ERYTHROMYCIN ETHYLSUCCINATE 500 MG FILM-COATED TABLETS - summary of medicine characteristics

Erythromycin Ethylsuccinate 500 mg film-coated Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

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

For the full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

‘Yellow coloured Oval shaped tablets, film-coated tablets (nominal dimensions- 18.7

mm x 8.7 mm x 7.4 mm) debossed “K” on one side and plain on other side.’

4.1 Therapeutic indications

Erythromycin Ethylsuccinate 500 mg film-coated tablets are indicated in adults, adolescents and children over 8 years of age in the following infections (see sections 4.4 and 5.1):

– 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: pre- and post- operative trauma, burns, rheumatic fever

– Other infections: osteomyelitis, urethritis, 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

Posology

For oral administration

Adults, adolescents 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

Paediatric population: Erythromycin Ethylsuccinate film-coated tablets are not suitable for children aged 8 years or less. Other, more suitable formulations are available.

Method of administration

The film-coated tablets must be taken orally, swallowed with a sufficient quantity of water or liquid.

4.3 Contraindi­cations

Erythromycin Ethylsuccinate Tablets 500 mg film-coated tablets must not be used

In patients hypersensitive to erythromycin or other macrolides or any of the excipients listed in section 6.1

In patients taking simvastatin, tolterodine, mizolastine, amisulpride, astemizole, terfenadine, domperidone, cisapride or pimozide (see section 4.5)

In patients taking ergotamine and dihydroergotamine (see section 4.5)

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)

4.4 Special warnings and precautions for use

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.

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.

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including macrolides, and may range in severity from mild to life-threatening (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.

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.

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

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

Erythromycin interferes with the fluorometric determination of urinary catecholamines.

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.

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

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.

Erythromycin is a substrate and inhibitor of CYP3A4, an enzyme belonging to the cytochrome p450 enzyme system.

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, cyclosporin, digoxin, dihydroergotamine, disopyramide, ergotamine, hexobarbitone, midazolam, phenytoin, quinidine, rifabutin, sildenafil, tacrolimus, terfenadine, domperidone, theophylline, triazolam, valproate, and warfarin, cilostazol, methylprednisolone, omeprazole, vinblastine, and antifungals e.g. fluconazole, ketoconazole, voriconazole and itraconazole. 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 Fertility, pregnancy and lactation

Pregnancy

A moderate amount of data on pregnant women (between 300–1000 pregnancy outcomes) indicate no malformative or feto/neonatal toxicity of Erythromycin Ethylsuccinate. Animal studies do not indicate reproductive toxicity (see section 5.3)

The use of Erythromycin Ethylsuccinate film-coated tablets may be considered during pregnancy.

Lactation

Erythromycin is excreted in human milk. Erythromycin has been reported to cause infantile hypertrophic pyloric stenosis in newborn infants (see section 4.4). Considering the risk presented to infant, a decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Erythromycin Ethylsuccinate film-coated tablets therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

There was no apparent effect on male or female fertility in rats treated with erythromycin base by oral gavage at 700 mg/kg/day (approximately 3 times the maximum human dose on a body surface area basis).

4.7 Effects on ability to drive and use machines

Erythromycin can cause undesired effects such as dizziness, which may affect the patient’s ability to drive or operate machinery.

4.8 Undesirable effects

Side effects are ranked under the heading of frequency, the most frequent first, using the following convention: very common: (>1/10); common (> 1/100, <1/10); uncommon (> 1/1,000, <1/100); rare (>1/10,000, <1/1000); very rare (<1/10,000); not known: cannot be estimated from available data.

Uncommon: Eosinophilia

Immune system disorders

Unknown: allergic reactions ranging from urticaria and mild skin eruptions to anaphylaxis have occurred.

