Zithromax

Azithromycin dihydrate.

Each tablet contains azithromycin dihydrate equivalent to azithromycin 250 or 500 mg. It also contains pregelatinized starch, anhydrous dibasic calcium phosphate, croscarmellose sodium, magnesium stearate and sodium lauryl sulphate. The film coating contains hydroxypropyl methylcellulose, triacetin and titanium dioxide (E171).
The 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 azithromycin 200 mg/5 mL. It also contains sucrose (1.94 g/100-mg dose), anhydrous tribasic sodium phosphate, hydroxypropyl cellulose, xanthan gum, artificial cherry, crème de vanilla and banana flavors as excipients.
The IV formulation is supplied in lyophilized form under a vacuum in a 10-mL vial equivalent to azithromycin 500 mg for IV administration. Upon reconstitution, azithromycin powder yields a solution containing the equivalent of azithromycin 100 mg/mL. It also contains anhydrous citric acid 384.6 mg and sodium hydroxide 198.3 mg.
Prolonged-Release Granules for Oral Suspension 2 g: Azithromycin dihydrate equivalent to azithromycin base 2 g.
Azithromycin is the first of a class of antibiotics designated chemically as azalides. Chemically, it is derived by insertion of a nitrogen atom into the lactone ring of erythromycin A. Azithromycin is 9-deoxy-9a-aza-9a-methyl-9a-homoerythromycin A. Its molecular weight is 749.

Pharmacotherapeutic Group: Macrolides. ATC Code: J01FA.
Pharmacology: Pharmacodynamics: 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.
Pharmacokinetics: Absorption: Following oral administration in humans, azithromycin is widely distributed throughout the body; bioavailability is approximately 37%. The time taken to peak plasma levels is 2-3 hrs. Plasma terminal elimination half-life closely reflects the tissue depletion half-life of 2-4 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 eg, 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 2-4 days. Approximately 12% of an IV administered dose is excreted in the urine over 3 days as the parent drug, the majority in the first 24 hrs. 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.
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 1-g dose of immediate-release azithromycin. Statistically significant differences in AUC_0-120 (8.8 mcg·hr/mL vs 11.7 mcg·hr/mL). C_max (1 mcg/mL vs 1.6 mcg/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.
Toxicology: Preclinical Safety Data: Phospholipidosis (intracellular phospholipid accumulation) has been observed in several tissues (eg, 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.
Microbiology: Azithromycin demonstrates activity in vitro against a wide range of bacteria including:
Gram-Positive Aerobic Bacteria: Staphylococcus aureus, Streptococcus pyogenes (group A β-haemolytic streptococci), Streptococcus pneumoniae, α-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 influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Acinetobacter and Yersinia spp, Legionella pneumophila, Bordetella pertussis, Bordetella parapertussis, Shigella and Pasteurella spp, Vibrio cholerae and parahaemolyticus, Plesiomonas shigelloides. Activities against Escherichia coli, Salmonella enteritidis, Salmonella typhi, Enterobacter spp, Aeromonas hydrophila and Klebsiella spp are variable and susceptibility tests should be performed. Proteus, Serratia and Morganella spp and Pseudomonas aeruginosa are usually resistant.
Anaerobic Bacteria: Bacteroides fragilis and Bacteroides spp, Clostridium perfringens, Peptococcus and Peptostreptococcus spp, Fusobacterium necrophorum and Propionibacterium acnes.
Organisms 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 spp and Listeria monocytogenes.
Opportunistic Pathogens Associated with HIV Infections: Mycobacterium avium-intracellulare complex, Pneumocystis carinii and Toxoplasma gondii.
Mechanism of Resistance: There are 2 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 MLS_B resistance. Erm(B) and erm(A) are found in clinical isolates of S. pneumoniae and S. pyogenes.
The AcrAB-TolC pump in Haemophilus 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 minimum inhibitory concentration (MIC) values should be obtained using standardised laboratory methods eg, those defined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) or CLSI (Clinical and Laboratory Standards Institute). EUCAST MIC breakpoints are: H. influenzae: S ≤0.12 and R >4, M. catarrhalis: S ≤0.5 and R >0.5 Streptococci including S. pneumoniae and S. pyogenes: S ≤0.25 and R >0.5 CLSI MIC breakpoints 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 strains 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.
Commonly Susceptible Species: Aerobic Gram-Positive Bacteria: Staphylococcus aureus, Streptococcus agalactiae, Streptococci (groups C, F, G) and viridans group streptococci.
Aerobic Gram-Negative Bacteria: Bordetella pertussis, Haemophilus ducreyi, Haemophilus influenzae*^$, Haemophilus parainfluenzae*, Legionella pneumophila, Moraxella catarrhalis* and Neisseria gonorrhoeae.
Others: Chlamydia pneumoniae*, Chlamydia trachomatis, Mycoplasma pneumoniae* and Ureaplasma urealyticum.
Species for which Acquired Resistance may be a Problem: Aerobic Gram-Positive Bacteria: Streptococcus pneumoniae*, Streptococcus pyogenes*.
Note: Azithromycin demonstrates cross-resistance with erythromycin-resistant gram-positive strains.
Inherently Resistant Organisms: Enterobacteriaceae, Pseudomonas.
*Species for which efficacy has been demonstrated in clinical trials.
^$Species with natural intermediate susceptibility.

