SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

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 colored 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 CLINICAL PARTICULARS

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 astemizole, terfanadine, cisapride or pimozide (see section 4.5)

•    In patients taking ergotamine and dihydroergotamine (see section 4.5)

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.

Prolonged cardiac repolarisation and QT interval, imparting a risk of developing cardiac arrhythmia and torsades de pointes, have been seen in treatment with other macrolides, including erythromycin (see section 4.8). Therefore as the following situations may lead to an increased risk for ventricular arrhythmias (including torsade de pointes) which can lead to cardiac arrest, erythromycin should be used with caution in patients with ongoing proarrhythmic conditions (especially women and elderly patients) such as patients:

-    With congenital or documented acquired QT prolongation.

-    Currently receiving treatment with other active substances known to prolong QT interval such as antiarrhythmics of class IA (quinidine) and class III (cisapride and terfenadine); antipsychotic agents such as pimozide; antidepressants such as citalopram.

-    With electrolyte disturbance, particularly in cases of hypokalaemia and hypomagnesaemia

-    With clinically relevant bradycardia, cardiac arrhythmia or severe cardiac insufficiency.

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.

Antibacterial agent-associated colitis and pseudo-membranous colitis have been reported with nearly all anti-bacterial agents, including erythromycine, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of erythromycin (see section 4.8). Discontinuation of therapy with erythromycin and the administration of specific treatment for Clostridium difficile should be considered. Medicinal products that inhibit peristalsis should not be given.

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

There have been post-marketing reports of colchicine toxicity when erythromycin was used concomitantly with colchicine. This interaction is potentially life-threatening, and may occur when using both drugs at their recommended doses.

There have been reports of infantile hypertrophic pyloric stenosis (IHPS) occurring in infants following erythromycin therapy. In one cohort of 157 newborns who were given erythromycin for pertussis prophylaxis, seven neonates (5%) developed symptoms of nonbilious vomiting or irritability with feeding and were subsequently diagnosed as having IHPS requiring surgical pyloromyotomy. 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.

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, aminophylline, astemizole, bromocriptine, carbamazepine, cyclosporin, digoxin, dihydroergotamine, disopyramide, ergotamine, hexobarbitone, indinavir, midazolam, phenytoin, quinidine, rifabutin, ritonavir, sildenafil, tacrolimus, terfenadine, theophylline, triazolam, valproate, and warfarin cilostazol, methylprednisolone, omeprazole, vinblastine, and antifungals e.g. fluconazole, ketoconazole, posaconazole, voriconazole and itraconazole. Appropriate monitoring should be undertaken and dosage should be adjusted as necessary. Particular care should be taken with medications known to prolong the QTc interval of the electrocardiogram.

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

HMG-CoA Reductase Inhibitors: erythromycin has been reported to increase concentrations of HMG-CoA reductase inhibitors (e.g. lovastatin and simvastatin). Rare reports of rhabdomyolysis have been reported in patients taking these drugs concomitantly.

Erythromycin use in patients who are receiving high doses of theophylline may be associated with an increase in serum theophylline levels and potential theophylline toxicity. In case of theophylline toxicity and/or elevated serum theophylline levels, the dose of theophylline should be reduced while the patient is receiving concomitant erythromycin therapy.

There have been post-marketing reports of colchicine toxicity with concomitant use of erythromycin and colchicine. (see section 4.4)

Hypotension, bradyarrhythmias and lactic acidosis have been observed in patients receiving concurrent verapamil, a calcium channel blocker.

Citalopram and escitalopram may have an additive effect to other drugs that prolong the QT interval. Caution is advised if citalopram and escitalopram are to be coadministered with erythromycin.

Drugs that induce CYP3A4 (such as rifampicin, phenytoin, carbamazepine, phenobarbital, St John's Wort) may induce the metabolism of erythromycin. This may lead to subtherapeutic levels of erythromycin and a decreased effect. The induction decreases gradually during two weeks after discontinued treatment with CYP3A4 inducers. Erythromycin should not be used during and two weeks after treatment with CYP3A4 inducers.

Drugs that inhibit CYP3A4 (e.g. cimetidine) may increase the plasma concentration of erythromycin. During concomitant administration of erythromycin and protease inhibitors, an inhibition of erythromycin metabolism has been observed.

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 patients’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.

Blood and lymphatic system disorders

Uncommon: Eosinophilia

Immune system disorders

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

Psychiatric disorders

Very rare: hallucinations

Nervous system disorders

Uncommon: vertigo, confusion Very rare: seizures

Cardiac disorders

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

Unknown: QTc interval prolongation, torsades de pointes

Ear and labyrinth disorders

Rare: deafness, tinnitus,

Very rare: reversible hearing loss

Vascular disorders

Unknown: hypotension

Gastrointestinal disorders

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

Very rare: infantile hypertrophic pyloric stenosis,

Unknown: pseudomembranous colitis

Hepatobiliary disorders

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

Renal and urinary disorders

Uncommon: interstitial nephritis

Rare: dark urine

General disorders and administration site conditions

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

4.9 Overdose

Symptoms: Hearing loss, severe nausea, vomiting and diarrhoea. Treatment: Gastric lavage, general supportive measures. Erythromycin is not removed by peritoneal dialysis or haemodialysis.

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:

Organism	MIC Breakpoint (mg /L)
	Susceptible (<S)	Resistant (R>)
Listeria monocytogenes	1.0	1.0
Haemophilus influenza	0.5	16.0
Moraxella catarrhalis	0.25	0.5
Staphylococcus spp	1.0	2.0
Streptococcus group A,B, C,G	0.25	0.5
Streptococcus pneumoniae	0.25	0.5
Campylobacter jejuni	4.0	4.0

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.

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 pg/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

Shelf life

2 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 THE AUTHORISATION

07/11/2014

10    DATE OF REVISION OF THE TEXT

07/11/2014