1. Name Of The Medicinal Product
Erythromycin Lactobionate for Intravenous Infusion 1g
2. Qualitative And Quantitative Composition
Each vial, before reconstitution, contains erythromycin 1 g (as lactobionate)
When reconstituted as recommended, each vial provides a concentrate for solution for infusion containing 50 mg/ml erythromycin as erythromycin lactobionate.
For excipients, see 6.1.
3. Pharmaceutical Form
Powder for concentrate for solution for infusion
Clear vials containing a white powder for reconstitution
4. Clinical Particulars
4.1 Therapeutic Indications
1. Upper respiratory tract infections (tonsillitis, pharyngitis, sinusitis, secondary bacterial infections).
2. Lower respiratory tract infections (pneumonia, bronchitis, primary atypical pneumonia, Legionnaire's disease).
3. Skin and soft tissue infections (furunculosis, erysipelas).
4. Other infections - diphtheria carriers and cases as an adjunct to antitoxin, syphilis and gonorrhoea (in cases of penicillin allergy), subacute bacterial endocarditis, otitis media.
4.2 Posology And Method Of Administration
Intravenous injection by:-
1. Continuous intravenous infusion.
2. Intermittent intravenous infusion.
Small volume intravenous infusion, minimum volume 100 ml, is the preferred method so as to minimise venous irritation.
Dosage and Administration
Intravenous administration of erythromycin is suitable to patients who are unable to tolerate oral medication or when it is necessary to produce a high blood concentration to control severe infections. Oral administration should replace parenteral administration as soon as practicable.
Due to the local irritative effects of erythromycin as well as reports of QT interval prolongation and ventricular arrhythmias (some of which have been fatal) being associated with elevated serum concentrations of erythromycin, the drug must not be administered rapidly by direct intravenous injection (intravenous push).
For continuous intravenous infusion the concentrated solution should be diluted to a concentration of 1 mg per ml. If required, solution strengths up to 5 mg/ml (0.5% solution) may be used, but should not be exceeded. Higher concentrations may result in pain along the vein. Bolus injection is not recommended.
For intermittent intravenous infusion the appropriate daily dose can be given as 4 doses once every 6 hours. The erythromycin concentration should not exceed 5mg per ml and the infusion should be administered over 60 minutes, as a rapid infusion is more likely to be associated with arrhythmias or hypotension. A longer period of infusion should be used in patients with risk factors or previous evidence of arrhythmias. Not less than 100ml of diluent should be used for preparing intermittent intravenous solutions.
Intravenous therapy should be replaced by oral administration at the appropriate time.
Adults: The usual adult dose is the equivalent of 25-50 mg/kg per day in divided doses of erythromycin, by intravenous infusion every 6 hours, or the equivalent of 1 to 2 g of erythromycin daily by intermittent intravenous infusion over 20 to 60 minutes every 6 hours or by infusion over 24 hours. The equivalent of 4 gram daily has been recommended for severe infections.
Small volume intravenous infusion, minimum volume 100 ml, is the preferred method so as to minimise venous irritation.
Children: 25-50 mg per kg by intravenous injection, daily in divided doses.
Elderly: Use adult dosage with care, taking into consideration any impairments in liver or biliary functions.
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.
Patients with impaired renal function: The low proportion of renal excretion would suggest that dosage modification in patients with impaired renal function may not be necessary. In severely impaired patients however, toxicity has been reported and dosage adjustment in these cases may be warranted.
4.3 Contraindications
Patients with known hypersensitivity to erythromycin.
Erythromycin is contraindicated with astemizole, terfenadine, cisapride or pimozide. The concurrent administration of these drugs with erythromycin has been associated with increased blood levels of astemizole, terfenadine, cisapride or pimozide, with an increased risk of life threatening cardiac arrhythmias.