Oral: Treatment of patient with mild to moderate infections (ie, pneumonia: See Precautions) caused by susceptible strains of the designated microorganisms in the specific conditions listed as follows:
Lower Respiratory Tract: Acute bacterial exacerbations of chronic obstructive pulmonary disease due to Haemophilus influenzae, Moraxella catarrhalis or Streptococcus pneumoniae.
Community-acquired pneumonia of mild 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 1st-line therapy of acute pharyngitis/tonsillitis due to Streptococcus pyogenes occurring in individuals who cannot use 1st-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 initiated before results of these tests are known; once the results become available, antimicrobial therapy should be adjusted accordingly.
IV: Treatment of community-acquired pneumonia (CAP) caused by susceptible organisms, including Legionella pneumophila, in patients who require initial IV therapy.
In combination with metronidazole, Zithromax IV is indicated for the treatment of pelvic inflammatory diseases (PID) caused by susceptible organisms, in patients who require initial IV therapy.
Azithromycin prolonged-release granules are indicated for the treatment of susceptible strains of bacteria in mild to moderate respiratory tract infections as follows: Acute bacterial exacerbations of chronic bronchitis due to Haemophilus influenzae, Moraxella catarrhalis, Haemophilus parainfluenzae or Streptococcus pneumoniae. Acute bacterial sinusitis due to Haemophilus influenzae, Moraxella catarrhalis or Streptococcus pneumoniae. Community-acquired pneumonia due to Chlamydia pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Mycoplasma pneumoniae or Streptococcus pneumoniae. Pharyngitis/tonsillitis caused by Streptococcus pyogenes.

Tablet and Powder for Oral Suspension: Zithromax should be administered as a single daily dose and can be taken with or without food.
The period of dosing with regard to infection is given as follows: Adults (Including the Elderly): Treatment of Sexually Transmitted Diseases Caused by Chlamydia trachomatis, Haemophilus ducreyi or Susceptible Neisseria gonorrhoeae: 1 g as a single oral dose. Elderly patients may be more susceptible to development of Torsades de pointes arrhythmia than younger patients (see Precautions).
For all other indications in which the oral formulation is administered, the total dosage of 1.5 g 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 2-5.
Children: The total dose in children is 30 mg/kg which should be given as a single daily dose of 10 mg/kg or as an alternative, given over 5 days with a single daily dose of 10-mg/kg dose on day 1, then 5 mg/kg on days 2-5.
There is no information on children <6 months.
Zithromax suspension should be administered using the spoon provided according to the following table: See table.


