ERYTHROMYCIN ETHYLSUCCINATE 250 MG / 5 ML GRANULES FOR ORAL SUSPENSION - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Erythromycin ethyl succinate 250 mg/5 ml Granules for Oral Suspension

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Erythromycin Ethylsuccinate EP 250 mg/5 ml

(where each mg of base is taken to be equivalent to 1000 units of activity)

Excipients with known effect

Each 5 ml of oral suspension contains 48.22 mg of sodium.

Each 5 ml of oral suspension contains 3.025 g of sucrose.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Granules for Oral Suspension

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Antibiotic for treatment of infections caused by erythromycin sensitive organisms especially gram positive pyogenic cocci and some gram-negative bacteria. It may be used in a wide variety of clinical infections.

Erythromycin is an appropriate alternative to penicillin in hypersensitive patients especially in pre or post operative patients.

Respiratory Tract Infections:

Acute and chronic bronchitis, legionnaires disease, tracheitis, bronchiectasis, pneumonia.

Skin and Soft Tissue Infections:

Acute infections of skin and soft tissue which are mild to moderately severe.

Eye/Ear infections:

Otitis media and otitis externa mastoiditis, chlamydial conjunctivitis, blepharitis.

Oral infections:

Gingivitis, Vincent's angina.

Gastro-intestinal Infections:

Staphylococcal enterocolitis, cholecystitis, campylobacter infections.

Other infections:

Gonorrhoea, syphilis, urethritis, diphtheria, pertussis.

4.2 Posology and method of administration

Method of Administration

Oral

Posology

Adults and Children over 8 Years

For mild to moderate infections 2 g daily in divided doses up to 4 g daily in severe infections;

250–500 mg every 6 hours or 0.5–1 g every 12 hours.

For acne vulgaris the usual dose is 250 mg three times daily before meals for one to four weeks and then reduced to twice daily until improvement occurs.

Children Aged 2 to 8 Years

For mild to moderate infections 1 g daily in divided doses;

250 mg every 6 hours

30 mg/kg/day in divided doses. For severe infections up to 50 mg/kg/day in divided doses.

Infants and Babies up to 2 Years

For mild to moderate infections 500 mg daily in divided doses;

125 mg every 6 hours

30 mg/kg/day in divided doses. For severe infections up to 50 mg/kg/day in divided doses.

Elderly

No special dosage recommendations.

Renal Impairment

If impairment is severe (GFR < 10 ml/min), the daily dose should not exceed 1.5 g due to risk of ototoxicity.

For severe infections dosage may be doubled. Duration of dosage regimen is dependant on the nature of the infection and is at the discretion of the physician.

4.3 Contraindi­cations

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

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

Erythromycin is contraindicated with ergotamine and dihydroergotamine.

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

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.

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 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.

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.

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 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.

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

This medicine contains 46.53 mg/5 ml of sodium. To be taken into consideration by patients on a controlled sodium diet.

4.5 Interaction with other medicinal products and other forms of interaction

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, theophylline, triazolam, valproate, vinblastine, and antifungals e.g. fluconazole, ketoconazole 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.

Drugs that induce CYP3A4 (such as rifampicin, phenytoin, carbamazepine, phenobarbital, St John's Wort) may induce the metabolism of erythromycin. This may lead to sub-therapeutic 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.

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.

Contraceptives: some antibiotics may in rare cases decrease the effect of contraceptive pills by interfering with the bacterial hydrolysis of steroid conjugates in the intestine and thereby reabsorption of unconjugated steroid. As a result of this plasma levels of active steroid may decrease.

Antihistamine H1 antagonists: care should be taken in the coadministration of erythromycin with H1 antagonists such as terfenadine, astemizole and mizolastine due to the alteration of their metabolism by erythromycin.

Erythromycin significantly alters the metabolism of terfenadine, astemizole and pimozide when taken concomitantly. Rare cases of serious, potentially fatal, cardiovascular events including cardiac arrest, torsade de pointes and other ventricular arrhythmias have been observed (see sections 4.3 and 4.8).

Anti-bacterial agents: an in vitro antagonism exists between erythromycin and the bactericidal beta-lactam antibiotics (e.g. penicillin, cephalosporin). Erythromycin antagonises the action of clindamycin, lincomycin and chloramphenicol. The same applies for streptomycin, tetracyclines and colistin.

Protease inhibitors: in concomitant administration of erythromycin and protease inhibitors, an inhibition of the decomposition of erythromycin has been observed.

