4.1. Therapeutic indications

Erythromycin Panpharma is indicated for treatment of the following appropriately diagnosed bacterial infections in adults and children caused by susceptible strains of organisms (see section 5.1) when oral administration is not possible or insufficient.

- Conjunctivitis,

- Pneumonia caused by atypical agents,

- Whooping cough,

- Urogenital infections,

- Severe gastroenteritis ,

- Diphtheria,

- Lymphogranuloma venereum.

Erythromycin is also indicated for the treatment of the following infections in patients with hypersensitivity to beta-lactams or when beta-lactams are not appropriate for other reasons:

- Otitis media in severe cases,

- Community acquired pneumonia (see section 4.4),

- Skin and soft tissue infections,

- Acute bacterial exacerbation of chronic bronchitis,

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

4.2. Posology and method of administration

Intravenous therapy must be replaced by oral administration at the appropriate time.

Posology

Adults and children over 12 years old or weighing > 40 kg

The usual dose is 1 to 2 g per day equivalent to 25 mg/kg/day in divided doses (generally 3-4 single doses).

Severe infections

Dosage can be increased up to 4 g per day equivalent to 50 mg/kg/day in severe infections.

The maximum daily dose is 4 g.

Children up to 12 years old or weighing ≤ 40 kg

1 months to up to 12 years old: The daily dose for infants and children up to 12 years old for most infections is 15-20 mg of erythromycin/kg of body weight divided over 3-4 single doses. This dose may be doubled depending on the indication.

Term newborn infants (birth to 1 month)

10-15mg/kg/day divided over 3 singles doses

Renal/hepatic impairment

Patients with impaired hepatic function:

In the presence of normal hepatic function, erythromycin is concentrated in the liver and excreted in the bile. Although the effect of hepatic dysfunction on the excretion of erythromycin and its half-life in such patients is not known, caution should be exercised in administering the antibiotic in such cases particularly if patients with acute hepatic insufficiency receive high doses of erythromycin. In that case, monitoring of serum levels and dosage reduction will be required.

Patients with impaired renal function:

The low proportion of renal excretion would suggest that dosage modification in patients with impaired renal function (slightly or moderately impaired renal function with creatinine clearance levels higher than 10ml/min) may not be necessary.

For patients with moderate to severely impaired renal function, however, toxicity has been reported and dosage adjustment in these cases may be warranted:

- Administration of doses of ≥ 4 g/day may increase the risk for the development of erythromycin-induced hearing loss in elderly patients, particularly those with reduced renal or hepatic function.

- In moderate to severely impaired renal function (with a level of serum creatinine of 2.0 mg/dl, kidney failure with anuria), the maximum daily dose for adolescents over 14 years old and adults (with a body weight over 50 kg) is 2 g erythromycin per day.

- In patients with severe renal insufficiency (creatinine clearance levels lower than 10ml/min), the erythromycin dose must be reduced to 50% to 75% of the normal dose, to be administered in accordance with the usual treatment regimen. The maximum daily dose must not exceed 2g.

Erythromycin is not removed by haemodialysis or peritoneal dialysis. For patients who have regular dialysis, an additional dose is therefore not recommended.

Elderly

Use adult dosage with care. Elderly patients, particularly those with reduced renal or hepatic function may be at increased risk for developing erythromycin-induced hearing loss, when erythromycin doses of 4 g/day or higher are given.

Method of administration

Precautions to be taken before handling or administering the medicinal product

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

Erythromycin can be administered in continuous or intermittent infusion.

The infusion should be administered over 60 minutes as a rapid infusion is more likely to be associated with local irritative effects as well as QT interval prolongation, arrhythmias or hypotension. A longer period of infusion should be used in patients with risk factors or previous evidence of arrhythmias. Not less than 200 ml of diluent should be used for preparing intermittent I.V. solutions so as to minimise venous irritation.

The erythromycin concentration should not exceed 5mg per ml and an erythromycin concentration of 1mg/ml (0.1% solution) is recommended.

Erythromycin should only be administered intravenously. Intra-arterial injection is strictly contraindicated. It can lead to angiospasm with ischaemia. Intramuscular administration and IV bolus injection are also contraindicated.

Intravenous therapy should be replaced by oral administration after 2-7 days. In the interest of sustaining successful treatment, erythromycin should be continued for a further 2-3 days after symptoms have disappeared.

4.3. Contraindications

Patients with known hypersensitivity to erythromycin, to any of the drug's excipients listed in section 6.1, or to other macrolide antibiotics.

Concomitant treatment with astemizole, terfenadine, disopyramide, cisapride, pimozide, ergot alkaloids (such as ergotamine and dihydroergotamine) simvastatin, atorvastatin or lovastatin.

