Erythromycin Stragen
SUMMARY OF PRODUCT CHARACTERISTICS
NAME OF MEDICINAL PRODUCT
Erythromycin Stragen 1 g powder for solution for infusion
QUALITATIVE AND QUANTITATIVE COMPOSITION
1 vial contains erythromycin lactobionate equivalent to 1g erythromycin.
PHARMACEUTICAL FORM
Powder for solution for infusion
White to slightly yellow powder.
CLINICAL PARTICULARS
4.1 Therapeutic indications
Pneumonia caused by Legionella, Mycoplasma pneumoniae, Chlamydia psittaci(ornithosis) or Chlamydia pneumoniae(TWAR). Pertussis. Diphtheria. Urogenital infections caused by Chlamydia trachomatis. Conjunctivitis and pneumonia in newborns caused by Chlamydia trachomatis.
Given the following indications, Erythromycin Stragen should be reserved for patients who are hypersensitive to penicillin or where penicillin is unsuitable for other reasons: nosocomial pneumonia; skin and soft tissue infections.
4.2 Posology and method of administration
Posology
Adults and children over 12years old or weighing more than 40 kg:
1520 mg/kg/day. Where necessary the dose may be increased to 4 g/day. May be given in divided doses every 6 or 8 hours (intermittent intravenous infusion) or as a continuous intravenous infusion.
Use in children up to 12 years old or weighing up to 40 kg
1 month 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.
Use in term newborn infants (birth to 1 month)
10-15 mg/kg/day divided over 3 singles doses.
Elderly:
No special dose recommendations.
Method of administration
Because rapid infusion is closely associated with arrhythmias or hypotension it is recommended that Erythromycin Stragen should be administered slowly. This should be particularly noted in patients with risk factors or previous signs of arrhythmias.
A low infusion rate is also recommended for patients with heart disease and for premature babies.
a) Intermittent infusion:
The prepared solution for infusion is infused slowly and intravenously (max. 5 ml/min for 20–60 minutes) to prevent local irritation.
b) Continuous infusion:
The prepared solution for infusion is administered as a continuous intravenous infusion for up to 24 hours.
Erythromycin Stragen must not be administered as a bolus injection.
For instructions on preparation of the medicinal product before administration, see section 6.6.
4.3 Contraindications
Hypersensitivity to the active substance or to other macrolides.
Simultaneous medication with astemizole, cisapride, disopyramide, ergot alkaloids (such as ergotamine and dihydroergotamine), pimozide or terfenadine (see section 4.5).
Erythromycin Stragen must not be used together with simvastatin, atorvastatin and lovastatin. Treatment with these medicines should be interrupted during treatment with Erythromycin Stragen (see section 4.5).
Erythromycin Stragenis contra-indicated for patients with congenital long QT syndrome or where long QT syndrome is present in the family (unless excluded by ECG) and for patients with known acquired QT prolongation.
4.4 Special warnings and precautions for use
Because erythromycin is primarily excreted via the liver, the exposure to erythromycin and the risk for adverse effects may increase in patients with impaired hepatic function. Therefore, caution should be exercised when administering erythromycin to patients with impaired hepatic function.
The low proportion of renal excretion indicates that plasma exposure to erythromycin is not altered in patients with impaired renal function. However, ototoxicity has been reported in patients with severe renal impairment and erythromycin should therefore be used with caution in these patients. Erythromycin is not removed by haemodialysis or peritoneal dialysis. For patients who have regular dialysis, an additional dose is therefore not recommended.
There are reports suggesting that erythromycin can aggravate the symptoms in Myasthenia gravis patients.
Close monitoring of patients with heart disease and premature babies.
Diarrhoea/pseudomembranous colitis caused by Clostridium difficile(CDAD) may arise from the use of almost all antibacterial agents, including erythromycin, and may range in severity from mild diarrhoea to fatal colitis (see section 4.8). Patients with diarrhoea should therefore be carefully monitored for CDAD. Thorough medical anamnesis is necessary because CDAD has been reported to appear several weeks after administration of antibacterial agents. If CDAD is suspected or confirmed, any ongoing treatment with erythromycin should be stopped if possible.
