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Azithromycin should be given as a single daily dose. Duration of the treatment for the different infection diseases is given below.
Children and adolescents with a body weight above 45 kg, adults and the elderly
The total dose is 1500 mg, administered as 500 mg once daily for 3 days. Alternatively, the same total dose (1500 mg) can be administered in a period of 5 days, 500 mg on the first day and 250 mg on day 2 to 5.
Children and adolescents with a body weight below 45 kg
Azithromycin tablets are not suitable for patients under 45 kg body weight. Other dosage forms are available for this group of patients.
Elderly patients
For elderly patients the same dose as for adults can be applied.
Patients with renal impairment
Dose adjustment is not required in patients with mild to moderate renal impairment (GFR 10-80 ml/min) Caution should be exercised when azithromycin is administered to patients with severe renal impairment
(GFR < 10 ml/min)
Patients with hepatic impairment
Dose adjustment is not required for patients with mild to moderate hepatic dysfunction.
Method of administration: For oral use only.
Azithromycin tablet should be given as a single daily dose. The tablets can be taken with or without food and should be taken with a glass of water
Azithromycin tablet is contraindicated in patients with known hypersensitivity to azithromycin, erythromycin, any macrolide, or ketolide drug.
It is contraindicated in patients with a history of cholestatic jaundice/hepatic dysfunction associated with prior use of azithromycin.
Hypersensitivity
Hepatotoxicity
Abnormal liver function, hepatitis, cholestatic jaundice, hepatic necrosis, and hepatic failure have been reported, some of which have resulted in death. Discontinue azithromycin immediately if signs and symptoms of hepatitis occur.
Infantile Hypertrophic Pyloric Stenosis (IHPS)
Following the use of azithromycin in neonates (treatment up to 42 days of life), IHPS has been reported. Direct parents and caregivers to contact their physician if vomiting or irritability with feeding occurs.
Pseudomembranous colitis
Pseudomembranous colitis has been reported with the use of macrolide antibiotics. This diagnosis should therefore be considered in patients who get diarrhoea after starting treatment with azithromycin.
Ergot derivatives
In patients receiving ergotamine derivatives, ergotism has been precipitated by coadministration of some macrolide antibiotics. There are no data concerning the possibility of an interaction between ergotamine derivatives and azithromycin. However, because of the theoretical possibility of ergotism, azithromycin and ergot derivatives should not be co-administered.
Cross resistance
Cross-resistance exists between azithromycin and other macrolides (erythromycin, clarithromycin, roxithromycin), lincosamides and streptogramin B (MLSB phenotype). Concomitant use of several medicinal products from the same or related group of antibacterial agents is not recommended.
Cardiovascular events
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 including azithromycin Therefore, as the following situations may lead to an increased risk for ventricular arrhytmias (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) such as patients:
QT Prolongation
Clostridium difficile-Associated Diarrhea (CDAD)
Exacerbation of Myasthenia Gravis
Exacerbations of symptoms of myasthenia gravis and new onset of myasthenic syndrome have been reported in patients receiving azithromycin therapy.
Use in Sexually Transmitted Infections
Azithromycin, (single dose 1 g packet) at the recommended dose, should not be relied upon to treat gonorrhea or syphilis.
Antibacterial agents used in high doses for short periods of time to treat non-gonococcal urethritis may mask or delay the symptoms of incubating gonorrhea or syphilis. All patients with sexually transmitted urethritis or cervicitis should have a serologic test for syphilis and appropriate cultures for gonorrhea performed at the time of diagnosis. Appropriate antibacterial therapy and follow-up tests for these diseases should be initiated if
infection is confirmed.
Development of Drug-Resistant Bacteria
Prescribing Azithromycin in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drugresistant bacteria.
Nelfinavir
Co-administration of nelfinavir at steady-state with a single oral dose of azithromycin resulted in increased azithromycin serum concentrations. Although a dose adjustment of azithromycin is not recommended when administered in combination with nelfinavir, close monitoring for known adverse reactions of azithromycin, such as liver enzyme abnormalities and hearing impairment, is warranted.
