1. Name Of The Medicinal Product
Primacine - Erythromycin Ethylsuccinate 125 mg/5 ml
Erythromycin Ethylsuccinate 125mg/5ml Granules for Oral Suspension
2. Qualitative And Quantitative Composition
Erythromycin ethylsuccinate ep 125 mg/5 ml
(Where each mg of base is taken to be equivalent to 1000 units of activity)
3. Pharmaceutical Form
Granules for Oral Suspension
4. Clinical Particulars
4.1 Therapeutic Indications
Antibiotic for treatment of infections caused by erythromycin sensitive organisms especially gram positive pyogenic cocci and some gram-negative bacteria. It may be used in a wide variety of clinical infections
Erythromycin is an appropriate alternative to penicillin in hypersensitive patients especially in pre or post operative patients
Respiratory Tract Infections:
Acute and chronic bronchitis, legionnaires disease, tracheitis, bronchiectasis, pneumonia
Skin and Soft Tissue Infections:
Acute infections of skin and soft tissue which are mild to moderately severe
Eye/Ear infections:
Otitis media and otitis externa mastoiditis, chlamydial conjunctivitis, blepharitis
Oral infections:
Gingivitis, Vincent's angina
Gastro-intestinal Infections:
Staphylococcal enterocolitis, cholecystitis, campylobacter infections
Other infections:
Gonorrhoea, syphilis, urethritis, diphtheria, pertussis
4.2 Posology And Method Of Administration
Route of Administration: Oral
Adults and Children over 8 Years
For mild to moderate infections 2 g daily in divided doses up to 4 g daily in severe infections;
250-500 mg every 6 hours or 0.5-1 g every 12 hours
For acne vulgaris the usual dose is 250 mg three times daily before meals for one to four weeks and then reduced to twice daily until improvement occurs
Children Aged 2 to 8 years
For mild to moderate infections 1 g daily in divided doses;
250 mg every 6 hours
30 mg/kg/day in divided doses. For severe infections up to 50 mg/kg/day in divided doses.
Infants and Babies up to 2 Years
For mild to moderate infections 500 mg daily in divided doses;
125 mg every 6 hours
30mg/kg/day in divided doses. For severe infections up to 50 mg/kg/day in divided doses.
Elderly
No special dosage recommendations
For severe infections dosage may be doubled.
Duration of dosage regimen is dependent on the nature of the infection and is at the discretion of the physician
4.3 Contraindications
Known sensitivity to erythromycin: acute porphyria: concomitant use of erythromycin with astemizole or terfenadine is contraindicated.
4.4 Special Warnings And Precautions For Use
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.
Pseudomembranous colitis has been reported with nearly all antibacterial agents, including macrolides, and may range in severity from mild to life-threatening (see section.4.8). 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 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.
There have been reports that erythromycin may aggravate the weakness of patients with myasthenia gravis.
Erythromycin interferes with the fluorometric determination of urinary catecholamines.
Rhabdomyolysis with or without renal impairment has been reported in seriously ill patients receiving erythromycin concomitantly with statins.
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.
Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
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, 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.
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.
HMG-CoA Reductase Inhibitors: erythromycin has been reported to increase concentrations of HMG-CoA reductase inhibitors (e.g. lovastatin and simvastatin). Rare reports of rhabdomyolysis have been reported in patients taking these drugs concomitantly.
Contraceptives: some antibiotics 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.
Antihistamine H1 antagonists: care should be taken in the coadministration of erythromycin with H1 antagonists such as terfenadine, astemizole and mizolastine due to the alteration of their metabolism by erythromycin.
Erythromycin significantly alters the metabolism of terfenadine, astemizole and pimozide when taken concomitantly. Rare cases of serious, potentially fatal, cardiovascular events including cardiac arrest, torsade de pointes and other ventricular arrhythmias have been observed (see sections 4.3 and 4.8).
Anti-bacterial agents: 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.
Protease inhibitors: in concomitant administration of erythromycin and protease inhibitors, an inhibition of the decomposition of erythromycin has been observed.
