(AZITHROMYCIN)
FORM AND PRESENTATION
Film-Coated Tablets: Azithromycin film-coated tablets are capsular shaped and contain azithromycin dihydrate equivalent to 250 mg, 500 mg, of azithromycin and engraved with either -ZTM 250," "ZTM 500,".
Powder for Oral Suspension: Azithromycin powder for oral suspension is presented as a dry powder which yields, on reconstitution with water, a white to off-white suspension containing the equivalent of 200 mg azithromycin per 5 ml.
Intravenous: Azithromycin is supplied in lyophilized from under a vacuum in a 10 ml vial equivalent to 500 mg azithromycin for intravenous administration. Upon reconstitution, azithromycin powder yields a solution containing the equivalent of 100 mg azithromycin per 1 ml.
DESCRIPTION
Powder for Oral Suspension -The powder for oral suspension contains sucrose (1,94 g per 100 mg dose), sodium phosphate tribasic anhydrous, hydroxypropyl, cellulose, xanthan gum, artificial cherry, creme de vanilla and banana flavors.
Tablets - The tablets contain pregelatinized starch, calcium phosphate dibasic anhydrous, croscarmellose sodium, magnesium stearate and sodium lauryl sulphate. The film coating contains hydroxypropyl methylcellulose, triacetin and titanium dioxide (E171).
Intravenous: The intravenous formulation contains citric acid (anhydrous) 384,6 mg, and sodium hydroxide 198.3 mg.
PHARMACOLOGICAL PROPERTIES
Pharmacodynamic Properties
Pharmacotherapeutic group; Macrolides, ATC code J01FA.
Azithromycin is the first of a subclass of macrolide antibiotics, known as azalides, and is chemically different from erythromycin. Chemically if is derived by insertion of a nitrogen atom into the lactone ring of erythromycin.
A. The chemical name of azithromycin is 9-deoxy-9a-aza-9a-methyl-9a-homoerythromycin A. The molecular weight is 749,0.
The mode of action of azithromycin is inhibition of protein synthesis in bacteria by binding to the 50s ribosomal subunit and preventing translocation of peptides.
Azithromycin demonstrates activity in-vitro against a wide range bacteria including:
Gram-positive Aerobic Bacteria: Staphylococcus aureus, Streptococcus pyogenes (group A beta-haemolytic streptococci), Streptococcus pneumoniae, alpha-haemolytic streptococci (viridans group) and other streptococci, and Corynebacterium diphtheriae. Azithromycin demonstrates cross resistance with erythromycin resistant gram-positive strains, including Streptococcus faecalis (enterococcus) and most strains of methicillin-resistant Staphylococci.
Gram negative Aerobic Bacteria: Haemophilus inftuenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Acinetobacter species, Yersinia species, Legionella pneumophila, Bordetella pertussis, Bordetella parapertussis, Shigella species, Pasteurella species, Vibrio cholera and parahaemolyticus, Plesiomonas Shigelloides. Activities against Escherichia coli. Salmonella enteritidis, Salmonella typhi, Enterobacter species, Aeromonas hydrophila and Klebsiella species are variable and susceptibility test should be performed. Proteus species, Serratia species, Morganella species, and Pseudomonas aeruginosa are usually resistant.
Anaerobic Bacteria: Bacteroides fragilis and Bacteroides species, Clostridium perfringens, Peptococcus species and Peptostreptococcus species, Fusobacterium necrophorum and Proprionibacterium acnes.
Organism of Sexually Transmitted Diseases: Azithromycin is active against Chlamydia trachomatis and also shows good activity against Treponema pallidum, Neisseria gonorrhoeae and Haemophilus ducreyi.
Other Organisms: Borrelia burgdorferi (Lyme disease agent), Chlamydia pneumoniae, Mycoplasma pneumoniae, Mycoplasma hominis, Ureaplasma urealyticum, Campylobacter species and Listeria monocytogenes.
Opportunistic Pathogens Associated with HIV Infections - Mycobacterium avium-intraceilulare complex, Pneumocystis carinii and Toxoplasma gondii.
