4.1. Therapeutic indications

This medicine is indicated in severe and immunocompromised cases of infections caused by sensitive organisms where high blood levels are required at the earliest opportunity or when the oral route is compromised.

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. Ear infection: otitis media and otitis externa, mastoiditis

4. Oral infections: gingivitis, Vincent's angina

5. Eye infections: blepharitis

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

7. Gastrointestinal infections: cholecystitis, staphylococcal enterocolitis

8. Prophylaxis: peri-operative secondary infection prophylaxis, severe trauma and burns secondary infection prophylaxis, endocarditis prophylaxis (dental procedures)

9. Septicaemia

10. Endocarditis

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

4.2. Posology and method of administration

Posology

Adults: severe and immunocompromised infections, 50mg/kg/day, preferably by continuous infusion (equivalent to 4g per day for adults).

Mild to moderate infections (oral route compromised) 25mg/kg/day.

Elderly: No special dosage recommendations.

Paediatric population

Newborn infant (birth to 1 month): 10-15mg/kg 3 times daily.

Children: 12.5mg/kg 4 times daily. Doses can be doubled in severe infections.

Method of administration

Bolus injection (IV) push) is contraindicated

Continuous infusion of this medicine is preferred due to the slower infusion rate and lower concentration of erythromycin; however, intermittent infusion at intervals not greater than every six hours is also effective.

Intravenous erythromycin should be replaced by oral erythromycin as soon as possible.

Preparations for administration:

For Intermittent Infusion of 1 gram dose:

Step 1 - add 20 ml of Water for Injections BP to the 1 g vial.

Step 2 - add 20 ml of Step 1 solution to 200-250 ml of Sodium Chloride Intravenous Infusion BP (0.9% Saline). This provides a 0.5%-0.4% solution.

If it is decided to administer the daily dose as an intermittent infusion, then the erythromycin concentration should not exceed 5 mg/ml and the time of each infusion should be between 20 and 60 minutes.

For Continuous Infusion of 1 gram dose:

Step 1 - add 20 ml of Water for Injections BP to the 1 g vial.

Step 2 - add 20 ml of Step 1 solution to 500-1000 ml of Sodium Chloride Intravenous Infusion BP (0.9% Saline). This provides a 0.2%-0.1% infusion

The infusion should be completed within eight hours of preparation to ensure potency.

Alternative Step 2 diluents:

Compound Sodium Lactate Injection BP (Hartmann's Solution).

Solutions containing glucose may also be used but sodium bicarbonate must first be added as a buffer to ensure neutrality.

5ml of sterile 8.4% w/v sodium bicarbonate solution will neutralise one litre of: Glucose Injection BP (5%), or of Sodium Chloride and Glucose Injection BP (usually 0.18% sodium chloride and 4.0% glucose).

The stability of solutions of this medicine is adversely affected below pH 5.5.

For further details please see section 6.6.

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 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).

Erythromycin is contraindicated with ergotamine and dihydroergotamine.

Concomitant administration of erythromycin and lomitapide is contraindicated (see section 4.5).

Bolus injection (IV push) is an unacceptable route of administration.

This medicine must be administered by continuous or intermittent intravenous infusion only.

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.

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.

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.

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.

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).

Benzyl alcohol may be added as a preservative. Benzyl alcohol has been reported to be associated with a fatal 'Gasping Syndrome' in premature infants.

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.

Paediatric population

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.

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, domperidone, 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.

Concomitant administration of erythromycin with lomitapide is contraindicated due the potential for markedly increased transaminases (see section 4.3).

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.

Corticosteroids: Caution should be exercised in concomitant use of erythromycin with systemic and inhaled corticosteroids that are primarily metabolised by CYP3A due to the potential for increased systemic exposure to corticosteroids. If concomitant use occurs, patients should be closely monitored for systemic corticosteroid undesirable effects.

Hydroxychloroquine and chloroquine: Erythromycin should be used with caution in patients receiving these medicines known to prolong the QT interval due to the potential to induce cardiac arrhythmia and serious adverse cardiovascular events.

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.

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

Pregnancy

The available epidemiological studies on the risk of major congenital malformations with use of macrolides including erythromycin during pregnancy provide conflicting results. Some 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 is a large amount of data from observational studies performed in several countries on exposure to erythromycin during pregnancy, compared to no antibiotic use or use of another antibiotic during the same period (>24,000 first trimester exposures). While most studies do not suggest an association with adverse fetal effects such as major congenital malformations, cardiovascular malformations or miscarriage, there is limited epidemiological evidence of a small increased risk of major congenital malformations, specifically cardiovascular malformations following first trimester exposure to erythromycin.

Therefore, erythromycin should only be used during pregnancy if clinically needed and the benefit of treatment is expected to outweigh any small increased risks which may exist.

Breast-feeding

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

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).

Fertility

No data available

4.7. Effects on ability to drive and use machines

No data available.

4.8. Undesirable effects

The list of undesirable effects shown below is presented by system organ class, MedDRA preferred term, and frequency using the following frequency conventions:

Rare (≥1/10,000 to <1/1,000)

Not known (cannot be estimated from the available data)

System Organ Class

Frequency

Adverse reactions

Infections and infestations

Rare

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

Blood and lymphatic system disorders

Not known

Eosinophilia

Immune system disorders

Not known

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

Psychiatric disorders

Not known

Hallucinations

Nervous system disorders

Not known

*Confusion, seizures and vertigo

Eye disorders

Not known

Mitochondrial Optic Neuropathy

Ear and labyrinth disorders

Not known

**Deafness, tinnitus

Cardiac disorders

Not known

Cardiac arrest, QTc interval prolongation, torsades de pointes, palpitations and cardiac rhythm disorders including ventricular tachyarrhythmias, ventricular fibrillation

Vascular disorders

Not known

Hypotension

Gastrointestinal disorders

Not known

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

Hepatobiliary disorders

Not known

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

Skin and subcutaneous tissue disorders

Not known

Acute generalised exanthematous pustulosis (AGEP)

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

Renal and urinary disorders

Not known

Interstitial nephritis

General disorders and administration site conditions

Not known

Chest pain, fever, malaise

Investigations

Not known

Increased liver enzyme values

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

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

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

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 website: 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.

Management

Gastric lavage, general supportive measures.