Special Warning : אזהרת שימוש

Warnings
Hepatic dysfunction, including increased liver enzymes and hepatocellular and/or cholestatic hepatitis, with or without jaundice, has been infrequently reported with erythromycin. As erythromycin is principally excreted by the liver, caution should be exercised when administering erythromycin to patients with impaired liver function.

In patients with impaired hepatic function or in those taking concomitant potentially hepatotoxic agents, liver function should be monitored, since a few reports of hepatic dysfunction have been received in patients taking erythromycin as the estolate, base or stearate. Extended administration requires regular evaluation particularly of liver function. Therapy should be dicontinued if significant hepatic dysfunction occurs.

Rhabdomyolysis with or without renal impairment has been reported in seriously ill patients receiving erythromycin concomitantly with lovastatin. Therefore, patients receiving concomitant lovastatin and erythromycin should be carefully monitored for creatine kinase (CK) and serum transaminase levels (see also Drug Interactions).


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Rhabdomyolysis has been reported with concomitant use of erythromycin and HMG- CoA reductase inhibitors.
Patients receiving erythromycin concurrently with drugs which can cause prolongation of the QT interval should be carefully monitored; the concomitant use of erythromycin with some of these drugs is contraindicated

Erythromycin may interfere with the determination of urinary catecholamines and 17- hydroxycorticosteroids levels.

There have been reports suggesting that erythromycin does not reach the fetus in adequate concentration 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.

Carcinogenesis:
Long term (2 year) oral studies conducted in rats up to 400 mg/kg/day and in mice up to 500 mg/kg/day with erythromycin stearate did not provide evidence of tumorigenicity.

Genotoxicity
Erythromycin was not genotoxic in assays for bacterial and mammalian mutagenicity and for clastogenicity in vitro. The clastogenic potential of erythromycin has not been investigated in vivo.

Impairment of Fertility:
There was no apparent effect on male or female fertility in rats treated with erythromycin base by oral gavage at 700 mg/kg/day (approximately 9 times the maximum human dose

Use in Pregnancy
There is no evidence of hazard from erythromycin in human pregnancy. It has been in widespread use for a number of years without apparent ill consequence. Animal studies have shown no hazard.
Erythromycin has been reported to cross the placental barrier in humans, but fetal plasma levels are generally low.
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 during pregnancy only if clearly needed 
Use in Breastfeeding
Erythromycin is excreted in breast milk, therefore, caution should be exercised when erythromycin is administered to nursing mothers.

Adverse Reactions
The most frequent side effects of erythromycin preparations are gastrointestinal and are dose-related. They include nausea, vomiting, abdominal pain, diarrhoea and anorexia.

Blood and lymphatic system disorders:
Eosinophilia.

Cardiac disorders
QTc interval prolongation, torsades de pointes, palpitations, and cardiac rhythm disorders including ventricular tachyarrhythmias (manifested by chest pain).


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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 (see section 4.4).

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

Hepatobiliary disorders
Cholestatic hepatitis, jaundice, hepatic dysfunction/abnormal liver function test results, hepatomegaly, hepatic failure, hepatocellular hepatitis (see section 4.4).

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, vertigo and tinnitus; however, a cause and effect relationship has not been established.

Psychiatric disorders
Hallucinations

Renal and urinary disorders
Interstitial nephritis
Skin and subcutaneous tissue disorders
Skin eruptions, pruritus, urticaria, exanthema, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme.

Vascular disorders
Hypotension.

Precautions
Since erythromycin is excreted principally by the liver, caution should be exercised in administering the antibiotic to patients with impaired hepatic function or concomitantly receiving hepatotoxic agents..
Liver function test should be performed when large doses of erythromycin are administered.


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Prolonged or repeated use may result in overgrowth of non-susceptible bacteria or fungi. Use of this medication for prolonged or repeated periods may result in oral thrush or a new vaginal yeast infection (oral or vaginal fungal infection). The doctor should be informed if the following appears: white patches in the mouth, a change in vaginal discharge or other new symptoms. Should superinfection occur, the drug should be discontinued and/or appropriate therapy instituted.

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including erythromycin, and may range in severity from mild to life threatening.
Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.

Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is a primary cause of "antibiotic-associated colitis". Clostridium difficile produces toxins A and B which contribute to the development of Clostridium difficile associated diarrhea (CDAD). Hypertoxin producing strains of Clostridium difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to discontinuation of the drug alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against Clostridium difficile colitis.

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

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 pertussis or neonatal Chlamydia trachomatis infections), 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.

When indicated, incision and drainage or other surgical procedures should be performed in conjunction with antibiotic therapy.

In the treatment of streptococcal infections, a therapeutic dosage of erythromycin should be administered for at least 10 days.

Owing to the presence of lactose, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose galactose malabsorption should not take this medicine.


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