.

Prolonged use of erythromycin has caused overgrowth of non-susceptible bacteria or fungi; this is a rare occurrence.

It has been reported that erythromycin may aggravate the weakness of patients with myasthenia gravis.

There have been reports suggesting erythromycin does not reach the foetus in adequate concentrations to prevent congenital syphilis. Infants born to women treated during pregnancy with oral erythromycin for early syphilis should be treated with an appropriate penicillin regimen.

Erythromycin may interfere with the determination of urinary catecholamines and 17-hydroxycorticosteroids levels.

This product contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Concomitant use of erythromycin with certain drugs metabolised by the cytochrome P450 system is likely to result in an increased frequency or seriousness of adverse effects associated with these drugs. The concomitant use of erythromycin with mizolastine, amisulpride, astemizole, cisapride, pimozide, sertindole and terfenadine is contraindicated due to the risk of QT prolongation and cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation and Torsades de pointes. The concomitant use of erythromycin with ergotamine and dihydroergotamine is contraindicated due to the risk of ergot toxicity. Concomitant use with simvastatin is contraindicated due to the risk of myopathy and rhabdomyolysis whilst concomitant use with tolterodine is contraindicated due to increased risk of overdose.

Other drugs metabolised by the cytochrome P450 system, such as acenocoumarol, atorvastatin, bromocriptine, buspirone, cabergoline, carbamazepine, ciclosporin, cilostazol, clozapine, digoxin, disopyramide, eletriptan, felodipine, hexobarbital, midazolam, phenytoin, quetiapine, quinidine, rifabutin, sildenafil, tacrolimus, tadalafil, theophylline, triazolam, valproate, warfarin and zopiclone, may be associated with elevated serum levels if administered concomitantly with erythromycin. Because of the risk of toxicity, appropriate monitoring should be undertaken, and dosage should be adjusted as necessary.

When oral erythromycin is given concurrently with theophylline, there is also a significant decrease in erythromycin serum concentrations, which could result in subtherapeutic concentrations of erythromycin.

Erythromycin should be used with caution if administered concomitantly with lincomycin, clindamycin or chloramphenicol, as competitive inhibition may occur. The concomitant use of erythromycin with alfentanil can significantly inhibit the clearance of alfentanil and may increase the risk of prolonged or delayed respiratory depression.

Patients receiving concomitant lovastatin and erythromycin should be carefully monitored as cases of rhabdomyolysis have been reported in seriously ill patients. Rhabdomyolysis has also been reported with concomitant simvastatin and erythromycin, and caution is therefore recommended when erythromycin is used concurrently with other HMG-CoA reductase inhibitors. It is recommended that

An increased plasma concentration of erythromycin has been reported with concomitant cimetidine treatment, leading to increased risk of toxicity, including reversible deafness.

Erythromycin may interfere with the determination of urinary catecholamines and 17-hydroxycorticosteroids.

4.6 Pregnancy and lactation

Pregnancy

Like all drugs erythromycin should be used in pregnancy only when clearly indicated. Erythromycin crosses the placental barrier.

Lactation

Nursing mothers: erythromycin is excreted in human milk and should be used in lactating women only if clearly needed.

4.7 Effects on ability to drive and use machines

None known.

4.8 Undesirable effects

Immune system disorders

Serious allergic reaction, including anaphylaxis has been reported.

Ear and labyrinth disorders

Transient hearing disturbances and deafness have been reported with doses of erythromycin usually greater than 4g daily, and usually given intravenously.

Cardiac disorders

Cardiac arrhythmias have been reported rarely in patients receiving erythromycin.

Gastrointestinal disorders

Nausea and abdominal discomfort can occur at elevated doses; diarrhoea and vomiting are less common.

Superinfections including pseudomembranous colitis have been occasionally reported to occur in association with erythromycin therapy. Pancreatitis has been reported rarely.

Hepatobiliary disorders

There have been reports of hepatic dysfunction, with or without jaundice, occurring in patients receiving erythromycin products due to combined

cholestatic and hepatocellular injury. Abnormal liver function tests may occur.

Skin and subcutaneous tissue disorders

There have been rare reports of rashes, including pruritus, urticaria and, very rarely, erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis.

There have been isolated reports of transient central nervous system side effects including confusion, hallucinations, seizures, and vertigo; however, a cause and effect relationship has not been established.

4.9 Overdose

Nausea, vomiting and diarrhoea have been reported.

Treatment

Gastric lavage and general supportive therapy. Erythromycin is not removed by peritoneal dialysis or haemodialysis.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Macrolide antibiotic, ATC code: J01FA01 Mode of action

Erythromycin acts by inhibition of protein synthesis by binding 50s ribosomal subunits of susceptible organisms, resulting in blockage of transpeptidation or translocation reactions, inhibition of protein synthesis and hence inhibition of cell growth. It does not affect nucleic acid synthesis. Its action is predominantly bacteriostatic.