Oral anticoagulants: there have been reports of increased anticoagulant effects when erythromycin and oral anticoagulants (e.g. warfarin) are used concomitantly.
Triazolobenzodiazepines (such as triazolam and alprazolam) and related benzodiazepines: erythromycin has been reported to decrease the clearance of triazolam, midazolam, and related benzodiazepines, and thus may increase the pharmacological effect of these benzodiazepines.
Post-marketing reports indicate that co-administration of erythromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterised by vasospasm and ischaemia of the central nervous system, extremities and other tissues (see section 4.3).
Elevated cisapride levels have been reported in patients receiving erythromycin and cisapride concomitantly. This may result in QTc prolongation and cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation and torsades de pointes. Similar effects have been observed with concomitant administration of pimozide and clarithromycin, another macrolide antibiotic.
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.
There have been post-marketing reports of colchicine toxicity with concomitant use of erythromycin and colchicine.
Hypotension, bradyarrhythmias and lactic acidosis have been observed in patients receiving concurrent verapamil, a calcium channel blocker.
Cimetidine may inhibit the metabolism of erythromycin which may lead to an increased plasma concentration.
Erythromycin has been reported to decrease the clearance of zopiclone and thus may increase the pharmacodynamic effects of this drug.
4.6 Pregnancy And Lactation
Studies have shown no evidence of teratogenicity or toxicity. As with all drugs, special care should be taken in the treatment of pregnant women. Erythromycin is readily excreted in breast milk
4.7 Effects On Ability To Drive And Use Machines
None known
4.8 Undesirable Effects
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 taking 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 disfunction, 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 and vertigo; 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.
4.9 Overdose
Symptoms: Mainly confined to nausea, vomiting and diarrhoea
Treatment: Gastric lavage and general supportive measures
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Erythromycin is a macrolide antibiotic which acts by interfering with bacterial protein synthesis and is bacteriostatic or bactericidal depending on its concentration and the type of organism. Sensitive organisms include:
gram-positive bacteria such as staph aureus, staph epidermis, strop pyogenes, strep pneumoniae, strep viridans, corynebacterium diptheriae and listeria Monocytogenes
gram-negative bacteria such as h influenzae, n meningitidis, n gonorrhoea, b pertussis, campylobacter strains and legionella pneumophilla
treponema pallidum ;
mycoplasma pneumoniae ;
chlamydia trachomatis.
5.2 Pharmacokinetic Properties
Absorption may be slightly delayed by food and the highest and earliest peak serum levels occur under fasting conditions -
Tmax = 2 - 4 hours;
Cmax - approx 0.5 ug/ml (from a 250 mg dose);
t1/2 = 1.6 ± 0.7 hours
Erythromycin is excreted in high concentrations in the bile and up to 5 % of an oral dose may appear in the urine; considerable amounts may also be inactivated in the body
5.3 Preclinical Safety Data
None stated
6. Pharmaceutical Particulars
6.1 List Of Excipients
Sodium Carboxymethylcellulose
Sodium citrate
Banana Flavour E4210 SD
Quinoline Yellow 14031 E104
Sodium Saccharin
Colloidal Silicon Dioxide
Sucrose (Caster Sugar)
6.2 Incompatibilities
Not appropriate
6.3 Shelf Life
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6.4 Special Precautions For Storage
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6.5 Nature And Contents Of Container
Amber glass bottles with pilfer evident cap
High density polyethylene bottles with pilfer proof screw caps
Pack sizes 100 ml and 140 ml
High density polyethylene bottles with Child Resistant Closures (CRC caps).
6.6 Special Precautions For Disposal And Other Handling
Reconstitute with water to 100 ml before use.
Reconstitute with water to 140 ml before use.
7. Marketing Authorisation Holder
Pinewood Laboratories Limited,
Ballymacarbry,
Clonmel,
Co. Tipperary,
Ireland
8. Marketing Authorisation Number(S)
PL 04917/0013
9. Date Of First Authorisation/Renewal Of The Authorisation
Renewal: 31/03/2006
10. Date Of Revision Of The Text
10-06-2011
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