Warfarin
Spontaneous postmarketing reports suggest that concomitant administration of azithromycin may potentiate the effects of oral anticoagulants such as warfarin, although the prothrombin time was not affected in the dedicated drug interaction study with azithromycin and warfarin. Prothrombin times should be carefully monitored while patients are receiving azithromycin and oral anticoagulants concomitantly.
Potential Drug-Drug Interaction with Macrolides
Interactions with digoxin, colchicine or phenytoin have not been reported in clinical trials with azithromycin. No specific drug interaction studies have been performed to evaluate potential drug-drug interaction. However, drug interactions have been observed with other macrolide products. Until further data are developed regarding drug interactions when digoxin, colchicine or phenytoin are used with azithromycin careful monitoring of patients is advised.
Pregnancy
There are no adequate and well-controlled studies on the use of azithromycin in pregnant women. In reproduction toxicity studies in animals azithromycin was shown to pass the placenta, but no teratogenic effects were observed. 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 the benefit outweighs the risk.
A decision should be taken whether breastfeeding is discontinued or that treatment with azithromycin is discontinued/initiated or not, taking into account the benefit of breastfeeding for the child and the benefit of treatment for the woman.
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.
There is no evidence to suggest that azithromycin may have an effect: on a patient’s ability to drive or operate machinery. Visual impairment and vision blurred may have an effect on a patient’s ability to drive or operate machinery.
Azithromycin induced Acute generalized Exanthematous Pustulosis (AGEP).
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
In clinical trials, most of the reported adverse reactions were mild to moderate in severity and were reversible upon discontinuation of the drug. Approximately 0.7% of the patients from the multiple-dose clinical trials discontinued Azithromycin therapy because of treatment-related adverse reactions. Serious adverse reactions included angioedema and cholestatic jaundice. Most of the adverse reactions leading to discontinuation were related to the gastrointestinal tract, e.g., nausea, vomiting, diarrhea, or abdominal pain.
Multiple-dose regimen
Overall, the most common adverse reactions in adult patients receiving a multiple-dose regimen of Azithromycin were related to the gastrointestinal system with diarrhea/loose stools (5%), nausea (3%), and abdominal pain (3%) being the most frequently reported.
No other adverse reactions occurred in patients on the multiple-dose regimen of Azithromycin with a frequency greater than 1%. Adverse reactions that occurred with a frequency of 1% or less included the following:
Adverse reactions that occurred in patients on the single 1 gram dosing regimen of Azithromycin with a frequency of 1% or greater included diarrhea/loose stools (7%), nausea (5%), abdominal pain (5%), vomiting (2%), dyspepsia (1%), and vaginitis (1%).
Postmarketing Experience
The following adverse reactions have been identified during post approval use of azithromycin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions reported with azithromycin during the postmarketing period in adult and/or pediatric patients for which a causal relationship may not be established include:
Allergic: Arthralgia, edema, urticaria, and angioedema.
Cardiovascular: Arrhythmias, including ventricular tachycardia, and hypotension. There have been reports of QT prolongation and torsade’s de pointes.
Gastrointestinal: Anorexia, constipation, dyspepsia, flatulence, vomiting / diarrhea pseudomembranous colitis, pancreatitis, oral candidiasis, pyloric stenosis, and tongue discoloration.
General: Asthenia, paresthesia, fatigue, malaise, and anaphylaxis.
Genitourinary: Interstitial nephritis, acute renal failure, and vaginitis.
Hematopoietic: Thrombocytopenia.
Liver/Biliary: Abnormal liver function, hepatitis, cholestatic jaundice, hepatic necrosis, and hepatic failure.
Nervous System: Convulsions, dizziness/vertigo, headache, somnolence, hyperactivity, nervousness, agitation, and syncope.
Psychiatric: Aggressive reaction and anxiety.
Skin/Appendages: Pruritus, and serious skin reactions including erythema multiforme, AGEP, Stevens-Johnson syndrome, toxic epidermal necrolysis, and DRESS.
Special Senses: Hearing disturbances including hearing loss, deafness, and/or tinnitus, and reports of taste/smell perversion and/or loss.
