Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2016 Publisher: PANPHARMA, ZI DU CLAIRAY, 35133 LUITRE, FRANCE
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.
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.
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.
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.
Caution must be exercised in the administration of parenteral fluids, especially those containing sodium ions, to patients receiving corticosteroids or corticotrophins.
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).
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.
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.
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.
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.
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).
Data suggest that erythromycin inhibits the metabolism of sildenafil. A starting dose of 25 mg sildenafil should be considered.
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.
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.
Erythromycin may inhibit the metabolism of warfarin, resulting in increased anticoagulant effects.
In case of concomitant treatment with erythromycin and fexofenadine plasma concentrations of fexofenadine increase 2-3-fold, probably due to increased absorption.
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.
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).
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.
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.
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.
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.
No data exists on the effect of erythromycin on fertility in human subjects. Animal studies showed that erythromycin has no teratogenic effects.
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.
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.
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).
Uncommon: Superinfections caused by resistant bacteria or fungi, e. g. oral and vaginal candidiasis
Rare: Pseudomembranous colitis
Uncommon: Allergic reactions
Rare: Allergic oedema/angioedema, anaphylactic reaction including anaphylactic shock, anaphylaxis
Rare: Anorexia
Not known: Hallucinations
Very rare: Unmasking or worsening of Myasthenia gravis
Not known: Transient central nervous system disorders, such as state of confusion, epileptic seizures, convulsions, hallucinations, headaches, sleepiness and vertigo.
Not known: Visual disturbances, including diplopia and blurred vision
Very rare: 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
Not known: 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
Uncommon: Thrombophlebitis
Not known: Hypotension
Not known: Dyspnoea (including asthmatic conditions)
Common: Gastrointestinal disorders mostly mild in nature in the forms of anorexia, retching, vomiting, abdominal pains, nausea, flatulence, discomfort, cramps, soft stools or diarrhoea.
Rare: Infantile hypertrophic pyloric stenosis (IHPS); pancreatitis
Rare: 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
Very rare: Cholestatic hepatitis or hepatitis-like symptoms, hepatomegaly, liver failure, hepatic dysfunction,
Uncommon: Hyperaemia and urticarial exanthema, pruritus, skin eruptions
Very rare: Erythema multiforme exudativum, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome, especially in children of all ages)
Rare: Swollen joints
Very rare: Interstitial nephritis
Uncommon: Pain and/or irritation at the site of injection
Rare: Drug fever
Not known: Chest pain, fever, malaise
Uncommon: Increase in certain liver enzymes (transaminases (ALT and AST), LDH, alkaline phosphotase, Y-GT and bilirubin
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 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}.
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.
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