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

Patients with severe hepatic impairment, or patients with severe decompensated heart failure (NYHA IV).

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)

Concomitant use with drugs which likewise can lead to QT interval prolongation, such as anti-arrhythmics classes IA and III, certain neuroleptics, tri- and tetracyclic antidepressants, arsenic trioxide, methadone and budipine, certain fluoroquinolones, Imidazole antifungal and anti-malarial drugs such as IV pentamidine.

4.4. Special warnings and precautions for use

It is generally not recommended to combine erythromycin with:

Alfuzosine, dopaminergic rye ergot alkaloids, buspirone, carbamazepine, cyclosporine, colchicine, disopyramide, ebastine, halofantrine, lumefantrine, tacrolimus, theophylline, tolterodine, triazolam.

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).

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.

Appropriate laboratory tests, including if necessary, electrolyte analyses, must be carried out when there are risk factors for electrolyte disturbances, such as diuretic and laxative medication, vomiting, diarrhoea, insulin use in emergency situations, kidney disease or anorexic conditions, since electrolyte disturbances promote the likelihood of arrhythmias.

Hypersensitivity reactions

Serious, life-threatening allergic reactions may occur during treatment with erythromycin, such as serious skin conditions like urticarial, erythema multiforme exudativum, Stevens-Johnson-syndrome or toxic epidermal necrolysis (especially in children of all ages), angioedema or anaphylaxis. Superinfection may occur with prolonged use, giving rise to overgrowth of non-susceptible organisms.

Patients treated with corticosteroids or corticotrophins

Caution must be exercised in the administration of parenteral fluids, especially those containing sodium ions, to patients receiving corticosteroids or corticotrophins.

Myasthenia gravis

There have been reports that erythromycin can exacerbate the symptoms of myasthenia gravis which may result in life threatening weakness of respiratory muscles. Adequate counter measures should be taken at any sign of respiratory distress (see section 4.8)

Pneumonia

In case of pneumonia by Streptococcus pneumoniae, erythromycin should be used only in patients with hypersensitivity to beta-lactams or when beta-lactams are not appropriate for other reasons. Otherwise, erythromycin can be used as first-line therapy only in case of pneumonia caused by atypical agents.

Clostridium difficile-associated diarrhoea (CDAD)/ Pseudomembranous colitis

As with other broad spectrum antibiotics, pseudomembranous colitis has been reported rarely with erythromycin, in varying degrees of severity from light diarrhoea to life-threatening colitis.

Practically all antibiotics, including erythromycin, are associated with Clostridium difficile-associated diarrhoea (CDAD). CDAD can occur up to two months after treatment with erythromycin as light diarrhoea to lethally progressive colitis. In this case, termination of treatment, depending on the indication, should be considered, and if necessary, appropriate treatment should be initiated (e,g, administration of special antibiotics/chemotherapeutic agents whose effectiveness have been clinically proven). Drugs, which inhibit peristalsis, are contraindicated in the case of pseudomembranous colitis.

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 infection with Bordetella pertussis or Chlamydia trachomatis), the benefit of erythromycin therapy needs to be carefully considered against the potential risk of developing IHPS. Patients or their caregivers should be informed to contact their physician if vomiting or irritability with feeding occurs.

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

Effects of erythromycin on other medicinal products

Erythromycin is an inhibitor of CYP3A4 and the transport protein P-glycoprotein. The extent of inhibition with different CYP3A4 substrates is difficult to predict. Erythromycin should therefore not be used during treatment with CYP3A4 substrates unless the plasma concentrations, effects or side effects of the substrate can be closely followed. A dose reduction of other medicinal products that are metabolised by CYP3A4 can be necessary and combination with erythromycin should take place with caution (e.g. acenocoumarol, alfentanil, bromocriptine, cilostazole, cyclosporine, hexobarbiton, colchicine, methylprednisolone, midazolam, omeprazole, tacrolimus, valproate, vinblastine, antimycotics such as fluconazole, ketoconazole and itraconazole). Alternatively, the treatment with CYP3A4 substrates should be discontinued during treatment with erythromycin.

Medicinal products that may prolong the QT interval

Erythromycin affects the metabolism of terfenadine, astemizole and pimozide during concomitant administration. Rare cases of severe, potentially fatal cardiovascular events such as cardiac arrest, torsades de pointes and other ventricular arrhythmias have been observed and therefore concomitant administration of these medicinal products is contraindicated (see section 4.3).

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 disopyramide and erythromycin and may be expected also in patients taking astemizole or pimozide. Concomitant administration with astemizole, cisapride, disopyramide and pimozide is contraindicated (see section 4.3).