Laboratory Abnormalities
Significant abnormalities (irrespective of drug relationship) occurring during the clinical trials were reported as follows:
With an incidence of 1-2%, elevated serum creatine phosphokinase, potassium, ALT (SGPT), GGT, and AST (SGOT).
With an incidence of less than 1%, leukopenia, neutropenia, decreased platelet count, elevated serum alkaline phosphatase, bilirubin, BUN, creatinine, blood glucose, LDH, and phosphate.
When follow-up was provided, changes in laboratory tests appeared to be reversible.
In multiple-dose clinical trials involving more than 3000 patients, 3 patients discontinued therapy because of treatment-related liver enzyme abnormalities and 1 because of a renal function abnormality.
In a phase 1 drug interaction study performed in normal volunteers, 1 of 6 subjects given the combination of azithromycin and rifabutin, 1 of 7 given rifabutin alone, and 0 of 6 given azithromycin alone developed a clinically significant neutropenia (<500 cells/mm3). Laboratory abnormalities seen in clinical trials for the prevention of disseminated Mycobacterium avium disease in severely immunocompromised HIV-infected patients.
Chronic therapy (median duration: 87.5 days, range: 1-229 days) that resulted in laboratory abnormalities in >5% of subjects with normal baseline values in the pivotal trial for treatment of disseminated MAC in severely immunocompromised HIV-infected patients treated with azithromycin 600 mg daily in combination with ethambutol include: a reduction in absolute neutrophils to <50% of the lower limit of normal (10/52, 19%) and an increase to five times the upper limit of normal in alkaline phosphatase (3/35, 9%). These findings in subjects with normal baseline values are similar when compared to all subjects for analyses of neutrophil reductions (22/75, 29%) and elevated alkaline phosphatase (16/80, 20%). Causality of these laboratory abnormalities due to the use of study drug has not been established.
Adverse events experienced in higher than recommended doses were similar to those seen at normal doses.
Symptoms
The typical symptoms of an overdose with macrolide antibiotics include reversible loss of hearing, severe nausea, vomiting and diarrhoea.
Treatment
In the event of overdose, the administration of medicinal charcoal and general symptomatic treatment and supportive measures are indicated as required.
Pharmacodynamic properties
Pharmacotherapeutic group: antibacterials for systemic use; macrolides; azithromycin.
Mode of action:
Azithromycin is an azalide, a sub-class of the macrolide antibiotics. By binding to the 50Sribosomal sub-unit, azithromycin avoids the translocation of peptide chains from one side of the ribosome to the other . As a consequence of this, RNA-dependent protein synthesis in sensitive organisms is prevented.
Pharmacodynamics:
Based on animal models of infection, the antibacterial activity of azithromycin appears to correlate with the ratio of area under the concentration-time curve to minimum inhibitory concentration (AUC/MIC) for certain
pathogens (S. pneumoniae and S. aureus).
PK/PD relationship:
For azithromycin the AUC/MIC is the major PK/PD parameter correlating best with the efficacy of azithromycin. Following the assessment of studies conducted in children, the use of azithromycin is not recommended for the treatment of malaria, neither as monotherapy nor combined with chloroquine or artemisinin based drugs, as non-inferiority to anti-malarial drugs recommended in the treatment of uncomplicated malaria was not established.
Pharmacokinetic properties
Absorption
After oral administration the bioavailability of azithromycin is approximately 37%. Peak plasma levels are reached after 2-3 hours (Cmax after a single dose of 500 mg orally was approximately 0.4 mg/l).
Distribution
Excretion
Plasma terminal elimination half-life closely reflects the tissue depletion half-life of 2 to 4 days. About 12% of an intravenously administered dose is excreted in the urine unchanged over a period of 3 days; the majority in the first 24 hours. Biliary excretion of azithromycin, predominantly in unchanged form, is a major route of elimination.
The identified metabolites (formed by N- and O- demethylising, by hydroxylising of the desosamine and aglycone rings, and by the splitting of the cladinose conjugate) are microbiologically inactive.
After a 5-day treatment slightly higher (29%) AUC values were seen in the elderly volunteers (>65 years of age) compared to the younger volunteers (< 45 years of age). However, these differences are not regarded as clinically relevant; therefore, a dose adjustment is not recommended.