Depending on the risk of increased QT, Erythromycin Stragen and other macrolides should be used with care on patients with coronary disease, a history of ventricular arrhythmias, uncorrected hypokalaemia and/or hypomagnesaemia, bradychardia (<50 bpm), or patients being treated with both Erythromycin Stragen and QT-prolonging medicines or strong CYP3A4 inhibitors (see section 4.5).
Erythromycin Stragen should not be used during and for two weeks after treatment with CYP3A4 inducers (such as rifampicin, phenytoin, carbamazepine, phenobarbital, St John’s wort). Simultaneous treatment with these medicines may result in sub-therapeutic levels of erythromycin and carry the risk of treatment failing (see section 4.5).
Erythromycin Stragen is an inhibitor of CYP3A4 and should only be used in specific situations where other medicines metabolised by CYP3A4 are being used (see sections 4.3 and 4.5).
There have been reports of cases of infantile hypertrophic pyloric stenosis (IHPS) occurring in infants following erythromycin therapy (see section 4.8). In a cohort of 157 newborns given erythromycin for pertussis prophylaxis, seven neonates (5%) developed symptoms of non-bilious vomiting or irritability during feeding and were subsequently diagnosed with IHPS which required surgical pyloromyotomy. The benefits of erythromycin therapy need to be weighed against the potential risk of developing IHPS. Parents should be advised to contact their GP in the event of vomiting or irritability during feeding.
4.5 Interaction with other medicinal products and other forms of interaction
Effect of Erythromycin Stragen on other medicines:
Erythromycin is a moderate inhibitor of CYP3A4 and an inhibitor of the transport protein P-glycoprotein. The degree of inhibition with different CYP3A4 substrates is difficult to predict. Erythromycin Stragen should therefore not be used during treatment with medicines which are CYP3A4 substrates unless plasma concentrations of the CYP3A4 substrate, the effect or side-effects can be closely monitored. It may be necessary to reduce the dosage of other medicines that are metabolised by CYP3A4 and care should be taken when combining them with erythromycin (e.g. acenocoumarol, alfentanil, bromocriptine, cilostazol, ciclosporin, hexobarbitone, colchicine, methylprednisolone, midazolam, omeprazole, tacrolimus, valproic acid, vinblastine, buspirone and antimycolytics such as fluconazole, ketoconazole and itraconazole). Alternatively, treatment with CYP3A4 substrate should be suspended during treatment with Erythromycin Stragen (e.g., simvastatin, atorvastatin and lovastatin; see section 4.3).
Medicines that may prolong the QT interval
Erythromycin affects the metabolism of terfenadine, astemizole, pimozide and tolterodine when they are taken at the same time. Rare cases of serious, potentially life-threatening cardiovascular events including heart stoppage, torsade de pointes and other ventricular arrhythmias have been observed, so simultaneous use of these medicines is contra-indicated (see sections 4.3 and 4.8).
Elevated levels of cisapride have been reported in patients also being treated with erythromycin. This may result in a prolonged QT interval and heart arrhythmia, including ventricular tachycardia, ventricular fibrillation and torsade de pointes. Similar symptoms have been seen in patients taking disopyramide and erythromycin at the same time and may be expected in patients taking astemizole and pimozide. Concomitant administration of astemizole, cisapride, disopyramide and pimozide is contra-indicated (see section 4.3).
Erythromycin may inhibit the metabolism of quinidine, with a 40% increase in Cmax in healthy trial subjects. There are occasional case reports of increased plasma concentrations and torsades de pointes. During treatment with erythromycin, the serum levels of quinidine should be monitored.
Caution is advised when Erythromycin Stragenis given to patients who are being treated with other medicines that may prolong the QT interval (see 4.4).
Sildenafil
Data indicate that erythromycin inhibits the metabolism of sildenafil. An initial dose of 25 mg sildenafil should be considered.
Benzodiazepines
Erythromycin has been reported to reduce the clearance of triazolam, alprazolam, clozapine and related benzodiazepines and hence to increase the pharmacological effect of these benzodiazepines. In healthy trial subjects previously treated with erythromycin, there is more rapid absorption of zopiclone resulting in higher plasma concentrations and a more pronounced hypnotic effect compared to controls.
