This information is intended for use by health professionals

1. Name of the medicinal product

Erythromycin Panpharma 1g powder for solution for infusion

2. Qualitative and quantitative composition

Erythromycin 1g

(as Erythromycin Lactobionate)

For 1 vial

For the complete list of excipients, see section 6.1.

3. Pharmaceutical form

White or slightly yellow hygroscopic powder for solution for infusion

4. Clinical particulars
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 caused by Chlamydia trachomatis,

- Pneumonia caused by atypical agents (Legionella pneumophila, Mycoplasma pneumoniae, Chlamydia psittaci or Chlamydia pneumoniae),

- Whooping cough (Pertussis),

- Urogenital infections caused by Chlamydia trachomatis,

- Severe gastroenteritis due to Campylobacter jejuni,

- 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 100 ml of diluent should be used for preparing intermittent I.V. solutions so as to minimise venous irritation. For 100 ml of infused solution, this corresponds to about 35 drops/minute, for 250 ml of infused solution 85-90 drops/minute and for 500 ml of infused solution 170-180 drops/minute.

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, or to other macrolide antibiotics.

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

Patients with severe hepatic impairment, congenital or acquired QT interval prolongation, disturbances in the electrolyte balance (particularly hypokalemia and hypomagnesaemia) and clinically relevant cardiac disorders (e. g. ventricular arrhythmias) or patients with severe decompensated heart failure (NYHA IV).

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.

QT prolongation

Prolongation of the QT interval and development of ventricular arrhythmias (some of which have been fatal), including atypical ventricular tachycardia (torsades de pointes), have been reported with intravenous administration of 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. 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 occurs.

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 (eg 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.

Warfarin

Erythromycin may inhibit the metabolism of warfarin, resulting in increased anticoagulant effects.

Fexofenadine

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

Statins

Erythromcyin inhibits the metabolism of several HMC-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. Erythromcyin must not be used concomitantly with simvastatin, atorvastatin or lovastatin. Treatment with these medicinal products must be discontinued during treatment with erythromycin.

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.

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.

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.

There are no appropriately controlled studies in pregnant women. Erythromycin should not be administered to pregnant women unless the benefits outweigh the potential risks. Observational studies in people reported cardiovascular abnormalities, when pregnant women took drugs containing erythromycin during early pregnancy. Erythromycin crosses the placenta and gives rise to foetal plasma levels which are approximately 5-20 % of maternal limits. However the risks associated with this phenomenon have not been clearly established.

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

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

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)

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 phosphotase, 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 {insert information on the relevant 'national reporting system' – details will be defined at national level}.

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.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: ANTIBACTERIAL FOR SYSTEMIC USE ATC code: J01FA01

Erythromycin is a semi-synthetic macrolide with a 14-membered lactone ring.

Mode of action

Erythromycin exerts its antimicrobial action by binding to the 50S ribosomal sub-unit of susceptible microorganisms and suppresses protein synthesis.

Erythromycin does not bind to cytoplasmic membranes of the host cells. This is a possible explanation of its low toxicity and safety record.

Erythromycin is bacteriostatic and bactericidal depending on its concentration and the type of organism. It inhibits protein synthesis by binding to ribosmal subunits, inhibiting translocation of aminocyl transfer RNA and inhibiting polypeptide synthesis without causing any alteration in the nucleic acid cycle.

Erythromycin is usually active against most strains of the following organisms both in vitro and in clinical infections:

Resistance:

Known resistance mechanisms in pathogens relevant to the indications:

- Efflux mechanisms can lead to macrolide resistance. Resistance to erythromycin can be caused by an increase in the number of efflux pumps in the cytoplasm membrane, which only affects the 14- and 15-membered macrolides (so-called “M”-phenotype).

- Methylation of the ribosomal binding sites. The affinity to the target site can be reduced by methylation of the 23S rRNS, resulting in resistance to macrolides (M), lincosamides (L) and Group B Strep gram positive (SB) (so-called “MLSB”-phenotype).

