Azithromycin Orifarm
SUMMARY OF PRODUCT CHARACTERISITICS
1. NAME OF THE MEDICINAL PRODUCT
Azithromycin Orifarm 250 mg film-coated tablets
Azithromycin Orifarm 500 mg film-coated tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Azithromycin Orifarm250 mg film-coated tablets:
Each tablet contains azithromycin dihydrate equivalent to 250 mg of azithromycin.
Excipientwith known effect: Lactose monohydrate. Each tablet contains 4.08 mg lactose monohydrate.
Azithromycin Orifarm500 mg film-coated tablets:
Each tablet contains azithromycin dihydrate equivalent to 500 mg of azithromycin.
Excipientwith known effect: Lactose monohydrate. Each tablet contains 8.16 mg lactose monohydrate.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL form
Film-coated tablet.
Azithromycin Orifarm250 mg film-coated tablets:
White, oval, biconvex, film coated tablets, with ‘APO’ engraved on one side and ’AZ250’ on the other.
Azithromycin Orifarm500 mg film-coated tablets:
White, oval, biconvex, film coated tablets, with ‘APO’ engraved on one side and ’AZ500’ on the other.
4. Clinical particulars
4.1 Therapeutic indications
Azithromycin Orifarmis indicated for the following bacterialinfections induced by micro-organisms susceptible to azithromycin (see sections 4.4 and 5.1):
- infections of the lower respiratory tract: acute bronchitis and mild to moderate community-acquired pneumonia;
- infections of the upper respiratory tract: sinusitis and pharyngitis/tonsillitis;
- acute otitis media;
- infections of the skin and soft tissues of mild to moderate severity e.g. folliculitis, cellulites, erysipelas;
- uncomplicated Chlamydia trachomatis urethritis and cervicitis.
Consideration should be given to official guidance on the appropriate use of antibacterial agents.
Azithromycin is not the first choice for the empiric treatment of infections in areas where the prevalence of resistant isolates is 10% or more (see section 5.1).
4.2 Posology and method of administration
Azithromycin Orifarmshould be taken in a single daily dose. The tablets should be swallowed whole and may be taken with or without food.The length of treatment for various infectious diseases is set out below.
Children and adolescents with a body weight above 45 kg, adults and the elderly:
The total dosage of azithromycin is 1500 mg, staggered over three days (500 mg once daily). Alternatively, the dosage may be staggered over five days (500 mg as a single dose on the first day, and then 250 mg once daily).
In the case of uncomplicated Chlamydia trachomatisurethritis and cervicitis, the dosage is 1000 mg as a single oral dose.
Genital infections caused by Neisseria gonorrhoeae: These infections should be treated by or in consultation with a specialist according to local treatment recommendations. Choice of antibiotic and dosage regimens should be based on the resistance pattern of the causative pathogen.
Children and adolescents with a body weight below 45 kg:
Tablets are not indicated for these patients. Other pharmaceutical forms of azithromycin may be used, such as suspensions.
Elderly patients:
Dose adjustment is not required for the elderly. Since elderly patients can be patients with ongoing proarrhythmic conditions a particular caution is recommended due to the risk of developing cardiac arrhythmia and torsades de pointes. (See section 4.4).
Patients with renal impairment:
Dose adjustment is not required in patients with mild to moderate renal impairment (GFR 10-80 ml/min) (see section 4.4).
Patients with hepatic impairment:
Dose adjustment is not required for patients with mild to moderate hepatic dysfunction (see section 4.4).
4.3 Contraindications
Hypersensitivity to the active substance, erythromycin, any macrolide or ketolide antibiotics or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
Allergic reactions:
In rare cases azithromycin is reported to have caused serious allergic (rarely fatal) reactions such as angio-neurotic oedema and anaphylaxis. Some of these reactions have caused recurrent symptoms and have required longer observation and treatment.
Renal failure:
No dose adjustment is necessary in patients with mild to moderate renal impairment (GFR 10-80 ml/min). Caution is advised in patients with severe renal impairment (GFR < 10 ml/min) as a 33% increase in systemic exposure to azithromycin was observed (see section 5.2).