Theophylline
Simultaneous medication with erythromycin and high doses of theophylline may cause theophylline levels in plasma to increase, with potential theophylline toxicity, probably because of inhibited metabolism. In the case of combination therapy, theophylline levels in plasma should be monitored to ensure that no toxic concentrations develop (dosage reduction). The erythromycin concentration in serum may decrease when oral erythromycin is administered at the same time as theophylline. This reduction could result in sub-therapeutic erythromycin concentrations.
Warfarin
Erythromycin may inhibit the metabolism of warfarin, resulting in enhanced anticoagulant effects.
Fexofenadine
When erythromycin and fexofenadine are administered together, the plasma concentration of fexofenadine increases two- to three-fold, probably because of increased absorption.
Statins
Erythromycin inhibits the metabolism of several HMG-CoA reductase inhibitors and produces increased plasma concentrations of these medicines. Erythromycin also increases the plasma concentration of simvastatin acid (5-fold). Rhabdomyolosis, which is associated with increased plasma concentrations, has occurred in rare cases of treatment with clarithromycin together with lovastatin or simvastatin. Erythromycin Stragen should not be used at the same time as simvastatin, atorvastatin and lovastatin. Treatment with these medicines should be interrupted during treatment with Erythromycin Stragen.
Ergot alkaloids (e.g. ergotamine and dihydroergotamine)
There are reported cases of clinical ergotism, characterised by vasospasm and ischaemia of the central nervous system, because of increased serum levels of ergot alkaloids in the case of simultaneous treatment with macrolide antibiotics. This combination is contra-indicated; see section 4.3.
Digoxin
Simultaneous use of erythromycin and digoxin may produce increased plasma concentrations of digoxin. Monitoring of the serum levels should be considered when administering and withdrawing erythromycin. It may be necessary to adjust the dose.
Calcium channel blockers
Hypotension, bradyarrhythmias and lactic acidosis have been observed in patients who were also taking verapamil, a calcium channel blocker.
Tyrosine kinase inhibitors
Concomitant medication with tyrosine kinase inhibitors (e.g. Imatinib) carries an increased risk of undesirable effects on the tyrosine kinase inhibitor by decreasing its metabolism.
Effects of other medicines on the pharmacokinetics of erythromycin:
Erythromycin is metabolised by the enzyme CYP3A4. Strong inhibitors of this enzyme (e.g. clarithromycin, itroconazole, ketoconazole) may therefore inhibit the metabolism of erythromycin, resulting in increased plasma concentrations. Depending on the risk of increased QT, Erythromycin Stragen should be used with care (see section 4.4).
Medicines that induce CYP3A4 (such as rifampicin, phenytoin, carbamazepine, phenobarbital, St John’s wort) may induce the metabolism of erythromycin. This can result in sub-therapeutic levels of erythromycin and reduced effect. The induction gradually decreases over two weeks after the end of treatment with CYP3A4 inducers. Erythromycin Stragen should not be used during and for two weeks after treatment with CYP3A4-inducers (see section 4.4).
Cimetidine may inhibit the metabolism of erythromycin, resulting in increased plasma concentrations.
When erythromycin and protease inhibitors are administered together, inhibition of erythromycin metabolism has been observed.
4.6 Pregnancy and lactation
Pregnancy:Erythromycin has been reported to cross the placental barrier in humans, but foetal plasma levels are generally low. Epidemiological studies suggest an increased risk of cardiovascular malformations after exposure to macrolide antibiotics during early pregnancy (based mainly on data for erythromycin). Reproduction toxicological animal studies on erythromycin are insufficient, but in studies of other macrolides that are potent hERG channel blockers like erythromycin, embryo death and malformations have been produced (including cardiovascular defects and cleft palate). Mechanistic studies show that substances which are potent blockers of the hERG channel cause cardiovascular defects and embryo death by producing arrhythmia in the embryo. Erythromycin should not be used by women who are pregnant or planning to become pregnant unless absolutely necessary.
Breastfeeding:Erythromycin is not recommended for nursing mothers unless the expected benefits outweigh the potential risks. In lactating women, erythromycin is excreted into human breast milk and can increase the risk for adverse effects in the infant. The benefits and risks of use during lactation must be carefully considered.
4.7 Effects on ability to drive and use machines
No effects observed.