Click on icon to see table/diagram/image


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 Zithromax is administered to patients with severe renal impairment (GFR <10 mL/min). (See Precautions.)
Patients 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 Precautions.)
IV: Adults: Treatment of CAP due to the Indicated Organisms: Recommended Dose: 500 mg IV as a single daily dose for at least 2 days. Intravenous therapy should be followed by oral Zithromax 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.
Treatment of PID due to the Indicated Organisms: Recommended Dose: 500 mg IV as a single dose for 1 or 2 days. Intravenous therapy should be followed by Zithromax 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 Zithromax.
IV Administration: After reconstitution and dilution, the recommended route of administration for Zithromax IV is by IV infusion only. Do not administer as an IV bolus or an IM injection (see Precautions and Cautions for Usage).
The infusate concentration and rate of infusion for Zithromax IV should be either 1 mg/mL over 3 hrs or 2 mg/mL over 1 hr. An IV dose of Zithromax 500 mg should be infused for a minimum duration of 1 hr.
The safety and efficacy of Zithromax IV for the treatment of infections in children has not been established.
Prolonged-Release Granules: Take on an empty stomach (at least 1 hr before or 2 hrs following a meal).
Adults and Adolescents: The recommended dose for adults and adolescents is a single 2-g dose of azithromycin prolonged-release granules. In the unlikely event that a patient vomits within 5 min of administration of azithromycin prolonged release granules, a 2nd dose should be taken.
Children: Azithromycin prolonged-release granules are not recommended for children ≤12 years.
Elderly: No dose adjustment is necessary in elderly patients requiring azithromycin therapy. Elderly patients may be more susceptible to development of Torsade de pointes arrhythmia than younger patients.
Renal Impairment: No dosage adjustment is recommended for patients with mild to moderate renal impairment (GFR 10-80 mL/min). Caution should be exercised when azithromycin prolonged-release granules are administered to patients with severe renal impairment (GFR <10 mL/min).
Hepatic Impairment: The pharmacokinetics of azithromycin in patients with hepatic impairment have not been established for azithromycin prolonged-release granules. Based on studies with immediate release-formulations, no dosage adjustment is recommended for patients with mild to moderate hepatic impairment. Azithromycin should be used with caution in patients with severe hepatic impairment.

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.

Patients with hypersensitivity to azithromycin, erythromycin, macrolide or ketolide antibiotic or to any excipient of Zithromax.

Hypersensitivity: As with erythromycin and other macrolides, rare serious allergic reactions, including angioedema and anaphylaxis (rarely fatal), and dermatologic reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis (rarely fatal), have been reported. Some of these reactions with azithromycin have resulted in recurrent symptoms and required a longer period of observation and treatment.
If an allergic reaction occurs, the drug should be discontinued and appropriate therapy should be instituted. Physicians should be aware that reappearance of the allergic symptoms may occur when symptomatic therapy is discontinued.
Hepatotoxicity: 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.
Abnormal liver function, hepatitis, cholestatic jaundice, hepatic necrosis, and hepatic failure have been reported, some of which have resulted in deaths. Discontinue azithromycin immediately if signs and symptoms of hepatitis occur.
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.
Ergot Derivatives: 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 nonsusceptible organisms, including fungi is recommended.
Clostridium difficile-Associated Diarrhea: Clostridium difficile associated 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.
If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
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 azithromycin, susceptibility test should be performed when patients are treated with Zithromax. Data establishing efficacy of azithromycin in subsequent prevention of rheumatic fever are not available. If an allergic reaction occurs, Zithromax should be discontinued and appropriate therapy should be instituted. The physician should be 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 judged to be inappropriate for outpatient oral therapy because of moderate to severe illness or risk factors eg, 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 illness (including immunodeficiency or functional asplenia).
In patients with severe renal impairment (GFR <10 mL/min), a 33% increase in the systemic exposure to azithromycin was observed (see Pharmacokinetics under Actions).
Diabetic Patients: 5 mL of reconstituted suspension contain sucrose 3.87 g. Due to sucrose content (3.87 g/5 mL of reconstituted suspension), Zithromax is not indicated for persons with fructose intolerance (hereditary fructose intolerance), glucose-galactose malabsorption or saccharase-isomaltase deficiency.
No dose adjustment is needed in patients with mild renal impairment (creatinine clearance >40 mL/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.
Prolongation of the QT Interval: Prolonged cardiac repolarization and QT interval, imparting a risk of developing cardiac arrhythmia and Torsade de pointes, have been seen in treatment with other macrolides, including azithromycin (see Adverse Reactions), therefore caution is required when treating: Patients with congenital or documented QT prolongation, patients currently receiving treatment with other active substances known to prolong QT interval eg, antiarrhythmics of classes IA and III; antipsychotic agents; antidepressants; and fluoroquinolones, patients with electrolyte disturbance, particularly in cases of hypokalaemia and hypomagnesemia, patients with clinically relevant bradycardia, cardiac arrhythmia or cardiac insufficiency, elderly patients: elderly patients may be more susceptible to drug-associated effects on the QT interval.
IV Administration: Zithromax IV should be reconstituted and diluted as directed and administered as an IV infusion over not less than 60 min. Do not administer as an IV bolus or IM injection (see Dosage & Administration and Cautions for Usage).
Effects on the Ability to Drive or Operate Machinery: There is no evidence to suggest that azithromycin may have an effect on a patient's ability to drive or operate machinery.
Use in pregnancy & 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.
Azithromycin has been reported to be secreted into human breast milk, but there are no adequate and well-controlled clinical studies in nursing women that have characterized the pharmacokinetics of azithromycin excretion into human breast milk.
In fertility studies conducted in rat, reduced pregnancy rates were noted following administration of azithromycin. The relevance of this finding to humans is unknown.