Mechanism of Resistance
There are two predominant resistance determinants. In clinical isolates of Streptococcus pneumoniae and Streptococcus pyogenes: mef and erm. Mef encodes an efflux pump that mediates resistance to 14-and 15-membered macrolides only, Mef has also been described in a variety of other species. The erm gene encodes a 23S-rRNA methyltransferase that adds methyl groups to adenine 2058 of the 23S rRNA (E. coli rRNA numbering system). The methylated nucleotide is in domain V and has been found to interact with lincosamides and streptogramin B, In addition to macrolides, resulting in a phenotype known as MLSB resistance. Erm(B) and erm(A) are found in clinical isolates of S. pneumoniae and S. pyogenes.
The AcrAB-ToIC pump in Haemophlius influenzae is responsible for the innate higher levels of MIC values to macrolides.
In clinical isolates, mutations in 23S rRNA, specifically in nucleotides 2057-2059 or 2611 in domain V, or mutations in ribosomal proteins L4 or L22 are rare.
Breakpoints
The recommended MIC breakpoints (µg/ml) for azithromycin (recommendation of the NCCLS) are:
Haemophilus spp.; S = 4 with no recommendation for resistance breakpoint*
Streptococci including S. pneumoniae and S. pyogenes; S = 0.5, R = 2
'The current absence of data on resistant strain precludes defining any category other than susceptible.
If strains yield MIC results other than susceptible, they should be submitted to a reference laboratory for further testing.
Bacterial Susceptibility
The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.
In-vitro susceptibility data do not always correlate with clinical results.
Commonly susceptible species
Aerobic Gram-positive bacteria:
Staphylococcus aureus. Streptococcus agalactiae, Streptococci (Group C, F, G) and Viridans group streptococci.
Aerobic Gram-negative bacteria:
Bordeteila pertussis. Haemophilus ducreyi, Haemophilus influenzae*$, Haemophilus parainfluenzae*, Legionella pneumophila, Moraxeila catarrhalis* and Neisseria gonorrhoeae.
Other
Chlamydia pneumoniae*, Chlamydia trachomatis, Mycoplasma pneumoniae* and Ureaplasma urealyticum.
Species for which acquired resistance has been reported
Aerobic Gram-positive bacteria:
Streptococcus pneumoniae*
Streptococcus pyogenes*
Note; azithromycin demonstrates cross-resistance with erythromycin-resistant gram-positive strains.
Inherently resistant organisms
Enterobacteriaceae
Pseudomonas
*Species for which efficacy has been demonstrated in clinical trails,
$Species with natural intermediate susceptibility
Pharmacokinetic Properties
Absorption
Following oral administration in humans, azithromycin is widely distributed throughout the body; bioavailabillty is approximately 37%. The time taken to peak plasma levels is 2-3 hours. Plasma terminal elimination half-life closely reflects the tissue depletion half-life of 2 to 4 days. In elderly volunteers (› 65 years), slightly higher AUC values were seen after a 5-day regimen than in young volunteers (›40 years), but these are not considered clinically significant, and hence no dose adjustment is recommended.
Distribution
In animal studies, high azithromycin concentrations have been observed in phagocytes. In experimental models, higher concentrations of azithromycin are released during active phagocytosis than from non-stimulated phagocytes. In animal models this results in high concentrations of azithromycin being delivered to the site of infection.
Pharmacokinetic studies in humans have shown markedly higher azithromycin levels in tissue than in plasma (up to 50 times the maximum observed concentration in plasma) indicating that the drug is heavily tissue bound. Concentrations in target tissues, such as lung, tonsil and prostate exceed the MIC90 for likely pathogens after a single dose of 500 mg.
Elimination
Plasma terminal elimination half-life closely reflects the tissue depletion half-life of 2 to 4 days. Approximately 12% of an intravenously administered dose is excreted in the urine over 3 days as the parent drug, the majority in the first 24 hours. Biliary excretion of azithromycin is a major route of elimination for unchanged drug following oral administration. Very high concentrations of unchanged drug have been found in human bile, together with 10 metabolites, formed by N- and O-demethylation, by hydroxylation of the desosamine and aglycone rings, and by cleavage of the cladinose conjugate. Comparison of HPLC and microbiological assays in tissues suggests that metabolites play no part in the microbiological activity of azithromycin.
Pharmacokinetics in Special Patient Groups
Elderly
In elderly volunteers (› 65 years), slightly higher AUC values were seen after a 5-day regimen than in young volunteers (‹40 years), but these are not considered clinically significant, and hence no dose adjustment is recommended.