Hepatic failure:
Since liver is the principal route of elimination for azithromycin, the use of azithromycin should be undertaken with caution in patients with significant hepatic disease. Cases of fulminant hepatitis potentially leading to life-threatening liver failure have been reported with azithromycin (see Section 4.8). Some patients may have had pre-existing hepatic disease or may have been taking other hepatotoxic medicinal products.
In case of signs and symptoms of liver dysfunction, such as rapid developing asthenia associated with jaundice, dark urine, bleeding tendency or hepatic encephalopathy, liver function tests/ investigations should be performed immediately. Azithromycin administration should be stopped if liver dysfunction has emerged.
Ergot alkaloids and Azithromycin Orifarm:
The concurrent use of ergot alkaloids and macrolide antibiotics has been found to accelerate the development of ergotism. The interactions between ergot alkaloids and azithromycin have not been studied. The development of ergotism is however possible, so that azithromycin and ergot alkaloid derivatives should not be administered simultaneously (see section 4.5).
QT prolongation:
Prolonged cardiac repolarisation and QT interval, imparting a risk of developing cardiac arrhythmia and torsades de pointes have been seen in treatment with other macrolides (see section 4.8). . Therefore as the following situations may lead to an increased risk for ventricular arrhythmias (including torsade de pointes) which can lead to cardiac arrest, azithromycin should be used with caution in patients with ongoing proarrhythmic conditions (especially women and elderly patients). Therefore Azithromycin should not be used:
- In patients with congenital or documented acquired QT prolongation.
- Concurrently with other active substances that prolong QT interval such as antiarrhythmics of classes IA and III, cisapride and terfenadine; antipsychotic agents such as pimozide; antidepressants such as citalopram; and fluroquinolones such as moxifloxacin and levofloxacin.
- In patients with electrolyte disturbance, particularly in cases of hypokalaemia and hypomagnesemia.
- In patients with clinically relevant bradycardia, cardiac arrhythmia or severe cardiac insufficiency.
Pharyngitis/tonsillitis:
Azithromycin is not the substance of first choice for the treatment of pharyngitis and tonsillitis caused by Streptococcus pyogenes. For this and for the prophylaxis of acute rheumatic fever penicillin is the treatment of first choice.
Acute otitis media:
Often, azithromycin is not the substance of first choice for the treatment of acute otitis media.
Sinusitis:
Often, azithromycin is not the substance of first choice for the treatment of sinusitis.
Azithromycin is not indicated for the treatment of infected burn wounds.
In case of sexually transmitted diseases a concomitant infection by T. pallidiumshould be excluded.
Pneumococcal infections:
As for other macrolides, high resistance rates of Streptococcus pneumoniae (> 30 %) have been reported for azithromycin in some European countries (see section 5.1). This should be taken into account when treating infections caused by Streptococcus pneumoniae.
Due to cross-resistance existing among macrolides, in areas with a high incidence of erythromycin resistance, it is especially important to take into consideration the evolution of the pattern of susceptibility to azithromycin and other antibiotics (see section 5.1).
Superinfections:
Attention should be paid to possible symptoms of superinfections caused by non-sensitive causal agents such as fungi. A superinfection may require an interruption of the azithromycin treatment and initiation of adequate measures.
Clostridium difficileassociated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including azithromycin, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. 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.
Mycobacterium Avium Complex:
Safety and efficacy for the prevention or treatment of Mycobacterium Avium Complex in children have not been established.
Myasthenia syndrome:
Exacerbations of the symptoms of myasthenia gravis and new onset of myasthenia syndrome have been reported in patients receiving azithromycin therapy (See Section 4.8).
Neurological or psychiatric diseases:
Azithromycin should be administered with caution to patients suffering from neurological or psychiatric diseases.
Pseudomembranous colitis:
After the use of macrolide antibiotics pseudomembranous colitis has been reported. This diagnosis should therefore be considered for patients who suffer from diarrhoea after start of the treatment with azithromycin. Should pseudomembranous colitis be induced by azithromycin, then anti-peristaltics should be contraindicated.
Long term use:
There is no experience regarding the safety and efficacy of long term use of azithromycin for the mentioned indications. In case of rapid recurrent infections, treatment with another antibiotic should be considered.