Erythromycin may inhibit the metabolism of quinidine resulting in a 40% increase in Cmax in healthy volunteers. There are case reports of increased plasma concentrations and torsades de pointes. In case of concomitant treatment with erythromycin the plasma levels of quinidine should be controlled.

Caution is recommended when erythromycin is given to patients treated with other medicinal products that may prolong the QT interval (see section 4.4).

Sildenafil

Data suggest that erythromycin inhibits the metabolism of sildenafil. A starting dose of 25 mg sildenafil should be considered.

Benzodiazepines

Erythromycin has been reported to decrease clearance of triazolam, alprazolam, clozapine and related benzodiazepines and thereby increasing the pharmacological effect of these medicinal products. In healthy volunteers pretreated with erythromycin the absorption of zopiclone is faster resulting in higher plasma concentrations and more pronounced hypnotic effect compared to controls.

Theophylline

Concomitant treatment with erythromycin and high doses of theophylline may result in increased plasma theophylline levels and potential theophylline toxicity, probably due to inhibition of metabolism. In case of concomitant treatment plasma levels of theophylline should be followed in order to avoid toxic plasma levels (dose reduction). The erythromycin plasma concentrations may be reduced in case oral erythromycin is given together with theophylline, possibly resulting in subtherapeutic erythromycin levels.

Oral anticoagulants

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

Fexofenadine

In case of concomitant treatment with erythromycin and fexofenadine plasma concentrations of fexofenadine increase 2-3-fold, probably due to increased absorption.

Statins

Erythromycin inhibits the metabolism of several HMG-CoA reductase inhibitors resulting in increased plasma concentrations of these medicinal products. Erythromycin also increases the plasma concentrations of simvastatin acid (5-fold). Rare cases of rhabdomyolysis, associated with elevated plasma levels, have been reported during concomitant treatment with clarithromycin and lovastatin or simvastatin. Erythromycin must not be used concomitantly with simvastatin, atorvastatin or lovastatin. Treatment with these medicinal products must be discontinued during treatment with erythromycin.

Lomitapide

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

Ergot alkaloids (e g ergotamine and dihydroergotamine)

There are case reports of clinical ergotism, characterised by vasospasm and ischaemia in CNS, extremities and other tissues, due to elevated plasma levels of ergot alkaloids during concomitant treatment with macrolide antibiotics. The combination is contraindicated (see section 4.3).

Digoxin

Concomitant treatment with erythromycin and digoxin may result in elevated plasma digoxin levels. Control of plasma levels should be considered during initiation and termination of erythromycin treatment. Dose adjustment may be necessary.

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.

Hypotension, bradyarrhythmia and lactic acidosis has been observed in patients concomitantly treated with the calcium channel blocker verapamil.

Effects of other medicinal products on the pharmacokinetics of erythromycin

Erythromycin is metabolised by CYP3A4. Thus, strong inhibitors of this enzyme may inhibit the metabolism of erythromycin resulting in elevated plasma levels.

Medicinal products that induce CYP3A4 (such as rifampin, phenytoin, carbamazepine, Phenobarbital, St. John's Wort (Hypericum perforatum)) can induce the metabolism of erythromycin. This may lead to subtherapeutic levels of erythromycin and consequently may reduce the effect. The induction is gradually reduced over a period of 2 weeks following discontinuation of treatment with CYP3A4 inducers. Erythromycin should not be used during treatment with CYP3A4 inducers and 2 weeks following discontinuation of therapy.

Cimetidine may inhibit the metabolism of erythromycin resulting in elevated plasma levels.

During concomitant treatment with erythromycin and protease inhibitors inhibition of erythromycin metabolism has been observed.

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. 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.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no animal reproductive toxicology studies with erythromycin available, but studies with other macrolides, that similar to erythromycin are potent hERG-channels blockers, have shown embryonic death and malformations (including cardiovascular defects and cleft palate). Mechanistic studies have shown that substances blocking the hERG-channel cause cardiovascular defects and embryonic death by inducing arrhythmia in the foetus.

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 have been reports that maternal macrolide antibiotics exposure within 10 weeks of delivery may be associated with a higher risk of infantile hypertrophic pyloric stenosis (IHPS).

Erythromycin should be used by women during pregnancy only if clearly needed.

Breastfeeding

Erythromycin is not recommended for nursing mothers unless the expected benefits outweigh the potential risks. In lactating women, erythromycin is secreted into breast milk in quantities of between 0.5 and 6.2 micrograms/ml. These quantities are not known to be harmful. About 50% of the drug crosses into the mother's milk and can cause gastrointestinal disorders in the infant, but possibly also the formation of pyloric stenosis. Furthermore, sensitivity or infection with blastomycetes is also possible.