Renal Impairment
The pharmacokinetics of azithromycin in subjects with mild to moderate renal impairment (GFR 10-80 ml/min) were not affected following a single one gram dose of immediate release azithromycin. Statistically significant differences in AUC0-120 (8.8 µg hr/ml vs. 11,7 µg hr/ml), Cmax(1.0 µg/ml vs. 1.6 µg/ml) and CLr (2,3 ml/min/kg vs. 0.2 ml/min/kg) were observed between the group with severe renal impairment (GFR ‹ 10 ml/min) and the group with normal renal function.
Hepatic Impairment
In patients with mild (Class A) to moderate (Class B) hepatic impairment, there is no evidence of a marked change in serum pharmacokinetics of azithromycin compared to those with normal hepatic function. In these patients urinary clearance of azithromycin appears to increase, perhaps to compensate for reduced hepatic clearance.
Preclinical Safety Data
Phospholipidosis (intracellular phospholipid accumulation) has been observed in several tissues (e.g. eye, dorsal root ganglia, liver, gallbladder, kidney, spleen, and/or pancreas) of mice, rats, and dogs given multiple doses of azithromycin. Phospholipidosis has been observed to a similar extent in the tissues of neonatal rats and dogs. The effect has been shown to be reversible after cessation of azithromycin treatment. The significance of the finding for animals and for humans is unknown.
THERAPEUTIC INDICATIONS
Azithromycin oral:
Azithromycin is indicated for the treatment of patient with mild to moderate infections (pneumonia: see Special Warnings and Special Precautions for Use) caused by susceptible strains of the designated microorganisms in the specific conditions listed below;
Lower Respiratory Tract
Accute bacterial exacerbations of chronic obstructive pulmonary disease due to Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae.
Community-acquired pneumonia of mi)d severity due to Streptococcus pneumoniae or Haemophilus influenzae in patients appropriate for outpatient oral therapy,
Upper Respiratory Tract
Streptococcal pharyngitis/ tonsillitis - As an alternative to first line therapy of acute pharyngitis/ tonsillitis due to Streptococcus pyogenes occurring in individuals who cannot use first line therapy,
Skin and Skin Structure
Uncomplicated skin and skin structure infections due to Staphylococcus aureus, Streptococcus pyogenes, or Streptococcus agalactiae. Abscesses usually require surgical drainage.
Sexually Transmitted Diseases
Non-gonococcal urethritis and cervicitis due to Chlamydia trachomatis.
Azithromycin, at the recommended dose, should not be relied upon to treat gonorrhea or syphilis. Antimicrobial 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 antimicrobial therapy and follow-up tests for these diseases should be initiated if infection is confirmed.
Appropriate culture and susceptibility tests should be performed before treatment to determine the causative organism and its susceptibility to azithromycin. Therapy with azithromycin may be inflated before results of these tests are known: once the results become available, antimicrobial therapy should be adjusted accordingly.
Azithromycin IV:
Azithromycin intravenous (IV) is indicated for the treatment of community acquired pneumonia (CAP) caused by susceptible organisms, including Legionella pneumophila, in patients who require initial intravenous therapy.
In combination with metronidazol, Azithromycin Intravenous (IV) is indicated for the treatment of pelvic inflammatory diseases caused by susceptible organisms, in patients who require initial intravenous therapy.
CONTRAINDICATIONS
The use of this product is contraindicated in patients with hypersensitivity to azithromycin, erythromycin, any macrolide or ketolide antibiotic or to any excipient.
SPECIAL WARNINGS AND SPECIAL PRECAUTIONS FOR USE
As with erythromycin and other macrolides, rare serious allergic reactions, including engioedema and anapylaxis (rarely fatal), have been reported. Some of these reactions with azithromycin have resulted in recurrent symptom and required a longer period of observation and treatment,
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.
In patients with mild (Class A) to moderate (Class B) hepatic impairment, there is no evidence of a marked change in serum pharmacokinetics of azithromycin compared to those with normal hepatic function. In these patients urinary recovery of azithromycin appears to increase, perhaps to compensate for reduced hepatic clearance. Hence no dose adjustment is recommended for patients with mild to moderate hepatic impairment.
