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

1 NAME OF THE MEDICINAL PRODUCT

Erythromycin 250 mg / 5 ml Oral Suspension

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 5 ml of reconstituted product contains 125 mg of erythromycin as erythromycin ethyl succinate.

Excipients with known effect

Contains up to 3.125g sucrose per 125mg/5ml.

For full list of excipients see 6.1.

3 PHARMACEUTICAL FORM

Granules for Oral Suspension

Yellow granules with a banana odour.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Antibiotic for the prophylaxis and treatment of infections caused by Erythromycin sensitive organisms in a wide variety of clinical indications.

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. Eye infections: blepharitis.

4. Ear infections: otitis media and otitis externa, mastoiditis.

5. Oral / dental infections: gingivitis, Vincent's angina.

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

7. Gastro intestinal infections: cholecystitis, staphylococcal enterocolitis.

8. Prophylaxis: pre- and post- operative trauma, burns, rheumatic fever.

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

Note: Erythromycin has also proved to be of value in endocarditis and septicaemia, but in these conditions initial administration of erythromycin lactobionate by the intravenous route is advisable.

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

4.2 Posology and method of administration

To be taken orally.

Adults and children over 8 years:

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

Elderly:

No special dosage recommendations.

Children:

a.) Aged 2 to 8 years

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

Normal dose: 250mg four times a day or 500 mg twice daily.

b) Infants and children up to 2 years

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

Normal dose: 125mg four times a day or 250 mg twice daily.

Duration of the dosage regimen is dependent on the nature of the infection and is at the discretion of the physician.

4.3 Contraindications

Known hypersensitivity to erythromycin.

Erythromycin is contra-indicated in patients taking simvastatin, tolterodine, mizolastine, amisulpiride, astemizole, terfenadine, domperidone, cisapride or pimozide.

Erythromycin is contra-indicated with ergotamine and dihydroergotamine.

4.4 Special warnings and precautions for use

Caution should be exercised in administering this antibiotic to patients with impaired hepatic function or those concomitantly receiving potentially hepatotoxic agents since this drug is excreted principally by the liver.

Hepatic dysfunction including increased liver enzymes and/or cholestatic hepatitis, with or without jaundice, has been infrequently reported with 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.

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.

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 & 4.5).

Rhabdomyolysis with or without renal impairment has been reported in seriously ill patients receiving erythromycin concomitantly with statins e.g. simvastatin. (See also Section 4.3 – Contraindications and Section 4.5 – Interactions with other medicinal products).

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 non-bilious 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.

Carefully consider the balance of benefits and risks before prescribing erythromycin for any patients taking hydroxychloroquine or chloroquine, because of the potential for an increased risk of cardiovascular events and cardiovascular mortality (see section 4.5).

This product contains sucrose and therefore caution should be exercised when administering this antibiotic to patients with diabetes mellitus, hereditary fructose intolerance, glucose-galactose malabsorption syndrome, or sucrase-isomaltase deficiency.

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.

4.5 Interaction with other medicinal products and other forms of interaction 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

The concomitant use of erythromycin with either terfenadine, astemizole or pimozide is therefore contraindicated.

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.

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.

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 di-hydroergotamine has been associated in some patients with acute ergot toxicity characterised by vasospasm and ischaemia of the central nervous system, extremities and other tissues (see section 4.3)

With the following drugs metabolised by the cytochrome P450 system an increase in serum concentration may occur when they are administered concurrently with omeprazole, erythromycin, acenocoumarol, alfentanil, astemizole, bromocriptine, carbamazepine, cilostazol, cyclosporin, digoxin, dihydroergotamine, disopyramide, domperidone, ergotamine, hexobarbitone, methylprednisolone, midazolam, mizolastine, phenytoin, quinidine, rifabutin, sildenafil, tacrolimus, terfenadine, theophylline, triazolam, valproate , vinblastine, warfarin and antifungals e.g. fluconazole, ketoconazole and itraconazole. Appropriate monitoring should be undertaken and dosage should be adjusted accordingly.Par­ticular care should be taken with medications known to prolong the OTc interval of the electrocardiogram.

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

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 subtherapeutic concentrations of erythromycin. Erythromyin plasma concentrations are increased when taken with cimetidine increasing risk of toxicity, including deafness.

Erythromycin reduces plasma concentration of zafirlukast.

Avoid concomitant use with mizolastine, reboxetine and tolterodine.