4.8 Undesirable effects
The most common undesirable effect is phlebitis and pain at the infusion site, which is estimated to occur in approx. 10% of patients.
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Cardiac disorders Common (≥1/100 to <1/10) Not known (cannot be estimated from the available data) |
Arrhythmia. QTc interval prolongation, torsades de pointes, palpitations, heart rhythm perturbations including ventricular tachyarrhythmias. |
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Ear and labyrinth disorders Rare (≥1/10,000 to <1/1,000) Not known (cannot be estimated from the available data) |
Reversible hearing loss (mainly in patients with renal insufficiency or high doses). Deafness, tinnitus. |
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Gastrointestinal disorders Common (≥1/100 to <1/10) Not known (cannot be estimated from the available data) |
Stomach-ache, nausea, diarrhoea. Discomfort in the upper abdomen, vomiting, pancreatitis, anorexia, infantile hypertrophic pyloric stenosis, pseudomembranous colitis (see section 4.4). |
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Skin and subcutaneous tissue disorders Common (≥1/100 to <1/10) Uncommon (≥1/1,000 to <1/100) Not known (cannot be estimated from the available data) |
Rash. Urticaria. Itching, exanthema, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme. |
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General disorders and administration site conditions Common (≥1/100 to <1/10) |
Phlebitis and pain at the infusion site. |
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Immune system disorders Rare (≥1/10,000 to <1/1,000) Not known (cannot be estimated from the available data) |
Anaphylaxis Allergic reactions |
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Hepatobiliary disorders Rare (≥1/10,000 to <1/1,000) Not known (cannot be estimated from the available data) |
Elevated liver enzyme values, bilirubin increase, intrahepatic cholestasis, hepatitis. Cholestatic hepatitis, jaundice, hepatic dysfunction, hepatomegaly, liver failure, hepatocellular hepatitis (see section 4.4). |
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Blood and lymphatic system disorders Not known (cannot be estimated from the available data) |
Eosinophilia |
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General disorders and administration site conditions Not known (cannot be estimated from the available data) |
Chest pain, fever, general discomfort. |
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Nervous system disorders Not known (cannot be estimated from the available data) |
Confusion, cramps, dizziness. |
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Psychiatric disorders Not known (cannot be estimated from the available data) |
Hallucinations |
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Renal and urinary disorders Not known (cannot be estimated from the available data) |
Interstitial nephritis |
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Vascular disorders Not known (cannot be estimated from the available data) |
Hypotension |
Local irritation at the infusion site may occur, but can be prevented to some extent by slow administration.
Fungal infestation of the oral cavity and lower abdomen may occur.
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 national reporting system listed in Appendix V.
4.9 Overdose
Toxicity:Low acute toxicity. 3 g to a 3-year-old who got active charcoal and 3.5 g to a 7-year-old who presented no symptoms. Symptom:Nausea, vomiting, diarrhoea. Reversible hearing loss, possible hallucinations. Possible pancreatitis. Allergic reactions and liver damage may occur.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antibacterial substance for systemic use, ATC code: J01FA01.
Erythromycin Stragen solution for infusion contains erythromycin lactobionate. Erythromycin lactobionate is a water-soluble salt of erythromycin suitable for intravenous injection. The effect is mainly bacteriostatic and is produced by binding to the bacterial ribosomes, inhibiting their protein synthesis.
Antibacterial spectrum
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Sensitive |
Streptococci and pneumococci Staphylococcus aureus and coagulase-negative staphylococci Arcanobacterium haemolyticum Corynebacterium diphteriae Moraxella catarrhalis Bordetella pertussis Legionella pneumophila Campylobacter Chlamydia trachomatis, pneumoniae and psittaci Mycoplasma pneumoniae Ureaplasma urealyticum Clostridium perfringens |
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Intermediate |
Haemophilus influenzae and parainfluenzae |
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Resistant |
Enterococci Pasteurella multocida Gram-negative intestinal bacteria and Pseudomonas Clostridium difficile Anaerobic gram-negative rods Mycoplasma hominis |
Resistance is found (110%) in beta-haemolytic streptococci, pneumococci and Staphylococcus aureusand is common (>10%) in coagulase-negative staphylococci.
Cross-resistance occurs between all macrolides and azithromycin. Some cross-resistance between macrolides and clindamycin.