Azithromycin Orifarmare not suitable for treatment of severe infections where a high concentration of the antibiotic in the blood is rapidly needed.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction with other medicinal products and other forms of interaction
Effect of other medicinal products on azithromycin
Antacids:
When studying the effect of simultaneously administered antacid on the pharmacokinetics of azithromycin, no overall change has been observed in the bioavailability, although the peak concentrations of azithromycin measured in the plasma did fall by 30 %. Azithromycin should be taken at least 1 hour before or 2 hours after the antacid.
Effect of azithromycin on other medicinal product
Ergotamine:
The combined use of ergot alkaloid derivatives (such as ergotamine) and azithromycin may in theory cause ergotism, and consequently their combined use is not recommended (see also section 4.4).
Medicinal products with a potential to prolong QT interval:
Prolonged cardiac repolarization and QT interval, imparting a risk of developing cardiac arrhythmia and torsades de pointes, have been seen in treatment with other macrolides including azithromycin. Therefore, azithromycin should not be used with other active substances that prolong QT interval such as cisapride, citalopram, fluroquinolones such as moxifloxacin and levofloxacin, pimozide and terfenadine (see section 4.4).
Astemizol and Alfentanil:
No data are available on interactions with astemizol and alfentanil. Caution should be exercised with concomitant use of these agents and azithromycin in view of the described potentation of its effect during concomitant use of the macrolide antibiotic erythromycin.
Cetirizine:
In healthy volunteers, coadministration of a 5-day regimen of azithromycin with cetirizine 20 mg at steady-state resulted in no pharmacokinetic interaction and no significant changes in the QT interval.
Cisapride:
Cisapride is metabolized in the liver by the enzyme CYP 3A4. Because macrolides inhibit this enzyme, concomitant administration of cisapride may cause the increase of QT interval prolongation, ventricular arrhythmias and torsade de pointes.
Terfenadine:
In pharmacokinetic studies there are no reports of interactions between azithromycin and terfenadine.
There have been rare cases reported where the possibility of such an interaction could not be entirely excluded; however there was no specific evidence that such an interaction had occurred. Azithromycin should be administered with caution in combination with terfenadine.
Digoxin (P-gp substrates):
Concomitant administration of macrolide antibiotics, including azithromycin, with P-glycoprotein substrates such as digoxin, has been reported to result in increased serum levels of the P-glycoprotein substrate. The increased serum levels of digoxin may also be caused by impaired metabolism of digoxin in the gut. Therefore, if azithromycin and P-gp substrates such as digoxin are administered concomitantly, the possibility of elevated serum concentrations of the substrate should be considered.
CYP3A4 substrates:
Even though azithromycin does not appear to inhibit the enzyme CYP3A4, caution is advised when combining the medicinal product with quinidine, cyclosporine or other medicinal products with a narrow therapeutic index predominantly metabolised by CYP3A4.
Azithromycin does not interact significantly with the hepatic cytochrome P450 system. It is not believed to undergo the pharmacokinetic drug interactions as seen with erythromycin and other macrolides. Hepatic cytochrome P450 induction or inactivation via cytochrome-metabolite complex does not occur with azithromycin.
Atorvastatin:
Coadministration of atorvastatin (10 mg daily) and azithromycin (500 mg daily) did not alter the plasma concentrations of atorvastatin (based on a HMG CoA-reductase inhibition assay). However, post-marketing cases of rhabdomyolysis in patients receiving azithromycin with statins have been reported.
Carbamazepine:
In a pharmacokinetic interaction study in healthy volunteers, no significant effect was observed on the plasma levels of carbamazepine or its active metabolite in patients receiving concomitant azithromycin.
Cimetidine:
In a pharmacokinetic study investigating the effects of a single dose of cimetidine, given 2 hours before azithromycin, on the pharmacokinetics of azithromycin, no alteration of azithromycin pharmacokinetics was seen.
Coumarin-type oral anticoagulants:
In a pharmacokinetic interaction study, azithromycin did not alter the anticoagulant effect of a single 15-mg dose of warfarin administered to healthy volunteers. There have been reports received in the post-marketing period of potentiated anticoagulation subsequent to co-administration of azithromycin and coumarin-type oral anticoagulants. Although a causal relationship has not been established, consideration should be given to the frequency of monitoring prothrombin time when azithromycin is used in patients receiving coumarin-type oral anticoagulants.