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.
Azithromycin has been reported to be secreted into human breast milk, but there are no adequate and well-controlled clinical studies in nursing women that have characterized the pharmacokinetics of azithromycin excretion into human breast milk.
In fertility studies conducted in rat, reduced pregnancy rates were noted following administration of azithromycin. The relevance of this finding to humans is unknown.

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.
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 Disorder: Thrombocytopenia.
Immune System Disorder: Anaphylaxis (rarely fatal) (see Precautions).
Metabolism and Nutrition Disorder: Anorexia.
Psychiatric Disorders: Aggressive reaction, nervousness, agitation and anxiety.
Nervous System Disorders: Dizziness, convulsions, headache, hyperactivity, paresthesia, somnolence and syncope. There have been rare reports of taste/smell perversion and/or loss.
Ear and Labyrinth Disorder: Deafness, tinnitus, hearing impaired, vertigo.
Cardiac Disorders: Palpitations and arrhythmias including ventricular tachycardia have been reported. There have been rare reports of QT prolongation and torsades de pointes (see Precautions).
Vascular Disorder: Hypotension.
Gastrointestinal Disorders: Vomiting/diarrhea (rarely resulting in dehydration), dyspepsia, constipation, pseudomembranous colitis, pancreatitis and rare reports of tongue discoloration.
Hepatobiliary Disorders: Hepatitis and cholestatic jaundice have been reported, as well as rare cases of hepatic necrosis and hepatic failure, which have rarely resulted in death (see Precautions).
Skin and Subcutaneous Tissue Disorders: Allergic reactions including pruritus, rash, photosensitivity, edema, urticaria and angioedema. Rarely, serious skin reactions including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported.
Musculoskeletal and Connective Tissue Disorder: Arthralgia.
Renal and Urinary Disorders: Interstitial nephritis and acute renal failure.
General Disorders and Administration Site Conditions: Asthenia has been reported, fatigue and malaise.

Antacids: In a pharmacokinetic study investigating the effects of simultaneous administration of antacid with azithromycin, no effect on overall bioavailability was seen although peak serum concentrations were reduced by approximately 30%. In patients receiving both Zithromax and antacids, the drugs should not be taken simultaneously.
Cetirizine: In healthy volunteers, co-administration of a 5-day regimen of Zithromax with cetirizine 20 mg at a steady state resulted in no pharmacokinetic interaction and no significant changes in the QT interval.
Didanosine (Dideoxyinosine): Co-administration of Zithromax 1200 mg/day with didanosine 400 mg/day in 6 HIV-positive subjects did not appear to affect the steady-state pharmacokinetics of didanosine as compared with placebo.
Digoxin: Many patients have received co-administration of azithromycin and cardiac glycosides, and no interactions have been reported.
Concomitant administration of macrolide antibiotics including azithromycin with P-glycoprotein substrates eg, digoxin, has been reported to result in increased serum levels of the P-glycoprotein substrate. Therefore, if azithromycin and P-gp substrates eg, digoxin are administered concomitantly, the possibility of elevated serum digoxin concentrations should be considered. Clinical monitoring, and possibly serum digoxin levels, during treatment with azithromycin and after its discontinuation are necessary.
Zidovudine: Single 1000-mg doses and multiple 1200- 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 Zithromax 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 P-450 system. It is not believed to undergo the pharmacokinetic drug interactions as seen with erythromycin and other macrolides. Hepatic cytochrome P-450 induction or inactivation via cytochrome-metabolite complex does not occur with azithromycin.
Ergot: Due to the theoretical possibility of ergotism, the concurrent use of Zithromax with ergot derivatives is not recommended (see Precautions).
Pharmacokinetic studies have been conducted between azithromycin and the following drugs known to undergo significant cytochrome P-450-mediated metabolism:
Atorvastatin: Co-administration 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 rhabdomyolisis 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 hrs 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 with a 500-mg/day oral dose of azithromycin for 3 days and were then administered with a single 10-mg/kg oral dose of cyclosporin, the resulting cyclosporin C_max and AUC_0-5 were found to be significantly elevated. Consequently, caution should be exercised before concurrent administration of these drugs. If co-administration is necessary, cyclosporin levels should be monitored and the dose adjusted accordingly.
Efavirenz: Co-administration of a 600-mg single dose of azithromycin and efivarenz 400 mg daily for 7 days did not result in any clinically significant pharmacokinetic interactions.
Fluconazole: Co-administration of a single dose of azithromycin 1200 mg did not alter the pharmacokinetics of a single dose of fluconazole 800 mg. Total exposure and half-life of azithromycin were unchanged by the co-administration of fluconazole, however, a clinically insignificant decrease in C_max (18%) of azithromycin was observed.
Indinavir: Co-administration of a single dose of azithromycin 1200 mg had no statistically significant effect on the pharmacokinetics of indinavir administered as 800 mg 3 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, co-administration 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: Co-administration of azithromycin (1200 mg) and nelfinavir at steady state (750 mg 3 times daily) resulted in increased azithromycin concentrations. No clinically significant adverse effects were observed and no dose adjustment is required.
Rifabutin: Co-administration of azithromycin and rifabutin did not affect the serum concentrations of either drug.
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 Adverse Reactions).
Sildenafil: In normal healthy volunteers, there was no evidence of an effect of azithromycin (500 mg daily for 3 days) on the AUC and C_max 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 co-administered to healthy volunteers.
Triazolam: In 14 healthy volunteers, co-administration of azithromycin 500 mg on day 1 and 250 mg on day 2 with triazolam 0.125 mg on day 2 had no significant effect on any of the pharmacokinetic variables for triazolam compared to triazolam and placebo.
Trimethoprim/Sulfamethoxazole: Co-administration of trimethoprim/sulfamethoxazole DS (160/800 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.