In patients receiving ergot derivatives, ergotism has been precipitated by co-administration of some macrolide antibiotics. There are no data concerning the possibility of an interaction between ergot and azithromycin.
However, because of the theoretical possibility of ergotism, azithromycin and ergot derivatives should not be co-administered.
As with any antibiotic preparation, observation for signs of superinfection with non-susceptible organism, including fungi is recommended.
Penicillin is the usual drug of choice in the treatment of Streptococcus pyogenes infections and the prophylaxis of rheumatic fever, Azithromycin is often effective in the eradication of susceptible strains of Streptococcus pyogenes from the nasopharynx. Because some strains are resistant to azithromcidn, susceptibility test should be performed when patients are treated with azithromycin. Data establishing efficacy of azithromycin in subsequent prevention of rheumatic fever are not available. If an allergic reaction occurs, the drug should be discontinued and appropriate therapy should be instituted, Physician should aware that reappearance of the allergic symptoms may occur when symptomatic therapy is discontinued.
Azithromycin should not be used in patients with pneumonia who are judge to be inappropriate for outpatient oral therapy because of moderate to severe illness or risk factors such as any of the following:
- patients with nosocomially acquired infections
- patients with known or suspected bacteremia
- patients requiring hospitalization
- elderly or debilitated patients, or
- patients with significant underlying health problems that may compromise their ability to respond to their illnes (including immunodeficiency of functional asplenia).
In patients with severe renal impairment (GFR ‹ 10 ml/min) a 33% increase in systemic exposure to azithromycin was observed (see section - Pharmacokinetic Properties),
No dose adjustment is needed in patients with mild renal impairment (creatinine clearance › 40 mg/min) but there are no data regarding azithromycin usage in patients with more severe renal impairment; thus, caution should be exercised before prescribing Zithromax in these patients.
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. A similar effect with azithromycin cannot be completely ruled out in patients at increased risk for prolonged cardiac repolarization (see section Undesirable Effects).
Intravenous Administration
Azithromycin for injection should be reconstituted and diluted as directed and administered as an intravenous infusion over not less than 60 minutes. Do not administer as an intravenous bolus or an intramuscular injection (see Section Posology and Method of Administration and section Instruction for Use and Handling, and Disposal).
INTERACTION WITH OTHER MEDICAMENTS AND OTHER FORMS OF INTERACTION
Antacids
In a pharmacokinetic study investigating the effects of simultaneous administration of antacid with azithromycin, no effect on overall biovailability was seen although peak serum concentrations were reduced by approximately 30%. In patients receiving both azithromycin and antacids, the drug should not be taken simultaneously.
Cetirizine: In healthy volunteers, coadministration of a 5-day regimen of azithromycin with cetirizine 20 mg at a steady-state resulted In no pharmacokinetic interaction and no significant changes in the QT interval.
Didanosine (Dideoxyinosine)
Coadministration of 1200 mg/day azithromycin with 400 mg/day didanosine in 6 HIV-positive subjects did not appear to affect the steady-slate pharmacokinetics of didanosine as compared with placebo.
Digoxin
Many patients have received coadministration of azithromycin and cardiac glycosides, and no interactions have been reported,
Some of the macrolide antibiotics have been reported to impair the microbial metabolism of digoxin in the gut in some patients. In patients receiving concomitant azithromycin a related azalide antibiotic and digoxin the possibility of raised digoxin levels should be borne in mind.
Zidovudine
Single 1000 mg doses and multiple 1200 mg or 600 mg doses of azithromycin had little effect on the plasma pharmacokinetics or urinary excretion of zidovudine or its glucuronide metabolite. However, administration of azithromycin increased the concentrations of phosphorylated zidovudine, the clinically active metabolite, in peripheral blood mononuclear cells. The clinical significance of this finding is unclear, but it may be of benefit to patients,
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 cytochrom-metabolite complex does not occur with azithromycin.
Ergot
Due to the theoretical possibility of ergotism, the concurrent use of azithromycin with ergot derivatives is not recommended (see section - Special Warnings and Special Precautions for Use)
Pharmacokinetic studies have been conducted between azithromycin and the following drugs known to undergo significant cytochrome P450 mediated metabolism.
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).
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.
