Amdipharm Limited

Erythrocin IV Lactobionate 1 g Powder for Concentrate for Solution for Infusion

Erythromycin Lactobionate equivalent to 1g of erythromycin.

For excipients, see section 6.1.

Powder for concentrate for solution for infusion (Powder for sterile concentrate).

A white to off-white powder.

In the treatment of infections due to micro-organisms sensitive to this anti-infective.

Adults, children and neonates:

Severe and immunocompromised infections, 50 mg/kg/day, preferably by continuous infusion, (equivalent to 4g per day for adults). Mild to moderate infections (oral route compromised) 25 mg/kg/day.

Elderly:

No special dosage recommendations.

Due to 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 (IV push).

As rapid infusion is more likely to be associated with arrhythmias or hypotension, it is recommended that erythromycin by IV infusion be given over a minimum of 60 minutes. A longer period of infusion should be used in patients with risk factors or previous evidence of arrhythmias.

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.

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.

When fully prepared Erythrocin IV Lactobionate 1 g Powder for Concentrate for Solution for Infusion should be virtually free of particulate matter prior to administration.

For further details please see section 6.6 (Instructions for Use/Handling).

Known hypersensitivity to macrolide antibiotics.

Use in patients with serious impairment of hepatic function.

Concomitant administration of erythromycin and any of the following drugs is contraindicated: terfenadine, astemizole, cisapride, pimozide, ergotamine and dihydroergotamine (see section 4.5).

Erythromycin must not be administered rapidly by direct intravenous injection (IV push) (see 4.2 Posology and Method of Administration).

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 hepatocellular and/or cholestatic hepatitis, with or without jaundice, has been infrequently reported with erythromycin.

The use of erythromycin in patients concurrently taking drugs metabolised by the cytochrome P450 system may be associated with elevations in serum levels of these drugs (see section 4.5). Serum concentrations should be closely monitored in patients receiving erythromycin.

Prolonged or repeated use of erythromycin may result in overgrowth of non-susceptible bacteria. If super-infection occurs, erythromycin should be discontinued and appropriate therapy instituted.

There have been reports of infantile hypertrophic pyloric stenosis (IHPS) occurring in infants following erythromycin therapy. In one cohort of 157 newborns who were given erythromycin for pertussis prophylaxis, seven neonates (5%) developed symptoms of non-bilious, vomiting or irritability with feeding and were subsequently diagnosed as having IHPS requiring surgical pyloromyotomy. Since erythromycin may be used in the treatment of conditions in infants which are associated with significant mortality or morbidity (such as pertussis or chlamydia), the benefit of erythromycin therapy needs to be carefully considered against the potential risk of developing IHPS. Parents should be informed to contact their physician if vomiting or irritability occur (see section 4.8).

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.

As with other broad spectrum antibiotics, pseudomembranous colitis has been reported rarely with erythromycin (see section 4.8).

Rhabdomyolysis with or without renal impairment has been reported in seriously ill patients receiving erythromycin concomitantly with lovastatin (see section 4.5).

There have been reports that erythromycin may aggravate the weakness of patients with myasthenia gravis.

Colchicine toxicity has been reported in patients receiving erythromycin concomitantly with colchicine (see section 4.5).

Laboratory Tests:

Erythromycin interferes with the fluorometric determination of urinary catecholamines.

Erythromycin significantly alters the metabolism of terfenadine and astemizole when taken concomitantly. Rare cases of serious cardiovascular adverse events, including cardiac arrest, Torsade de Pointes, and other ventricular arrhythmias, and also, in the case of terfenadine, death, have been observed.

Elevated cisapride levels have been reported in patients receiving erythromycin concomitantly. This may result in QT prolongation and cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation and Torsade de Pointes. Similar effects have been observed with concomitant administration of pimozide and other macrolide antibiotics, e.g. clarithromycin.

Post-marketing reports indicate that co-administration of erythromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterised by vasospasm and ischemia of the extremities and other tissues including the central nervous system (see section 4.3).

