ERYTHROPED A TABLETS - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Erythroped A Tablets.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Erythromycin as Erythromycin Ethylsuccinate Ph. Eur. 500mg/tablet

3 PHARMACEUTICAL FORM

Tablets.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

For the prophylaxis and treatment of infections caused by erythromycinsen­sitive organisms.

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

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

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

– Ear infection: otitis media and otitis externa, mastoiditis

– Oral infections: gingivitis, Vincent's angina

– Eye infections: blepharitis

– Skin and soft tissue infections: boils and carbuncles, paronychia,

abscesses, pustular acne, impetigo, cellulitis, erysipelas

– Gastrointestinal infections: cholecystitis, staphylococcal enterocolitis

– Prophylaxis: peri- and post-operative trauma, burns, rheumatic fever.

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

4.2 Posology and method of administration

For oral administration

Adults and children over 8 years: For mild to moderate infections 2g daily in divided doses. Up to 4g daily in severe infections.

Elderly: No special dosage recommendations.

Note: For younger children, infants and babies, Erythroped, erythromycin ethylsuccinate suspensions, are normally recommended. The recommended dose for children age 2 – 8, for mild to moderate infections, is 1 g daily in divided doses. The recommended dose for infants and babies, for mild to moderate infections, is 500 mg daily in divided doses. For severe infections doses may be doubled.

4.3 Contraindications

Known hypersensitivity to erythromycin. Erythromycin is contraindicated in patients taking simvastatin, tolterodine, mizolastine, amisulpride, astemizole, terfenadine, domperidone, cisapride or pimozide.

Erythromycin should not be given to patients with a history of QT prolongation (congenital or documented acquired QT prolongation) or ventricular cardiac arrhythmia, including torsades de pointes (see section 4.4 and 4.5).

Erythromycin should not be given to patients with electrolyte disturbances (hypokalaemia, hypomagnesaemia due to the risk of prolongation of QT interval).

Erythromycin is contraindicated with ergotamine and dihydroergotamine.

4.4 Special warnings and precautions for use

Cardiovascular Events:

Prolongation of the QT interval, reflecting effects on cardiac repolarisation imparting a risk of developing cardiac arrhythmia and torsades de pointes, have been seen in patients treated with macrolides including erythromycin (see sections 4.3, 4.5 and 4.8). Fatalities have been reported.

Erythromycin should be used with caution in the following;

Patients with coronary artery disease, severe cardiac insufficiency, conduction disturbances or clinically relevant bradycardia.

Patients concomitantly taking other medicinal products associated with QT prolongation (see section 4.3 and 4.5).

Elderly patients may be more susceptible to drug- associated effects on the QT interval (see section 4.8).

Epidemiological studies investigating the risk of adverse cardiovascular outcomes with macrolides have shown variable results. Some observational studies have identified a rare short term risk of arrhythmia, myocardial infarction and cardiovascular mortality associated with macrolides including erythromycin. Consideration of these findings should be balanced with treatment benefits when prescribing erythromycin.

Erythromycin is excreted principally by the liver, so caution should be exercised in administering the antibiotic to patients with impaired hepatic function or concomitantly receiving potentially hepatotoxic agents. Hepatic dysfunction including increased liver enzymes and/or cholestatic hepatitis, with or without jaundice, has been infrequently reported with erythromycin.

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including macrolides, and may range in severity from mild to lifethreatening (see section.4.8). Clostridium difficile-associated diarrhoea (CDAD) has been reported with use of nearly all antibacterial agents including erythromycin, and may range in severity from mild diarrhoea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon, which may lead to overgrowth of C. difficile. CDAD must be considered in all patients who present with diarrhoea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

As with other macrolides, rare serious allergic reactions, including acute generalised exanthematous pustulosis (AGEP) have been reported. 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.

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.

There have been reports that erythromycin may aggravate the weakness of patients with myasthenia gravis.

Erythromycin interferes with the fluorometric determination of urinary catecholamines.

Rhabdomyolysis with or without renal impairment has been reported in seriously ill patients receiving erythromycin concomitantly with statin.

There have been reports of infantile hypertrophic pyloric stenosis (IHPS) occurring in infants following erythromycin therapy. Epidemiological studies including data from meta-analyses suggest a 2–3-fold increase in the risk of IHPS following exposure to erythromycin in infancy. This risk is highest following exposure to erythromycin during the first 14 days of life. Available data suggests a risk of 2.6% (95% CI: 1.5 –4.2%) following exposure to erythromycin during this time period. The risk of IHPS in the general population is 0.1–0.2%. Since erythromycin may be used in the treatment of conditions in infants which are associated with significant mortality or morbidity (such as pertussis or chlamydia), the benefit of erythromycin therapy needs to be weighed against the potential risk of developing IHPS. Parents should be informed to contact their physician if vomiting or irritability with feeding occurs.

4.5 Interaction with other medicinal products and other forms of interaction

Concomitant use of erythromycin with terfenadine or astemizole is likely to result in an enhanced risk of cardiotoxicity with these drugs. The concomitant use of erythromycin with either astemizole or terfenadine is therefore contraindicated.