In a pharmacokinetic study investigating the effects of a single dose of cimetidine, given 2 hours before azithromycin, on the pharmacokinetic 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 coadministration 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 Cmax and AUC0-5 were found to be significantly elevated. Consequently, caution should be exercised before concurrent administration of these drugs. If coadministration 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: Coadministraton 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: Coadministration of a single dose of 1200 mg azithromycin had no statistically significant effect on the pharmacokinetics of indinavir administered as 800 mg three times dally for 5 days.
Methylprednisolone
In a pharmacokinetic interaction study in healthy volunteers, azithromycin had no significant effect on the pharmacokinetics of methylpredmsolone.
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:
Coadministration of azithromycin (1200 mg) and nelfinavir at steady state (750 mg three times daily) resulted in increased azithromycin concentrations. No clinically significant adverse effects were observed and no dose adjustment is required.
Rifabutin
Coadministration of azithromycin and rifabutin did not affect the serum concentrations of either drug.
Neutroprenia 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-Undesirable Effects).
Sildenafil
In normal healthy volunteers, there was no evidence of an effect of azithromycin (500 mg daily (or 3 days) on the AUC and Cmax of sildenafil or its major circulating metabolite.
Terfenadine
Pharmacokinetic studies have reported no evidence of an interaction 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.
Theophylline
There is no evidence of a clinically significant pharmacokinetic interaction when azithromycin and theophylline are coadministered to healthy volunteers,
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,
Pregnancy and Lactation
Animal reproduction studies have been performed at doses up to moderately maternally toxic dose concentrations. In these studies no evidence of harm to the fetus due to azithromycin was found. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, azithromycin should be used during pregnancy only if clearly needed.
There are no data on secretion in breast milk As many drugs are excreted in human milk, azithromycin should not be used in the treatment of a lactating woman unless the physician feels that the potential benefits justify the potential risks to the infant.
Effect on Ability to Drive and Use Machines
There is no evidence to suggest that azithromycin may have an effect on a patient's ability to drive or operate machinery.
UNDESIRABLE EFFECTS
Azithromycin is well tolerated with a low incidence of side effects.
In clinical trials, the following undesirable effects have been reported:
Blood and Lymphatic System Disorders: - Transient episodes of mild neutropenia have occasionally been observed in clinical trials, although a casual relationship to azithromycin has not been established.
Ear and Labyrinth Disorders: - Hearing impairment (including hearing loss, deafness and/or tinnitus) have been reported in some patients receiving azithromycin. Many of these have been associated with prolonged use of high doses in investigational studies. In those cases where follow-up information was available the majority of these events were reversible.
Gastrointestinal Disorders: - Nausea, vomiting, diarrhea, loose stools, abdominal discomfort (pain/ cramps), and flatulence.
Hepatobiliary Disorders: - Abnormal liver function.
Skin and Subcutaneous Tissue Disorders: - Allergic reactions including rash and angioedema.
General Disorders and Administration Site Conditions; - Local pain and inflammation at the site of infusion.
In post-marketing experience, the following additional undesirable effects have been reported:
Infections and Infestations: Moniliasis, and vaginitis.
Blood and Lymphatic System Disorders: - Thrombocytopenia
Immune System Disorders. -Anaphylaxis (rarely fatal) (see section - Special Warnings and Special Precautions for Use).
Metabolism and Nutrition Disorders: Anorexia.
Psychiatric Disorders- -Aggressive reaction, nervousness, agitation, and anxiety.
Nervous System Disorders: - Dizziness, convulsions (as seen with other macrolides), headache, hyperactivity, paresthesia, somnolence, and syncope. There have been rare reports of taste/ smell perversion and/or loss.
However, a causal relationship has not been established.
Ear and Labyrinth Disorders. - Vertigo
Cardiac Disorders: - Palpitations and arrhytmias including ventricular tachycardia (as seen with other macrolides) have been reported. There have been rare reports of QT prolongation and torsades de pointes, A causal relationship between azithromycin and these effects has not been established (see section Special Warnings and Special Precautions for Use)
Vascular Disorders: - Hypotension.
Gastrointestinal Disorders: - Vomiting/diarrhea (rarely resulting in dehydration), dyspepsia, constipation, pseudomembranous colitis, pancreatitis, and rare reports of tongue discoloration
Hepatobiliary Disorders- - Hepatitis and choleslatic jaundice have been reported, as well as rare cases of hepatic necrosis and hepatic failure, which have rarely resulted in death. However, a casual relationship has not been established.