The concomitant use of the above drugs with erythromycin is contraindicated (see 4.3 Contraindications).

Concurrent use of erythromycin and 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 erythromycin therapy.

When oral erythromycin is given concurrently with theophylline, there is also a significant decrease in erythromycin serum concentrations. The decrease could result in sub-therapeutic concentrations of erythromycin.

The use of erythromycin in patients who are receiving digoxin, may result in potentiation of the effects of digoxin due to reduction in the rate of excretion. Monitoring of serum digoxin levels should be considered.

Rhabdomyolysis with or without renal impairment has been reported in seriously ill patients receiving erythromycin concomitantly with lovastatin.

Erythromycin is an inhibitor of CYP 3A4. The use of erythromycin in patients concurrently taking drugs metabolised by the cytochrome P450 system may be associated with elevations in serum levels of these other drugs. There have been reports of interactions of erythromycin with astemizole, carbamazepine, cyclosporin, hexabarbital, phenytoin, alfentanil, disopyramide, bromocriptine, valproate, tacrolimus, quinidine, cilostazol, methylprednisolone, rifabutin, sildenafil, vinblastine, terfenadine.

Serum concentrations of drugs metabolised by the cytochrome P450 system should be monitored closely in patients concurrently receiving erythromycin.

Triazolbenzodiazepines (such as triazolam and aplrazolam) and related benzodiazepines: Erythromycin has been reported to decrease the clearance of triazolam, midazolam and zopiclone and thus may increase pharmacologic effect of these benzodiazepines.

HMG-CoA Reductase Inhibitors: Erythromycin has been reported to increase concentrations of HMG-Co-A reductase inhibitors (e.g. lovastatin and simvastatin). Rare reports of rhabdomyolysis have been reported in patients taking these drugs concomitantly (see section 4.4).

There have been reports of increased anticoagulant effects when erythromycin and oral anticoagulants were used concomitantly.

There have been post-marketing reports of colchicine toxicity with concomitant use of erythromycin and colchicine (see section 4.4)

Long term (2 year) oral studies conducted in rats up to about 400mg/kg/day and in mice up to about 500mg/kg/day with erythromycin base did not provide evidence of tumorigenicity. Mutagenicity studies conducted did not show any genotoxic potential, and there was no apparent effect on male or female fertility in rats with erythromycin base by oral gavage at 700 mg/kg/day.

There is no evidence of teratogenicity or any other adverse effect on reproduction in female rats dosed by oral gavage at 350 mg/kg/day (7 times the human dose) of erythromycin base prior to and during mating, during gestation, and through weaning.

No evidence of teratogenicity or embryotoxicity was observed when erythromycin base was given by oral gavage to pregnant rats and mice at 700 mg/kg/day (14 times the human dose), and to pregnant rabbits at 125 mg/kg/day (2.5 times the human dose).

A slight reduction in birth weights was noted when female rats were treated prior to mating, during mating, gestation and lactation at a high oral dosage of 700 mg/kg/day of erythromycin base; weights of the offspring were comparable to those of the controls by weaning. No evidence of teratogenicity or effects on reproduction was noted at this dosage. When administered during late gestation and lactation periods, this dosage of 700 mg/kg/day (14 times the human dose) did not result in any adverse effects on birth weight, growth and survival of offspring.

There are no adequate and well-controlled studies in pregnant women.

However, observational studies in humans have reported cardiovascular malformations after exposure to medicinal products containing erythromycin during early pregnancy.

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

Erythromycin should not be used in women breast feeding infants.

None reported.

The most frequently reported side effects of oral erythromycin preparations are gastrointestinal and are dose-related. They include nausea, vomiting, abdominal pain, diarrhoea and anorexia.

As with other macrolides, hepatic dysfunction including increased liver enzymes and hepatocellular and/or cholestatic hepatitis, with or without jaundice, has been infrequently reported with erythromycin.

Pseudomembranous colitis has been rarely reported in association with erythromycin therapy and may range in severity from mild to life threatening (see section 4.4).