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 the intravenous administration of erythromycin. Limited data suggest that these adverse effects may be associated with abnormally elevated serum erythromycin concentrations following rapid administration. Erythromycin therefore must not be administered rapidly by direct intravenous injection (intravenous push).
Concomitant use of erythromycin and simvastatin or lovastatin is contraindicated (see section 4.4 and 4.5).
4.4 Special Warnings And Precautions For Use
Allergic reactions ranging from urticaria to anaphylaxis have been reported with intravenous erythromycin.
There have been reports that erythromycin may aggravate the weakness of patients with myasthenia gravis.
Superinfection may occur with prolonged use, giving rise to overgrowth of non susceptible organisms.
Erythromycin is excreted principally via the liver and caution should be exercised when using erythromycin in patients with a degree of hepatic impairment.
In severe renal impairment the half life may be prolonged to 4-7 hours requiring a dose modification.
Reports of rhabdomyolysis in patients administered erythromycin concomitantly with lovastatin or simvastatin have been received and so such concomitant use is contraindicated. Caution should also be exercised in patients receiving other statins concomitantly with erythromycin.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Penicillin: Erythromycin, in low bacteriostatic concentrations, may inhibit the actions of bactericidal drugs. In high concentrations, erythromycin may act synergistically with penicillin.
Use of erythromycin in patients receiving digoxin, warfarin, carbamazepine or high doses of theophylline may result in potentiation of the effects due to impairment of excretion. A possible interaction between Erythromycin and Vinblastine has been reported in which patients receiving the two agents concurrently may experience myalgia, neutropenia and fever. It is recommended that patients should avoid receiving erythromycin and vinblastine at the same time.
When administered concurrently with erythromycin, increases in serum concentrations may occur for the drugs metabolised by the cytochrome P450 system such as alfentanil, bromocriptine, hexobarbitone, midazolam, phenytoin, tacrolimus, triazolam, valproate, acenocoumarol. Appropriate monitoring should be undertaken and dosage should be adjusted as necessary. Concomitant use of simvastatin or lovastatin with erythromycin is contraindicated (see section 4.3 and 4.4) and erythromycin can lead to increased serum level of other statins by inhibiting the CYP3A4 isoenzyme.
Increased plasma levels of cyclosporin may occur in patients on erythromycin.
Ergotism has been reported in patients receiving erythromycin in combination with ergot.
Concomitant use of erythromycin with astemizole, terfenadine, cisapride or pimozide is likely to result in an increased risk of cardiotoxicity with these drugs, and is therefore contraindicated (see Contra-indications).
Concomitant use of theophylline and erythromycin has resulted in increased theophylline levels resulting in toxicity and decreased erythromycin levels which could lead to subtherapeutic concentrations.
Concomitant use of erythromycin and medications that cause prolongation of the QT interval has been reported to lead to cardiac toxicity or Torsades de Pointes.
Caution should be used with the concomitant use of erythromycin with statins.
Interactions between erythromycin and verapamil or clozapine have been reported.
Laboratory tests used for measurement of urinary catecholamines, SGOT and 17-hydroxycorticosteroids, may be affected if a colorimetric test is used. This interference may complicate interpretation of liver function tests. Suppression of growth of Lactobacillus casei by erythromycin, may interfere with serum folate measurements.
4.6 Pregnancy And Lactation
Use in Pregnancy and Lactation:
Erythromycin crosses the placenta and gives rise to foetal plasma levels which are approximately 5-20% of maternal levels. However the risks associated with this phenomenon have not been clearly established. Erythromycin should not be administered to pregnant women unless the 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. Erythromycin is not recommended for nursing mothers unless the expected benefits outweigh the potential risks.
4.7 Effects On Ability To Drive And Use Machines
Not applicable.
4.8 Undesirable Effects
Hepatic: Administration may be followed, in up to 10% of cases, by increases in AST and ALT enzymes, which sometimes recur on challenge.
Cholestatic hepatitis. Jaundice.
Gastrointestinal: Pseudomembranous colitis has been reported rarely with erythromycin.
