Erythromycin

Drugs that induce CYP3A4 (such as rifampicin, phenytoin, carbamazepine, phenobarbital, St John’s Wort) may induce the metabolism of erythromycin. This may lead to sub-therapeutic levels of erythromycin and a decreased effect. The induction decreases gradually during two weeks after discontinued treatment with CYP3A4 inducers. Erythromycin should not be used during and two weeks after treatment with CYP3A4 inducers.

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

There have been reports of increased anticoagulant effects when erythromycin and oral anticoagulants (e.g. warfarin) are used concomitantly.

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.

Some antibiotics, as erythromycin, may in rare cases decrease the effect of contraceptive pills by interfering with the bacterial hydrolysis of steroid conjugates in the intestine and thereby reabsorption of unconjugated steroid. As a result of this plasma levels of active steroid may decrease.

An in vitro antagonism exists between erythromycin and the bactericidal beta-lactam antibiotics (e.g. penicillin, cephalosporin). Erythromycin antagonises the action of clindamycin, lincomycin and chloramphenicol. The same applies for streptomycin, tetracyclines and colistin.

In concomitant administration of erythromycin and protease inhibitors, an inhibition of the decomposition of erythromycin has been observed.

Increases in serum concentrations of the following drugs metabolised by the cytochrome P450 system may occur: when administered concurrently with erythromycin: acenocoumarol, alfentanil, astemizole, bromocriptine, carbamazepine, cilostazol, cyclosporin, digoxin, dihydroergotamine, disopyramide, ergotamine, hexobarbitone, methylprednisolone, midazolam, omeprazole, phenytoin, quinidine, rifabutin, sildenafil, tacrolimus, terfenadine, domperidone, theophylline, triazolam, valproate, vinblastine, and antifungals e.g. fluconazole, ketoconazole and itraconazole. Appropriate monitoring should be undertaken and dosage should be adjusted as necessary. Particular care should be taken with medications known to prolong the QTc interval of the electrocardiogram.

Cimetidine may inhibit the metabolism of erythromycin which may lead to an increased plasma concentration.

There have been post-marketing reports of colchicine toxicity with concomitant use of erythromycin and colchicine.

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.

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

Care should be taken in the coadministration of erythromycin with H1 antagonists such as mizolastine due to the alteration of their metabolism by erythromycin.

Erythromycin may inhibit the metabolism of quinidine resulting in a 40% increase in C_max 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.

Data suggest that erythromycin inhibits the metabolism of sildenafil. A starting dose of 25 mg sildenafil should be considered.

Erythromycin use in patients who are receiving 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 concomitant erythromycin therapy. There have been published reports suggesting when oral erythromycin is given concurrently with theophylline there is a significant decrease in erythromycin serum concentrations. This decrease could result in sub-therapeutic concentrations of erythromycin.

Erythromycin has been reported to decrease the clearance of triazolam, midazolam, alprazolam and related benzodiazepines, and thus may increase the pharmacological effect of these benzodiazepines.

Hypotension, bradyarrhythmias and lactic acidosis have been observed in patients receiving verapamil, a calcium channel blocker, in co-administration with erythromycin.

Erythromycin has been reported to decrease the clearance of zopiclone and thus may increase the pharmacodynamic effects of this drug.

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 weighed against the potential risk of developing IHPS. Parents should be informed to contact their physician if vomiting or irritability with feeding occurs.

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.

Erythromycin interferes with the fluorometric determination of urinary catecholamines.

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including macrolides, and may range in severity from mild to life-threatening. Clostridium difficile-associated diarrhoea (CDAD) has been reported with use of nearly all antibacterial agents including erythromycin, and may range in severity from mild diarrhoea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon, which may lead to overgrowth of C. difficile. CDAD must be considered in all patients who present with diarrhoea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

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.

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 has been reported to cross the placental barrier in humans, but foetal plasma levels are generally low.

There have been reports that maternal macrolide antibiotics exposure within 7 weeks of delivery may be associated with a higher risk of infantile hypertrophic pyloric stenosis (IHPS).

Erythromycin can be excreted into breast-milk. Caution should be exercised when administering erythromycin to lactating mothers due to reports of infantile hypertrophic pyloric stenosis in breast-fed infants.

Fertility

No data exists on the effect of erythromycin on fertility in human subjects. Animal studies showed that erythromycin has no teratogenic effects.

None known.

Oral administration

Blood and lymphatic system disorders: Eosinophilia.

Cardiac disorders: QTc interval prolongation, torsades de pointes, palpitations, and cardiac rhythm disorders including ventricular tachyarrhythmias.

Ear and labyrinth disorders: Deafness, tinnitus.

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

Gastrointestinal disorders:

The most frequent side effects of oral erythromycin preparations are gastrointestinal and are dose-related. The following have been reported: upper abdominal discomfort, nausea, vomiting, diarrhoea, pancreatitis, anorexia, infantile hypertrophic pyloric stenosis.

Pseudomembranous colitis has been rarely reported in association with erythromycin therapy.

General disorders and administration site conditions: Chest pain, fever, malaise.

Hepatobiliary disorders: Cholestatic hepatitis, jaundice, hepatic disfunction, hepatomegaly, hepatic failure, hepatocellular hepatitis.

Immune system disorders: Allergic reactions ranging from urticaria and mild skin eruptions to anaphylaxis have occurred.

Investigations: Increased liver enzyme values.

Nervous system disorders: There have been isolated reports of transient central nervous system side effects including confusion, seizures and vertigo; however, a cause and effect relationship has not been established.

Psychiatric disorders: Hallucinations.

Eye disorders: Mitochondrial Optic Neuropathy.

Renal and urinary disorders: Interstitial nephritis.

Skin and subcutaneous tissue disorders: Skin eruptions, prurituls, urticaria, exanthema, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme.

Not known: acute generalised exanthematous pustulosis (AGEP).

Vascular disorders: Hypotension.

IV administration

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.

List of adverse reactions

Adverse reactions from post-marketing experience are listed below 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).

Infections and infestations

Uncommon: Superinfections caused by resistant bacteria or fungi, e. g. oral and vaginal candidiasis

Rare: Pseudomembranous colitis

Immune system disorders

Uncommon: Allergic reactions

Rare: Allergic oedema/angioedema, anaphylactic reaction including anaphylactic shock, anaphylaxis

Metabolism and nutrition disorders

Rare: Anorexia

Psychiatric disorders

Not known: Hallucinations

Nervous system disorders

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.

Eye disorders

Not known: Visual disturbances, including diplopia and blurred vision

Ear and labyrinth disorders

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

Cardiac disorders

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

Vascular disorders

Uncommon: Thrombophlebitis

Not known: Hypotension

Respiratory, thoracic and mediastinal disorders

Not known: Dyspnoea (including asthmatic conditions)

Gastrointestinal disorders

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

Hepatobiliary disorders

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,

Skin and subcutaneous tissue disorders

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)

Musculoskeletal and connective tissue disorders

Rare: Swollen joints

Renal and urinary disorders

Very rare: Interstitial nephritis

General disorders and administration site conditions

Uncommon: Pain and/or irritation at the site of injection

Rare: Drug fever

Not known: Chest pain, fever, malaise

Investigations

Uncommon: 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.