Cyclosporin:
In a pharmacokinetic study with healthy volunteers that were administered a 500 mg/day oral dose of azithromycin for 3 days and were then administered a single 10 mg/kg oral dose of cyclosporin, the resulting cyclosporin Cmaxand AUC0-5were found to be significantly elevated. Consequently, caution should be exercised before considering concurrent administration of these drugs. If coadministration of these drugs is necessary, cyclosporin levels should be monitored and the dose adjusted accordingly.
Efavirenz:
Coadministration of a 600 mg single dose of azithromycin and 400 mg efavirenz daily for 7 days did not result in any clinically significant pharmacokinetic interactions.
Fluconazole:
Coadministration of a single dose of 1200 mg azithromycin did not alter the pharmacokinetics of a single dose of 800 mg fluconazole. Total exposure and half-life of azithromycin were unchanged by the coadministration of fluconazole, however, a clinically insignificant decrease in Cmax(18%) of azithromycin was observed.
Indinavir:
Co administration of a single dose of 1200 mg azithromycin had no statistically significant effect on the pharmacokinetics of indinavir administered as 800 mg three times daily for 5 days.
Methylprednisolone:
In a pharmacokinetic interaction study in healthy volunteers, azithromycin had no significant effect on the pharmacokinetics of methylprednisolone.
Midazolam:
In healthy volunteers, coadministration of azithromycin 500 mg/day for 3 days did not cause clinically significant changes in the pharmacokinetics and pharmacodynamics of a single 15 mg dose of midazolam.
Nelfinavir:
Concomitant administration of 1200 mg azithromycin and steady state nelfinavir (750 mg 3 times daily) resulted in on average 16% decrease of nelfinavir AUC, an increase of azithromycin AUC and Cmaxwith 113% and 136%, respectively. No dose adjustment is necessary but patients should be monitored for known side effects of azithromycin.
Rifabutin:
Coadministration of azithromycin and rifabutin did not affect the serum concentrations of either active substance. Neutropenia was observed in subjects receiving concomitant treatment of azithromycin and rifabutin. Although neutropenia has been associated with the use of rifabutin, a causal relationship to combination with azithromycin has not been established (see section 4.8).
Sildenafil:
In normal healthy male volunteers, there was no evidence of an effect of azithromycin (500 mg daily for 3 days) on the AUC and Cmax, of sildenafil or its major circulating metabolite.
Theophylline:
Azithromycin has not affected the pharmacokinetics of theophylline when healthy volunteers received azithromycin and theophylline simultaneously. Theophylline levels may be increased in patients taking azithromycin.
Triazolam:
In 14 healthy volunteers, coadministration of azithromycin 500 mg on Day 1 and 250 mg on Day 2 with 0.125 mg triazolam on Day 2 had no significant effect on any of the pharmacokinetic variables for triazolam compared to triazolam and placebo.
Trimethoprim/sulfamethoxazole:
Coadministration of trimethoprim/sulfamethoxazole DS (160 mg/800 mg) for 7 days with azithromycin 1200 mg on Day 7 had no significant effect on peak concentrations, total exposure or urinary excretion of either trimethoprim or sulfamethoxazole. Azithromycin serum concentrations were similar to those seen in other studies.
Didanosine:
Co-administration of 1200 mg/day azithromycin with 400 mg/day didanosine in 6 HIV-positive subjects did not appear to affect the steady-state pharmacokinetics of didanosine as compared with placebo.
Zidovudine:
1000 mg single doses and 1200 mg or 600 mg multiple doses of azithromycin had only a slight effect upon the pharmacokinetics of zidovudine or its glucuronide metabolite in the plasma or upon excretion in the urine. However, the administration of azithromycin increased the concentrations of phosphorylated zidovudine, the clinically active metabolite, in mononuclear cells in the peripheral circulation. The clinical significance of this finding is unclear, but it may be of benefit to patients.