There have been reports that erythromycin may aggravate the weakness of patients with myasthenia gravis.

There have been isolated reports of transient central nervous system side effects including confusion, hallucinations, seizures, tinnitus and vertigo, and also of cardiac effects such as chest pain, dizziness and palpitations; however, a cause and effect relationship has not been established in either case.

As with other macrolides, QT prolongation, ventricular tachycardia, and Torsades de Pointes have rarely been reported with erythromycin.

There have been reports of pancreatitis and convulsions.

Allergic reactions ranging from urticaria and mild skin eruptions to anaphylaxis, erythema multiforme, Stevens-Johnson Syndrome and toxic epidermal necrolysis have rarely been reported.

There have been isolated reports of reversible hearing loss occurring chiefly in patients with renal insufficiency and in patients receiving high doses of erythromycin.

Cases of infantile hypertrophic pyloric stenosis (IHPS) occurring in infants following erythromycin therapy have been reported (see section 4.4.). This has been associated with vomiting and irritability with feeding in infants.

There have been reports of interstitial nephritis coincident with erythromycin use.

Symptoms: Hearing loss, severe nausea, vomiting and diarrhoea.

Treatment: Gastric lavage, general supportive measures.

Erythromycin is not removed by peritoneal dialysis or haemodialysis.

Following intravenous infusion, erythromycin is widely distributed throughout body tissues, including lung tissues.

Intravenous infusion of 500mg Erythromycin Lactobionate at a constant rate over 1 hour in fasting adults produced a mean serum erythromycin level of approximately 7 mcg/ml at 20 minutes, 10 mcg/ml at 1 hour, 2.6 mcg/ml at 2.5 hours and 1 mcg/ml at 6 hours. Erythromycin diffuses readily into most body fluids. Only low concentrations are normally achieved in the spinal fluid, but passage of the drug across the blood - brain barrier increases in meningitis.

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 into the bile is not known. From 12 - 15% of intravenously administered erythromycin is excreted in active form in the urine.

Long - term (2 years) oral studies conducted in rats with erythromycin base did not provide evidence of tumorigenicity. Mutagenicity studies have not been conducted. There was no apparent effect on male or female fertility in rats fed erythromycin (base) at levels up to 0.25% of diet. There is no evidence of teratogenicity or any other adverse effect on reproduction in female rats fed erythromycin base (up to 0.25% of diet) prior to and during mating, during gestation and through weaning of 2 successive litters. There are, however, no adequate and well - controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used in pregnancy only if it is clearly needed. Erythromycin has been reported to cross the placental barrier in humans, but foetal plasma levels are generally low.

Not applicable.

None Known

3 years.

Unopened vial: Do not store above 30°C.

The product should be used immediately after reconstitution. When aseptically prepared the solution may be kept for not more than 24 hours if stored under refrigeration at a temperature between 2^oC and 8^oC.

Type I, Ph. Eur., clear glass vial containing 1g of erythromycin.

For single use only, discard any unused contents.

The product must be reconstituted (step 1) and then further diluted (step 2) prior to administration.

Preparation of 1 g dose for Intermittent Infusion:

For Continuous Infusion of 1 gram dose:

Add 20 ml of Step 1 solution to 500-1000 ml of 0.9%Sodium Chloride Intravenous Infusion BP. The resulting diluted solution contains 2 mg/ml – 1 mg/ml of erythromycin.

As rapid infusion is more likely to be associated with arrhythmias or hypotension, it is recommended that erythromycin IV is given over a minimum of 60 minutes. A longer period of infusion should be used in patients with risk factors or previous evidence of arrhythmias.

When fully prepared Erythrocin IV Lactobionate 1 g Powder for Concentrate for Solution for Infusion should be virtually free of particulate matter prior to administration.

Amdipharm Limited

Temple Chambers

3 Burlington Road

Dublin 4

Ireland

PA 1142/8/1

Date of first authorisation: 28 January 1980

Date of last renewal: 28 January 2005

March 2008

POM