SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

TILORYTH 250mg

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Active ingredient:

Erythromycin base 250mg

3. PHARMACEUTICAL FORM

Gastro-resistant capsules

4    CLINICAL PARTICULARS

4.1.    Therapeutic Indications

These are based on the antibacterial activity and pharmacokinetic characteristics of erythromycin. They take account both of the clinical studies carried out with this drug and of its place in the range of antibacterial products on the market.

Erythromycin is an antibiotic effective in the treatment of bacterial disease caused by susceptible organisms.

Examples of its use include:

■    Ear, nose and throat, stomatological.

■    Upper and lower respiratory tract infections of mild to moderate severity.

■    Bacterial endocarditis.

■    Skin and soft tissue infections including pustular acne.

■    Dental infections

■    Osteoarticular

■    Genito-urinary infections, including gonorrhoea, syphilis and chlamydia infections.

■    To the chemoprophylaxsis of acute articulator rheumatism relapse in the case of contraindication to penicillin G or V.

Erythromycin is usually active against the following organisms in vitro and in clinical infection: Streptococcus pyogenes, Alpha haemolytic streptococci, Staphylococcus aureus, Streptococcus pneumoniae, Mycoplasma pneumoniae, Treponema pallidum, Corynebacterium diphtheria, Corynebacterium minutissimum, Entamoeba histolytica, Listeria monocytogenes, Neisseria gonorrhoeae, Bordetella pertussis, Legionella pneumophila, Haemophilus influenzae, Chlamydia trachomatis, Propionibacterium acnes.

4.2. Posology and Method of Administration

Oral administration

The capsules must be swallowed whole and not chewed.

The drug should be given just before or with meals.

Adults:

250 - 500 mg every 6 hours or 500 - 1000 mg every 12 hours where more serious infection is suspected. Up to 4g daily in divided doses for severe infections.

Children:

Up to 8 years - Tiloryth 250 mg is not considered suitable for administration to children under the age of 8 years.

Over 8 years - As for adults.

Early syphilis:

500 mg 4 times daily for 14 days

Non-gonococcal urethritis:

500 mg 4 times daily for 7 days

Streptococcal infections:

For active infection - a full therapeutic dose is given for at least ten days. In continuous prophylaxis against recurrences of streptococcal infections in patients with evidence of rheumatic fever heart disease, the dose is 250mg twice daily. For the prevention of bacterial endocarditis in patients with valvular disease scheduled for dental or surgical procedures of the upper respiratory tract, adult dose is 1.0 gram (children 20mg/kg) 2 hours before surgery. Following surgery, 500mg for adults (children 10mg/kg) orally every six hours for 8 doses.

Bacterial Endocarditis

The adult dose is 1 g 2 hours before the surgery and 500 mg, following surgery. The child dose is 20mg/kg, before surgery and 10/mg, following surgery. The dosage, following surgery, for adults and children is to be given orally every six hours for 8 doses.

Amoebic dysentery:

Dosage for adults is 250mg four times daily for 10 to 14 days; for children 30-50mg/kg/day in divided doses for 10 to 14 days.

Legionnaires’ disease:

1-4g daily in divided doses until clinical signs and symptoms indicate a clinical cure.

Prolonged treatment may be required.

Pertussis:

30-50mg/kg/day given in divided doses for 5-14 days, depending upon eradication of a positive culture.

Acne:

Initially, one capsule(250 mg) twice daily, which may be reduced to a maintenance dose of one capsule( 250 mg) once daily after one month according to response.

Prolonged treatment may be required.

4.3 Contraindications

■    Allergy to erythromycin or sucrose intolerance.

■    Association with the vasoconstrictor ergot alkaloids, notably ergotamine and dihydroergotamine (cf. interaction with other medicaments).

■    Severe liver insufficiency.

■    Migraine crisis treated with ergot derivatives (cf. interaction with other medicaments).

■    Erythromycin is contraindicated in patients taking astemizole, terfenadine, cisapride, pimozide (cf. Interaction with other medicaments), simvastatin, tolterodine, mizolastine, amisulpride or sertindole..

Use in patients hypersensitive to erythromycin or to any of the excipients

4.4 Special Warnings and Special Precautions for Use

In cases of hepatic insufficiency the administration of erythromycin is not recommended. If it is necessary, then regular supervision with hepatic tests and eventually a reduced dosage regimen is necessary.

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, Also liver function should be monitored, since a few reports of hepatic dysfunction have been received in patients taking erythromycin as the estolate, base or stearate. Extended administration requires regular evaluation particularly of liver function. Therapy should be discontinued if significant hepatic dysfunction occurs..

Prolonged or repeated administration of erythromycin could favour the growth of non susceptible organisms bacteria or fungi or the appearance of mycoses, this is a rare occurrence.

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.

Asthmatic subjects treated with theophylline should be subject to special control for clinical symptoms of intoxication and eventually to drug monitoring for plasma concentrations of theophylline (cf.. Section 5.7; Interaction with other medicaments).