4.6 Fertility, pregnancy and lactation
Pregnancy:
There are no adequate and well controlled studies in pregnant women. Animal reproduction studies show passage across the placenta. No teratogenic effects were observed in rat reproduction studies (see section 5.3). The safety of azithromycin has not been confirmed with regard to the use of the active substance during pregnancy. Therefore, azithromycin should only be used during pregnancy if clearly necessary and when no adequate alternatives are available.
Lactation:
Azithromycin passes into breast milk. Because it is not known whether azithromycin may have adverse effects on the breast-fed infant, nursing should be discontinued during treatment with azithromycin. Among other things diarrhoea, fungus infection of the mucous membrane as well as sensitisation is possible in the nursed infant.
Fertility:
In fertility studies conducted in rat, reduced pregnancy rates were noted following administration of azithromycin. The relevance of this finding to humans is unknown.
4.7 Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed.
However, the possibility of undesirable effects like dizziness and convulsions should be taken into account when performing these activities.
Undesirable effects
About 13% of patients included in clinical trials reported adverse events most commonly gastro-intestinal disorders.
Adverse reactions reported as more than an isolated case (identified through clinical trials and postmarketing surveillance) are listed below, by system organ class and by frequency. Frequencies are defined as:
Very common (≥ 1/10)
Common (≥ 1/100 to < 1/10)
Uncommon (≥ 1/1,000 to < 1/100)
Rare (≥ 1/10,000 to <1/1,000)
Very rare (< 1/10,000),
Not known (frequencycannot be estimated from the available data)
Adverse reactions possibly or probably related to azithromycin based on clinical trial experience and post-marketing surveillance:
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Very Common (≥1/10) |
Common (≥1/100 to <1/10) |
Uncommon (≥1/1000 to < 1/100) |
Rare (≥ 1/10,000 to <1/1,000) |
Frequency Not Known |
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Infections and Infestations |
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Candidiasis Vaginal infection Pneumonia Fungal infection Bacterial infection Pharyngitis Gastroenteritis Respiratory disorder Rhinitis Oral candidiasis |
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Pseudomembranous colitis (see section 4.4) |
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Blood and Lymphatic System Disorders |
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Leukopenia Neutropenia Eosinophilia |
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Thrombocytopenia Haemolytic anaemia |
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Immune System Disorders |
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Angioedema Hypersensitivity |
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Anaphylactic reaction (see section 4.4) |
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Metabolism and Nutrition Disorders |
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Anorexia |
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Psychiatric Disorders |
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Nervousness Insomnia, |
Agitation |
Aggression Anxiety Delirium Hallucination |
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Nervous System Disorders |
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Headache |
Dizziness Somnolence Dysgeusia Paraesthesia |
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Syncope, convulsion Hypoestheia Psychomotor hyperactivity Anosmia Ageusia Parosmia Myasthenia gravis (see Section 4.4) |
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Eye Disorders |
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Visual impairment |
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Ear and Labyrinth Disorders |
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Ear disorder Vertigo |
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Hearing impairment including deafness and/or tinnitus |
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Cardiac Disorders |
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Palpitations |
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Torsades de pointes (see section 4.4) Arrhythmia (see section 4.4) including ventricular tachycardia Electrocardiogram QT prolonged (see section 4.4) |
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Vascular Disorders |
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Hot flush |
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Hypotension |
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Respiratory, thoracic and mediastinal disorders |
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Dyspnoea, Epistaxis |
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Gastrointestinal Disorders |
Diarrhea |
Vomiting Abdominal pain Nausea |
Constipation Flatulence Dyspepsia, Gastritis dysphagia Abdominal distension Dry mouth Eructation Mouth ulceration Salivary hypersecretion |
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Pancreatitis Tongue discolouration |
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Hepatobiliary Disorders |
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Hepatic function abnormal Jaundice cholestatic |
Hepatic failure (which has rarely resulted in death) (see section 4.4) Hepatitis fulminant Hepatic necrosis |
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Skin and Subcutaneous Tissue Disorders |
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Rash Pruritus Urticaria, Dermatitis Dry skin Hyperhidrosis |
Photosensitivi ty reaction |
Stevens-Johnson syndrome Toxic epidermal necrolysis Erythema multiforme |
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Musculoskeletal and Connective Tissue Disorders |