The metabolism of terfenadine and astemizole is significantly altered when either are taken concomitantly with erythromycin. Rare cases of serious cardiovascular events have been observed, including Torsades de pointes, other ventricular arrhythmias and cardiac arrest. Death has been reported with the terfenadine / erythromycin combination.

Mizolastine has a weak potential to prolong QT interval and has not been associated with arrhythmias, however, the metabolism of mizolastine is inhibited by erythromycin, therefore concomitant use should be avoided.

Elevated cisapride levels have been reported in patients receiving erythromycin and cisapride concomitantly. This may result in QT prolongation and cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation and Torsades de pointes. Similar effects have been observed with concomitant administration of pimozide and clarithromycin, another macrolide antibiotic.

Concurrent use of erythromycin and ergotamine or dihydroergotamine has been associated in some patients with acute ergot toxicity characterised by the rapid development of severe peripheral vasospasm and dysaesthesia.

Increases in serum concentrations of the following drugs metabolised by the cytochrome P450 system may occur : when administered concurrently with erythromycin: acenocoumarol, alfentanil, astemizole, bromocriptine, carbamazepine, cilostazol, cyclosporin, digoxin, dihydroergotamine, disopyramide, ergotamine, hexobarbitone, methylprednisolone, midazolam, omeprazole, phenytoin, quinidine, rifabutin, sildenafil, tacrolimus, terfenadine, domperidone, theophylline, triazolam, valproate, vinblastine, antifungals e.g fluconazole, ketoconazole and itraconazole and warfarin. Appropriate monitoring should be undertaken and dosage should be adjusted as necessary.

Erythromycin has been reported to decrease the clearance of zopiclone and thus may increase the pharmacodynamic effects of this drug

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

There have been reports of increased anticoagulant effects when erythromycin and oral anticoagulants (e.g. warfarin, rivaroxaban) are used concomitantly.

4.6 Pregnancy and lactation

There is no evidence of hazard from erythromycin in human pregnancy. It has been in widespread use for a number of years without apparent ill consequence. Animal studies have shown no hazard.

Erythromycin has been reported to cross the placental barrier in humans, but foetal plasma levels are generally low.

There have been reports that maternal macrolide antibiotics exposure within 7 weeks of delivery may be associated with a higher risk of infantile hypertrophic pyloric stenosis (IHPS).

Erythromycin can be excreted into breast-milk. Caution should be exercised when administering erythromycin to lactating mothers due reports of infantile hypertrophic pyloric stenosis in breast-fed infants.

4.7 Effects on ability to drive and use machines

None stated.

4.8 Undesirable effects

Occasional side effects such as nausea, abdominal discomfort, vomiting and diarrhoea may be experienced. Reversible hearing loss associated with doses of erythromycin usually greater than 4g per day has been reported. Allergic reactions are rare and mild, although anaphylaxis has occurred. Skin reactions ranging from mild eruptions to erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis have rarely been reported. There are no reports implicating erythromycin products with abnormal tooth development, and only rare reports of damage to the blood, kidneys or central nervous system. There have been reports of mitochondrial optic neuropathy and infantile hypertrophic pyloric stenosis.

Cardiac arrhythmias have been very rarely reported in patients receiving erythromycin therapy. There have been isolated reports of chest pain, dizziness and palpitations, however, a cause and effect relationship has not been established.

Symptoms of hepatitis, hepatic dysfunction and/or abnormal liver function test results may occur.

Cardiac disorders

Cardiac arrest, ventricular fibrillation (frequency not known)

Skin and subcutaneous tissue disorders

Not known: acute generalised exanthematous pustulosis (AGEP)

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 at: www.mhra.gov.uk/yellowcard

4.9 Overdose

Symptoms: hearing loss, severe nausea, vomiting and diarrhoea. Treatment: gastric lavage, general supportive measures.

5 PHARMACOLOGICAL PROPERTIES

5.1. Pharmacodynamic Properties

ATC code: J01FA01

Erythromycin exerts its antimicrobial action by binding to the 50S ribosomal sub-unit of susceptible microorganisms and suppresses protein synthesis.

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

Peak blood levels normally occur within 1 hour of dosing of erythromycin ethylsuccinate granules. The elimination half life is approximately 2 hours.

Doses may be administered 2, 3 or 4 times a day.

Erythromycin ethylsuccinate is less susceptible than erythromycin to the adverse effect of gastric acid. It is absorbed from the small intestine. It is widely distributed throughout body tissues. Little metabolism occurs and only about 5% is excreted in the urine. It is excreted principally by the liver.

5.3 Preclinical safety data

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6.1

Calcium hydrogen phosphate, sodium starch glycollate, starch maize, povidone, magnesium stearate, hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide, quinoline yellow (E 104), sorbic acid.

6.2 Incompatibilities

None stated.

6.3 Shelf life

24 months.

6.4 Special precautions for storage

None.

6.5 Nature and contents of container

Polypropylene bottles of 50, 100 or 500 tablets.

Blister: PVC/aluminium of 4 or 28 tablets.

6.6 Special precautions for disposal

Not applicable.

7 MARKETING AUTHORISATION HOLDER

Amdipharm UK Limited

Capital House, 85 King William Street,

London EC4N 7BL, UK