Instructions for Use, Handling and Disposal: Tablets: The tablets should be swallowed whole.
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 <15 kg, the suspension should be measured as closely as possible.
For children weighing ≥15 kg, the suspension should be administered using an appropriate measuring device.
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 Zithromax 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 the reconstituted solution contains azithromycin 100 mg.
Chemical and physical in-use stability of the reconstituted product has been demonstrated for 24 hrs below 30°C. When diluted according to the instructions, the diluted solution is chemically and physically stable for 24 hrs at or below 30°C or for 7 days if stored under refrigeration 5°C.
From a microbiological point of view, Zithromax IV 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 hrs at 2°-8°C, unless reconstitution and dilution have taken place in controlled and validated aseptic conditions.
Dilute this solution further prior to administration according to the instructions as follows: Dilution: To provide Zithromax over a concentration range of 1-2 mg/mL, transfer 5 mL of the Zithromax 100-mg/mL solution into the appropriate amount of any of the diluents.
For a final infusion solution concentration of 1 or 2 mg/mL, add 500 or 250 mL diluent to the solution, respectively.
The reconstituted solution can be diluted with: Normal saline (0.9% sodium chloride), ½ normal saline (0.45% sodium chloride), 5% dextrose in water, lactated Ringer's solution, 5% dextrose in ½ normal saline (0.45% sodium chloride) with 20 mEq potassium chloride, 5% dextrose in lactated Ringer's solution, 5% dextrose in ¹/₃ normal saline (0.3% sodium chloride), 5% dextrose in ½ 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.
Azithromycin Prolonged-Release Granules 2 g: Constitution: Add 60 mL water and replace cap. Shake well.
Patient Instructions: Azithromycin prolonged-release granules 2 g bottles: Keep the container tightly closed. Do not store above 30°C. Use the prepared suspension within 12 hrs. Shake well before use. Drink the entire contents of the bottle.

Tablet: Store in a dry place below 30°C.
Shelf-Life: 36 months.
Suspension: Store at 15°-30°C. Reconstituted suspension should be stored below 30°C and should be used within 5 days after reconstituted.
Shelf-Life: 36 months.
Powder for Infusion: Store in a dry place below 25°C.
Shelf-Life: 36 months.
Prolonged-Released Granules: Dry Granules: Do not store above 30°C.
Shelf-Life: 36 months.
Following Constitution: Store at 25°C.
Shelf-Life: 12 hrs.

Macrolides

J01FA10 - azithromycin ; Belongs to the class of macrolides. Used in the systemic treatment of infections.

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