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Osteoarthritis, Myalgia Back pain Neck pain |
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Arthralgia |
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Renal and Urinary Disorders |
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Dysuria Renal pain |
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Renal failure acute Nephritis interstitial |
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Reproductive system and breast disorders |
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Metrorrhagia, Testicular disorder |
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General Disorders and Administration Site Conditions |
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Oedema Asthenia Malaise Fatigue Face edema Chest pain Pyrexia Pain Peripheral edema |
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Very Common (≥1/10) |
Common (≥1/100 to <1/10) |
Uncommon (≥1/1000 to < 1/100) |
Rare (≥ 1/10,000 to <1/1,000) |
Frequency Not Known |
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Investigations |
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Lymphocyte count decreased Eosinophil count increased Blood bicarbonate decreased Basophils increased Monocytes increased Neutrophils increased |
Aspartate aminotransferase increased Alanine aminotransferase increased Blood bilirubin increased Blood urea increased Blood creatinine increased Blood potassium abnormal Blood alkaline phosphatase increased Chloride increased Glucose increased platelets increased Hematocrit decreased Bicarbonate increased abnormal sodium |
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Injury and poisoning |
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Post procedural complication |
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Adverse reactions possibly or probably related to Mycobacterium Avium Complex prophylaxis and treatment based on clinical trial experience and post-marketing surveillance. These adverse reactions differfrom those reported with immediate release or the prolonged release formulations, either in kind or in frequency:
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Very Common (≥1/10) |
Common (≥1/100 to <1/10) |
Uncommon (≥1/1000 to < 1/100) |
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Metabolism and Nutrition Disorders |
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Anorexia |
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Nervous System Disorders |
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Dizziness Headache Paraesthesia Dysgeusia |
Hypoesthesia |
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Eye Disorders |
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Visual impairment |
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Ear and Labyrinth Disorders |
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Deafness |
Hearing impaired Tinnitus |
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Cardiac Disorders |
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Palpitations |
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Gastrointestinal Disorders |
Diarrhea Abdominal pain Nausea Flatulence Abdominal discomfort Loose stools |
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Hepatobiliary Disorders |
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Hepatitis |
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Skin and Subcutaneous Tissue Disorders |
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Rash Pruritus |
Stevens-Johnson syndrome Photosensitivity reaction |
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Musculoskeletal and Connective Tissue Disorders |
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Arthralgia |
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General Disorders and Administration Site Conditions |
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Fatigue |
Asthenia Malaise |
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 [to be completed nationally].
4.9 Overdose
The undesirable effects at dosages in excess of the recommended dosages were similar to those after normal dosages. The typical symptoms of an overdose with macrolide antibiotics include reversible loss of hearing, severe nausea, vomiting and diarrhoea. In cases of overdose the administration of medicinal charcoal and general symptomatic treatment and measures to support vital functions are indicated where necessary.
5. PHARMACOLOGICAL PROPERTIES
Pharmacodynamic properties
Pharmacotherapeutic group: Antibacterials for systemic use, macrolides
ATC code: J01FA10
Azithromycin is a macrolide antibiotic belonging to the azalide group. The molecule is constructed by adding a nitrogen atom to the lactone ring of erythromycin A.
Mode of action:
The mechanism of action of azithromycin is based upon the suppression of bacterial protein synthesis, by binding to the ribosomal 50S sub-unit and thus inhibiting the translocation of peptides.
PK/PD relationship:
For azithromycin the AUC/MIC is the major PK/PD parameter correlating best with the efficacy of azithromycin.
Mechanism of resistance:
Generally, the resistance of different bacterial species to macrolides has been reported to occur by three mechanisms associated with target site alteration, antibiotic modification, or altered antibiotic transport (efflux). The efflux in streptococci is conferred by the mef genes and results in a macrolide-restricted resistance (M phenotype). Target modification is controlled by erm encoded methylases.
A complete cross resistance exists among erythromycin, azithromycin, other macrolides and lincosamides for Streptococcus pneumoniae, beta-haemolytic streptococcus of group A, Enterococcus spp. and Staphylococcus aureus, including methicillin resistant Staphylococcus aureus (MRSA).