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

Triazolobenzo­diazepines (such as triazolam and alprazolam) and related benzodiazepines: erythromycin has been reported to decrease the clearance of triazolam, midazolam, and related benzodiazepines, and thus may increase the pharmacological effect of these benzodiazepines.

Post-marketing reports indicate that co-administration of erythromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterised by vasospasm and ischaemia of the central nervous system, extremities and other tissues (see section 4.3).

Elevated cisapride levels have been reported in patients receiving erythromycin and cisapride concomitantly. This may result in QTc 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.

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 published reports suggesting when oral erythromycin is given concurrently with theophylline there is a significant decrease in erythromycin serum concentrations. This decrease could result in sub-therapeutic concentrations of erythromycin.

There have been post-marketing reports of colchicine toxicity with concomitant use of erythromycin and colchicine.

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

Cimetidine may inhibit the metabolism of erythromycin which may lead to an increased plasma concentration.

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

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no adequate and well-controlled studies in pregnant women. However, observational studies in humans have reported cardiovascular malformations after exposure to medicinal products containing erythromycin during early pregnancy.

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).

Breastfeeding

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

4.7 Effects on ability to drive and use machines

None known

4.8 Undesirable effects

Eosinophilia.

Allergic reactions ranging from urticaria and mild skin eruptions to anaphylaxis have occurred.

Hallucinations

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

Mitochondrial Optic Neuropathy

Deafness, tinnitus

There have been isolated reports of reversible hearing loss occurring chiefly in patients with renal insufficiency or taking high doses.

QTc interval prolongation, torsades de pointes, palpitations, and cardiac rhythm disorders including ventricular tachyarrhythmias.

Cardiac arrest, ventricular fibrillation (frequency not known).

Hypotension.

The most frequent side effects of oral erythromycin preparations are gastrointestinal and are dose-related. The following have been reported:

upper abdominal discomfort, nausea, vomiting, diarrhoea, pancreatitis, anorexia, infantile hypertrophic pyloric stenosis.

Pseudomembranous colitis has been rarely reported in association with erythromycin therapy (see section 4.4).

Cholestatic hepatitis, jaundice, hepatic dysfunction, hepatomegaly, hepatic failure, hepatocellular hepatitis (see section 4.4).

Skin eruptions, pruritus, urticaria, exanthema, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme.

Not known: acute generalised exanthematous pustulosis (AGEP).

Interstitial nephritis

Chest pain, fever, malaise.

Increased liver enzyme values.

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 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 and general supportive measures.

Erythromycin is not dialysable.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Macrolides, Lincosamides and Streptogramins, Macrolides, ATC code: J01F A01

Mechanism of action

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

Absorption is facilitated if the stomach is empty.

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.

The drug is not removed by either peritoneal dialysis or haemodialysis. It diffuses readily into intracellular fluids and antibacterial activity can be achieved at essentially all sites. There is some retention in liver and spleen. Only low concentrations are achieved in cerebrospinal fluid, unless the meninges are inflamed. Diffusion into the aqueous humour, but not the vitreous humour of the eye is good. A significant proportion is bound to serum proteins.

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. PHARMACEUTICAL PARTICULARS

6.1. List of Excipients

Sodium Carboxymethyl­cellulose

Sodium Citrate

Banana Flavour E4210 SD

Quinoline Yellow 14031 E104

Sodium Saccharin

Colloidal Silicon Dioxide

Sucrose (Caster Sugar)

6.2. Incompatibilities

Not appropriate

6.3 Shelf life

Granules:

3 years (Glass)

3 years (Plastic)

Reconstituted syrup:

14 days (Glass and Plastic)

6.4.

Granules:

Reconstituted Syrup:

Do not store above 250c

Do not store above 150c

6.5. Nature and Contents of Container

Amber glass bottles with pilfer evident cap

High density polyethylene bottles with pilfer proof screw caps

Pack sizes 100 ml and 140 ml.

High density polyethylene bottles with Child Resistant Closures (CRC caps).

6.6 Special precautions for disposal and other handling

To reconstitute, first shake bottle to loosen powder. Reconstitute with water to 100 ml and shake the bottle vigorously until granules are fully suspended before use.

To reconstitute, first shake bottle to loosen powder. Reconstitute with water to 140 ml and shake the bottle vigorously until granules are fully suspended before use.

7. MARKETING AUTHORISATION HOLDER

Pinewood Laboratories Limited

Ballymacarbry,

Clonmel,

Co Tipperary,

Ireland

8. MARKETING AUTHORISATION NUMBER(S)

PL 04917/0014