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.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.

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

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.

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.

Observational data have shown that co-administration of azithromycin with hydroxychloroquine in patients with rheumatoid arthritis is associated with an increased risk of cardiovascular events and cardiovascular mortality. Because of the potential for a similar risk with other macrolides when used in combination with hydroxychloroquine or chloroquine, careful consideration should be given to the balance of benefits and risks before prescribing erythromycin for any patients taking hydroxychloroquine or chloroquine.

4.6 Fertility, Pregnancy and lactation

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.

The risk -benefit balance should be considered for each individual patient before prescribing erythromycin during 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).

Erythromycin can be excreted into breast milk. Caution should be exercised when erythromycin is administered to lactating mothers due to 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

The following adverse reactions listed by body system, have been reported with erythromycin:

Blood and lymphatic system disorders:

Eosinophilia

Immune system disorders:

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

Psychiatric disorders:

Hallucinations

Nervous system disorders:

There have been isolated reports of transient central nervous system side effects including confusion, seizures and vertigo

Eye disorders;

Mitochondrial Optic Neuropathy

Ear and Labyrinth Disorders

Deafness, tinnitus. There have been isolated reports of Reversible hearing loss occurring mainly in patients with renal insufficiency or receiving high doses doses of Erythromycin

Cardiac disorders:

QTc interval prolongation, torsades de pointes, palpitations, and cardiac rhythm

disorders including ventricular tachyarrhythmias

Vascular disorders:

Hypotension

Gastrointestinal disorders:

The most frequent side effects of oral erythromycin preparations are gastro- intestinal 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 reported in association with erythromycin.

Hepato-biliary disorders:

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

Skin and subcutaneous tissue disorders:

Skin eruptions, pruritus, urticaria, exanthema, angioedema, Stevens-Johnson Syndrome and toxic epidermal necrolysis

Not known: acute generalised exanthematous pustulosis (AGEP)

Renal and Urinary Disorders:

Interstitial nephritis

General disorders and administration site conditions:

Chest pain, fever, malaise.

Investigations:

Increased liver enzyme values.

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: General supportive measures.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Erythromycin is a macrolide antibiotic, ATC code J01F A, which acts by interfering with a bacterial protein synthesis and is bacteriostatic or bactericidal depending on its concentration and the type of organism.

Sensitive organisms include:

(1) Gram positive bacteria such as Staphylococci aureus and epidermis, Streptococci pyogenes, pneumoniae and viridans, Corynebacterium diphtheriae and Listeria monocytogenes.

(2) Gram negative bacteria such as Heamophilus influenzae, Neisseria meningitidis, Neisseria gonorrhoeae, Bordetella pertussis, Campylobacter strains and Legionella pneumophila.

(3) Treponema pallidum

(4) Mycoplasma pneumoniae

(5) Chlamydia trachomatis

5.2 Pharmacokinetic properties

An ester well absorbed from the gastrointestinal tract, absorption may be slightly delayed by food and the highest and earliest peak serum levels occur under fasting conditions.

tmax = 2 to 4 hours

Cmax = approx. 0.5 micrograms/ml (from a 250 mg dose)

t ^ = 1.6 ± 0.7 hours

Erythromycin is excreted in high concentrations in the bile and up to 5% of an oral dose may appear in the urine; considerable amounts may also be inactivated by the body.

5.3 Preclinical safety data

No relevant information additional to that contained elsewhere in the SPC.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Carboxymethyl­cellulose sodium

Sodium citrate

Banana flavour

Quinoline yellow E104

Saccharin sodium

Silica, colloidal anhydrous

Sucrose

6.2 Incompatibilities

Not Applicable

6.3 Shelf life

36 months unopened.

14 days after reconstitution.

6.4 Special precautions for storage

Store in the original container. Do not store above 25°C prior to reconstitution.

After reconstitution, store suspension at 2°C – 8°C. Do not freeze.

6.5 Nature and contents of container

Nature: Amber type III glass bottle with polyethylene screw on cap.

Contents: 60.5 g

Reconstitution of the granules provides 100 ml of suspension.

6.6 Special precautions for disposal

Add 60 ml of water, invert the bottle and shake vigorously for 1 minute.

7 MARKETING AUTHORISATION HOLDER

Chelonia Healthcare Limited

11 Boumpoulinas Street, 3rd floor, 1060 Nicosia

Cyprus