Penicillin susceptible Streptococcus pneumoniae are more likely to be susceptible to azithromycin than are penicillin resistant strains of Streptococcus pneumoniae. Methicillin resistant Staphylococcus aureus (MRSA) is less likely to be susceptible to azithromcyin than methicillin susceptible Staphylococcus aureus (MSSA).
The induction of significant resistance in both in vitro and in vivo models is <1 dilution rise in MICs for Streptococcus pyogenes, Haemophilus influenzae, and Enterobacterciae after nine sub lethal passages of active substance and three dilution increase for Staphylococcus aureus and development of in vitro resistance due to mutation is rare.
Breakpoints
Azithromycin susceptibility breakpoints for typical bacterial pathogens:
EUCAST:
- Staphylococcusspp.: susceptible ≤ 1 mg/l; resistant >2mg/l
- Haemophilus spp.: susceptible ≤0.12 mg/l; resistant >4 mg/l
- Streptococcus pneumoniae and Streptococcus A, B, C, G: susceptible ≤ 0.25 mg/l; resistant ≥ 0.5mg/l
- Moraxella catarrhalis: ≤ 0.5 mg/l; resistant > 0.5 mg/l
- Neisseria gonorrhoeae:≤ 0.25 mg/l; resistant > 0.5 mg/l
There are no currently recommended EUCAST breakpoints for the atypical pathogens against which azithromycin has demonstrated clinically significant activity, such as Chlamydia spp., Mycobacterium avium complex, Mycoplasma spp., Borrelia spp. and Helicobacter pylori.
The prevalence of resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. This information provides only an approximate guidance on the probability of an organism being susceptible to azithromycin.
Table : Antibacterial spectrum of azithromycin
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Commonly susceptible species. |
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Aerobic Gram-negative |
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Haemophilus influenzae |
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Moraxella catarrhalis |
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Neisseria gonorrhoeae |
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Other microorganisms |
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Chlamydophila pneumoniae |
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Chlamydia trachomatis |
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Legionella spp. |
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Mycobacterium avium |
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Mycoplasma pneumoniae |
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Species for which acquired resistance may be a problem. |
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Aerobic Gram-positive |
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Staphylococcus aureus (methicillin-susceptible) |
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Streptococcus pneumoniae |
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Streptococcus pyogenes (erythromycin-intermediate) |
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Others |
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Ureaplasma urealyticum |
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Inherently resistant organisms |
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Aerobic Gram-positive |
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Staphylococci MRSA, MRSE |
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Aerobic Gram-negative |
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Escherichia coli |
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Klebsiella spp. |
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Pseudomonas aeruginosa |
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Anaerobic |
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Bacteroides fragilis group |
° At the time of publication there are no current data. In primary literature, standard works and treatment guidelines susceptibility is assumed.
1 Resistance rate in some studies ≥10%
5.2 Pharmacokinetic properties
Absorption:
Following oral administration, the bioavailability of azithromycin is approximately 37 %. Peak plasma levels are reached after 2-3 hours. The mean maximum concentration observed (Cmax) after a single dose of 500 mg is approximately 0.4 μg/ml.
Distribution:
Orally administered azithromycin is widely distributed over the whole body.
Pharmacokinetic studies have shown considerably higher azithromycin concentrations in the tissues (up to 50 times the maximum concentration observed in the plasma) than in the plasma. This indicates that the substance is extensively bound in the tissues (steady-state volume of distribution approximately 31 l/kg).
With the recommended dosage no accumulation in the serum/plasma occurs. Accumulation does occur in the tissues where the levels are much higher than in the serum/plasma. Concentrations in target tissues such as lung, tonsil, and prostate exceed the MIC90for likely pathogens after a single dose of 500 mg.
In experimental in-vitro and in-vivo studies, azithromycin accumulates in phagocytes; release is promoted by active phagocytosis. In animal models this process appeared to contribute to the accumulation of azithromycin in tissue. The binding of azithromycin to plasma proteins is variable, and varies from 52 % at 0.05 μg/ml to 18 % at 0.5 μg/ml, depending on the serum concentration.
Metabolism and Excretion:
The terminal plasma elimination half-life follows the tissue depletion half-life of 2 to 4 days.