Gastrointestinal disturbances such as abdominal discomfort and cramp, nausea, vomiting and diarrhoea are common after both oral and parenteral administration.
Pancreatitis (rare)
Cardiovascular: Thrombophlebitis, venous irritation. Irritation can be reduced by either slow IV injection, or preferably a small volume IV infusion.
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 the intravenous administration of erythromycin. Limited data suggest that these adverse effects may be associated with abnormally elevated serum erythromycin concentrations following rapid administration.
Auditory/Vestibular: In very high doses, erythromycin may cause transient perceptive deafness.
Dermatological: Mild allergic reactions, urticaria, skin eruptions, rashes with fever, and reports of erythema multiforme reaction have been noted.
Stevens-Johnson syndrome and toxic epidermal necrolysis have rarely been reported.
4.9 Overdose
The toxicity is low. Overdosage may be associated with ototoxicity. No specific treatment has been proposed other than general supportive measures.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Erythromycin binds to the ribosomes of bacteria and affects protein synthesis without affecting nucleic acid 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.
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.
Metabolism:
In studies using rabbit microsomes it has been shown that erythromycin is demethylated to des-N-methyl erythromycin and formaldehyde.
Excretion:
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.
Half-Life:
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
There is no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.
6. Pharmaceutical Particulars
6.1 List Of Excipients
None.
6.2 Incompatibilities
Erythromycin should not be reconstituted with inorganic salt solutions. Use only Water for Injections.
The stability of solutions of erythromycin lactobionate is adversely affected below pH 5.5.
5 ml of sterile 8.4% sodium bicarbonate solution will neutralise 1 litre of Glucose Injection B.P. 5% and should be added to the bag prior to addition of erythromycin lactobionate.
6.3 Shelf Life
As packaged for sale - 2 years
After reconstitution/dilution - Chemical and physical in-use stability has been demonstrated for 24 hours at 25°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 should not be longer than 24 hours at a temperature not exceeding 25°C.
6.4 Special Precautions For Storage
As packaged for sale – Do not store above 25°C. Keep container in the outer carton.
After reconstitution/dilution – see 6.3
6.5 Nature And Contents Of Container
Clear Type I glass vial with rubber stopper, in singles and packs of 10.
6.6 Special Precautions For Disposal And Other Handling
For single use. Discard any unused contents.
Subsequent dilution into infusion fluids should be made prior to administration. Recommended fluids are Sodium Chloride Injection B.P. 0.9%, or Dextrose 5% Injection B.P.
Erythromycin lactobionate vials labelled as containing 1 gram of erythromycin should be initially reconstituted by adding 20 ml of Sterile Water for Injections B.P. without preservative, to provide a solution containing 50 mg per ml. No other diluent should be used to prepare this initial solution. It is important to ensure that the product is completely dissolved by vigorous shaking before transferring to infusion containers. Prior to administration the concentrated solution should be further diluted in glass or flexible plastic containers of 0.9% Sodium Chloride Injection. If, for clinical reasons, 0.9% saline is not suitable, then neutralised Glucose Intravenous Infusion B.P. 5% w/v may be used. Neutralised glucose solution is prepared by the addition of 5ml of sterile 8.4% w/v sodium bicarbonate solution to each litre of Glucose Intravenous Injection B.P. 5% w/v.
It is necessary to buffer the glucose solution in this way because the stability of erythromycin lactobionate is adversely affected below pH 5.5.
It is recommended that a clarifying filter is used to minimise the particulate levels in resultant infusions
7. Marketing Authorisation Holder
Hospira UK Limited
Queensway
Royal Leamington Spa
Warwickshire, CV31 3RW
United Kingdom
8. Marketing Authorisation Number(S)
PL 04515/0054
9. Date Of First Authorisation/Renewal Of The Authorisation
17th November 1998
10. Date Of Revision Of The Text
December 2007
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