Mechanism(s) of resistance

Several mechanisms of acquired resistance to erythromycin have been described, the most common being plasmid mediated ability to methylate ribosomal RNA, resulting in decreased binding of the antimicrobial. This can result in cross resistance between erythromycin, other macrolides and lincosamides because they share a common binding site on the ribosome. This type of resistance is referred to as the MLS_B phenotype, seen in staphylococci, and to a somewhat lesser extent in streptococci as well as other species including Bacteroidesfragilis, Clostridium perfringens, Corynebacterium diphtheria, Listeria and Legionella spp.

Decreased binding of the antibacterial to the ribosome may also occur as a result of chromosomal mutation, resulting in alteration of the ribosomal proteins in the 50S subunit, which conveys one step high level erythromycin

resistance. This form of resistance has been demonstrated in Escherichia Coli and some strains of Strep. pyogenes and probably occurs in Staph. aureus.

Other forms of resistance may be due to the elaboration of a plasmid determined erythromycin esterase, inactivating the drug, or to decreased drug penetration, the latter being partly responsible for the resistance of gram negative bacteria like the Enterobacteriaceae, but has also been shown to be acquired as a plasmid mediated determinant in some organisms. Production of a protein which increases drug efflux from the cell is thought to explain the MS form of resistance, in which organisms are resistant to the 14 C ring macrolides and streptogramins, but retain sensitivity to 16 carbon ring macrolides and lincosamides.

The incidence of resistance varies greatly with the area and organism concerned, and although the emergence of resistance is rarely a problem in short term treatment of infection it is quite common in conditions where prolonged treatment is required, e.g. endocarditis due to Staph. aureus.

Breakpoints

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 infection is questionable.

EUCAST clinical MIC breakpoints to separate susceptible (S) pathogens from resistant ® pathogens are:

EUCAST Species-related breakpoints (Susceptible</Resistant>) Units: mg/L
Staphylococcus	Streptococcus A,B,C,G	S. pneumoniae	H. influenzae	M. catarrhalis
<1/>2	<0.25/>0.5	<0.25/>0.5	<0.5/>16	<0.25/>0.5

For Neisseria gonorrhoeae and other species MIC breakpoint not defined.

Macrolides have been used in the treatment of infections with Campylobacter jejuni (erythromycin MIC <4 mg/L for wild type isolates). Erythromycin is usually active against most strains of the following organisms both in vitro and in clinical infections:

Gram positive bacteria - Listeria monocytogenes, Corynebacterium diphtheriae (as an adjunct to antitoxin), Staphylococci spp, Streptococci spp (including Enterococci).

Gram negative bacteria- Haemophilus influenzae, Neisseria meningitidis, Neisseria gonorrhoeae, Legionella pneumophila, Moraxella (Branhamella) catarrhalis, Bordetella pertussis, Campylobacter spp.

Mycoplasma - Mycoplasma pneumoniae, Ureaplasma urealyticum.

Other organisms - Treponema pallidum, Chlamydia spp, Clostridia spp, L-forms, the agents causing trachoma and lymphogranuloma venereum.

Note: The majority of strains of Haemophilus influenzae are susceptible to the concentrations reached after ordinary doses.

5.2 Pharmacokinetic properties

HICYN is a dosage form of erythromycin base presented as microgranules coated with a gastro-resistant film.

The pharmacokinetic parameters are as follows.

Absorption

In healthy subjects, with one administration of 2 capsules before meals, the concentration peak was attained at a mean of 2.9 hours, the apparent half-life of elimination was 1.9 hours, the mean maximum concentration being 2.47 mg/l.

Distribution

Erythromycin diffuses well into the tissues of the organism, notably in the lungs, the tonsils and the prostate.

Erythromycin diffuses only lightly in the cerebrospinal fluid. Erythromycin traverses the placental barrier. It becomes concentrated in milk.

Binding with plasma proteins: the binding of erythromycin base with plasma proteins is about 65%, with a predominance for alpha 1 acid glycoprotein (approximately 55%). (Study with erythromycin C 14).

Biotransformation

Erythromycin is partly metabolised by the liver.

Excretion

Erythromycin concentrates in the liver and is eliminated in active form, principally by the bile, at concentrations superior to those of serum.

Renal elimination is in the order of 2 to 5% for the unchanged form.

5.3 Preclinical safety data

Pre-clinical safety data does not add anything of further significance to the prescriber.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Neutral microgranules (Sucrose 75%, corn starch 25%)

Hypromellose

Triacetin

Methacrylic acid and ethyl acrylate copolymer Talc

Capsules (gelatin)

6.2    Incompatibilities

None

6.3    Shelf life

24 months

6.4    Special precautions for storage

Not applicable.

6.5    Nature and contents of container

Cardboard boxes of 28 and 30 capsules containing enteric coated microgranules in doses of 250 mg, in thermoformed PVC/aluminium blisters. Polypropylene bottles of 100 capsules.

Dispensing only under medical prescription.

6.6    Special precautions for disposal

No special requirements.

7    MARKETING AUTHORISATION HOLDER

Athlone Pharmaceuticals Limited. Ballymurray,

Co.Roscommon,

Ireland.

8    MARKETING AUTHORISATION NUMBER(S)

PL 30464/0061

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

12/12/2008

10    DATE OF REVISION OF THE TEXT

24/09/2012