Approximately 12 % of an intravenously administered dose is excreted in unchanged form with the urine over a period of 3 days; the major proportion in the first 24 hours. Concentrations of up to 237 μg/ml azithromycin, 2 days after a 5-day course of treatment, have been found in human bile.Tenmetabolites have been identified (formed by N- and O-demethylation, by hydroxylation of the desosamine and aglycone rings, and by splitting of the cladinose conjugate). Investigations suggests that the metabolites do not play a role in the microbiological activity of azithromycin.
Pharmacokinetics in Special populations:
Renal Insufficiency:
Following a single oral dose of azithromycin 1 g, mean Cmaxand AUC0-120increased by 5.1% and 4.2% respectively, in subjects with mild to moderate renal impairment (glomerular filtration rate of 10-80 ml/min) compared with normal renal function (GFR>80ml/min). In subjects with severe renal impairment, the mean Cmaxand AUC0-120increased 61% and 35% respectively compared to normal.
Hepatic insufficiency:
In patients with mild to moderate hepatic impairment, there is no evidence of a marked change in serum pharmacokinetics of azithromycin compared to normal hepatic function. In these patients, urinary recovery of azithromycin appears to increase perhaps to compensate for reduced hepatic clearance.
Elderly:
The pharmacokinetics of azithromycin in elderly men was similar to that of young adults; however, in elderly women, although higher peak concentrations (increased by 30-50%) were observed, no significant accumulation occurred.
In elderly volunteers (>65 years), higher (29 %) AUC values were always observed after a 5-day course than in younger volunteers (<45 years). However, these differences are not considered to be clinically relevant; no dose adjustment is therefore recommended.
Infants, toddlers, children and adolescents:
Pharmacokinetics have been studied in children aged 4 months – 15 years taking capsules, granules or suspension.. At 10 mg/kg on day 1 followed by 5 mg/kg on days 2-5, the Cmaxachieved is slightly lower than adults with 224 ug/l in children aged 0.6-5 years and after 3 days dosing and 383 ug/l in those aged 6-15 years. The half-lifeof 36 h in the older children was within the expected range for adults.
5.3 Preclinical safety data
In animal studies using exposures 40 times those achieved at the clinical therapeutic dosages, azithromycin was found to have caused reversible phospholipidosis, but as a rule there were no associated toxicological consequences. The relevance of this finding to humans receiving azithromycin in accordance with the recommendations is unknown.
Electrophysiological investigations have shown that azithromycin prolongs the QT interval.
Carcinogenic potential:
Long-term studies in animals have not been performed to evaluate carcinogenic potential.
Mutagenic potential:
There was no evidence of a potential for genetic and chromosome mutations in in-vivo and in-vitro test models.
Reproductive toxicity:
No teratogenic effects were observed in embryotoxicity studies in rats after oral administration of azithromycin. In rats, azithromycin dosages of 100 and 200 mg/kg bodyweight/day led to mild retardations in fetal ossification and in maternal weight gain. In peri- and postnatal studies in rats, mild retardations following treatment with 50 mg/kg/day azithromycin and above were observed.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tablet core:
Calcium hydrogen phosphate,dihydrate
Hydroxypropylcellulose (E463)
Croscarmellose sodium
Magnesium stearate (E572)
Tablet coat:
Hypromellose (E464)
Lactose monohydrate
Titanium dioxide (E171)
Triacetin
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
Do not store above 25 °C.
Nature and contents of container
White opaque, PVC/aluminium foil blisters.
White, round HDPE bottles with a blue PP Lift N Peel cap closure.
Azithromycin Orifarm250 mg film-coated tablets:
Blister:2, 3, 4, 6, 7, 9, 10, 12, 14, 20, 24, 28, 30, 35, 98, 99, 100 tablets
Bottle: 30 tablets
Azithromycin Orifarm500 mg film-coated tablets:
Blister: 2, 3, 4, 6, 7, 10, 28, 30, 35 tablets
Bottle: 30 tablets
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7. MARKETING AUTHORISATION HOLDER
Orifarm Generics A/S
8. MARKETING AUTHORISATION NUMBER(S)
[To be completed nationally]
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
13 November 2009 / 30 December 2011
10. DATE OF REVISION OF THE TEXT
2016-02-18
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