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 regime.

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 lovastatin (statins) or with concomitant use of erythromycin and HMG-CoA reductase inhibitors (see sections 4.3 and 4.5)..

Erythromycin interferes with the fluorometric determination of urinary catecholamines and 17-hydroxycorticosteroids levels..

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.

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 and 4.5). Owing to the presence of lactose, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Antihistamine H1 antagonists: Concomitant use of erythromycin with terfenadine, mizolastine or astemizole is likely to result in an enhanced risk of cardiotoxicity with these drugs due to the alteration of their metabolism by erythromycin. The concomitant use of erythromycin with either astemizole or terfenadine is therefore contraindicated.

The metabolism of terfenadine, pimozide 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. (see sections 4.3 and 4.8).

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. Particular care should be taken with medications known to prolong the QTc interval of the electrocardiogram.

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 ischaemia of the central nervous system, extremities and other tissues and dysaesthesia (see section 4.3).

Increases in serum concentrations of the following drugs metabolised by the cytochrome P450 system may occur when administered concurrently with erythromycin: acenocoumarol, atorvastatin , buspirone, cabergoline, clozapine, eletriptan, felodipine, quetiapine, tadalafil, zopiclone 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 , itraconazole and warfarin. Because of the risk of toxicity, 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

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 also a significant decrease in erythromycin serum concentrations. The decrease could result in subtherapeutic concentrations of 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 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 seriously ill patients taking these drugs concomitantly, and caution is therefore recommended when erythromycin is used concurrently with other HMG-CoA reductase inhibitors. It is recommended that therapy with simvastatin is suspended during the course of treatment. .

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.

Anti-bacterial agents: an in vitro antagonism exists between erythromycin and the bactericidal beta-lactam antibiotics (e.g. penicillin, cephalosporin). Erythromycin should be used with caution if administered concomitantly with lincomycin, clindamycin or chloramphenicol, as 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.

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 of erythromycin leading to increased risk of toxicity, including reversible deafness..

Cytochrome P450 interactions:

Concomitant use of erythromycin with certain drugs metabolised by the cytochrome P450 system is likely to result in an increased frequency or seriousness of adverse effects associated with these drugs. The concomitant use of erythromycin with mizolastine, amisulpride, astemizole, cisapride, pimozide, sertindole and terfenadine is contraindicated due to the risk of QT prolongation and cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation and Torsades de pointes.

Concomitant use with simvastatin is contraindicated due to the risk of myopathy and rhabdomyolysis whilst concomitant use with tolterodine is contraindicated due to increased risk of overdose.

The concomitant use of erythromycin with alfentanil can significantly inhibit the clearance of alfentanil and may increase the risk of prolonged or delayed respiratory depression.

4.6 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.

Erythromycin should be used in pregnancy only when clearly indicated. Breast-feeding:

Erythromycin is found excreted in the mother's milk at concentrations which can be superior to maternal serum concentrations, and can cause mild gastro-intestinal symptoms in breast-fed infants. Caution should be exercised when erythromycin is administered to a nursing mother and should be used in lactating women only if clearly needed.

4.7. Effects on Ability to Drive and Use Machines

None known.

4.8 Undesirable effects

Blood and lymphatic system disorders:

Eosinophilia.

Cardiac disorders

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

Ear and labyrinth disorders

Deafness and Transient hearing disturbances have been reported with doses of erythromycin usually greater than 4g daily, and usually given intravenously, tinnitus, Very rare reversible auditive disturbances (hearing loss) have been reported in particular with aged patients or with patients with renal insufficiency, or with patients having received high doses.

Gastrointestinal disorders

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

upper abdominal discomfort and nausea (can occur at elevated doses); vomiting and diarrhoea (are less common), gastralgia, pancreatitis (has been reported rarely), anorexia, infantile hypertrophic pyloric stenosis.

As with other broad spectrum antibiotics, Superinfections including pseudomembranous colitis has been reported rarely with erythromycin therapy. (see section 4.4).

General disorders and administration site conditions Chest pain, fever, malaise.

Hepatobiliary disorders

Symptoms of hepatitis, Cholestatic hepatitis, jaundice, hepatic dysfunction, with or without jaundice occurring in patients receiving erythromycin products and due to combined cholestatic and hepatocellular injury although less commonly than with erythromycin estolate hepatomegaly, hepatic failure, hepatocellular hepatitis (see section 4.4) and/or abnormal liver function test results may occur.

Immune system disorders

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

Investigations

Increased liver enzyme values.

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 reactions ranging from mild eruptions to erythema multiforme, pruritus, urticaria, exanthema, angioedema, Stevens-Johnson Syndrome, rare reports of skin rashes and toxic epidermal necrolysis have rarely been reported.

Vascular disorders Hypotension.