- The enzymatic inactivation of macrolides is only of minor clinical significance.

There is complete cross-resistance in the “M”-phenotype of erythromycin with clarithromycin, roxithromycin or azithromycin. In the “MLSs“-phenotype, there is additional cross-resistance to clindamycin and Group B Strep gram positive bacteria. There is a partial cross resistance to the 16-membered macrolide, spiramycin.

Susceptibility testing breakpoints:

The testing of erythromycin is made using the usual dilution series for erythromycin. As a result, minimal inhibitory concentrations (MIC) for susceptible and resistant bacteria were identified. The recommended EUCAST (European Committee on Antimicrobial Susceptibility Testing) MIC breakpoints for erythromycin are presented below in the table for MIC testing (mg/L):

EUCAST clinical MIC breakpoints for erythromycin (version 2.0, valid from 2014-01-01):

Pathogen

Susceptible (mg/L)

Resistant (mg/L)

Staphylococcus spp.

≤1

>2

Streptococcus groups A,B,C,G

≤ 0.25

> 0.5

Streptococcus pneumoniae

≤ 0.25

> 0.5

Haemophilus influenzae

≤ 0.5

>16

Moraxella catarrhalis

≤ 0.25

> 0.5

Campylobacter jejuni

4

4

Campylobacter coli

8

8

Non species related breakpoints

IE*

IE*

*"IE" indicates that there is insufficient evidence that the species in question is a good target for therapy with the drug. A MIC with a comment but without an accompanying S, I or R categorisation may be reported.

The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is known and the utility of the agent in at least some types of infections is questionable.

Usually susceptible species:

Aerobic Gram-positive bacteria

Corynebacterium diphtheriae

Corynebacterium minutissimum

Streptococcus pyogenes

Aerobic Gram-negative bacteria

Bordetella pertussis

Campylobacter jejuni

Moraxella catarrhalis

Other bacteria

Chlamydia trachomatis

Chlamydia pneumoniae

Chlamydia psittaci

Legionella pneumophila

Mycoplasma pneumoniae

Species for which acquired resistance may be a problem:

Aerobic Gram-positive bacteria

Staphylococcus aureus (Methicillin-susceptibility)

Streptococcus pneumoniae

Aerobic Gram-negative bacteria

Haemophilus influenzae

Other bacteria

Treponema pallidum

Inherently resistant species:

Aerobic Gram-negative bacteria

Escherichia coli

Klebsiella spp.

Pseudomonas aeruginosa

Aerobic Gram-positive bacteria

Staphylococcus aureus (Methicillin-resistant)+

5.2 Pharmacokinetic properties

Distribution

The apparent volume of distribution of erythromycin is around 45% of body weight in normal subjects. This large distribution volume is consistent with the extensive tissue penetration of erythromycin.

Erythromycin diffuses readily into most body fluids, except the cerebrospinal fluid. However, in cases of meningeal inflammation, higher concentrations are apparent.

Biotransformation

In studies using rabbit microsomes it has been shown that erythromycin is demethylated to des-N-methyl erythromycin and formaldehyde.

Elimination

In the presence of normal hepatic function, erythromycin is concentrated in the liver and excreted in the bile; the effect of hepatic dysfunction on excretion of erythromycin by the liver is not known.

From 12% to 15% of intravenously administered erythromycin is excreted in active form in the urine.

The drug is also excreted in the faeces.

Pharmacokinetic/pharmacodynamic relationship(s)

The plasma elimination half-life in patients with normal renal function is about 2 hours. In severe renal impairment the half-life may be prolonged to between 4 and 7 hours.

5.3 Preclinical safety data

The acute and chronic oral toxicity of erythromycin is low.

No evidence has been verified of teratogenicity or any other adverse reaction in the reproduction of female rats, who received oral tube administration of 350 mg/kg/day (7 times the human dose) of Erythromycin base prior to or during mating, pregnancy and during weaning.