Very rare: hallucinations

Uncommon: vertigo, confusion

Very rare: seizures

Uncommon: cardiac rhythm disorders including ventricular tachyarrhythmias, chest pain and palpitations

Unknown: QTc interval prolongation, torsades de pointes, cardiac arrest, ventricular fibrillation

Rare: deafness, tinnitus,

Very rare: reversible hearing loss

Unknown: hypotension

Common: upper abdominal discomfort, nausea, vomiting, diarrhoea, anorexia

Rare: pancreatitis

Very rare: infantile hypertrophic pyloric stenosis,

Unknown: pseudomembranous colitis

Common: hepatic dysfunction

Rare: cholestatic hepatitis, jaundice, hepatomegaly, hepatic failure, hepatocellular hepatitis

Skin and subcutaneous tissue disorders

Unknown: skin eruptions, pruritus, urticaria, exanthema, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, acute generalised exanthematous pustulosis (AGEP)

Uncommon: interstitial nephritis

Rare: dark urine

Uncommon: dizziness

Rare: fever, malaise

Reporting of suspected adverse reactions

Reporting of 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 professional are asked to report any suspected adverse reactions via Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Symptoms: Hearing loss, severe nausea, vomiting and diarrhoea.

Treatment: Gastric lavage, general supportive measures.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic Group: Erythromycin – ATC Code: J01FA01

Mechanism of action

Erythromycin acts by binding to 50s ribosomal subunit of susceptible microorganisms and thus interfering with their protein synthesis. Nucleic acid synthesis is not affected.

Resistance

Resistance mainly occurs via target site modification by an rRNA-methylating enzyme by Erm-type methyltransferases

Interaction with other antibacterial agents

The binding site of macrolides on the ribosome overlaps that of chloramphenicol or lincosamides such as clindamycin explaining pharmacologic antagonism between these antibiotic classes as well as crossresistance.

Susceptibility testing endpoints

The European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints for susceptibility testing are presented below:

PK/PD relationship

As with other macrolide antimicrobial agents, the percent time above the minimum inhibitory concentration (MIC) of the infecting organism over the dosing interval (%T > MIC) has been shown to be the parameter that best correlates with the efficacy of erythromycin.

Clinical efficacy against specific pathogens

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.

Commonly susceptible species

Streptococcus pyogenes

Streptococcus pneumoniae

Listeria monocytogenes

Moraxella cattharlaris

Legionella pneumophila

Species for which acquired resistance may be a problem

Staphylococcus aureus

Campylobacter jejuni

Inherently resistant organisms

Haemophilus influenza

Neisseria gonorrhoeae

5.2 Pharmacokinetic properties

Absorption

In healthy volunteers, after administration of 500mg in tablet form, the peak concentration in plasma (Cmax) of erythromycin was 1.1 qg/ml. Peak blood levels normally occur within 1–3 hours of dosing of erythromycin tablets. The rate of absorption is increased when erythromycin is taken immediately before food.

Distribution

Erythromycin distributes widely into tissues where it persists longer than in the blood. Erythromycin accumulates in theleukocytes. Erythromycin is moderately protein bound and does not cross the blood-brain barrier.

Biotransformation

Erythromycin undergoes hepatic metabolism and is hydrolyzed to anhydro forms (anhydroerythro­mycin [AHE] and other metabolites).

Elimination

The elimination half-life is approximately 2 hours. Erythromycin is excreted principally by the liver. After oral administration, <5% is recovered from the urine in active form.

Special populations

Hepatic impairment: In patients with liver diseases, steady-state serum concentrations higher than usual would be achieved. This may be significant and require dosage adjustment, especially during long courses of erythromycin therapy

Renal impairment: The degree of modification of macrolide pharmacokinetics by renal insufficiency or hepatic disease is usually not considered clinically relevant, and no recommendation for dose modification is necessary in these patients.

Elderly population: The pharmacokinetics of macrolides are modified in elderly patients. Accordingly, their use must be accompanied by a closer than usual clinical monitoring of the elderly patients.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of single dose toxicity, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction and development.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core: Pregelatinized starch Anhydrous calcium hydrogen phosphate Sodium starch glycolate Povidone, Magnesium stearate

Tablet coating: Opadry Yellow 03G520008 (Hypromellose, Titanium dioxide, Macrogol, Quinoline Yellow Aluminium Lake, Iron Oxide Yellow)

6.2 Incompatibilities

Not applicable

6.3 Shelf life

4 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Blister: PVC/Aluminium

Pack sizes: 10, 12, 14, 24, 28, 30, 56 & 84 film-coated tablets

Not all pack sizes may be marketed

6.6 Special precautions for disposal

No special requirements

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

7 MARKETING AUTHORISATION HOLDER

Dawa Limited

5, Sandridge Close,

Harrow, Middlesex, HA1 1XD

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 30684/0229

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

07/11/2014