Skin and Subcutaneous Tissue Disorders: - Allergic reactions including pruritus, rash, photosensitivity, edema, urticaria and angioedema. Rarely: serious skinreactions including erythema multiforme. Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported.
Musculoskeletal and Connective Tissue Disorders: - Arthralgia,
Renal and Urinary Disorders: - Interstitial nephritis and acute renal failure.
General Disorders and Administration Site Conditions: -Asthenia has been reported, although a casual relationship has not been established, fatigue, and malaise.
POSOLOGY AND METHOD OF ADMINISTRATION
Azithromycin oral:
Azithromycin should be administered as a single daily dose. The period of dosing with regard to infection is given below.Azithromycin tablets and powder for oral suspension can be taken with or without food.
In Adults - For the treatment of sexually transmitted diseases caused by Chlamydia trachomatis, Haemophilus ducreyi, or susceptible Neisseria gonorrhoeae the dose is 1000 mg as a single oral dose.
For all other indications in which the oral formulation is administered, the total dosage of 1500 mg should be given as 500 mg daily for 3 days. As an alternative, the same total dose can be given over 5 days with 500 mg given on day 1, then 250 mg daily on days 2 to 5.
In children - There is no information on children under six months of age.
The total dose of 30 mg/kg should be given as a single daily dose of 10 mg/kg, or as an alternative, given over 5 days with single daily dose of 10 mg/kg dose on day 1, then 5 mg/kg on days 2-5.
Azithromycin suspension should be administered according to the guide provided below:
AZITHROMYCIN SUSPENSION 30 mg/kg Total Treatment Dose
| |||
Weight (kg)
|
3-Day Regimen
|
5-Day Regimen
|
Bottle Size
(mg)
|
| 15 - 25 | 200 mg (5 mL) once daily on days 1 - 3 | 200 mg (5mL) on day 1, then 100 mg (2.5 mL) once daily on days 2 - 5 | 600 |
| 26 - 35 | 300 mg (7.5 mL) once daily on days 1 - 3 | 300 mg (7.5 mL) on day 1, then 150 mg (3.75mL) once daily on days 2 - 5 | 900 |
| 36 - 45 | 400 mg (10 mL) once daily on days 1 - 3 | 400 mg (10 mL) on day 1, then 200 mg (5mL) once daily on days 2 - 5 | |
| › 45 | Dose as per adults | Dose as per adults | |
In the Elderly - The same dosage as in adult patients is used in the elderly,
In the Patients with Renal Impairment - No dose adjustment is necessary 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) (see section Special Warnings and Special Precautions for Use and Section Pharmacokinetic Properties).
In Patiens with Hepatic Impairment - The same dosage as in patients with normal hepatic function may be used in patients with mild to moderate hepatic impairment (see - Special Warnings and Special Precautions for Use),
Azithromycin IV:
For the treatment of adult patients with CAP due to the indicated organisms, the recommended dose of intravenous azithromycin is 500 mg as a single daily dose by the IV route for at least two days. Intravenous therapy should be followed by oral azithromycin at a single daily dose of 500 mg to complete a 7 to 10 day course of therapy. The timing of the conversion to oral therapy should be done at the discretion of the physician and in accordance with clinical response.
For the treatment of adult patients with PID due to the indicated organisms, the recommended dose of
intravenous azithromycin is 500 mg as a single dose by IV route for one or two days. Intravenous therapy should be followed by azithromycin by the oral route at a single daily dose of 250 mg to complete a 7-day course of therapy. The time of the conversion to oral therapy should be done at the discretion of the physician and in accordance with clinical response. If anaerobic microorganisms are suspected of contributing to the infection, an antimicrobial anaerobic agent may be administered in combination with azithromycin.
Intravenous Administration: After reconstitution and dilution, the recommended route of administration for intravenous azithromycin in by IV infusion only. Do not administer as an Intravenous bolus or an intramuscular injection (see Section Special Warnings and Special Precautions for Use and section Instruction for Use and Handling, and Disposal).
The infusate concentration and rate of infusion for azithromycin intravenous (IV) should be either 1 mg/ml over 3 hours or 2 mg/ml over 1 hour. An intravenous dose of 500 mg azithromycin should be infused for a minimum duration of one(1) hour.