Erythromycin resistance in streptococci and pneumococci is common in some parts of the rest of Europe.
The resistance situation varies geographically and details of the local resistance conditions should be obtained from a local microbiological laboratory.
5.2 Pharmacokinetic properties
Distribution
The serum concentrations attained vary according to the dose and rate of administration. As a guide, we may say that after injection of 500 mg over 30 minutes, a serum concentration of 10 micrograms/ml or more may be expected. Erythromycin is distributed to a great extent to other tissues. There are varying figures for plasma protein binding, but it is usually put at 6080%. Particularly high concentrations are obtained, depending on the excretion conditions, in the liver and bile. On the other hand, not much erythromycin passes through the blood-brain barrier. Erythromycin crosses the placental barrier, the transplacental transfers has been estimated to approximately 10%.
Elimination
With normal hepatic function, erythromycin is concentrated in the liver and excreted mainly via bile and faeces, which means that the anaerobic intestinal flora may be affected. Erythromycin is also partially metabolised by CYP3A4 to its N-demethylated metabolite. From 12% to 15% of intravenously administered erythromycin is excreted in active form in the urine.
The elimination half-life in patients with normal renal function is 1.5 to 3.0 hours. In patients with severe renal impairment the half-life may be prolonged to between 4 and 7 hours.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential.
Reproduction toxicological animal studies on erythromycin are insufficient. In studies of other macrolides that are potent hERG channel blockers like erythromycin, embryo death and malformations have been produced (including cardiovascular defects and cleft palate). Mechanistic studies show that substances which are potent blockers of the hERG channel cause cardiovascular defects and embryo death by producing arrhythmia in the embryo.
6. PHARMACEUTICAL PROPERTIES
6.1 List of excipients
None.
6.2 Incompatibilities
In the absence of compatibility studies, Erythromycin Stragen must not be mixed with other medicinal products except those mentioned in section 6.6.
The stability of erythromycin is affected by the pH of the infusion solution. It should not be added to solutions with a pH under 5, but should then be injected, e.g. into a side branch at the infusion site.
6.3 Shelf life
Unopened: 3 years.
After reconstitution:
After reconstitution, chemical and physical in-use stability in water for injection has been demonstrated for 24 hours when stored at room temperature and for 14 days when stored in a refrigerator at 2-8° C.
After reconstitution and dilution:
After reconstitution and dilution, chemical and physical in-use stability has been demonstrated for 24 hours at room temperature when the solution is diluted in 0.9% (9 mg/ml) sodium chloride solution for injection or Glucose 5% and for 12 hours at room temperature when the solution is diluted in Hartman’s solution.
From a microbiological point of view, once opened, 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 at 2-8°C, unless reconstitution has taken place in controlled and validated aseptic conditions
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
For storage conditions of the reconstituted/diluted medicinal product, see section 6.3.
6.5 Nature and contents of container
Glass vial type I with rubber closure type I.
1 x 1 g powder for solution for infusion
10 x 1 g powder for solution for infusion
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Preparation of 1 g of powder for solution for infusion
1.Preparation of basesolution:
A 5% base solution (50 mg erythromycin/ml) is prepared by dissolving the powder in the vial (1 g erythromycin) in 20 ml water for solution for infusion. The base solution must be diluted further before administration.
2.Dilution of basesolution
a) Solution for infusion for intermittent infusion:
20 ml base solution is further diluted by adding to 200250 ml of a suitable solution for infusion (see below).
b) Solution for infusion for continuous infusion:
20 ml base solution is further diluted by adding to 500 ml or 1000 ml of a suitable solution for infusion (see below).
Solution for infusion suitable for dilution of base solution:
- 0.9% (9 mg/ml) sodium chloride solution for injection
-Glucose 5%
-Hartman’s solution.
Solutions containing glucose must first have sodium bicarbonate added as a buffer to assure neutrality.
Ensure that the finished solution for infusion is free from particles before administration.
7. MARKETING AUTHORISATION HOLDER
<[To be completed nationally]>
8. MARKETING AUTHORISATION NUMBER(S)
<[To be completed nationally]>
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
<[To be completed nationally]>
10. DATE OF REVISION OF THE TEXT
2016-05-13