The benefits and risks of use during lactation must be carefully considered.

Fertility

No data exists on the effect of erythromycin on fertility in human subjects. Animal studies showed that erythromycin has no teratogenic effects.

4.7. Effects on ability to drive and use machines

The occurrence of side effects of erythromycin may affect the ability to drive and use machines.

Experience to date shows that erythromycin has negligible influence on the ability to concentrate and react.

4.8. Undesirable effects

Summary of the safety profile

The adverse event profile presented below is based on post-marketing experience. The most frequently reported adverse reactions were gastrointestinal disorders mostly mild in nature in the forms of anorexia, retching, vomiting, abdominal pains, nausea, flatulence, discomfort, cramps, soft stools or diarrhoea.

Tabulated list of adverse reactions

Adverse reactions from post-marketing experience are listed in the following table per System Organ Class and per frequency. The frequency is defined as follow: Very common (≥1/10) common (≥1/100-<1/10) uncommon (≥1/1000-<1/100) rare (≥1/10000-<1/1000) very rare (<1/10000) not known (Frequency cannot be estimated from the available data).

MedDRA SOC

Frequency category

Common

Uncommon

Rare

Very rare

Not known

Infections and infestations

Superinfections caused by resistant bacteria or fungi, e. g. oral and vaginal candidiasis

Pseudomembranous colitis

Blood and lymphatic system disorders

Eosinophilia

Immune system disorders

Allergic reactions

Allergic oedema/angioedema, anaphylactic reaction including anaphylactic shock, anaphylaxis

Metabolism and nutrition disorders

Anorexia

Psychiatric disorders

Hallucinations

Nervous system disorders

Unmasking or worsening of Myasthenia gravis

Transient central nervous system disorders, such as state of confusion, epileptic seizures, convulsions, hallucinations, headaches, sleepiness and vertigo.

Eye disorders

Visual disturbances, including diplopia and blurred vision

Ear and labyrinth disorders

Tinnitus and mainly transient loss of hearing or deafness, primarily in patients with renal and/or hepatic impairment or patients who are treated with high doses

Cardiac disorders

Palpitation and cardiac arrhythmias, atrioventricular block, QT interval prolongation, ventricular extra systole, ventricular arrhythmia (torsades des pointes), and ventricular tachycardias particularly in patients, who have already shown a prolonged QT interval on an ECG or concomitantly use potentially pro-arrhythmic or QT-interval influencing substances, cardiac arrest,

ventricular fibrillation

Vascular disorders

Thrombophlebitis

Hypotension

Respiratory, thoracic and mediastinal disorders

Dyspnoea (including asthmatic conditions)

Gastrointestinal disorders

Gastrointestinal disorders mostly mild in nature in the forms of anorexia, retching, vomiting, abdominal pains, nausea, flatulence, discomfort, cramps, soft stools or diarrhoea.

Infantile hypertrophic pyloric stenosis (IHPS); pancreatitis

Hepatobiliary disorders

Cholestasis and cholestatic jaundice, especially in long-term treatment (2-3 weeks) and especially in pre-existing liver damage, and in repeat treatments and in patients with allergies

Cholestatic hepatitis or hepatitis-like symptoms, hepatomegaly, liver failure, hepatic dysfunction,

Skin and subcutaneous tissue disorders

Hyperaemia and urticarial exanthema, pruritus, skin eruptions

Erythema multiforme exudativum, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome, especially in children of all ages)

Acute generalised exanthema-tous pustulosis (AGEP)

Musculoskeletal and connective tissue disorders

Swollen joints

Renal and urinary disorders

Interstitial nephritis

General disorders and administration site conditions

Pain and/or irritation at the site of injection

Drug fever

Chest pain, fever, malaise

Investigations

Increase in certain liver enzymes (transaminases (ALT and AST), LDH, alkaline phosphatase, Y-GT and bilirubin

Paediatric population

Vomiting or irritability in connection with meals in infants. Instances of infantile hypertrophic pyloric stenosis (IHPS) have appeared in infants after treatment with erythromycin

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization 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 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

The toxicity is low. Overdosage may be associated with ototoxicity, hearing loss, cholestasis, ventricular arrhythmias, severe nausea, vomiting and diarrhoea. The symptoms are typically reversible and will disappear when treatment with erythromycin is discontinued. No specific treatment has been proposed other than general supportive measures. In the event of an overdose, treatment with erythromycin should be paused or terminated depending on the symptoms. Erythromycin cannot be removed with peritoneal or haemodialysis.