The safety and efficacy of intravenous azithromydn for the treatment of infections in children has not been established.
Instruction for Use and Handling, and Disposal
Powder for Oral Suspension: Tap the bottle to loosen the powder. To the 600-mg bottle, add 9 ml of water, Shake well. Shake immediately prior to use.
For children weighing less than 15 kg, the suspension should be measured as dosely as possible. For children weighing 15 kg or more, the suspension should be administered using an appropriate measuring device.
Tablets: The tablets should be swallowed whole.
Intravenous (IV) Solution Preparation for IV Administration:
Reconstitution: Prepare the initial IV solution for infusion by adding 4.8 ml of sterilized Water for injection to the 500 mg vial and shaking the vial until all of the drug is dissolved. Since azithromycin IV is supplied under vacuum it is recommended that a standard 5 ml (non-automated) syringe be used to ensure that the exact amount of 4.8 ml of sterilized Water for Injection is dispensed. Each ml of reconstituted solution contains 100 mg azithromycin,
Chemical and physical in-use stability of the reconstituted product has been demonstrated for 24 hours below 30°C, When diluted according to the instructions, the diluted solution is chemically and physically stable for 24 hours at or below 30°C or for 7 days if stored under refrigeration 5°C.
From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally be no longer than 24 hours at 2 to 8°C, unless reconstitution and dilution have taken place in controlled and validated aseptic conditions,
Dilute this solution further prior to administration as instructed below:
Dilution: To provide azithromycin over a concentration range of 1.0-2,0 mg/ml. transfer 5 ml of the 100 mg/ml azithromycin solution into the appropriate amount of any of the diluents listed below:
| Final Infusion Solution Concentration (mg/ml) | Amount of Diluent (ml) |
| 1.0 mg/ml | 500 ml |
| 2.0 mg/ml | 250 ml |
The Reconstituted Solution can be diluted with:
Normal Saline (0.9 sodium chloride)
1/2 Normal Saline (0.45 sodium chloride)
5% Dextrose In Water
Lactated Ringer's Solution
5% Dextrose in 1/2 Normal Saline (0.45% sodium chloride) with 20 mEq KCl
5% Dextrose in Lactated Ringer's Solution
5% Dextrose in 1/3 Normal Saline (0,3% sodium chloride)
5% Dextrose in 1/2 Normal Saline (0.45% sodium chloride)
Normosol®-M in 5% Dextrose
Normosol®-R in 5% Dextrose
Parenteral drug products should be inspected visually for particulate matter prior to administration. If particulate matter is evident in reconstituted fluids, the drug solution should be discarded.
Overdosage
Adverse events experienced in higher than recommended doses were similar to those seen at normal doses,
In the event of overdosage, general symptomatic and supportive measures are indicated as required.
SUPPLY
Tablets 250 mg: Box of 1 blister @ 6 coated tablets Reg No. DKL9319803309A1
Tablets 500 mg: Box of 1 blister @ 3 coated tablets Reg No. DKL9519804017A1
Powder for Oral Suspension 200 mg/5 ml: plastic bottle containing 600 mg powder (15 ml);
Reg.No, DKI9684800538A1
Zithromax IV 500 mg/vial; vial 10 ml; Reg. No, DKI0596400244A1
PRESCRIPTION ONLY
HARUS DENGAN RESEP DOKTER
STORE IN DRY PLACE BELOW 30°C
Larutan suspensi harus disimpan di tempat kering di bawah suhu 30°C dan harus habis
diminum dalam 5 hari setelah dilarutkan. (Reconstituted suspension should be stored below 30°C and should be used within 5 days after reconstituted).
ZITHROMAX Tablet 250 mg, 500 mg
Manufactured by:
PT. Pfizer Indonesia
PO Box 2706, Jakarta, Indonesia
ZITHROMAX Powder for Oral Suspension
Manufactured by:
Pfizer Italia.S.r.l, Italy
Imported by PT. Pfizer Indonesia
PO Box 2706, Jakarta, Indonesia
ZITHROMAX Powder for Solution for Infusion
Manufactured by
Ben Venue Laboratories, Inc.
Ohio, USA,
Packed by
Pfizer PGM, Amboise, France
Imported by:
PT Pfizer Indonesia
PO Box 2706, Jakarta, Indonesia
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