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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Erythromycin Tablets BP 250mg

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 250mg Erythromycin BP.

3    PHARMACEUTICAL FORM

Tablet.

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

2) Lower respiratory tract infections

3) Eye infections

4) Ear infections

5)    Oral/dental infections

6) Skin and soft-tissue infections

7)    Gastro-intestinal infections

8) Sexually transmitted diseases

9) Prophylaxis

Erythromycin has been shown to have in-vitro activity against the following micro-organisms:

Gram-positive Cocci: Staphylococci and Streptococci

Haemophilus influenzae, L-forms, Neisseria, Mycoplasma pneumoniae,

Legionella pneumophila, Branhamella catarrhalis, Bordetella pertussis,

Corynebacterium diphtheriae (as an adjunct to antitoxin), Treponema pallidum, Chlamydia trachomatis, Ureaplasma urealytica, Clostridia, Campylobacter.

4.2 Posology and method of administration

Adults: Usual dosage is 250mg every 4 to 6 hours. This may be increased to 4g or more per day according to the severity of the infection.

Children:Age and weight of the child, and severity of the infection are important factors in determining the correct dosage.

The usual regimen is 30-50mg/kg/day in divided doses. For more severe infections, this dosage may be doubled.

If administration on a twice daily schedule is desirable in adults or children, one-half of the total daily dose may be given every 12 hours, one hour before meals.

Elderly: No special dosage recommendations.

Route of Administration: Oral.

4.3 Contraindications

Known sensitivity to erythromycin.

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

Erythromycin is contraindicated with ergotamine and dihydroergotamine.

4.4 Special warnings and precautions for use

Erythromycin is excreted principally by the liver, so caution should be exercised in administering the antibiotics 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.

Caution should be exercised in administering this antibiotic to patients with renal impairment and patients with a predisposition to QT interval prolongation. This product should not be used in patients with porphyria.

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.

Care should be taken when administering this product to patients who are pregnant or breastfeeding.

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. 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.

4.5 Interactions with other Medications 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, antifungals e.g fluconazole, ketoconazole and itraconazole, and warfarin. 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.

The use of erythromycin in patients who are receiving warfarin may result in the potentiation of the effect of warfarin due to reduction in the rate of excretion.

Concomitant use of erythromycin with simvastatin, tolterdine, mizolastine, amisulpride, terfenadine or astemizole is likely to result in an enhanced risk of cardio | toxicity with these drugs._The concomitant use of erythromycin with either simvastatin, tolterodine, mizolastine, amisulpride, astemizole or terfenadine is therefore contra-indicated.

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) 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 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.

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

Erythromycin is excreted in breast milk, therefore, caution should be exercised when erythromycin is administered to a nursing mother.

4.7 Effects on ability to drive and use machines

No effect.

4.8 Undesirable effects

Blood and lymphatic system disorders:

Eosinophilia.

Cardiac disorders

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

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.

Ear and labyrinth disorders

Deafness, tinnitus.

There have been isolated reports of reversible hearing loss occurring chiefly in patients with renal insufficiency or high doses (Doses greater than 4g per day).

Gastrointestinal disorders

The most frequent side effects of erythromycin are gastrointestinal and are dose-related.

Nausea, vomiting, abdominal discomfort and diarrhoea occur infrequently with usual doses.

The following have been reported:

Pancreatitis, anorexia, infantile hypertrophic pyloric stenosis.

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

General disorders and administration site conditions

Fever, malaise.

Hepatobiliary disorders

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

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

Immune system disorders

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

Nervous system disorders

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.

Psychiatric disorders

Hallucinations

Renal and urinary disorders

Interstitial nephritis

Skin and subcutaneous tissue disorders

Skin eruptions, pruritus, urticaria, exanthema, angioedema.

Skin reactions ranging from mild eruptions to erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis have rarely been reported.

Vascular disorders

Hypotension.

The rare possibility of super infection caused by overgrowth of non-susceptible bacteria or fungi should be considered during prolonged or repeated therapy, especially when other antibacterial agents are simultaneously employed.

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.

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 are hearing loss, severe nausea, vomiting and diarrhoea.

Treatment is gastric lavage, general supportive measures.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic Group: Macrolides- 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

Tmax =    4 H.

Cmax =    0.3-0.5 pg/ml

Vd=    0.78 + 0.44 l/kg

t /=    1.6 + 0.7H

Clearance = 9.1 -4.1ml/minute/kg

Erythromycin is adversely affected by gastric acid. For this reason erythromycin tablets are enteric coated.

It is absorbed from the small intestine. It is widely distributed throughout body tissues. Little metabolism occurs and only about 5% is eliminated in the urine. It is excreted principally by the liver.

5.1 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

Maize starch, croscarmellose sodium type A, povidone (Kollidone K90), talc, magnesium stearate, hydroxypropyl methylcellulose, polyethylene glycol 6000, dispersed red 18152 (E110 and E124), methacrylic acid copolymer, polysorbate 80.

6.2 Incompatibilities

None known.

6.3 Shelf life

2 years.

6.4 Special precautions for storage

Protect from light, store in a cool dry place (below 20^oC). Keep containers tightly closed.

6.5 Nature and contents of container

(i)    Securitainers with polyethylene tamper-evident seals: 21, 100, 250, 500, 1,000.

(ii)    250 pm PVC/20pm aluminium blister packs:

28, 56, 84, 100.

6.6 Special precautions for disposal

Not applicable.

7    MARKETING AUTHORISATION HOLDER

Ennogen Pharma Limited Unit G4,