No evidence was observed of teratogenicity or embryo toxicity when erythromycin base was administered by oral tube to pregnant female rats and mice at a dose of 700 mg/kg/day (14 times the human dose), and to pregnant female rabbits at a dose of 125 mg/kg/day (2.5 times the human dose).

A slight reduction was detected in birth weights when female rats were treated prior to mating, during mating, pregnancy and breastfeeding, with a high oral dose of 700 mg/kg/day of erythromycin base; the weights of the litter were comparable to those of the controls by the time of weaning. No evidence of teratogenicity or effects on reproduction were observed at this dose. When administered during the final stage of pregnancy and breastfeeding, this dose of 700 mg/kg/day (14 times the human dose) did not result in any adverse effects in birth weight, growth or survival of the litter.

Carcinogenicity, Mutagenicity, Changes in Fertility

Long-term studies (2 years) with the oral formulation of erythromycin stearate, conducted in rats up to almost 400 mg/kg/day and in mice up to almost 500 mg/kg/day, did not reveal any evidence of tumorigenicity.

The mutagenicity studies conducted did not reveal any genotoxic potential, and no evident effects were observed on the fertility of male or female rats treated with 700 mg/kg/day of erythromycin base via oral tube.

6. Pharmaceutical particulars
6.1 List of excipients

None.

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

Erythromycin lactobionate in solution does not blend, mainly because of the pH shifts, with β-lactam antibiotics, aminoglycosides, tetracyclines, Chloramphenicol, Colistin, Aminophylline, barbiturates, Diphenylhydantoin, Heparin, Phenothiazine, riboflavin (vitamin B2), vitamin B6 and vitamin C. Therefore, Erythrocin-i.v. should not be mixed with the named drugs in an infusion solution.

The addition of other solutions, which alter the range from pH 6-8, reduces the stability of erythromycin lactobionate.

Attention: Sodium chloride solutions or other solutions which contain inorganic salts should not be used to prepare the stock solution (see section 6.6 “Special precautions for disposal and other handling”), as it may cause precipitation.

6.3 Shelf life

36 months

For the reconstituted solution: Chemical and physical in-use stability has been demonstrated for 24 h in the refrigerator (2 to 8°C).

For the diluted solution: Chemical and physical in-use stability has been demonstrated for 24 h in the refrigerator (2 to 8°C).

From a microbiological point of view, the product should be used immediately.

If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours in the refrigerator, unless reconstitution/dilution has taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storage

No special storage condition.

For storage conditions after reconstitution of the medicinal product, see section 6.3 and section 6.6.

6.5 Nature and contents of container

Colourless type III vials clear glass vial. Pack size of 1, 10 or 25 glass vials.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Each vial is for single use only.

Erythromycin is reconstituted and then further diluted prior to infusion.

Preparation of the solution for administration:

A double dilution is required. An initial solution corresponding to 50 mg/ml of erythromycin base is prepared by adding 20 ml of water for injections to the content of the vial of Erythromycin Panpharma 1 g (shake abundantly until complete dissolution). For this step, a 0.9% sodium chloride solution should not be used.

The reconstituted solution can be kept in the refrigerator for 24 hours.

The diluted solution for administration: only a 0.9% sodium chloride solution or water for injection or a 5% glucose solution are to be used. It is prepared under the same conditions by mixing the content of the vial of Erythromycin Panpharma 1 g (20 ml) to 500 ml of 0.9% sodium chloride solution or water for injection or 5% glucose solution. The diluted solution can be kept in the refrigerator for 24 hours. The diluted solution is administered without addition any other substance whatsoever.

In children, adjust the quantity of initial solution for dilution and the volume of perfusion to the dosage chosen according to the child's weight.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. Marketing authorisation holder

PANPHARMA

ZI DU CLAIRAY

35133 LUITRE

FRANCE

8. Marketing authorisation number(s)

PL 44124/0002

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 27/06/2016

10. Date of revision of the text

27/06/2016