Cardiac arrhythmias have been reported rarely in patients receiving erythromycin.

4.9 Overdose

Overdosage symptoms are severe nausea, hearing loss, vomiting and diarrhoea. Recommended treatment is gastric lavage and general supportive therapy and/or administration of activated charcoal together with general supportive measures.

Neither haemodialysis nor peritoneal dialysis are capable of extracting erythromycin.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Distribution:

-    Erythromycin diffuses well into the tissues, notably in the lungs, the tonsils and the prostate.

-    Erythromycin diffuses only slightly into the cerebrospinal fluid.

-    Erythromycin traverses the placental barrier. It concentrates in the milk.

-    Binding with plasma proteins: the binding of erythromycin base with plasma proteins is about 65%, with a predominance for alpha 1 acid glycoprotein (approximately 55%). (Study with erythromycin C 14)

Biotransformation:

Erythromycin is partly metabolised by the liver.

Excretion:

-    Erythromycin concentrates in the liver and is eliminated in active form, principally by the bile, at concentrations superior to those of serum.

-    Renal elimination is in the order of 2 to 5% for the unchanged form.

Antibacterial Activity

The natural antibacterial spectrum of erythromycin is as follows:

Species normally susceptible	MIC (Ug/ml)
Streptococcus pyogenes (group A, beta hemolytic)	0.005 - 0.2
Streptococcus sanguis	0.02 - 3.1
Bordetella pertussis	0.02 - 1.6
Corynebacterium diptheriae	0.006 - 3.1
Listeria monocytogenes	0.1 - 0.3
Clostridium perfringens	0.1 - 6
Mycoplasma pneumoniae	0.00 1 - 0.02
Chlamydia trachomatis	0.1 - 0.5
Legionella pneumophila	0.06 - 0.5
Treponema pallidum	-
Leptospira	-

Campylobacter jejuni	0.05 - >50
Ureaplasma urealyticum	2 - >4

Non-constantly susceptible species	MIC (ug/ml)
Streptococcus pneumoniae (pneumococcus)	0.001 - - 0.2
Neisseria meningitidis (meningococcus)	0.1 - 1.6
Neisseria gonorrhoea (gonococcus)	0.005 - 0.4
Haemophilus influenzae	0.1 - 6
Bacteroides fragilis	0.1 - >100
Vibrio cholerae
Staphylococcus aureus	0.005 - >100
Resistant species	MIC > 4 mcg/ml
Enterobacteri aceae	0.1 - >100
Pseudomonas	-

-    When constant strain susceptibility has not been established for a certain species, in vitro testing of the strain is the only method of establishing whether it is sensitive, intermediary or resistant.

-    Among the streptococcus pyogenes of Group A a few rare strains are resistant.

-    A microbiological antagonism exists between erythromycin and lincomycin and clindamycin.

-    Cross resistance is usual between the various macrolides.

Microorganisms having an MIC less than 1 or possibly 2 mcg/ml are usually considered as susceptible.

-    For microorganisms with an MIC situated between 2 and 4 mcg/ml the failure frequency increases depending on the site of infection.

5.2. Pharmacokinetic Properties

In healthy subjects, following administration of 2 capsules before meals, the concentration peak was attained at a mean of 2.9 hours, the apparent half-life of elimination was 1.9 hours, the mean maximum concentration being 2.47 mg/l.

5.3 Preclinical safety data

Animal studies have revealed no evidence of impaired fertility or foetal harm related to erythromycin. However, there are no adequate studies in pregnant women. Preclinical safety data does not add anything of further significance to the prescriber. Because animal studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

6. PHARMACEUTICAL PARTICULARS 6.1. List of Excipients

Neutral microgranules (sucrose 75%, corn starch 25%)

Hydroxypropyl methylcellulose

Triacetin

Methacrylic acid and ethyl acrylic copolymer Talc

Hard gelatin capsules

Opacode S-1-8 144 Black (Printing Ink).

6.2. Incompatibilities

None known.

6.3. Shelf-Life

36 months.

48 months for medicine contained in glass bottle.

6.4. Special Precautions for Storage

Keep bottles tightly closed.

Keep in the original container. Protect from light.

Do not store above 25 °C.

6.5. Nature and Content of Container

Cardboard boxes of 28 or 30 capsules containing enteric coated microgranules in doses of 250mg of erythromycin, in thermoformed PVC/aluminium blisters. Glass bottle with polypropylene cap to contain 100 capsules.

Dispensing only under medical prescription.

6.6. Special precautions for disposal and other handling

The capsules must be swallowed whole and not chewed.

7 MARKETING AUTHORISATION HOLDER

Tillomed Laboratories Limited

3 Howard Road

Eaton Socon

St. Neots

Cambridgeshire

PE198ET

8. MARKETING AUTHORIZATION NUMBER

PL 11311/0028

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

5^th October 1995

10 DATE OF REVISION OF THE TEXT

24/09/2012